Transcript Nonclinical studies

Good Laboratory Practices for Biotechnology Research
BIOE 470/570, Regulation of Drugs and Medical Devices
Oregon State University
February 19, 2014
Carol A. Pratt, Ph.D., JD
K&L Gates LLP
Portland, Oregon
503-226-5762
[email protected]
copyright 2014 Carol A. Pratt
Good Laboratory Practices (GLPs)
 A quality system of management controls for research laboratories
and organizations to try to ensure the uniformity, consistency,
reliability, reproducibility, quality, and integrity of non-clinical safety
tests.
 An international set of principles
Good Laboratory Practice (GLP) embodies a set of principles that provides a
framework within which laboratory studies are planned, performed, monitored,
recorded, reported and archived. These studies are undertaken to generate data by
which the hazards and risks to users, consumers and third parties, including the
environment, can be assessed ... GLP helps assure regulatory authorities that the
data submitted are a true reflection of the results obtained during the study and can
therefore be relied upon when making risk/safety assessments.
[Medicines and Healthcare Products Regulatory Agency - UK (MHRA)]
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FDA’s Good Laboratory Practices (GLPs)
 Initiated in 1978
 Response to high profile fraud in pharmaceutical and chemical
industries
 Statutory requirements
 Federal Food Drug & Cosmetic Act (multiple sections)
 Regulatory requirements
 21 CFR Part 58: Good Laboratory Practices for
Nonclinical Laboratory Studies
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http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm
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FDA GLP Requirements: 21 CFR Part 58
 Applies to:
 Nonclinical laboratory studies
 Intended to support applications to FDA for marketing or
research permits
 For products that require approval/clearance by the FDA
 Purpose:
 Assure the quality and integrity of safety data submitted to the
FDA (which is used by FDA to make product approval
decisions)
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Nonclinical studies: 21 CFR Part 58.3(d)
 Nonclinical laboratory study
 prospective in vitro or in vivo experiments
 on “test articles” (products subject to FDA premarket approval)
 Drugs, biologics, medical devices, food additives, food colors
 in “test systems”
 Any animal, plant, microorganism, or subparts thereof to which the
test article is administered or added
 under laboratory conditions
 to determine safety
 Why are GLPs limited to safety studies?
 Products must be safe and effective for their intended purpose
 In the US, safety has priority over efficacy
 Historically related to drug development cycle
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Drug Development Cycle
In vitro and in vivo (animal)
studies to screen compounds,
determine physical/chemical
characteristics and test
safety.
Preclinical
GLPs
Larger, multi-site study – initial test of
efficacy in patients based on doses from
Phase 1. Determine sample size.
Phase 1
FIRST IN HUMAN Study –
Small, tightly controlled study
in healthy subjects to
determine safety and dose
ranging (pharmacokinetics).
Phase 2
Phase 3
Large, multisite study in
patients to test efficacy.
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Drug Development Cycle
Safe for Human Use?
GLPs – 21 CFR Part 58
Preclinical
Cell and
Animal Studies
GCPs:
Human subjects: 21 CFR Part 50, 56
Investigational Drugs/Biologics: 21 CFR Part 312
Investigational Devices: 21 CFR Part 812
Phase 1
Phase 2
Phase 3
Clinical Trials –
Human Subjects
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Nonclinical Laboratory Studies
 “Do not include:
 Studies using human subjects or human specimens
 Exploratory studies to determine:
 If a test article has any potential utility (efficacy), or
 Physical/chemical characteristics of test article
 Medical devices*
 Bench tests involving chemical or physical testing
 GLPs n/a if there is no “test system” (animal, plant or microorganism)
 Early feasibility studies of potential utility
*FDA Draft Guidance, The Applicability of Good Laboratory Practice in Premarket Device Submissions: Questions and
Answers (8/28/13)
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GLPs - 21 CFR Part 58
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER A--GENERAL
PART 58
GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES
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Subpart A--General Provisions
Subpart B--Organization and Personnel
Subpart C--Facilities
Subpart D--Equipment
Subpart F--Test and Control Articles
Subpart G--Protocol for and Conduct of a Nonclinical Laboratory Study
Subparts H-I [Reserved]
Subpart J--Records and Reports
Subpart K--Disqualification of Testing Facilities
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm
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GLPs - 21 CFR Part 58
 Personnel
 Must have adequate education, training, and experience
 Each study must have a designated study director
 Study protocol
 Study must be conducted according to a written, approved
protocol
 Any changes to protocol must be pre-approved and signed by
study director
 Testing facilities – must:
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Comply with animal care facility requirements
Have separate areas for performing laboratory tests
Have separate areas for receipt, storage and use of test articles
Have written SOPs to comply with GLP requirements
Must have a quality assurance unit (QAU)
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GLPs - 21 CFR Part 58
 Data records
 All data must be recorded directly, promptly and legibly in ink
 Data entries must be:
 Dated on the date of entry, and
 Signed or initialed by the person making the entry
 Any change in an entry must be dated, signed or initialed at the
time of the change and explained.
Practice Tip #1
Document, Document,
Document
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FDA Proposed Expansion of GLPs
 FDA’s GLPs are less comprehensive than international
standards
 ISO – 9000: Quality Management *
 International Organization for Standardization (ISO)
 ISO-9001 Certification: certification of compliance with ISO-9000
family of requirements
 Requires certification (unlike the FDA)
 More comprehensive than FDA’s GLPs
 Proposed new rule (Federal Register, 75, 80012, 12/21/10)
 Change GLP regulations to be more similar to ISO 9001
 Pressure on the FDA for international harmonization of regulatory
requirements to accommodate global companies / markets
*http://www.iso.org/iso/iso_catalogue/management_and_leadership_standards/quality_management.htm
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FDA Proposed Expansion of GLPs
 Would apply to all studies conducted by nonclinical laboratory
facilities
 Studies of efficacy and of physical/chemical characteristics
 Multisite studies
 Modify personnel, study director roles
 Electronic and computerized systems
 Specify additional sponsor responsibilities
 Development/approval of the study protocol
 Compliance with Animal Welfare Act
 More detailed records of inspectional findings by the Quality
Assurance Unit
 More detailed records about test article characteristics (strength,
purity, stability, etc.)
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Enforcement of GLPs
 Rejection of data
 FDA may reject the data supporting the marketing or research
application
 Angry sponsor!
 Breach of contract lawsuit, damages
 Inspections
 FDA’s Bioresearch Monitoring Program
 Inspection of nonclinical and clinical studies and facilities
 Inspection findings – Form 483
 Must respond with a written corrective action plan within 15 days
 Pass re-inspection
 Not public
 Warning Letters
 Disqualification of testing facility
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Enforcement of GLPs – Warning Letters
 Warning Letters
 Are public – published on FDA website
 Usually issued only if facility has inadequate response to a Form
483
 Must respond in writing within 15 days
 Address current violations
 Corrective action plan (CAP) – revise/add procedures to ensure
violation do not occur in the future
 The CAP is most important
 20/80 Rule (20% backward looking; 80% forward looking)
 Inadequate response can lead to shut down or legal action
without further notice
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GLP Warning Letter - Example
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Isis Services Warning Letter
 Isis Services is a preclinical contract research
organization (CRO)
 Involved medical device nonclinical laboratory studies
 Result of an FDA inspection
 “This inspection is a part of FDA’s Bioresearch Monitoring
Program, which includes inspections designed to verify
compliance with Title 21 of the Code of Federal Regulations (21
CFR), Part 58 - Good Laboratory Practice (GLP) for Nonclinical
Laboratory Studies.”
 Form FDA 483 was issued
 Company’s written response to the Form 483 was “inadequate”
Isis warning letter:
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/ucm263814.htm
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Isis Warning Letter
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Failure to ensure that each individual engaged in the conduct of or
responsible for supervision of a nonclinical laboratory study has
education, training, and experience, and failure to ensure that the
testing facility maintains a current summary of training and
experience. [21 CFR 58.29(a) and (b)]
 No evaluations for employees on xxxx dates
 No record that employees attended required training sessions
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Failure of testing facility and study directors to fulfill their
responsibilities. [21 CFR 58.31, 58.33]
 The testing facility failed to designate a study director before the study was
initiated
 The testing facility let the sponsor designate study directors
 The testing facility failed to provide documentation that study directors were
trained on the SOP for Study Directorship
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Isis Warning Letter
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Failure of the quality assurance unit to determine that no deviations
from approved protocols or SOPs were made without proper
authorization and documentation, and to review the final study report
to assure that such report accurately describes the methods and
SOPs. [21 CFR 58.35(b)(5) and (6)]
 There is no documentation to show that final study reports for xxx studies were
reviewed
 XX wrote the contributing scientist reports for studies xxx; however, there is no
documentation of him participating in the studies, nor were there any
amendments adding him to the studies.
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Failure to retain the final study reports. [21 CFR 58.190]
 Final reports were provided with company’s response to the Form 483 but were
not available during the inspection
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Isis Warning Letter
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“You must address these violations and establish procedures to
ensure that any ongoing or future studies are conducted in
compliance with the Act and applicable FDA regulations.
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Within fifteen working days of receipt of this letter, you must provide
written documentation of the specific additional corrective actions that you
have taken or will take to address all of the violations noted above and to
prevent recurrence of similar violations in current or future nonclinical
laboratory studies conducted by your facility. Any submitted corrective
action plan must include projected completion dates for each action to be
accomplished. In addition, please provide a complete list of all nonclinical
laboratory research of FDA-regulated devices for the last five years,
including the name of the study and the test article, the names of the study
director and sponsor, and the current status of the studies.
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We will review your company’s response and determine whether it is
adequate. Failure to respond to this letter and take appropriate corrective
action could result in FDA taking regulatory action without further notice
to you, including disqualification proceedings in accordance with 21 CFR
58.202.”
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IIT Warning Letter
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IIT Warning Letter
 Failure of testing facility management to assure that test
articles or mixtures were appropriately tested for identity,
strength, purity, stability, and uniformity, as applicable [21 CFR
58.31(d)].
 The protocol stated that the sponsor would test the dose formulations prior to
shipment and samples of the dose formulation would be sent to the sponsor for
xx analysis during study weeks 5, 13, 26, 52, 78 and 103.
 You subsequently amended the protocol, approximately one year after dosing
ended and two weeks before the final report was signed by the study director, to
indicate that the dose formulation results would be submitted separately by the
sponsor.
 Although the sponsor did submit the results to the agency after the inspection,
the testing facility failed to assure that the appropriate testing was conducted
in order for the study director to include the necessary information in the final
report.
 Take Home Message – the testing facility is responsible for complying with
GLPs regardless of the sponsor’s actions/non-actions
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2005/ucm075728.htm
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IIT Warning Letter
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Failure to include a description of all circumstances that may have
affected the quality or integrity of the data in final study reports [21
CFR 58.185(a)(9)].
 As described, the study director lacked critical information regarding the dose
formulation administered to animals in study xx. Characteristics of the dose
formation are essential to the study director's assessment of study outcomes,
and the absence of this information limits the quality and the integrity of the data
for study xx.
 In your . . . final report you did not communicate that you lacked the critical data,
or that you had reservations about drawing study conclusions without knowing
the actual doses of xx administered to the animals.
 We acknowledge your February 4, 2005 response that the sponsor instructed
you to finalize the final report using the data that were available at the time.
Since your attempts to obtain required information from the sponsor were
unsuccessful, your final report conclusions should have communicated such
critical limitations as circumstances that affected the quality and integrity of the
data; because you did not know whether the intended doses of xx were actually
administered to the animals, the study director could not provide a meaningful
assessment of study outcome.
 Thus, your conclusion in the final report summary that there was no evidence of
a carcinogenic effect in any organ . . . could not be reached in light of the
missing information and should have conveyed that you lacked critical data to
draw study conclusions.
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IIT Warning Letter
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Not all nonclinical laboratory studies were conducted in accordance
with the protocol [21 CFR 58.130(a)].
 The protocol for study xx required the consent of the study director or study
pathologist prior to sacrificing moribund animals. Five study animals were
sacrificed without documentation of the required consent.
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Failure to have an approved written protocol for each study [21 CFR
58.120(a)]
 You conducted study-specific activities for studies xx before the protocol was
approved.
 In particular, animals were randomized into study specific dosing groups before
the study was initiated.
 In your response dated February 4, 2005, you suggested that animal
randomization is considered "pre-start" data collection, similar to the acquisition
of a test article's certificate of analysis.
 Because animal randomization depends upon a protocol-defined group number
and size, FDA considers such activities to be part of conducting the study. Thus,
you conducted specific study-related activities without an approved protocol
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Practice Tip #2
Follow The Protocol
Practice Tip #1
Document Deviations From
the Protocol
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GLPs: Laboratory Notebooks
 Provide detailed, accurate, dated record of experimental
plans, results, conclusions and ideas
 Provides details to allow replication of results
 Scientific integrity
 Reliability of results
 Basis for invention disclosures (is a result patentable?)
 Provides information for patents (specifications, claims)
 Used as corroborating evidence of inventorship, if disputed
 Who knew what when?
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Laboratory Notebooks
 Industrial
 Notebooks are owned by the company
 Inventions are owned by the company
 Employee is the inventor
 Company owns the patent rights
 Employee must assign IP rights to employer as a condition of
employment
 Employment Agreement requires employees to maintain
notebooks and records
 Company SOPs set out procedures for maintaining notebooks
and records
 Notebooks are stored by the company
 No copies kept by the employee
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Laboratory Notebooks
 Academia
 Notebooks are owned by the faculty member
 University owns the invention (IP) and patent rights
 Faculty must assign IP rights to university as a condition of
employment
 Faculty member is inventor
 University typically gives some percentage of income from patents
to faculty scientist
 Notebooks (usually) are not required
 Discretion of faculty
 Recommended by technology transfer office
 Leaves academics vulnerable to inventorship/patent disputes
 May not be able to provide corroborating evidence of contribution to
invention or the date of invention
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Industrial Laboratory Notebooks
 Assigned to employee researcher
 Notebook assigned a company number and assigned to an
individual scientist
 Bound notebooks
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Secured pages (unlike 3-ring notebook)
Commercially available
Usually ~ 300 pages
Page 1: sign-out page
 Name of scientist
 Date issued and date completed
 Purpose/projects
 Page 2: Instructions for record keeping
 Table of Contents
 Entry pages
 Format provides structure for important record keeping
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Industrial Laboratory Notebooks
 Page format
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Subject or Project:
From page:
To page:
Identity of person entering data:
 Recorded by:
 Date:
 Witness
 Read & Understood By:
 Date:
 Witness should be technically competent to understand and be
unbiased (not involved in the study)
 No witness = no corroboration
 Some courts have used witness signing date as the effective date
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GLPs for Laboratory Notebooks
 Entry should be made immediately after work is done
(must be “contemporaneous”)
 Enter time
 Individual page should not be used for more than one date
 If have empty space on page, draw a “X” through empty space.
 Write legibly and in ink
 Each section should have a clear, descriptive heading
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Introduction
Experimental Plan
Observations and Data
Discussion of Results
Conclusions
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GLPs for Laboratory Notebooks, cont’d
 Entries
 Level of detail
 Provide sufficient detail such that an independent person could
replicate experiment based on the notebook
 Related loose material should be taped onto the notebook page
 Printouts, graphs
 Gels
 Statistical analyses
 Related information stored elsewhere should be referenced in
notebook
 Example: “Photographs of cells stored in Binder # __.”
 Corrections/changes
 Do not write over original entry
 Explain reason for correction
 Initial and date
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GLPs for Laboratory Notebooks, cont’d
 Maintenance of notebooks
 Should not be allowed off company site
 Should be kept in a locked place overnight
 Photocopies
 Strictly regulated by company policy to protect IP
 May not be allowed at all
 Storage of notebooks
 Completed notebooks should be copied to microfilm or
microfiche
 Original notebook should be archived indefinitely
 May be needed for evidence in litigation that could take place
years later
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Role of Laboratory Notebooks in Protecting IP
 Determine inventorship
 Correct inventorship
 Valid patents must include all rightful inventors
 Protect patents from challenge
 First to invent system – interference proceedings
 First to file system – derivation proceedings
 Determine ownership
 Flows from assignment by inventors
 Basis for allocation of royalties
 Commercialization of IP rights
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Inventorship
 Key = conception
 “The threshold question in determining inventorship is who
conceived the invention.”
 The formation in the mind of the inventor of a “definite and
permanent idea” of the “complete and operative invention”
 A mental act
 Inventor need not know the invention will work (that = reduction
to practice)
 Reduction to practice
 Actual: carrying out of the invention (make/test the invention)
 Constructive: file a patent application
 Provides corroborating evidence of conception
 Research records, patent application
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Role of GLPs in Protecting Intellectual Property
 How to prove conception (a “mental act”)?
 Key issue: who knew what when?
 “Inventor must prove conception by corroborating evidence of
oral testimony, preferably by showing a contemporaneous
disclosure.” ([Burroughs v. Barr Labs (1994), AZT dispute]
 Laboratory notebooks
 Are the industry standard for contemporaneous
documentation
 It is critical to document what you know and when you knew
it
 An evidentiary record of:
 Conception
 Reduction to practice
 Compliance with GLP requirements help document IP rights
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Role of Laboratory Notebooks in Protecting IP
 First-to-invent system
 Previous U.S. patent system (prior to March 2013)
 Key to determining inventorship was date of conception
 Laboratory notebooks were key evidentiary record used in high
profile lawsuits
 Outcome of cases hinged on records that had been kept 3 – 5
years previously (before the trial)
 Employees may no longer at the company
 Witnesses may be gone
 Employees/witnesses may work for competitor (plaintiff)
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First-to-File System
 Leahy-Smith America Invents Act (“AIA”)
 Based on first to file patent application
 Effective March 16, 2013
 Harmonizes the US and most other countries
 Reflects acceptance of a global marketplace for goods and IP
 Provides bright-line rule for IP rights
 Don’t have to prove conception (what the inventor ‘knew’) by
corroborating evidence
 Race to the PTO
 Resolving inventorship disputes
 Laboratory notebooks will still play a key role in resolving
inventorship disputes
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First-to-File System
 Impact of first-to-file system
 Will encourage earlier filing of patent applications
 Provisionals filed to establish priority date
 Need to be followed with non-provisional within 1 year
 Pressure to file early may result in inadequate enablement of patent
claims
 May make patents vulnerable to later invalidity claims
 Correct identity of inventors
 Each inventor has right to patent
 Failure to name all inventors can result in invalid patent
 Inventorship disputes will involve derivation proceedings
 Petitioner must show by substantial evidence:
 Petitioner = the inventor (= conception)
 Petitioner communicated the invention to the first applicant (invention
derived from the communication)
 Laboratory notebooks should document conception and
communication with collaborators and colleagues
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Example of Role of Laboratory Notebooks in
Inventorship Litigation
 OHSU v. XYZ Pharmaceuticals (Sponsor)
 Academic – industry preclinical research collaboration
 Research agreement
 “Joint inventions will be jointly owned”
 Facts
 Sponsor gave compounds to Dr. OHSU to test in cell culture assay
 There was an unexpected finding from Dr. OHSU’s experiment
 3 months later, Sponsor filed 3 patent applications related to the
unexpected finding. Sponsor was sole inventor
 OHSU claimed that Dr. OHSU was a co-inventor and should be
added to the patents
 Sponsor claimed they had expected the finding based on in-house
experiments they conducted prior to Dr. OHSU’s experiment
 OHSU sued Sponsor to have inventorship corrected by adding Dr.
OHSU to the patents
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OHSU v. XYZ Pharmaceuticals
 Key issues
 Who conceived the invention?
 Could Sponsor produce corroborating evidence of their claim that they
had conceived the invention prior to receiving results from Dr. OHSU?
 Evidence
 Dr. OHSU’s laboratory records corroborated the content and date of Dr.
OHSU’s alleged findings
 Sponsor’s laboratory notebooks did not corroborate their assertion that
they knew before Dr. OHSU which compounds would work
 3 weeks prior to Dr. OHSU’s experiment, Sponsor’s scientist’s notebook
contained statement of experimental plan but no results or data
 Page was witnessed 2 months after page date (which was after OHSU
experiment)
 Outcome: case settled
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Practice Tip #3
Look Ahead – Today’s Record is
Tomorrow’s Evidence
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Summary
 Compliance with GLP requirements is important
for:
 FDA compliance
 Assuring safety of products for first use in human clinical
trials
 Getting products approved by the FDA
 Protection of IP
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Good Laboratory Practices for Biotechnology
Research
Questions?
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