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

A bit of historical fiction 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: Witness Testimony Physical Evidence 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

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

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

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 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 bentlea@ccf.org 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 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

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 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

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