Transcript WFIRM Laboratory Notebooks - RIT - People

Alan Bentley
Cleveland Clinic - Innovations
The Inconceivable Ramifications of a Shoddy
Lab Notebook on the Lives of Millions
Millions? Really?!?
A bit of historical fiction
Background
 You have discovered a new lead compound and have
tested it in animal models to prove it has therapeutic effect
in treating prostate cancer.
 After many months of thorough testing of this compound
and numerous analogs in vivo, you submit a paper for
publication describing your research findings.
 Several months later, your article publishes.
Protecting your invention
 You hear a talk from the Innovations group explaining the
importance of disclosing your invention, how to fill out an
invention disclosure form, and the impact of publication on
patenting


Outside the U.S. publishing before patenting = forfeiting of
patent rights
In the U.S., there is a 1-year grace period in which to file a
patent application after public disclosure or publication (whew!)
 You file an Invention Disclosure Form, submit it with
Innovations, and provide a copy of the publication
 Innovations files a patent application before the 1-year
deadline – the technology is licensed to a pharmaceutical
company (your ‘Partner’) for commercialization
The patent process
 About a year or so after your patent application is filed,
Innovations makes you aware of a U.S. patent application
filed by a smallish Japanese pharma company that has
just published – claiming the same genus of compounds

Patent applications in the U.S. publish about 18 months after
filing
 Some digging reveals that the patent application was
licensed exclusively to Large Pharma

This is slightly peculiar, because Large Pharma just entered the
market with a strong selling prostate cancer drug with
respectable, but not terribly inspiring efficacy
 Six months later (the 18th month mark), your patent
application publishes
The controversy
 The U.S. Patent Office notices that your patent application
and the one licensed to Large Pharma cover the same
subject matter, and it declares an Interference.
 Innovations explains that the application licensed to Large
Pharma predates your filing date by six months



The U.S. has a “first to invent” system, not a “first to file system
like the rest of the world, so there is still a chance you can
prevail in the U.S.
No chance outside the U.S., due to the first to invent system, but
If you can show that you conceived the invention before the
Japanese pharma company, you get the patent over them!!!
The lab notebook
 You bring out your lab notebooks, which memorialize your
conception of the invention
 You recall from the notes, and from other events that
occurred at that time, that you conceived the invention
about 8 months before the Large Pharma patent
application date
 You should be good to go
Technicalities
 Unfortunately, the USPTO (or a court, in similar scenarios)
is unable to consider your notebook as evidence of the
point of first conception



The notebook is not dated
The notebook is not witnessed by others
Therefore, there is no corroboration
The ramifications
 The Clinic loses the patent to Large Pharma, and loses out on
licensing revenue – it gets screwed
 Your Partner is pretty upset about the results, and about losing its
monopoly on the compound, losing its freedom to operate, and
therefore losing the last 2+ years of development activity and the
corresponding $10M – it get screwed
 The inventors lose out on a potentially sizable royalty stream – they
get screwed
 Large Pharma does not develop the compound, since their current
product has dominant market share – people with prostate cancer
lose out on a better therapeutic – millions get screwed
A famous cases involving lab
notebooks
Stern v Trustees of Columbia University
Stern v. The Trustees of Columbia
University
CAFC – Decided January 17, 2006
 Invention: directed towards the use of prostaglandins in
treating glaucoma
 Issue: Unwitnessed laboratory notebooks are insufficient
to support a claim of coinventorship
Stern v. The Trustees of Columbia
University
CAFC – Decided January 17, 2006
 Background:
 Columbia owns ‘353 patent naming Lazlo Bito as the inventor
 In 1980, Stern (medical student) did a one semester ophthalmology
research elective in Bito’s laboratory
 Experiments Stern conducted while working in Bito’s laboratory
showed that topical application of a single dose of prostaglandin
reduced IOP in rhesus monkeys and cats.
 After Stern’s departure from Columbia, Bito conceived the ’353
patent while studying the effects of repeated prostaglandin
application on the IOP in rhesus monkeys.
 Bito applied for the patent in 1982 and, in 1986, it was issued.
Stern v. The Trustees of Columbia
University
CAFC – Decided January 17, 2006
The Lab Notebook Angle:
 Stern argued that his notebooks clearly indicate that he
contributed to numerous claims in the ‘353 patent, and he should
therefore be added as an inventor
 Stern’s notebooks were not co-signed or witnessed
 The courts ruled that unwitnessed laboratory notebooks on their
own are insufficient to support his claim of co-inventorship.
Stern v. The Trustees of Columbia
University
CAFC – Decided January 17, 2006
The courts ruled
 “Because a patent carries a statutory presumption of validity, 35
U.S.C. § 282, Stern had the burden of showing by clear and
convincing evidence, after all reasonable inferences were drawn
in his favor, that he was an inventor of the ’353 patent”
 The court determined that Stern’s contribution is insufficient to
support a claim of co-inventorship due to lack of corroborating
evidence
Corroborating evidence
 What kind of evidence can corroborate an invention
date earlier than the filing date:
1. Witness Testimony
2. Physical Evidence
3. Other facts and circumstances independent of info
received from the inventor
Witness testimony
 Witness must have been able to autonomously evaluate
the inventor’s development of the invention
 Court does not require “constant supervision” but wants
evidence of opportunity for “regular, independent
evaluation” of the inventor’s progress
Physical evidence
 Does not itself require corroboration to demonstrate its
content
 Does require corroboration for dates of conception
 When showing conception, courts have consistently ruled
that notebooks witnessed by an individual who did not
carefully examine the subject matter of the witnessed
pages IS sufficient corroborating evidence
Physical evidence
 Court rulings: Un-witnessed, the inventor’s notebooks are
accorded no more weight than the inventor’s testimony in
this instance since they were not witnessed or signed.
 Physical evidence (such as lab notebooks) is given
greatest weight as corroborating an inventor’s testimony
when there is independent examination/verification of the
evidence by a witness who directly evaluated the
development of the invention and provided a signature
Corroboration - Other facts and
circumstances independent of inventor
 Organizational structure and protocol of the facilities
where the inventor engaged in research
 A protocol regarding reporting and evaluation of lab
notebooks determines the strength of corroborating
evidence
 Showing a policy for regular recognized evaluation
procedures strengthens witness testimony and physical
evidence (lab notebooks)
 Generally a weaker form of evidence
Conclusion regarding corroboration
The BEST method for proving:
-Conception date
-Reasonable diligence toward reduction to practice
Is...
Physical Evidence
i.e.
The LABORATORY NOTEBOOKS
Let’s not lose sight of the big picture
Reasons for keeping a good lab notebook
Our scientific obligation
 Allows your work to be reproduced faithfully
 By yourself
 By others
 Science must be reproducible!!!
 Facilitates accurate reporting & publication
 Organizes how you do Science
 Formulate ideas clearly
 Specify materials & methods
 Plan experiments well
 Obtain maximum value from data
 Protects intellectual property
 Supports future clinical development
Our moral obligation
 A major goal of the Clinic is to translate our research into
the development of new technologies and therapies that
will help patients
We have a moral and legal obligation to patients and to
those who provide funds for our work to maintain
accurate, complete records, and to protect the Clinic’s
intellectual property
Surely nobody of any import bothered
with the lab notebook…
I can think of a few
Leonardo da Vinci’s notebook
Studies of
reflections from
concave mirrors.
Italy, probably
Florence, from
1508.
British Library
Arundel MS 263,
f.86v-87
We can read and understand Leonardo’s notebooks from 500 years ago
Leonardo da Vinci’s Notebook
Darwin, Einstein, and Pauling
Darwin
Einstein
Pauling
Alexander Graham Bell’s notebook
March 10th 1876: “Mr. Watson – Come here – I want to see you”.
Francis Crick’s notebook
Model building
Centrifuging egg white
Methods set forth clearly
Results in Nobelists’ notebooks
C. H. Best –
Blood sugar
S. Luria –
Bacteriophage growth
M. Rodbell –
Glucagon release
Mendel, Edison, and Curie
Mendel
Edison
Curie
Suggestions for a good lab book
1. Bound notebooks, consecutive entries
2. No blank pages or spaces… fill in with line
3. Use non-erasable ink pen
4. To delete simply strike through
5. Write legibly
Other recommends
 Ideas (inventions) and data should be recorded in a
bound Laboratory Notebook
 Related electronic files, films, etc. should be recorded


Enter hard copies of these “secondary sources”, if possible
Enter description of file / film / etc. in the lab notebook
 All entries should be signed, dated, and witnessed
Level of specificity
 Record:
 Ideas & inventions
 Experimentation records & observations
 All work details
 Entries should have sufficient information so that they can
be understood by a reader not directly involved in the
project, and so that one of comparable technical skill
would be able to repeat your work and obtain
essentially equivalent results
And finally…a good story
The case of Peter Taborsky
The Case of Peter Taborsky
 Taborsky
 26 y.o. undergraduate in Chemistry and Biology
 Working at USF- College of Engineering in Dr. Robert
Carnahan’s Lab 1987- Florida Progress sponsors research
($20k) in Dr. Carnahan’s lab looking for way to make sewage
treatment less expensive and more efficient
 Contract between FP and USF gave all research results to
FP
 Taborsky was part of the team
The Case of Peter Taborsky
 Project was terminated
 Taborsky began getting paid from other budgets
 Taborsky continues to experiment on project
 Taborsky finds a solution to the sewage treatment problem
 Carnahan tells Taborsky, the research results are FP’s and
if he assigns his rights to FP they will hire him to a staff
position
 Taborsky drops out of school and takes his NOTEBOOKS
with him
The Case of Peter Taborsky
 USF files criminal charges for “theft of trade secrets”
 1990- Taborsky found guilty:
 One year suspended sentence
 One year under house arrest
 15 years' probation
 Judge stated that he could not use or profit from his notes or his
invention
 Taborsky files for patents anyway
 Nine months later USF and FP files for the same patents
 1992 - USPTO issues two patents to Taborsky
The Case of Peter Taborsky
 Judge orders Taborsky to assign the rights of his patents
or be sent to prison
 Taborsky refused and is sent to prison for 3 and ½ years
 Thank goodness nobody at this institution is are strong-
willed!
Alan Bentley
Director of Commercialization
CCF Innovations
[email protected]
4-6752
Helpful hints for a good lab book
Alan Bentley
Director of Commercialization
CCF Innovations
Notebook entries
 Record your ideas and data as you work
 All experiments should be recorded, regardless of outcome
Do not wait for results or record only “successful” experiments
Never remove pages from your notebook


 Maintain an up-to-date Table of Contents
 Titles of experiments & projects to which they correspond

Helpful to assign a unique number to each experiment
 Record entries legibly, neatly and in permanent ink (black)
 Do not use pencil
 Do not erase or use white-out
 Cross out & correct if needed

Initial & date changes to the record
Page numbers & dates
 Conception of ideas and experimental work should be
recorded in chronological order on numbered pages


Multiple experiments may be in progress – pages for any 1
experiment need not be contiguous
 Fill in boxes “Continued from page”, “Continued to page”
Each page should contain entries for only 1 experiment
 Date every page
 Use a consistent, unambiguous system
 Include day, month, year


November 10, 2005 Nov-10-05 10 Nov 2005
11/10/05 may be ambiguous (10 Nov, or 11 Oct?)
XI-10-05
 Indicate in “Notes” on inside cover if month or day comes first
Objective
 Start each entry with a clear statement of the objective
Objective: To determine the percentage of cells in human placenta
that express various antigens characteristic of amniotic fetal stem
(AFS) cells. In particular to determine if c-Kit+ (CD117+) cells are
present, because that is the marker used to isolate AFS cells from
amniotic fluid & chorionic villus biopsies….
Materials & Methods /
Experimental Plan
 All essential facts should be recorded so that the work can
be repeated accurately



Methods, equipment, conditions, times, temperatures, pH, …
Materials
 Include source: Company, catalog #, lot # if commercial
 Quality, yields, characterizing data…
Protocols, experimental design, calculations
 Can cite your own methods for repeat / routine procedures
 Notebook pages / your standard protocols
 Can cite standard / routine published methods
 Give full literature reference
 Note variations from previous experiments or publications
Show all necessary details
 Components in each
sample / tube

Exact volumes, weights, #s
 Source of reagents
 Company, catalog #, lot #
 Work out complete protocol
in advance - not “on the fly”


If protocol file is on
computer (e.g., a
spreadsheet), affix a printed
copy in the notebook
Include calculations
Results should be recorded clearly
 Graphs, charts, analytical data should be attached or
copied into the record


Tape or paste within confines of page; don’t obscure written
entries
Label data & describe the results so that they can be
understood
 Material that cannot be attached easily (e.g., gels, films)
should be copied, photographed or scanned for entry into
the notebook

Label & date films, etc., to correspond to notebook entries
 Electronic files too large to enter should be described, with
location specified, and maintained in a permanent form,
labeled with reference to notebook entries
Attaching charts
 Tape or paste into book
 Initial
 Label clearly
 Describe results
 Electronic files should be
cross-referenced to
notebook entry


Book & page no.
 ex) W104-1 ff
Experiment no.
 ex) MEF003
Conclusions
 The record should draw a
conclusion and evaluate
the experimental results, if
possible
 Be factual

Avoid subjective statements
Signatures
 Every notebook page should be signed and dated by the
investigator
 Every page also should be signed and dated by an
individual who has read and understood the entry



This witness should not be connected with the work as an
inventor, nor have taken part in the experimental work described
The witness should understand the technical field of the entry
Witnessing should occur in a timely manner
 Preferably within 1 week of the entry
 Signing & witnessing are important for the protection of
the Clinic’s intellectual property
Ownership /
Loss or theft
 The Laboratory Notebook is the property of the Clinic
 Investigators’ notebooks & any additional primary data records /
files should remain at the Clinic
 In general, departing investigators should be able to take copies
of their notebooks & other data upon leaving the Clinic, with
limited exceptions
 Report the loss or theft of a Laboratory Notebook
immediately
 Without direct faculty approval, the Laboratory Notebook
should not leave Clinic premises