1. Alan Bentley Cleveland Clinic - Innovations
The Inconceivable Ramifications of a Shoddy
Lab Notebook on the Lives of Millions

2. A bit of historical fiction
Millions? Really?!?
A bit of historical fiction

3. 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.

4. 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

5. 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

6. 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!!!

7. 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

8. 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

9. 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

10. A famous cases involving lab notebooks
Stern v Trustees of Columbia University

11. 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

12. 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.

13. 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.

14. 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

15. Corroborating evidence
What kind of evidence can corroborate an invention date earlier than the filing date:
Witness Testimony
Physical Evidence
Other facts and circumstances independent of info received from the inventor

16. 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

17. 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

18. 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

19. 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

20. Conclusion regarding corroboration
The BEST method for proving:
-Conception date
-Reasonable diligence toward reduction to practice
Is...
Physical Evidence
i.e.
The LABORATORY NOTEBOOKS

21. Let’s not lose sight of the big picture
Reasons for keeping a good lab notebook

22. 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

23. 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

24. Surely nobody of any import bothered with the lab notebook…
I can think of a few

25. 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

26. Leonardo da Vinci’s Notebook

27. Darwin, Einstein, and Pauling

28. Alexander Graham Bell’s notebook
March 10th 1876: “Mr. Watson – Come here – I want to see you”.

29. Francis Crick’s notebook
Model building
Centrifuging egg white
Methods set forth clearly

30. Results in Nobelists’ notebooks
C. H. Best –
Blood sugar
S. Luria –
Bacteriophage growth
M. Rodbell –
Glucagon release

31. Mendel, Edison, and Curie

32. Suggestions for a good lab book
Bound notebooks, consecutive entries
No blank pages or spaces… fill in with line
Use non-erasable ink pen
To delete simply strike through
Write legibly

33. 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

34. 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

35. And finally…a good story
The case of Peter Taborsky

36. The Case of Peter Taborsky
26 y.o. undergraduate in Chemistry and Biology
Working at USF- College of Engineering in Dr. Robert Carnahan’s Lab 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

37. 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

38. 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
USPTO issues two patents to Taborsky

39. 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!

40. Alan Bentley
Director of Commercialization
CCF Innovations
4-6752

41. Helpful hints for a good lab book
Alan Bentley
Director of Commercialization
CCF Innovations

42. 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

43. 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, Nov Nov XI-10-05
11/10/05 may be ambiguous (10 Nov, or 11 Oct?)
Indicate in “Notes” on inside cover if month or day comes first

44. 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….

45. 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

46. 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

47. 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

48. Attaching charts Tape or paste into book Label clearly
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

49. Conclusions
The record should draw a conclusion and evaluate the experimental results, if possible
Be factual
Avoid subjective statements

50. 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

51. 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