Patent Docs

Rep. Burgess Introduces Genetic Diagnostic Testing Bill

By Kevin E. Noonan --

A decade after completion of the Human Genome Project, and after more than a decade of hyperbole regarding the promise and benefits of "personalized medicine," genetic diagnostic testing has come to the attention of Congress.  For example, Representative Debbie Wasserman Schultz (D-FL) introduced a provision of the Leahy-Smith America Invents Act (LSAIA) that would have "guaranteed" availability of "second opinion" testing for any patented genetic diagnostic test (see "Manager's Amendment (and Others) to H.R. 1249 -- Second Opinions in Genetic Diagnostic Testing").  She withdrew this amendment in the face of strong opposition from the American Civil Liberties Union and other groups, who pursue a complete ban on such testing as well as other aspects of biotechnology; she later introduced a standalone bill (H.R. 2276) that would "require the Director of the United States Patent and Trademark Office to conduct a study on effective ways to provide confirming genetic diagnostic test activity where gene patents and exclusive licensing exist" (see "Bio/Pharm Legislation Watch"); these provisions were added to the LSAIA enacted into law as a mandate that the U.S. Patent and Trademark Office perform a study directed to such a determination.  And Congressman Xavier Becerra continues to introduce a bill that would ban all gene patenting, at least prospectively (see "He's Baaack!").

The latest Congressional foray into genetic diagnostic testing comes from Rep. Michael Burgess (R-TX) (at left), who introduced legislation that would prohibit the Food and Drug Administration from regulating genetic diagnostic testing, based on the apprehension that such regulation would cripple innovation and that such testing would be "subsumed" by the bureaucracy.  Such testing is already regulated (as is all other laboratory testing) by the Centers for Medicare and Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments (CLIA).  Rep. Burgess discussed his bill on November 17th at a "bi-partisan policy forum" sponsored by The Hill and the American Clinical Laboratory Association.  The bill was prompted, in part, by FDA announcements that it intends to regulate "direct-to-consumer" genetic diagnostic tests.  Rather than cast the legislation as a ban, his bill (the "Modernizing Laboratory Test Standards for Patients Act of 2011," H.R. 3207) provides for regulation of such genetic diagnostic tests under the current CLIA regime, but with new guidelines and regulations directed towards greater clinical validity of such tests.  The bill also provides for the establishment of a Laboratory Developed Test (LDT) Test Registry Data Bank (for promoting "transparency") and a reporting requirement for clinical laboratories regarding death or serious injury that occurred as the result of a LDT.

In this regard, the bill requires disclosure for LDTs of the following information to the Data Bank:

• The location of the laboratory.
• The certification and licensure information of the laboratory.
• The purpose of the test.
• The claimed use or uses of the test.
• A description of the test methodology.
• Information regarding the analytical validity of the test.
• Information regarding the clinical validity of the test for each of its claimed uses.
• Information describing the status of the test as an existing test (as described under paragraph (4)), a new test pending review (under subsection (c)), or an authorized new test (under subsection (c)(4)(B)).

For so-called "direct-to-consumer" (DTC) DNA testing, the information required to be submitted includes all the aforementioned and in addition:

(i)  The identity, location, and registration information of the test-offering entity.
(ii)  The identity of the certified laboratory that will perform the test, and the certification and licensure information for such laboratory.
(iii)  information to demonstrate that the consumer will be provided with access to pre-test and post-test counseling by a physician or qualified genetic counselor.

Rep. Burgess has garnered the support of 4 co-sponsors (Rep. Marsha Blackburn, R-TN; Rep. Howard Coble, R-NC; Rep. Robert Latta, R-OH, and Rep. Erik Paulsen, R-MN).  The bill was referred to the House Committee on Energy and Commerce, and specifically the Subcommittee on Health, on October 14, 2011.

Docs at BIO: Session on IP Challenges for Personalized Medicine

By Andrew Williams --

On June 29, a panel at the 2011 BIO International Conference discussed the topic of "IP Challenges for Personalized Medicine: Navigating Bilski, Myriad, and Prometheus."  This session addressed one of the most prevalent issues at this year's conference -- are the courts going to alter the intellectual property landscape for biomarkers and personalized medicine?  As moderator, Jennifer Gordon of Baker Botts L.L.P. began the session by providing a definition for personalized medicine -- a definition that included at its core the ability to "classify individuals into sub-populations."  And how is this accomplished?  By identifying biomarkers (compositions of matter), and building diagnostics around them (methods).  As a result, Dr. Gordon identified three IP challenges:  (1) potential limitations on meaningful claim coverage for composition of matter claims; (2) potential limitations on meaningful claim coverage for companion diagnostic claims; (3) and the proliferation of patent thickets that results when many patents cover a particular diagnostic.

Hans Sauer, Associate General Counsel of BIO, addressed the first of these challenges by introducing and discussing the Myriad case (Association for Molecular Pathology v. USPTO).  Dr. Sauer pointed out the differences of this case as compared to other patent cases, specifically noting that the plaintiffs brought this suit on behalf of breast cancer survivors by attempting to reach the patent holder of a diagnostic test related to the risk of developing breast and ovarian cancer.  This is distinct from the typical patent case in which both of the parties are commercial actors.  In his general observations of the case, Dr. Sauer noted that there are two types of claims at issue, broad method claims and composition-of-matter claims, otherwise referred to here as "gene patents."  And gene patents, because they are claimed as isolated DNA, are legally indistinguishable from other biological chemicals such as proteins and antibodies.  Dr. Sauer opined that what the courts are being asked to decide is what does it take to go from a discovery to an invention?  In other words, how much human intervention is enough?  Of course, merely isolating and purifying a composition of matter has never been enough to obtain a patent, because a patentee still needs to meet the requirements that the invention be new, useful, and non-obvious, for example.  The Patent Office does not simply give away gene patents.  Therefore, as Dr. Sauer concluded, patent eligibility might not be the best tool to address these issues.

Mark Seka, Global Head of IP for Novartis Molecular Diagnostics, addressed the second identified challenge, the limitation on meaningful claim coverage for companion diagnostic claims, by specifically discussing the Prometheus case (Prometheus Laboratories, Inc. v. Mayo Collaborative Services).  At the outset, Mr. Seka noted that personalized medicine is basically a spin-off technology from the human genome project, and that the original mapping was just the beginning.  Because it is very costly to bring such a diagnostic invention to market, the cases currently making their way through the court system are threatening the ability of commercial enterprises to recoup their investments through the protection of their intellectual property.  Mr. Seka noted that the Prometheus case involved two types of claims, those that test a patient's blood to determine the presence of an analyte with a therapeutic administrative step, and those that just contain the testing step.  The Federal Circuit reversed a summary judgment ruling that the claims are patent ineligible because they recite a natural phenomenon.  The Federal Circuit used the machine or transformation test, and found that because both types of claims involved a transformation, they were both patent eligible.  However, in the wake of the Supreme Court's Bilski ruling, in which it held that the machine or transformation test was not the only test to determine patent eligibility, the Court remanded the case to the Federal Circuit to render a decision consistent with the Bilski ruling.  Mr. Seka noted that the Supreme Court did not dispense with the machine or transformation test, and so the Federal Circuit was able to reach the same result.  Of course, just recently, four Justices voted to take up the Prometheus in the next term, so the uncertainty continues.

Dr. Sauer played devil's advocate by asking Mr. Seka whether the patentees in Prometheus were just using old knowledge, and therefore asked if they were really entitled to patent protection.  After all, weren't the drugs old, and didn't the patentees just discover that the drug was metabolized -- is that enough for patent protection?  Mr. Seka responded two-fold.  First, the issue being decided is not whether the methods are novel, but rather whether you can even get in the door of the Patent Office with such claims.  Second, it is the correlation that is the silver bullet -- the invention converted an ineffective treatment to an effective one.  Dr. Sauer followed up by questioning Mayo's motivation in bringing such a suit, and asking why Mayo finds such claims so objectionable.  A possible answer was supplied by the final panelist -- because access to treatment is being blocked.

Kristin Neuman, on behalf of MPEG LA, LLC, addressed the final challenge -- that of patent thickets, or multiple patents covering a diagnostic method owned by multiple parties (Ms. Neuman's presentation can be found here).  She started out noting that there is something different about diagnostic claims, because the market would like these tests to be freely available.  In fact, she believes that the Myriad case is actually about the business model of exclusivity.  As an alternative, she suggested that the proper model might be that of the non-exclusive license.  MPEG LA was involved in pioneering modern patent pool licensing with the MPEG-2 standard, allowing multiple users to acquire patent rights from multiple patent holder.  Such licensees account for most MPEG-2 products in the market, including TVs, DVD players, set-top boxes, etc.  Ms. Neuman noted that a similar issue exists in for personalized medicine, citing a study looking at Lynch Syndrome, which is a predisposition to various cancers.  They found that ten institutions, including both universities and companies, owned patents related to this syndrome.  The problem is that one patent holder can hold back access to the technology.  Ms. Neuman explained that the goal of MPEG LA was to help clear patent rights to make the technology widely available to the public.  As a result, they are developing Librassay^TM, which is a web-based store of molecular diagnostic patent rights.  The vision of Librassay is larger than any single disease or test, and is not limited to gene patents.  With this system, the patents are grouped in meaningful categories to help customize a particular license while maintaining reasonable fees.  Dr. Sauer asked if there were any other services included, such as enforcement.  Ms. Neuman explained that the pool wouldn't enforce the patent rights, but it could help the owners coordinate their resources.  However, MPEG LA's experience has been that there are very few enforcement actions because it is easier to join the pool than hold out.

Overall, the panel thoughtfully addressed the challenges that were identified at the outset, and provided interesting and thought-provoking perspectives from individuals that deal with these issues, sometimes on a daily basis.  In addition, the panel provided plenty of interaction for the speakers, both from within the panel, and from the audience.  Clearly, those in attendance, as well as just about every other member of the patent bar, will be paying close attention to how these issues play out in the upcoming year.

The Genetics of Complex Behaviors: It Really Isn't That Simple

    By Kevin E. Noonan --

Early last week, the Journal of the American Medical Association published a study ("Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression") by Neil Risch at the University of California, San Francisco and colleagues at the National Institutes of Mental Health, Johns Hopkins University, Yale University School of Medicine, the Rockefeller University, the University of Pittsburgh School of Medicine, and Virginia Commonwealth University that showed no statistically-significant link between depression and the short HTT allele.  The study provided a statistical meta-analysis of data accumulated for 14,250 participants from 14 separate studies from the medical literature and a second meta-analysis of 10,943 participants from 10 of these studies.  These results were contrary to the results published by Avshalom Caspi and collaborators (including Terrie E. Moffitt (at right), Knut Schmidt Nielsen Professor, Departments of Psychology and Neuroscience, Psychiatry and Behavioral Sciences, and Institute for Genome Sciences and Policy, Duke University) that individuals bearing at least one copy of a specific genetic polymorphism in a serotonin transporter gene were more susceptible to depression as a consequence of environmental (life) stressors (see Caspi et al., 2003, "Influence of Life Stress on Depression:  Moderation by a Polymorphism in the 5-HTT Gene," Science 301: 386-89).

Dr. Moffitt has graciously provided us with three points in rebuttal to the conclusions of the Risch study, set forth in her own words:

1.    The JAMA article ignores the wider body of scientific evidence.  In the past 6 years, extensive research in experimental neuroscience using both animals and humans has validated the original report by showing that 5-HTTLPR short allele-carriers are excessively vulnerable to stress.  Experimental studies that expose human participants to stressors in the laboratory show that individuals having the 5-HTTLPR short genotype have greater stress responses on measures of cognitive reactivity (e.g., Beevers et al., 2007, J. Abnorm. Psychol. 116: 208-12; Fox et al., 2009, Proc. Biol. Sci. 276: 1747-51), hormonal  reactivity (e.g., Chen et al., 2009, Psychoneuroendocrinology 34: 681-86; Gotlib et al., 2008, Biol. Psychiatry. 63: 847-51), physiological reactivity (e.g., Lonsdorf et al., 2009, Psychol. Sci. 20: 198-206) and reactivity in the brain's emotion-circuitry (e.g., Hariri et al., 2006, Arch. Gen. Psych. 62: 146-52; Canli et al. 2006, Proc. Natl. Acad. Sci. U.S.A. 103: 16033-38).  This vulnerability of 5-HTTLPR S carriers has also been confirmed in animal research (e.g., Carola et al., 2008, Biol. Psychiatry. 63: 840-46; Barr et al., 2004, Biol. Psych. 55: 733-38; Kalin et al., 2008, Mol. Psychiatry. 13: 1021-27, online at DOI: 10.1038/mp.2008.37; Watson et al., 2009, PLoS One, published online January 14, 2009).  Further validation comes from studies which have shown that 5-HTTLPR Short allele carriers are vulnerable not only to depression, but also to other mental-health problems caused by stress, including PTSD and anxiety (e.g., Gunthert et al., 2007, Psychosom. Med. 69: 762-68; Kilpatrick et al., 2007, Am. J. Psychiatry. 164: 1693-99).

2.    The selection of studies for meta-analysis clearly fails to represent the pool of papers in the literature.  4 out of 17 positive replications were included (24%) but 6 out of 9 published negative
studies (67%), a bias that violates a basic requirement of the meta-analysis method to examine a representative sample of the existing literature.  Further, the article opted not to analyze several well-designed studies of individuals exposed to stress.  For example, studies of children who are victims of abuse (e.g., Cicchetti et al., 2007, Dev. Psychopathol. 19: 1161-80; Kaufman et al., 2004, Proc. Natl. Acad. Sci. U.S.A. 101: 17316-21) and patients suffering hip fractures, strokes and coronary heart disease (Kohen et al., 2008, Arch. Gen. Psychiatry. 65: 1296-302; Lenze et al., 2008, Amer. J. Geriatric Psych. 13: 428-32; Otte et al., 2007, Am. J. Psychiatry. 164: 1379-84) have reported positive findings for this "GxE" hypothesis.  Several other positive replications from studies with very strong research designs were omitted from the meta-analysis as well (Kendler et al., 2005, Arch. Gen. Psych. 62: 529-35; Drachmann-Bukh et al., 2009, J. Affect. Disord. 2009 Mar. 30 (e-publ. ahead of print at doi:10.1016/j.jad.2009.02.023); Lazary et al., 2008, Biol. Psychiatry. 64: 498-504).

3.    Within the smaller subset of studies in the meta-analysis, there is important heterogeneity.  The article says this heterogeneity was not statistically significant.  However, we have learned that the test fell just short of statistical significance.  One obvious characteristic that varies widely across studies in the meta-analysis is measurement quality.  As one example, meta-analysis gives more mathematical weight to studies with the largest samples.  But in this case the big studies had to collect their data through telephone calls or self-complete postal questionnaires, which are known to be weak methods of measuring life events and depression.  Not surprisingly, these big studies with weak measures tended not to find positive results, tilting the meta-analysis toward a null finding.  In the existing literature of tests of this GxE hypothesis, 13 studies have replicated the finding, using measures collected in face-to-face clinical assessments, and 10 studies failed to replicate the finding, using measures collected via phone or postal questionnaires.  This clear methodological pattern was ignored in the meta-analysis.  This is one example of heterogeneity could have been followed up in a meta-analysis, there may be others.

Dr. Moffitt concluded her response to Dr. Risch's work by noting that "[w]hat is needed is not less research into gene-environment interaction, as Risch et al. recommend, but more research of better quality, and a more thorough and thoughtful evaluation of it."

Dr. Moffitt has extensive experience in studying the biological basis of complex behaviors, and in addition to her Duke University appointment is also Professor of Social Behaviour and Development, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London and Associate Director, Dunedin Multidisciplinary Health and Development Research Unit, Dunedin School of Medicine, Dunedin, New Zealand.

This controversy illustrates one of the many pitfalls frequently faced by academic inventors motivated by the dual (and occasionally conflicting) needs of disseminating the results of their studies as rapidly as possible and protecting the intellectual property aspects of their work to maximize the likelihood that it can be commercialized (and not merely expropriated by others based on its disclosure in the academic literature).  As a result, often the research is not as developed as it might be if it were developed by a commercial concern initially.  This situation presents particular challenges to university technology transfer offices and their clients, university faculty and university administrations.  It is an imperfect system, which motivates some to say there is a flaw in the basic premise of promoting university patenting under the Bayh-Dole regime.  However, the alternative (not protecting university-generated inventions) is indeed worse, since then the public stands no chance of seeing the fruits of these labors helping to finance the next generation of technologies.

The Uncertain Future of Genetic Diagnosis of Human Behavior

    By Kevin E. Noonan --

Sickle cell anemia was the first known human disease associated with a genetic polymorphism (an A→T single nucleotide polymorphism, or SNP), resulting in the substitution of a valine residue (encoded by a GTG codon) for a glutamic acid residue (encoded by a GAG codon) in the beta chain of human hemoglobin.  The work, by Linus Pauling and colleagues at Cal Tech was published in the November 25, 1949 issue of the journal Science, about three and a half years before Watson and Crick deciphered the structure of DNA.  Today, sixty years of molecular biology, including the Human Genome Project, has produced the promise of identifying genetic markers for many human diseases, to be used for molecular diagnosis and particularized treatment going under the generic term of "personalized medicine."

Although monogenic traits have proven amenable to currently-available diagnostic methods (for diseases including cystic fibrosis, Tay-Sachs disease, Huntington's disease, and Duchenne muscular dystrophy), complex traits, particularly psychiatric and other behavioral disorders have proven more resistant to these methodologies.  Thus, it was a particularly exciting development six years ago when Dr. Avshalom Caspi and his colleagues reported in a landmark study in the journal Science that individuals bearing at least one copy of a specific genetic polymorphism were more susceptible to depression as a consequence of environmental (life) stressors (see Caspi et al., 2003, "Influence of Life Stress on Depression:  Moderation by a Polymorphism in the 5-HTT Gene," Science 301: 386-89).  The polymorphism occurs in the promoter region of the serotonin transporter gene (5-HTT), and the alleles are distinguished by the presence of 14 (the "short" allele) or 16 (the "long" allele) copies of a 20-23 basepair repeat motif.  Individuals with the homozygous long/long ("l/l") genotype were shown to express 1.4-1.7 fold greater amounts of the transporter gene mRNA, to have 2-fold higher levels of labeled serotonin uptake and to bind 30-40% more serotonin than the cells of individuals with the heterozygous short/long ("s/l") or homozygous short/short ("s/s") genotypes.

This study was performed on a cohort of 847 non-Maori children in Dunedin, New Zealand, who were followed from ages 3 to 26 (specifically, at ages 3, 5, 7, 9, 11, 13, 15, 18, 21 and 26).  Stressors examined in the study included problems in employment, finances, housing, health, and relationships, as well as childhood maltreatment.  In the study, males experienced more stressors than females; overall, 30% of study participants experienced no stressful life events, 25% experienced one, 20% experienced two, 11% experienced three, and 15% experienced four or more life stressful events.  These results themselves did not have any statistically-significant relationship to the 5-HTT allele genotypes.  17% of study participants were classified as having experienced depression, a level comparable to the results seen in the general population in the U.S.  When these results were compared with the genotypes of the study participants, a statistically-significant correlation (P = 0.02) was found between depression and the presence of the "s" allele, i.e., individuals bearing at least one "s" allele ("s/l" and "s/s" individuals) were more likely to be depressed as a consequence of equivalent numbers of life stressful events.  The authors were careful to emphasize that this correlation did not show a conclusive association between the "s" allele and a predisposition to depression, however.

This study was widely hailed as providing new insight into predicting depression, at least in young adulthood.  The study garnered accolades such as "absolutely spectacular" work, and Steven Pinker opined that the study provided "successful documentation of the elusive phenomena known as 'gene-environment interactions,' [which] are like the weather, according to Mark Twain:  Everyone talks about them, nobody does anything about them -- until now."  The study results also seemed consistent with what was known about neurobiology, in that the serotonin transporter is the target for antidepressants like Prozac®, and was also consistent with other research results that showed more intense brain reactions to fearful stimuli in individuals bearing the "s" allele.

However, the correlation between stress-induced depression and the short promoter of the human HTT gene has not held up.  As widely reported on Tuesday, Neil Risch at the University of California, San Francisco and colleagues at the National Institutes of Mental Health, Johns Hopkins University, Yale University School of Medicine, the Rockefeller University, the University of Pittsburgh School of Medicine, and Virginia Commonwealth University showed no statistically-significant link between depression and the short HTT allele.  The study, published yesterday in the Journal of the American Medical Association (see "Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression") was a meta-analysis of data accumulated for 14,250 participants of 14 separate studies from the medical literature and a second meta-analysis of 10,943 participants from 10 of these studies.  These statistical analyses by Risch and his colleagues failed to show any increased susceptibility to depression as a result of environmental stressors as reported by the Caspi study for individuals bearing the short promoter variant of the HTT gene in either homozygous (s/s) or heterozygous (s/l) genotypes.  Although these studies are not without their own acknowledged shortcomings, they cast doubt on the validity of the correlations reported six years ago from a much smaller sample size (albeit the earlier study presented more in-depth assessments on the existence, frequency, and significance of the environmental stressors).

These results could not have come at a worse time for Dr. Caspi and his collaborators.  These scientists filed a patent application on their predictive method, published as U.S. Publication No. 2005/0037405.  On May 19th, the U.S. Patent and Trademark Office mailed a Notice of Allowance to the inventors, for claims including the following:

1.    A method for assessing predisposition to depression in a human subject who has experiences a stressful life event, the method comprising the steps of
    determining whether the subject carries one or more copies of a short promoter allele of a 5-HTT gene; and
    concluding that the subject is predisposed to depression if the subject carries the short promoter allele.

At a minimum, the Risch study may have raised a Rule 56 obligation on the inventors, their counsel, and anyone else involved in prosecuting the application that could forestall allowance of this claim.  The results also may raise validity issues of operability and enablement.

There has been justifiable skepticism by some about the capacity for genetic analyses to predict complex behaviors (see, for example, Hamer, 2002, "Rethinking Behavior Genetics," Science 298: 71-72).  These most recent results illustrate once again how difficult it will be to translate the promise of personalized medicine into clinically-validated diagnostic tests, particularly for complex or multigenic traits and diseases.  Of course, these problems make patent protection even more important to support investment in the uncertain promise of personalized medicine.