Case-Study Discussion Assignment - Week 3 - Data, IP and Tech Transfer Cases

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Case-Study Discussion Group Assignment from C234 – 2020 – Week 2 Mentor/Mentee Relationships and Laboratory Safety – FACULTY DISCUSSION LEADER Case 1 1 *: Who Identified HIV? * based on real events Perspective 1 – Luc Montagnier: Principal Investigator at Pasteur Institute Perspective 2 – Robert Gallo: Principal Investigator at the National Institutes of Health (US) Perspective 3 – Margaret Heckler, Secretary of Health and Human Services (US) In the early 1980s, immunodeficiency-related deaths were soaring around the world but the cause was unknown. Luc Montagnier and colleagues at the Pasteur Institute hypothesized that a virus was responsible. In 1983, Montagnier and colleagues successfully isolated a retrovirus from the lymphoid tissue of an affected AIDS patient, which they termed “Lymphadenopathy Associated Virus” (LAV), and published their findings in Science , stating the role LAV in causing AIDS was “yet to be determined.” 2 Dr. Robert Gallo, an esteemed virologist at the NIH credited with discovering Human T-Cell Lymphotropic Viruses (HTLV-1, -2), requested samples of the LAV virus. Dr. Montagnier provided them, with the agreement that they would publish their findings together. A year later, Dr. Gallo published a series of papers in Science 3 , where he reports discovery and isolation of “HTLV-3”, a separate AIDS-causing virus collected from AIDS and pre-AIDS patients, not including Dr. Montagnier as an author. In the papers, images of Dr. Gallo’s HTLV-3 virus bear no similarity to HTLV-1 or -2 but do look suspiciously similar to Dr. Montagnier’s LAV virus, leading many to question whether Dr. Gallo had stolen Dr. Montagnier’s virus. Dr. Gallo’s Science papers reference the LAV virus, noting that LAV had not yet been properly characterized and could not be compared with HTLV-3. Dr. Gallo uses the HTLV-3 virus to develop a blood-based antibody test, which is fast-tracked to patent approval with the support of the Secretary of Health and Human Services, Margaret Heckler. Whether Montagnier or Gallo was first to isolate HIV was the subject of an acrimonious dispute for many years, relevant to scientific bragging rights for both France and the US and the licensing revenue from the blood test. Gallo’s research home, the NIH led many years of poorly directed misconduct investigations into Gallo’s lab, with no evidence of wrongdoing found. Finally, after an independent investigation into the matter was commissioned by the new DHHS Office of Research Integrity (that was finally established outside of NIH). The investigators found that recordkeeping and oversight in Gallo’s lab were poor and that Dr. Gallo’s HTLV-3 virus matched one of the LAV strains from Dr. Montagnier’s lab. The investigators conclude that the use of the LAV strain was likely inadvertent, a sample must have accidentally contaminated the pooled culture on which Dr. Gallo’s lab was working. Dr. Gallo maintains that his group is the first to show that the virus caused AIDS , while Dr. Montagnier’s lab was the first to isolate HIV . In 1987, French President Francois Mitterrand and American President Ronald Reagan agree their countries would split the blood test royalties 50-50 and the retrovirus was renamed HIV. In 2008, Montagnier and Françoise Barré-Sinoussi were awarded the Nobel Prize for the discovery of HIV, while Robert Gallo was not named on the prize. Dr. Montagnier’s Questions  How can a lab protect its IP while still collaborating with other labs? Dr. Gallo’s Questions  As a PI, what actions can you take to protect your lab from potential accusations of misconduct?  What types of lab policies or procedures help labs defend themselves and their research? Margaret Heckler’s Questions  Was US Dep’t of Health and Human Services neutral in this investigation?  How should a university handle accusations of misconduct of its researchers? Can it be impartial? 1 Adapted from case submitted by C234 student, Albert Sek, Spring 2015. 2 Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vézinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L (1983). "Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)". Science 220 (4599): 868–871. 3 Popovic M, Sarngadharan MG, Read E, Gallo RC (1984). "Detection, isolation, and continuous production of cytopathic retroviruses (HTLV- III) from patients with AIDS and pre-AIDS". Science 224 (4648): 497–500.

Case 2 4 : Operon Operation Perspective 1 – Susan Barnes Perspective 2 – Jesse Packard Perspective 3 – Fran David Susan Barnes, a cell biologist, has isolated a novel soil microorganism with powerful apoptosis-inducing activity against eukaryotic cells. She mentions this discovery to a colleague of hers at a biotechnology company, BioZen, where the implications of the finding are quickly disseminated. The vice president for research, Jesse Packard, invites Susan to give a seminar to the scientists at BioZen. After her seminar, the Jesse tells Susan that the company should be able to provide a grant to support some of her work and asks her to prepare a five-page funding proposal. The anticancer implications of the agent she discovered have commercial importance to the company. Susan writes a proposal that says she aims to purify the active compound and test levels of apoptosis in various cell lines. The grant application is submitted and material transfer agreement (MTA) including IP protection for the microorganism and its active compound is executed, crediting Susan and her university with discovering the compound. The company will have first right of refusal to license the active compound from Susan's university, pending her results. The grant is paid as a one-time $75,000 award and stipulates that Susan should share research materials with the company on a non-exclusive basis. About one month into the project, Jesse asks Susan to send BioZen a culture of the microorganism, and she honors this request. A team of scientists led by Fran David at BioZen have come up with some predictions about enzymes that are likely to be involved in the synthesis of this apoptosis-inducing agent. Over the course of the next several months, Fran David’s team clones the corresponding genes and determines that the pathway for synthesis of the compound is composed of the products of 19 linked genes. They determine the nucleotide sequence of this 35-kb operon that could theoretically be transfected into an organism to induce in vitro production of the apoptosis-inducing compound. Fran writes up description of the operon and submits it to BioZen’s legal department to begin a provisional patent application for a compound-producing cell line. It will be up to the legal department to decide if the patent application should be submitted based on the MTA and prior art. Susan Barnes:  What is an MTA?  Do you think BioZen’s provisional patent application for an operon that could be transfected into an organism to produce the active compound would violate the MTA? If so and BioZen moves forward with the patent, how would you pursue the matter? Jesse Packard:  Do you think BioZen or Susan’s university holds the rights to the biosynthetic operon? What if the MTA did not explicitly prohibit use of precursors to the compound?  How can universities protect the IP rights of research developed within the institution, while still allowing commercialization, industry-sponsored research, and translation of science into practice? Fran David:  Do you think the important intellectual part of the work was the discovery of the apoptosis- inducing microorganism, isolation of the active compound, or identification of the relevant genes coding the active compound? 4 Adapted from: Macrina, F.L. (2005). Chapter 9: Ownership of Data and Intellectual Property, Case Study 9.10, . Scientific Integrity, Third Edition (pp. 237-242). Washington, DC: ASM Press.

Case 3 5 : Lost Labels Perspective 1 – Donna Adkins Perspective 2 – Miguel Lopez Perspective 3 – Dr. Malcolm Franklin Donna Adkins, a biomedical sciences graduate student, is using blood samples from 100 human patient volunteers to test antibody levels against two different viruses. Though the patient’s identities are not recorded per patient privacy guidelines, she has recorded the relevant clinical histories of these patients in her lab notebook, corresponding to the individual samples. She has carefully tagged the tubes with coded self-adhesive labels and stored them in 5 racks of 20 in the freezer. She assays the samples in three of the five racks and obtains interesting results. She records her results meticulously in her lab notebook, cross-referencing the antibody values to the clinical patient data. Donna asks a postdoc in the lab, Miguel Lopez, to witness these lab notebook pages because the results have implications for the development of an important diagnostic test. Miguel signs her lab notebook pages as requested. A few days later, when Donna opens the freezer to retrieve the sera in the fourth rack, she makes a disturbing discovery. All the labels have become loose from the tubes in racks 1 and 2. (She later finds out she used the wrong kind of self-sticking labels on these tubes, resulting in their failure to adhere at temperatures of -70°C.) Donna proceeds to number all the tubes in racks 1 and 2 by order of their rack location. Then she repeats the antibody assays on these samples. She arranges her resulting data into a summary table that she compares with her original assays of these samples. She is relieved that the data compare favorably; and she re-labels the tubes consistent with their original designations. She goes to Miguel for advice on her actions and asks him how she should record these events in her data book. Miguel suggests that since she carefully matched the previous results, adding the update about the issue with racks 1 & 2 would just confuse the record. Later, Donna’s mentor, Dr. Malcolm Franklin, noticed a large quantity of loose labels in the freezer. He asks around the lab them until Donna relays what happened with the blood serum antibody experiment. He is disappointed that Donna didn’t record the error and resulting action in her lab notebook and immediately sets a lab meeting to discuss data record keeping protocol. Donna Adkins:  How should you have recorded the retesting of racks 1 & 2 in your lab notebook?  Should the experiment/data/procedure in error be removed from a lab notebook? Miguel Lopez:  What should have been your advice to Donna?  Do you think you should record data that reconfirms original results? Why? Dr. Malcolm Franklin:  In addition to proper data recording procedures, what will you tell your trainees about deciding when it is necessary to repeat an experiment? How should they handle it if they get different results each time? 5 Adapted from: Macrina, F.L. (2005). Chapter 11: Scientific Record Keeping, Case Study 11.9, Scientific Integrity, Third Edition (pp. 289- 294). Washington, DC: ASM Press.

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Case 4 6 : Perspective 1 – Janet Ginsburg Perspective 2 – Declan Brown Perspective 3 – Adam Green Dr. Declan Brown's research group recently published an important paper in a leading physiology journal. Four months after the publication of the manuscript, Dr. Brown is contacted by a European colleague, who has been unable to reproduce the results presented in two figures of the paper. Dr. Brown emails copies of the pertinent laboratory protocols and reagent recipes to his colleague and thinks no more of the discrepancy. Two months later, a graduate student in a competitor's laboratory contacts Dr. Brown and reports that he was unable to reproduce the results. After this second call, Dr. Brown meets with Adam Green, the postdoctoral fellow who did the experiments in question. He asks Adam to bring his lab notebook to the meeting so they can review the results together. Once in Dr. Brown's office, Adam confesses that he was remiss in keeping his lab notebook. He says that he tended to record the details of the experimental conditions and corresponding results on loose paper as he worked and later transcribe them neatly into his lab notebook. However, there was a period of several days during the key experiments when he misplaced the loose sheets. He did not use a file-naming scheme for his electronic physiology records, so without the notebook pages, it was hard to match the stored data with the relevant experimental conditions. Adam relied on his memory to match the stored results with the experimental conditions. After completing the figures for the manuscript, Adam was pleased to find that his data supported Dr. Brown's hypothesis. Dr. Brown is very upset with Adam. Although he does not believe the Adam purposefully fabricated data, he cannot believe he would allow potentially suspect results to be published. Unsure of what to do next, he discusses the matter with a colleague in his department who does similar work, Janet Ginsburg, and asks her for advice. Janet Ginsburg:  What do you advise Dr. Brown to do first? Declan Brown:  What sort of action will you take with your postdoctoral trainee, Adam? Adam Green:  What would have been the best procedure for recording your electrophysiology data?  What should you have done as soon as you discovered the lost records? 6 Adapted from: Macrina, F.L. (2005). Chapter 11: Scientific Record Keeping, Case Study 11.10, Scientific Integrity, Third Edition (pp. 289- 294). Washington, DC: ASM Press.

Case 5 7 : Mother of Invention Perspective 1 – Eleanor Michael Perspective 2 – Mitchell Tanner Perspective 3 – Aaron Paul A month before defending her dissertation, Eleanor Michael files an invention disclosure with her university’s intellectual property office on a novel invention developed as part of her doctoral research. Mitchell Tanner is assigned as Eleanor’s intellectual property officer. He meets with Eleanor and her thesis advisor, Dr. Aaron Paul, and discusses the invention disclosure. When asked about inventorship, Dr. Paul responds that both he and Eleanor are the inventors. After the meeting, Eleanor stays behind to discuss something with Mitchell. She explains that when she joined Dr. Paul’s laboratory, she conducted a thorough review of the literature and developed a hypothesis that she felt was not addressed by previous research. Even though the hypothesis represented a deviation from most of the research ongoing in Dr. Paul’s laboratory, he allowed her to pursue it and provided funding from one of his grants for her work. Over the course of her research in his laboratory, Eleanor independently developed her research project to test and analyze her hypotheses. The nature of the project meant that Dr. Paul was not always able to provide much assistance, and so she sought expertise from others when required, particularly for data analysis. Although Eleanor performed most of her own research, she noted that she did require the help of a technician to overcome a technical hurdle in one small, but ultimately significant, area. Based on the events leading to the invention, Eleanor is not sure whether Dr. Paul should be listed as a co-inventor. Mitchell Tanner feels that the invention has enough commercial potential that the university should definitely file a patent application. Further, he thinks the application should be filed before Eleanor’s public dissertation defense in order to protect worldwide patenting rights, so the question of inventorship should be resolved quickly. Eleanor agrees. She does not feel, however, that Dr. Paul is truly an inventor but does not want to cause any problems with her advisor right before her dissertation defense. Eleanor Michael:  What criteria for inventorship do you feel Dr. Paul lacks?  Since the question of inventorship must be determined before your dissertation defense, how might you approach the issue? Mitchell Tanner:  How do you think intellectual property officers at a university handle disputes about inventorship?  Since patent invention has a legal definition of participation in the conception of an invention, how might you determine whether a potential inventor meets this criterion?  Must co-inventors have equal shares of the invention? Aaron Paul:  What criteria for inventorship do you meet?  Do you think your position as Principal Investigator, including curating funding, resources and personnel makes you a viable co-author and/or co-inventor on everything produced through your laboratory? Why or why not?  If during the patent application process it becomes clear that there is a question of whether your participation meets the criteria for invention, will this hurt your mentoring relationship with Eleanor? 7 Adapted from: “Case Study - A Question of Inventorship.” Responsible Conduct of Research Online Study Guide. University of New Hampshire, 2008. Web. May 15, 2012.. <https://www.unh.edu/rcr/IP-CaseStudyGoTo.htm>

Case-Study Discussion Assignment - Week 3 - Data, IP and Tech Transfer Cases

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