1Alan Bentley Cleveland Clinic - Innovations The Inconceivable Ramifications of a ShoddyLab Notebook on the Lives of Millions
2A bit of historical fiction Millions? Really?!?A bit of historical fiction
3BackgroundYou 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.
4Protecting 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 patentingOutside the U.S. publishing before patenting = forfeiting of patent rightsIn 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 publicationInnovations files a patent application before the 1-year deadline – the technology is licensed to a pharmaceutical company (your ‘Partner’) for commercialization
5The patent processAbout 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 compoundsPatent applications in the U.S. publish about 18 months after filingSome digging reveals that the patent application was licensed exclusively to Large PharmaThis is slightly peculiar, because Large Pharma just entered the market with a strong selling prostate cancer drug with respectable, but not terribly inspiring efficacySix months later (the 18th month mark), your patent application publishes
6The controversyThe 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 monthsThe 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, butIf you can show that you conceived the invention before the Japanese pharma company, you get the patent over them!!!
7The lab notebookYou bring out your lab notebooks, which memorialize your conception of the inventionYou 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 dateYou should be good to go
8TechnicalitiesUnfortunately, the USPTO (or a court, in similar scenarios) is unable to consider your notebook as evidence of the point of first conceptionThe notebook is not datedThe notebook is not witnessed by othersTherefore, there is no corroboration
9The ramificationsThe Clinic loses the patent to Large Pharma, and loses out on licensing revenue – it gets screwedYour 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 screwedThe inventors lose out on a potentially sizable royalty stream – they get screwedLarge 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
10A famous cases involving lab notebooks Stern v Trustees of Columbia University
11Stern v. The Trustees of Columbia University CAFC – Decided January 17, 2006 Invention: directed towards the use of prostaglandins in treating glaucomaIssue: Unwitnessed laboratory notebooks are insufficient to support a claim of coinventorship
12Stern v. The Trustees of Columbia University CAFC – Decided January 17, 2006 Background:Columbia owns ‘353 patent naming Lazlo Bito as the inventorIn 1980, Stern (medical student) did a one semester ophthalmology research elective in Bito’s laboratoryExperiments 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.
13Stern 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 inventorStern’s notebooks were not co-signed or witnessedThe courts ruled that unwitnessed laboratory notebooks on their own are insufficient to support his claim of co-inventorship.
14Stern 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
15Corroborating evidence What kind of evidence can corroborate an invention date earlier than the filing date:Witness TestimonyPhysical EvidenceOther facts and circumstances independent of info received from the inventor
16Witness testimonyWitness must have been able to autonomously evaluate the inventor’s development of the inventionCourt does not require “constant supervision” but wants evidence of opportunity for “regular, independent evaluation” of the inventor’s progress
17Physical evidenceDoes not itself require corroboration to demonstrate its contentDoes require corroboration for dates of conceptionWhen 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
18Physical evidenceCourt 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
19Corroboration - Other facts and circumstances independent of inventor Organizational structure and protocol of the facilities where the inventor engaged in researchA protocol regarding reporting and evaluation of lab notebooks determines the strength of corroborating evidenceShowing a policy for regular recognized evaluation procedures strengthens witness testimony and physical evidence (lab notebooks)Generally a weaker form of evidence
20Conclusion regarding corroboration The BEST method for proving:-Conception date-Reasonable diligence toward reduction to practiceIs...Physical Evidencei.e.The LABORATORY NOTEBOOKS
21Let’s not lose sight of the big picture Reasons for keeping a good lab notebook
22Our scientific obligation Allows your work to be reproduced faithfullyBy yourselfBy othersScience must be reproducible!!!Facilitates accurate reporting & publicationOrganizes how you do ScienceFormulate ideas clearlySpecify materials & methodsPlan experiments wellObtain maximum value from dataProtects intellectual propertySupports future clinical development
23Our moral obligationA major goal of the Clinic is to translate our research into the development of new technologies and therapies that will help patientsWe 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
24Surely nobody of any import bothered with the lab notebook… I can think of a few
25Leonardo da Vinci’s notebook Studies of reflections from concave mirrors. Italy, probably Florence, from 1508.British Library Arundel MS 263, f.86v-87We can read and understand Leonardo’s notebooks from 500 years ago
32Suggestions for a good lab book Bound notebooks, consecutive entriesNo blank pages or spaces… fill in with lineUse non-erasable ink penTo delete simply strike throughWrite legibly
33Other recommendsIdeas (inventions) and data should be recorded in a bound Laboratory NotebookRelated electronic files, films, etc. should be recordedEnter hard copies of these “secondary sources”, if possibleEnter description of file / film / etc. in the lab notebookAll entries should be signed, dated, and witnessed
34Level of specificity Record: Ideas & inventionsExperimentation records & observationsAll work detailsEntries 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
35And finally…a good story The case of Peter Taborsky
36The Case of Peter Taborsky 26 y.o. undergraduate in Chemistry and BiologyWorking 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 efficientContract between FP and USF gave all research results to FPTaborsky was part of the team
37The Case of Peter Taborsky Project was terminatedTaborsky began getting paid from other budgetsTaborsky continues to experiment on projectTaborsky finds a solution to the sewage treatment problemCarnahan tells Taborsky, the research results are FP’s and if he assigns his rights to FP they will hire him to a staff positionTaborsky drops out of school and takes his NOTEBOOKS with him
38The Case of Peter Taborsky USF files criminal charges for “theft of trade secrets”1990- Taborsky found guilty:One year suspended sentenceOne year under house arrest15 years' probationJudge stated that he could not use or profit from his notes or his inventionTaborsky files for patents anywayNine months later USF and FP files for the same patentsUSPTO issues two patents to Taborsky
39The Case of Peter Taborsky Judge orders Taborsky to assign the rights of his patents or be sent to prisonTaborsky refused and is sent to prison for 3 and ½ yearsThank goodness nobody at this institution is are strong-willed!
40Alan BentleyDirector of CommercializationCCF Innovations4-6752
41Helpful hints for a good lab book Alan BentleyDirector of CommercializationCCF Innovations
42Notebook entries Record your ideas and data as you work All experiments should be recorded, regardless of outcomeDo not wait for results or record only “successful” experimentsNever remove pages from your notebookMaintain an up-to-date Table of ContentsTitles of experiments & projects to which they correspondHelpful to assign a unique number to each experimentRecord entries legibly, neatly and in permanent ink (black)Do not use pencilDo not erase or use white-outCross out & correct if neededInitial & date changes to the record
43Page numbers & datesConception of ideas and experimental work should be recorded in chronological order on numbered pagesMultiple experiments may be in progress – pages for any 1 experiment need not be contiguousFill in boxes “Continued from page”, “Continued to page”Each page should contain entries for only 1 experimentDate every pageUse a consistent, unambiguous systemInclude day, month, yearNovember 10, Nov Nov XI-10-0511/10/05 may be ambiguous (10 Nov, or 11 Oct?)Indicate in “Notes” on inside cover if month or day comes first
44Objective 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….
45Materials & Methods / Experimental Plan All essential facts should be recorded so that the work can be repeated accuratelyMethods, equipment, conditions, times, temperatures, pH, …MaterialsInclude source: Company, catalog #, lot # if commercialQuality, yields, characterizing data…Protocols, experimental design, calculationsCan cite your own methods for repeat / routine proceduresNotebook pages / your standard protocolsCan cite standard / routine published methodsGive full literature referenceNote variations from previous experiments or publications
46Show all necessary details Components in each sample / tubeExact volumes, weights, #sSource of reagentsCompany, 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 notebookInclude calculations
47Results should be recorded clearly Graphs, charts, analytical data should be attached or copied into the recordTape or paste within confines of page; don’t obscure written entriesLabel data & describe the results so that they can be understoodMaterial that cannot be attached easily (e.g., gels, films) should be copied, photographed or scanned for entry into the notebookLabel & date films, etc., to correspond to notebook entriesElectronic files too large to enter should be described, with location specified, and maintained in a permanent form, labeled with reference to notebook entries
48Attaching charts Tape or paste into book Label clearly InitialLabel clearlyDescribe resultsElectronic files should be cross-referenced to notebook entryBook & page no.ex) W104-1 ffExperiment no.ex) MEF003
49ConclusionsThe record should draw a conclusion and evaluate the experimental results, if possibleBe factualAvoid subjective statements
50SignaturesEvery notebook page should be signed and dated by the investigatorEvery page also should be signed and dated by an individual who has read and understood the entryThis witness should not be connected with the work as an inventor, nor have taken part in the experimental work describedThe witness should understand the technical field of the entryWitnessing should occur in a timely mannerPreferably within 1 week of the entrySigning & witnessing are important for the protection of the Clinic’s intellectual property
51Ownership / Loss or theft The Laboratory Notebook is the property of the ClinicInvestigators’ notebooks & any additional primary data records / files should remain at the ClinicIn general, departing investigators should be able to take copies of their notebooks & other data upon leaving the Clinic, with limited exceptionsReport the loss or theft of a Laboratory Notebook immediatelyWithout direct faculty approval, the Laboratory Notebook should not leave Clinic premises