02 May 2015

Gene Patents

'The mouse that trolled: the long and tortuous history of a gene mutation patent that became an expensive impediment to Alzheimer's research' by Tania Bubela, Saurabh Vishnubhakat and Robert Cook-Deegan in (2015) Journal of Law and the Biosciences presents
 the tale of the academic discovery of a rare mutation for early-onset Alzheimer's disease that was patented by a sole inventor and licensed to a non-practicing entity (NPE), the Alzheimer's Institute of America (AIA). Our aims are (1) to relate this story about patents, research tools, and impediments to medical progress, and (2) to inform ongoing debates about how patents affect research, disposition of university inventions, and the distribution of benefits from publicly funded research. We present an account of the hunt for Alzheimer's genes, their patenting, assignment, and enforcement based on literature, litigation records and judicial decisions. While AIA's litigation eventually failed, its suits against 18 defendants, including one university, one foundation, and three non-profit organizations were costly in court years, legal fees, and expert time. Reasons for the failure included non-disclosure of co-inventors, State laws on ownership and assignment of university inventions, and enablement. We discuss the policy implications of the litigation, questioning the value of patents in the research ecosystem and the role of NPEs (“patent trolls”) in biotechnological innovation. The case illustrates tactics that may be deployed against NPEs, including, avenues to invalidate patent claims, Authorization and Consent, legislative reforms specifically targeting NPEs, reforms in the America Invents Act, and judicial action and rules for judicial proceedings. In the highly competitive research environment of Alzheimer's genetics in the 1990s, patents played a minor, subordinate role in spurring innovation. The case produces a mixed message about the patent system. It illustrates many mistakes in how patents were obtained, administered, and enforced, but, eventually, the legal system rectified these mistakes, albeit slowly, laboriously, and at great cost.
 The authors comment
This case study is a cautionary tale about a patented genetic discovery, a double mutation in a gene conferring high risk of Alzheimer's disease. The patent was licensed as a research tool to expand understanding of the molecular and genetic basis of Alzheimer's disease. Our goals are first, to relate an intricate, fascinating story about patents, research tools, and impediments to medical progress and, second, to inform ongoing debates about whether and how patents can affect research, disposition of ownership of university inventions, and the just distribution of benefits from publicly funded medical research.
Randall Rader, in his dissent as former Chief Judge of the US Court of Appeals for the Federal Circuit (CAFC) in Momenta Pharma. v Amphastar Pharma, concluded that ‘patents on research tools and biomedical innovations do not significantly slow the pace of research and do not deter researchers from pursuing promising projects’. Patent owners, he said, do not sue researchers because ‘experiments do not produce income or a source of damages’. Indeed, disclosure in patent documents ‘encourages publication and sharing of research results’. Our case study is a counterexample to temper Chief Judge Rader's sanguine assessment. While it describes an unusual outlier example and is not an argument against patents, this case study suggests that without a clear research exemption, or other mechanisms to enable access to research tools, biomedical researchers can face patent infringement litigation that imposes significant costs and slows down both academic and commercial scientific inquiry.
The story began in the early 1980s with research into the genetics of Amyloid Precursor Protein (APP) and its linkage to early-onset Alzheimer's disease. Key researchers were active in Europe and the USA. Patents on a particular double mutation, APPswe, were filed in the early 1990s, listing a clinician-researcher, Dr Michael Mullan, as sole inventor. The patents covered nucleotide sequences coding for a rare double mutation identified in two Swedish families. The patents also claimed cell lines, transgenic mouse models, and assay and screening methods incorporating the mutation. The institutions that hosted the research were deliberately excluded from the patent rights. Stakeholders affected by the patents included other researchers and their institutions, pharmaceutical and biotechnology companies, philanthropists, foundations, and venture capital firms. The lead researcher, Mullan, assigned key patents to a non-practicing entity, the Alzheimer's Institute of America (AIA), which enforced rights against research uses. The patent rights were used to generate revenues, but the disposition of those revenues is difficult to trace. AIA may have sponsored some of Mullan's further research but is not acknowledged as a funder in the research publications from Mullan's team. The families from whom the mutations were isolated received none of the financial benefits, and are likely unaware that their mutation was used to enrich one researcher and a venture capitalist with the result of impeding Alzheimer's research. Ironically, after nearly a decade of litigation, claims in the patents might or might not have been deemed valid under current patent jurisprudence. We will never know, because the patents were deemed invalid based on inappropriate assignment and inventorship.
The case study is of interest because it illustrates a non-practicing entity (NPE) using patent rights over research tools to extract revenue from those striving to understand and treat Alzheimer's disease. AIA's enforcement against non-profit research institutions caused considerable consternation in Alzheimer's research circles. The case study touches on key points in ongoing debates about the value of patents in the research ecosystem. Did patent rights create incentives to do the research? Almost certainly not, at least for the initial discovery, since the samples were collected and grants secured long before the patent story began to unfold. How were contributions to the research evaluated and rewarded? How did legal frameworks enable university ownership, even without federal funding in the USA? How was enforcement of patent rights against non-profit research institutions enabled, and who was benefited? What mechanisms were brought to bear to mitigate the impact of the enforcement litigation? The case illustrates many mistakes in how patents were granted, administered, and enforced, but, in the end, the legal system rectified many of these errors, albeit after long delay and at great expense.
We begin with a brief account of the genetics of early-onset familial Alzheimer's disease and the discovery of the APP gene, then move on to the patents, and finally discuss patent assignment and enforcement: the resolution of many infringement lawsuits, and the lessons learned. Our account is based on data available in the public record from disparate sources: scientific publications, patents, news and commentary, biographies, and most importantly, litigation records and judicial decisions. The legal proceedings include findings of fact by the district court judge and/or jury based on the evidence presented. The role of the trial judge (and the jury in some details) is to assess the credibility of documentary evidence and oral testimony. This assessment leads to an accounting of what ‘really’ happened, even though in litigation, there are by definition multiple sides to the story. Appendix 1 presents a graphic chronology of the key events in the story.