Sunday, May 4, 2014

A Brief Comment on Patents and Particularly Pharmacogenomics and Personalized Medicine

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To begin this discussion of patents in pharmaceutical policy, let me first set out two basic points that I think are central to pharmaceutical policy. First, I believe that strong patent protection, at least in developed countries, is an essential component of pharmaceutical policy. Second, I believe that the rapid development and implementation of pharmacogenomics and personalized medicine are absolutely critical for pharmaceutical policy. However, I do not necessarily believe that the development and implementation of pharmacogenomics and personalized medicine require the same breadth of patent protection afforded to the development of new drugs. Patent protection, and with it the rewards of the exclusive rights to make, use, or sell the patented invention, has been a feature of the legal landscape in every country in which significant numbers of new drugs have been developed since the modern pharmaceutical industry began. There have been proposals to do away with patents.  Prizes seem to be a recurrent suggested alternative to patents.1  However, I think it is clear that prizes are not a viable alternative reward for the occasional success in a risky and expensive enterprise. No one suggests prizes on the scale of the profits that are earned through patent protection when that risky and expensive enterprise succeeds.  It is simply not logical that the amounts of capital required to drive pharmaceutical innovation and drug development would be invested under a prize system, or any other system which significantly reduces the rewards obtainable with strong patent protection. However, that is not to say the details of the current system get the balance right. A number of years ago I suggested that much broader patents should be awarded for the significant innovation that is accomplished by the discovery and validation of a new target for drug development.2 While the Court of Appeals for the Federal Circuit (the principal forum for patent law in the U.S. other than the Supreme Court) has moved further in the other direction (over the vigorous dissent of Judge Rader),3 I still believe in the core of that argument and will expand on that problem in a future post. For now, it is sufficient to say that the validation of new biological targets for pharmaceutical therapy are the biggest (and riskiest) innovations in the drug development enterprise. Ideally the patent system would provide financial rewards that are proportional to the degree of innovation. That is not the system we have, but it is a reasonable and reasonably obtainable goal.

So, what about pharmacogenomics and personalized medicine? Since the Supreme Court narrowed the availability of patent protection for human gene sequences and diagnostic methods in Association for Molecular Pathology v. Myriad Genetics and Mayo Collaborative Servs. v. Prometheus Labs., Inc., there have been dire predictions about the consequences for personalized medicine and pharmacogenomics. Very recently Professor Chris Holman, who has made great contributions to the discussion of patents in the context of biotechnology and pharmaceuticals, responded with similar alarm4 to a recent federal district court decision in Ariosa Diagnostics, Inc. v. Sequenom, Inc.5 For purposes of this discussion, the Ariosa holding can be boiled down to this: A patent claim to a method of diagnosis that relies on conventional methods of amplifying and sequencing naturally occurring DNA is invalid because it is a claim to a naturally occurring phenomena or a correlation between naturally occurring phenomenom and a particular result. The Ariosa district court found such claims barred by Prometheus and Mayo:

The Supreme Court has never stated that any use of a natural phenomenon is patentable. To the contrary, the Supreme Court has held that "simply appending conventional steps, specified at a high level of generality, to laws of nature, natural phenomena, and abstract ideas cannot make those laws, phenomena, and ideas patentable." Prometheus, 132 S. Ct. at 1300. It is only an innovative or inventive use of a natural phenomenon that is afforded patent protection. See Myriad, 133 S. Ct. at 2119.... (Ariosa, "Discussion" paragraph 5).

The concern of Holman and others is straightforward: If claims that use "naturally occurring genetic variations" to diagnose disease or to diagnose pharmacologically relevant characteristics of a patient are unpatentable, it will be impossible for the human genetic diagnostics industry to survive and, in that case, pharmacogenomics and personalized medicine will not develop at a reasonable rate. That is certainly a valid concern and a logical one, so long as the underlying premise is true-- which is that the identification of relevant human genetic variations remains an expensive undertaking and utilization of the information requires a unique device or reagent for each such correlation. However, it seems increasingly likely that developments in genetic testing will rely on whole-genome sequencing ("WGS") technology along with ever more powerful computer technology for genomic analysis.

Let me elaborate on what this means. In the past, research to sequence even a portion of the genome of a patient's tumor or normal tissue was a costly and painstaking undertaking that required significant funding dedicated to that project. Validation of any variations found was also a painstaking and costly process that took significant time as more patients' tissues and control tissues were added to the database to refine the estimates of the correlation between particular variations and the risk of disease. For example, leaving all other questions of Myriad Genetics contribution to science and marketplace ethics aside, when Myriad began offering BRCA1 and BRCA2 testing, the risk estimates for particular mutations varied widely, the studies that produced those risk estimates relied on relatively small numbers of subjects, and each study was a significant investment of time and resources.6 While there are numerous technological issues still to resolve in the rapidly increasing clinical application of WGS,7 it is clear that the direction of genetic analysis is rapidly moving towards WGS, improved WGS platform devices, and improved computer algorithms for reading and analyzing the genomic information produced by WGS. Pharmaceutical companies will be investing in and using pharmacogenomics and should be required to submit pharmacogenomic data to the FDA to improve their clinical trial designs, data analysis, and drug use. Both diagnosis and personalized medicine will develop at an accelerating rate as the platform tools are improved. Professor Holman is a great scholar in the field of pharmaceutical patents and a real scientist as well as a law professor, but I think his concerns about the Ariosa decision may be unwarranted. Personalized medicine is more likely to be driven by WGS, pharmaceutical development, and the FDA, without the kinds of gene patents relied on by diagnostics companies before developments in genomics changed the game.

1See for example Linda P. Nussbaum and John D. Radice, Where Do We Go Now? The Hatch-Waxman Act Twenty-Five Years Later: Successes, Failures, And Prescriptions For The Future, 41 Rutgers L.J. 229 (2009) (and sources cited at footnotes 105-110).
2Robert A. Bohrer, Reach-through Claims for Drug Target Patents: Rx for Pharmaceutical Policy, 26(1) Nature Biotechnology 55 (January 2008).
3 Ariad Pharmaceuticals, Inc v. Eli Lilly And Company, 598 F3d 1336 (Fed. Cir. 2010).
4 Christopher M. Holman, The Holman Report: District Court’s Interpretation of Mayo in Ariosa Diagnostics Does Not Bode Well for Patent Eligibility of Diagnostics and Personalized Medicine, 33 Biotechnology Law Report 46 (April 2014).
5 No. C 11-06391 SI., 2013 WL 5863022 (N.D.Cal. Oct 30, 2013).
6Anyone interested in the literature of BRCA1and 2 risk estimation from before Whole-Genome Sequencing (WGS) became widely available at increasingly lower costs should read a classic meta-analysis of the BRCA risk data, A. Antoniou et al, Average Risks of Breast and Ovarian Cancer Associated with BRCA1 or BRCA2 Mutations Detected in Case Series Unselected for Family History: A Combined Analysis of 22 Studies, 72(5) Am. J. Human Genetics 1117-1130 (April 2003).

7 Frederick E. Dewey, M.D. et al, Clinical Interpretation and Implications
of Whole-Genome Sequencing, 311(10) J. Amer. Med. Assoc. 1035 (March 12, 2014).

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