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TECHNOLOGY TRANSFER Patent Process Built into Framework for DiscoveryIn a medical school, it is only natural to hope that research discoveries may lead to new medical treatments or therapeutic devices.
Valeria Fantin and Philip Leder are co-inventors of a molecule that appears to target the mitochondrial Achilles' heel of some cancer cells, inducing apoptosis. (Photo by Graham Ramsay) It is more than wishful thinking: it is the law. For 22 years, since passage of the Bayh-Dole Act and related legislation, government-funded researchers have been urged to report promising discoveries. Likewise, their employers have been encouraged to patent and market those discoveries to companies that can transform them into useful products for the public. All this has been an unexpected education for Valeria Fantin, a postdoctoral fellow who recently acquired a surprising addition to her curriculum vitae: co-inventor status on an international patent application for her discovery of small molecules that may selectively kill tumor cells. Fantin's first encounter with the early steps in the technology transfer process offers an instructive snapshot of what is becoming a routine part of being a scientist. Young researchers like Fantin are increasingly likely to experience the business end of the bench-to-bedside pipeline. Patent applications from U.S. and Canadian members of the Association for University Technology Managers increased in fiscal 2000 to 6,375. That is a 15 percent jump from the previous year and more than triple the number filed in 1991, according to the organization's latest survey. How to Package PromiseIt all starts with a report of the invention. In fall 2000, Fantin and Philip Leder, the John Emory Andrus Professor of Genetics and chair of the Genetics Department, began looking for small molecules that would stop the growth of breast cancer cells without killing normal cells. Specifically, they were interested in mouse mammary epithelial cells transformed into cancer cells by overexpression of the neu oncogene. Too much protein made by the equivalent human oncogene HER-2 is a culprit in 20 to 30 percent of human breast cancers and is the target of the drug Herceptin. Trying out a high-throughput technique, Fantin loaded the oncogene into mouse mammary epithelial cells and systematically tested extremely low doses of thousands of small molecules from a collection known as the Russian library, available at the Institute for Chemistry and Cell Biology.Of 16,000 screened molecules, six were particularly effective against the cells with the overexpressed oncogene but also spared the unaltered cells in parallel control assays. Next, Fantin tested the molecules against a panel of other mouse tumor cell lines and human breast cancer cell lines. "That's when it became interesting," she said. "We knew it was toxic to an array of cancer cells, but we didn't know why."
Technology transfer in the Harvard medical community. More than 12,000 faculty, postdocs, and graduate students are considered full-time members of the Harvard medical community, but Harvard Medical School handles only the inventions of its employees on the Quad and Dental School. Ten technology transfer offices at independent HMS-affiliated hospitals and institutions oversee the inventions of their employees with Harvard academic titles. Note that patent applications are filed one to two years after reports of inventions, and patents are issued about two to three years after the application is filed. All figures in the chart are from fiscal 2001. (*Figures in row are estimates.) Fantin and Leder's research sponsorship agreement with the Howard Hughes Medical Institute (HHMI) obligates them to report new inventions, as do grants from the National Institutes of Health. Leder, whose lab has generated a thick portfolio of patents in animal model systems and drug targets, recognized a classic example of an invention that needed to be reported. He called the HMS Office of Technology Licensing and Industry Sponsored Research, which administers University-owned inventions by researchers on the Quad and at the Dental School (see chart). From there, the technology licensing office notified HHMI. Some inventions cannot be patented and others do not need patent protection, but this report of invention suggested potential commercially viable therapeutic agents. HMS licensing associate Maryanne Fenerjian directed patent attorneys to file a U.S. provisional patent application in January 2001, an efficient way to start the process of protecting an invention in this country and others. To obtain patents in most countries, a patent application must be filed before any public disclosure, including a presentation at a meeting or publication of a paper. Inventor vs. AuthorAt this stage, researchers can be surprised to learn that inventorship is not the same as authorship, said Ken Levin, HMS senior technology manager. "Authorship is determined under academic conventions. Inventorship is determined with the guidance of an attorney and can change as the scope of the patent changes under review from the patent and trademark office."For example, only Fantin and Leder's names appear as inventors on the international and provisional U.S. applications. But their paper in the July Cancer Cell lists three additional co-authors. Featured on the journal's cover, the paper focuses only on the most potent of the molecules, named F16 for its random place in row F column 16 on assay plate number 44. Then there is the difference between good science and a good invention. "Results are not the invention," said Fenerjian, who has a PhD in cellular and molecular biology from Harvard, postdoctoral experience at MGH, and a law degree from Suffolk University. "They're the tools that suggest what the invention is and that it will work." After the first patent application was filed, Fantin continued to report new findings from her work on the molecules to Fenerjian. She also met with a scientifically trained patent attorney who evaluated the legal claims, researched prior knowledge in the field, and wrote the claims on the application. Subsequent experiments on F16 pinpointed mitochondria as the sites of activity and showed the molecule's effectiveness in a mouse model of breast cancer. HMS filed a second, expanded U.S. provisional application with these data in June 2001. When Fantin consulted with Luca Scorrano in the laboratory of Stanley Korsmeyer at DFCI for confirmation of the mitochondrial action, Fenerjian advised her to share everything but the structure with her collaborators until the application then under preparation could be filed. That clashed with Fantin's ideals of a free exchange of scientific information, but Korsmeyer and Luca were good sports, and it did not interfere with the immediate experiments. Unclear about the timelines, Fantin delayed some sections of her manuscript a few months until she could fully discuss the structure with her collaborators. "In general, we don't ask people to postpone talks--just tell us when they give a talk--and we will never tell people to hold publication back," said Fenerjian. In the end, Fantin counts her experience as interesting and valuable. "The bottom line is that you don't lose your freedom as a scientist," she said. "You're just tied to a different schedule with additional deadlines." --Carol Cruzan Morton |
