As the Affordable Care Act (ACA) begins to shape some parameters of the health care system in the U.S., there are many details to be worked out. A centerpiece of the law is that states can set up health care exchanges for the purpose of pooling uninsured residents so they can obtain health coverage in an economically efficient manner. The goal is to provide a system that will facilitate access to comprehensive medical coverage and prescription drug benefits. However, several obstacles to the concept of the state exchanges are evident: states may decide not to set up a health care exchange or, alternatively states that do set up an exchange can define the contours of the coverage provided. Under the ACA, the concept of essential health benefits (EHB) has been central: the ACA mandates a set of guaranteed services that an insured can expect from any insurance plan covered by the ACA, including those provided through a health care exchange ("such as hospitalization, prescription drugs, and maternity and newborn care.") One of the ten categories of EHB is "laboratory services." In November, HHS issued proposed rules for covered insurance plans and state health care exchanges, detailing the EHB that are required to comply with the ACA. In a letter to The Centers for Medicare & Medicaid Services (CMS) (the laboratory-regulating agency in HHS) the College of American Pathologists (CAP) has called on HHS to clarify the definition of laboratory services, noting that some states are differentiating genetic testing from other tests, which will narrow the diagnostic options for those covered.
The CAP strongly supports the inclusion of genetic and genomic testing, when medically necessary for clinically relevant diagnostic purposes, pre-disposition studies, and treatment, as a laboratory service required under PPACA for all qualified health plans in federal or state health insurance exchanges…..We therefore urge the agency to clarify that genetic and genomic testing, as a subset of laboratory services that are mandated for coverage under the Affordable Care Act, be included as a covered service offered by any qualified health plan under a state or federally operated health exchange.
As the health care exchanges begin to take shape in 2013, the particular issue of genetic testing in the ACA mandate highlights how genomic medicine is taking a distinct profile in the health care system, but such individuation could be used to segregate new technologies due to concerns about cost. It is essential that any disparate treatment of genetic services be flagged early as the ACA begins to define health care access in the U.S.
The recent meeting of the National Science Advisory Board on Biosecurity this month was a public event to consider the status of gain-of function experiments with highly pathogenic avian influenza H5N1 (HPAI). Such experiments were the basis of two controversial papers published earlier this year that elevated concerns over whether scientific research carried the danger of producing dangerous viruses that posed threats to human health. The meeting considered biosafety issues as well as the new NIH research funding framework. The development of a more stringent review process for NIH funding of such research is underway; public comments on the proposed policy are invited until January 10, 2013. Reports from the meeting indicate an emerging consensus from the participants that the current voluntary moratorium on HPAI research should be ended. Separately, the comment period to respond to the CDC’s question of whether HPAI viruses should now be included in the most stringent class of biological agents, Tier 1, has been extended to January 13, 2013.
A recent review paper by Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and colleagues looks at 20 years of emerging infectious diseases (EID). The concept of EID was elevated into prominence with the publication of an Institute of Medicine report in 1991 that considered EID as threats to U.S. health. The 20 year period since encompasses the AIDS and SARS pandemics, although the AIDS crisis began in the 1980’s. Both are viral diseases, and the difficulty in designing effective treatment regimens underscores the fears associated with a possible emergence of pandemic influenza. The concept of EID as a critical focus of public health research and surveillance is well-established, and the SARS pandemic in 2003 illustrated not only the obvious scientific challenges, but how international cooperation (e.g., data-sharing) was essential to tracking outbreaks. Another recent paper in PLOS Medicine analyzes pandemic preparation with reference to lessons learned from SARS and other international public health crises, noting that although pandemics will appear in the developed countries because of global travel, etc., the likelihood of initial pathogen emergence in less-developed countries means that public health infrastructure remains a general gatekeeper to the world's overall health. The authors caution that disease-specific programs (e.g., AIDS-specific, vertical) can shift focus and resources from baseline public health maintenance in a manner that facilitates the development of pandemic outbreaks. In an effort to locate the “proximate driver implicated in each outbreak” the authors find that the most significant predicate is the “breakdown of public health measures includes inadequate sanitation and hygiene, e.g., the shortage of potable water, poor immunization coverage or the lack of infrastructure to purchase and deliver vaccine, and the deterioration of vector-borne and zoonotic disease control.” Thus, pandemic preparedness relies on a combination of high-tech and low-tech measures; determining the genome sequence of an emerging virus is routine today, but such a technical achievement does not supplant the need for investment in the low-tech infrastructure that helps to limit the spread of any emerging pathogen.
The FDA has released a draft environmental assessment (EA) for the proposed introduction of genetically engineered salmon as a food product (AquaBounty Technologies AquAdvantage salmon). To produce the GE salmon, Atlantic salmon is engineered to contain the growth hormone gene from Pacific Chinook salmon, which causes the fish to grow in less time; the gene is placed under the control of a promoter from ocean pout, which causes elevated expression of the hormone. The fish are to be only sterile females (although not 100%; the FDA notes that "proposed conditions of use specify that a minimum of 95% of the AquAdvantage Salmon eggs sold for commercial production use would be triploid (sterile)"). The production plans submitted to the FDA include the preparation of the GE fish eggs in Canada, and the actual production of the fish in Panama. Thus, neither process will occur in the U.S. The introduction of the new gene to the salmon triggers an FDA review of the genetic addition as a new animal drug application (NADA) (Federal Food, Drug & Cosmetic Act, 21 USC § 321 et seq.). The NADA review, conducted by the Center for Veterinary Medicine, must consider both food safety and environmental consequences of the proposed product; the 2010 FDA assessment concluded that food from these salmon “is as safe as food from conventional salmon, and there is a reasonable certainty of no harm from consumption of food” from these fish. The new EA prepared by the FDA pursuant to National Environmental Policy Act (NEPA) procedures – and its finding of no significant impact (FONSI) – means that the FDA will not be preparing an environmental impact statement for the introduction of the fish.
Food safety advocates have criticized the FDA’s record of assessments to date, and have called on the legislators to ban the production of the fish. The Alaska Congressional delegation is already on the record opposing the introduction of the GE salmon (see here). In addition, current FDA policy will not require the GE salmon to be labeled. The retail sale of fish requires at least country of origin labeling; the sale of food products in fish markets or restaurants does not carry any such labeling. What remains unsettled (and may further antagonized with this recent report) is whether efforts by food safety advocates to transfer GE fish into the more “conventional” category of food additive review processes will succeed; whether labeling could be required (the experience with other GE foods to date would suggest not); and even whether the environmental assessment to date is adequate (critics say no: not all fish were tested in the native conditions of production; reproductively-capable fish are present and could escape). More broadly, can a veterinary-based product review supply adequate oversight for the introduction of a genetically engineered food into the market? Does the review process for GE salmon establish a paradigm for other GE animal or fish products? The most direct response might come from Congressional action which singles out the GE salmon for targeted legislative regulation or prohibition (see here). The Alaska delegation has already responded, with Sen. Mark Begich (D-AK) sharply critical of the EA report, and calling for the public to provide comments to the FDA.
Earlier this year, the controversy over recent scientific experiments that produced potentially pandemic-level viruses (highly pathogenic avian influenza H5N1; HPAI) largely centered on the merits of publishing such research. The National Science Advisory Board for Biosecurity (NSABB) initially recommended against publication by scientific journals, but later relented and supported publication (one in full, one edited). The broader question of whether such experiments should be funded by the National Institutes of Health (NIH) at all – the HPAI H5N1 work in both laboratories received NIH support – was left unanswered. However, in March, the NIH published its policy for the oversight of life sciences dual research of concern (DURC) (research capable of benign and malicious uses, such as the recent HPAI H5N1 experiments). More recently, the NSABB has returned to the difficult questions regarding the funding of DURC. At last week's NSABB meeting, the NIH unveiled a potentially more exacting review process to determine whether or how the “gain-of-function” experiments that produced the HPAI H5N1 viruses should be funded. "Gain-of-function” refers to research that is undertaken to investigate the genetic structure of viruses, but, in the process, results in the production of an even more dangerous virus. Could such an outcome be avoided? To illustrate how NIH would assess that possibility, the proposed NIH framework asks that applicants declare that their work is unlikely to produce a “gain of function” virus, unless that could demonstrate that such a virus is likely to occur naturally. Can that be meaningfully answered? The
wild card in the attempt to set up a risk-managed funding program is how scientists can imagine the biological sources of risk
before actual research has identified or confirmed such details.
The proposed framework from NIH also links public funding with public disclosure: “As a general matter, HHS should only fund research that is reasonably anticipated at the proposal stage to generate information, products, and technologies that can be openly communicated.” This statement recalls the controversy earlier this year, where the risks from already completed research were to be managed by publication controls imposed after the fact. The NSABB will hold a public workshop on gain-of function experiments with HPAI H5N1 viruses on Dec.17-18, 2012 to discuss "the implications of such research for global public health, risks and concerns associated with this research; the risks of not pursing this type of research; fundamental principles regarding the conduct and oversight of such research; and conditions under which such research might be conducted." The lineage of these discussions post-9/11 goes back to the 2004 National Research Council report, Biotechnology Research in an Age of Terrorism (Fink Report), as well as the NSABB’s own 2007 framework, which amplified the Fink Report’s concerns and signaled the need for points of intervention at the funding or communication stages of the research trajectory. Thus, these questions are not new; they are just made more acute by recent events and HPAI H5N1 viruses have become the pathogens of concern. To illustrate that point, the Centers for Disease Control (CDC) has published an announcement in the Federal Register asking for comments on whether HPAI H5N1 influenza should be added to the CDC list of select agents (such classification would authorize closer monitoring of research projects). Further, HHS has carved out a class of select agents with the greatest risk of misuse (Tier 1) and asks whether the classification should obtain for this influenza strain, given its properties. Comments are due by December 17, 2012.
Today, the Supreme Court granted the petition for certiorari in the gene patent litigation, Association for Molecular Pathology (AMP) v. Myriad Genetics et al. The case focuses on the Myriad Genetics patents on the BRCA1 and BRCA2 (breast cancer) genes. This grant of review follows several years of the patentable subject matter challenge from a coalition of plaintiffs that has made its way through the lower courts, ending this summer with the Federal Circuit upholding the gene patents (again, following the Supreme Court remand to reconsider in view of Mayo v. Prometheus). Three questions were presented in the petition to the court: the patent eligibility of the genes, the eligibility of some method claims, and the last question involving the clarification of standing in the case. The Court will only consider the first question: Are human genes patentable? The Court must consider how to define an an isolated gene (isolated DNA) – as either a product/law of nature (not patentable) or a nonnaturally occurring processed product (patentable). Earlier this year, the Court issued its opinion in Mayo, invalidating a patent claim to a method of optimizing drug dosage which had the effect of preempting a law of nature (a natural correlation). At stake in AMP is how to define the product of nature doctrine in modern biotechnology - whether genes are to be defined by structure (the chemistry argument) or function (the genetic argument). The Federal Circuit took the chemistry route this past summer in its AMP decision, finding enough chemical alteration of an isolated gene to confer patent eligibility. In an amicus brief I filed this summer, I argued that the genetic fidelity (natural DNA sequence) of the isolated genes means that such patenting preempts the genetic code (law of nature), and, in addition, the genetic fidelity further characterizes the molecule as an unpatentable product of nature. From either analytic route, I conclude that genes are not patentable: the genes have a specific patent ineligibility because such patenting preempts a law of nature, and they have a general patent ineligibility because they are products of nature. The first theory (preempting a law of nature) resonates with Mayo; the latter theory (product of nature) resonates with Funk Bros. v. Kalo (1948). Genetic fidelity is not trivial; it is essential to the use of an isolated gene as a testing reagent.
What will the Supreme Court decide? The Supreme Court has exhibited a sensibility which accords significant weight to its role in protecting a public domain in science (the Court has established and refined a set of judicially-created exclusions - laws of nature, natural phenomena, abstract ideas - from patentable subject matter over the years, despite statutory silence). In Mayo, the Court stated that "even though rewarding with patents those who discover new laws of nature and the like might well encourage their discovery, those laws and principles, considered generally, are ‘the basic tools of scientific and technological work’” (quoting Gottschalk v. Benson (1972). The Court did not hesitate to strike a blow against business method patents in Bilski v. Kappos (2010), despite more than a decade of such patenting. With reference to Mayo - and to Justice Breyer's public domain-centered dissent in Labcorp v. Metabolite (2006) - there is a fair chance that the Court could side with the 2010 district court opinion, which found that the "claimed isolated DNA is not markedly different from native DNA as it exists in nature," and, as a result, the gene patent claims were invalid. AMP v. Myriad is not only important for the further clarification of the patent eligibility doctrine, but it has implications for the genetic testing industry (business models that depend on patenting isolated biological molecules) and for women's health (possible future development of a robust marketplace and an unfettered research climate for genetic testing involving the critical BRCA1 and BRCA2 genes). The case has also been a model for assembling a complex coalition of plaintiffs (researchers, genetic counselors, women patients, cancer survivors, breast cancer and women's health groups, and scientific associations) whose diverse interests illustrate the real-world consequences of what may appear to be solely theoretical patent law doctrines.
The limits of what can be patented in the life sciences continue to be refined by this period of active litigation in which foundational questions over patentable subject matter - 35 U.S.C. 101 - are receiving judicial attention. The Federal Circuit has just expanded on its jurisprudence for the patent eligibility of diagnostic testing methods which utilize either biochemical or genetic markers to determine the clinical status of an individual. In Perkin-Elmer, Inc. v. Intema Limited, the court invalidated patent method claims which relied on a series of prenatal measurements of known biological markers, performed through blood testing or ultrasound, to determine whether a woman has an elevated risk of carrying a fetus with Down’s syndrome. In Mayo v. Prometheus, decided earlier this year, the Supreme Court invalidated a patent claim to a method of optimizing drug dosing because the claim did no more than capture a natural biological correlation. Patent law doctrine does not allow the patenting of laws of nature, natural phenomena or abstract ideas. Yet, deciding whether a patent claim adds inventive weight to natural subject matter is not a simple test. The courts have often focused on whether a patent claim would actually "preempt" the use of a natural biological fact or phenomena if it were to issue. Would the patent holder effectively capture uninvented scientific information? This question has also been considered in the gene patent case, Association for Molecular Pathology (AMP) v. PTO, where the Federal Circuit invalidated method claims which did no more than use the fact that certain DNA mutations are correlated with elevated breast cancer risk. In Perkin-Elmer, referencing AMP, the court said that "the stricken claims there are indistinguishable from those before us." Further, the court stated that " Intema also claims a law of nature: the relationship between screening marker levels and the risk of fetal Down’s syndrome." With reference to the invalidated claims in AMP, the Perkin-Elmer court stated that "the stricken claims there are indistinguishable from those before us."The lineage of this decision is clear: “The Supreme Court’s decision in Mayo and this court’s recent decision in [AMP] dictate the result we reach today.” This case thus builds on the Mayo and Myriad framework for the analysis of method claims in the life sciences that are anchored in the recitation of a law of nature or natural correlation. In a reference to the possibility that the patent claims impermissibly preempt, the court stated that "anyone who wants to use this mental step or natural law must follow the claimed process." Thus, valid method claims in the diagnostic arts require more customized treatments of natural subject matter in order to qualify as an “inventive concept” and to avoid preemption over basic scientific subject matter. Further to the march of patentable subject matter cases through the courts, we await the Supreme Court's decision on the plaintiffs' petition for certiorari filed in AMP v. USPTO; the petition is scheduled for the Court’s conference tomorrow.
During most of 2012, a voluntary moratorium on high-risk H5N1 influenza virus experiments has been in place, following a controversy last winter. At that time, it was revealed that two laboratories had succeeded in creating apparently pandemic-capable H5N1 influenza strains, and were on the verge of publishing their research. The post-9/11 climate in the U.S. had seen the establishment of the National Science Advisory Board for Biosecurity (NSABB) to oversee and advise NIH on dual-use research (potential information, techniques and materials that can be used for benign or malicious purposes). A 2004 National Research Council (NRC) report had called for a more exacting institutional review of grant proposals for “experiments of concern” – that would have included these projects, as they are called "gain of function" experiments - the research produces a more, not less, dangerous virus. Last year, as concern grew over the announcement that new pandemic-level viruses had been produced in a laboratory, an immediate sense of crisis ensued, with the NSABB recruited to advise the journals regarding the suitability of publication. The debate focused on whether publication details should be released or curtailed (details included which DNA mutations made the influenza virus more deadly). There was no official attempt to shut down publication; however, the NSABB initially recommended that the scientific journals decline publication. It later reversed course and endorsed the publication of one in full (here), and one redacted (here).
Further, an international effort by influenza researchers led to agreement on a voluntary moratorium on gain-of-function experiments with H5N1. Their statement declared a “voluntary pause of 60 days on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals.” This moratorium continues to be in place (and it echoes the 1975 Asilomar conference declaration of a voluntary moratorium on some recombinant DNA research). In July, Dr. Anthony Fauci (director of NIAID, which funded the initial research) had argued for a continued pause. A more recent debate over the continuing need for such a pause occurred in the journal mBio (American Society for Microbiology, ASM). Proponents of restarting such work argue that pandemic preparedness requires anticipating how the influenza virus can adapt and become more dangerous; others caution more delay and cite a combination of biosafety and dual-use research concerns. What’s clear is that these issues are not new and are not resolved; they were certainly anticipated by 2001 as the anthrax attacks raised the stakes for domestic terrorist incidents involving pathogens. As suggested by the 2004 NRC Report, NIH needs to frontload a dual-use review process at the level of funding decisions; such a review could authorize funding if the biosecurity measures are satisfactory but proactively manage a publication strategy, depending on results. Further, the mandatory physical security for such research (containment) needs to be standardized (it is not) before such work is funded. We might be on the verge of more official response to these unresolved questions. At the upcoming NSABB meeting next week, the committee will be discussing dual use research guidelines and NIH funding criteria for high-risk H5N1 influenza research.
The Supreme Court has agreed to hear the challenge to Maryland's DNA database expansion in a case that will test the constitutionality of DNA profiling practices in law enforcement which increasingly include those arrested for various crimes (federal and in 28 states). The case is King v. Maryland, handed down last September. As reported earlier here, when King was handed down, the Supreme Court (at least Justice Roberts) appeared to signal its disagreement with the Maryland court, to the point of granting the state’s request for a stay. The Maryland DNA Collection Act mandates DNA
collection from those arrested for a “crime of violence, an attempted
crime of violence, a burglary, or an attempted burglary.” The collection and profiling of those individuals leads to their inclusion in the state and federal (CODIS) DNA databases (current CODIS statistics show about 1.2 million arrestee profiles in the national database, and about 10 million profiles of convicted offenders). The Court will contend with the continuing project of defining the “reasonable expectation of privacy,” derived from Katz v. U.S. (1967), to weigh the constitutional challenge against asserted government interests in prevention and prosecution of crimes. Privacy interests are further attenuated (reduced) for those in the criminal justice system; to date, two federal appellate courts have considered the DNA profiling of arrestees and upheld the practice against 4th Amendment challenges. In 2011, in U.S. v. Mitchell, the 3rd Circuit upheld the federal DNA Fingerprint Act, enacted in 2006, which authorizes DNA collections from those arrested for federal crimes. Just this year, in Haskell v. Harris, the 9th Circuit upheld the California state law that authorized DNA collection from arrestees. However, Haskell has now been reheard by the 9th Circuit en banc (see here), and this case has taken a new turn with new research from the ENCODE consortium suggesting that DNA profiling may be more biologically informative than previously thought (is the DNA profile in CODIS no longer a neutral identifier, and thus less private, altering the Katz analysis?). Scientific consensus may be getting murkier, leading to more, not less, legal ambiguity.
Somewhat surprisingly, this will be the first case on DNA databases that the Supreme Court has taken, having denied certiorari for the earlier phase of 4th Amendment challenges to DNA collection, which focused on the claims of those actually convicted of crimes (e.g., U.S. v. Kincade, 9th Cir. 2004). The federal courts are generally in consensus in rejecting 4th Amendment challenges from those whose DNA profile is included in a government database because of an actual conviction. This case becomes the Court's second look in a year at the 4th Amendment in the context of developing technologies. In U.S. v. Jones, issued in January, the Court ruled that the warrantless use of GPS tracking on a motor vehicle violated the 4th Amendment, employing the anti-trespass norms embedded in the 4th Amendment to find an unreasonable government intrusion into a protected personal zone. Both Jones and King (when decided) will now provide further elaboration of how 4th Amendment protections coexist with rapidly changing technological capabilities; these are the type of cases that have been long-awaited since the 2001 U.S. v. Kyllo, where the Court ruled that warrantless thermal imaging of a home violated the 4th Amendment.
The election results are in, with consequences for several high-profile biotechnology issues at stake. Voters rejected California's Proposition 37, which would have required the labeling of genetically engineered (GE) foods in the state (see here). A vigorous campaign occurred in the state, of which opponents outspent supporters by about 5 to 1. An effective source of opposition to the measure was based on arguments that this new law would have adverse economic consequences - for consumers (higher prices), businesses (compliance) and a cash-strapped state (administrative costs). The final vote was 53% opposed, 46% in favor; this would have been the first state to enact such a law. The movement to label GE foods continues, with upcoming efforts on deck in Washington and Oregon. In a separate issue, the reelection of President Obama cements his policy of allowing federal funds to be used for embryonic stem cell research (see here), so this biotechnology sector has stability for at least several years. At a meta-level, impacting the major life science agencies such as NIH and the FDA, neither house of Congress changed hands (keeping committee leaderships in place), so that leadership of key committees in the House, such as the Committee on Science, Space and Technology, remains a GOP preserve, while the Democrats retain control of the Senate and its Committee on Health, Education, Labor and Pensions (HELP). The Obama reelection also locks in the Affordable Care Act (see here). Lastly, Charles Darwin received 4,00 write-in votes in a Georgia congressional election where the incumbent Rep. Paul Broun (R), a member of the House Committee on Science, Space and Technology, is an outspoken opponent of the theories of evolution, embryology, and Big Bang cosmology. Broun was reelected.
Can the federal government expand the use of a patented invention that was developed using federal research grants? The Bayh-Dole Act of 1980 sought to accelerate the transfer of federally funded research into practice, real world use; toward that end, the law allows federal grantees (such as a university) to pursue patent rights for the fruits of the federally funded work. A little-known provision in the Bayh-Dole Act gave authority to any federal agency that funds research, such as the National Institutes of Health (NIH), to order a “march-in” of patent rights where the funding agency determines such action is necessary to achieve the goals of the statute. This authority is held by any federal granting agency/department (e.g., NASA, DOE, DOD). Effectively, then, NIH can compel a patent owner to allow third parties to make and use the patented invention. The patent owner would be reasonably compensated for the use. March-in authority is justified when "action is necessary to alleviate health or safety needs which are not reasonably satisfied by the contractor, assignee, or their licensees" or "action is necessary to meet requirements for public use." The march-in provision of the law has never been used by NIH, despite several formal requests over the years, citing the unaffordability of an AIDS drug, unavailability of a federally-funded stem cell technology, or drug (Fabrazyme) inaccessibility due to manufacturing shortages. In all of these instances, NIH has conducted a review of the request, but declined to exercise its authority. A 2009 GAO study found that most federal granting agencies considered the march-in authority to be useful, but expressed concerns about a "chilling effect" on commercialization and technology transfer from any actual exercise of the right.
A new march-in petition to NIH has been filed by a coalition, including Knowledge Ecology International (KEI) and Public Interest Research Group (PIRG), asking the NIH to exercise march-in authority to increase access to the widely used Abbott AIDS drug, ritonavir (Norvir) (citing comparative per pill prices of $12.63/U.S. vs. e.g., $1.54/Italy, $1.46/France). This latest petition echoes a march-in request made to NIH in 2004, where a sudden increase in the price of Norvir immediately threatened access for AIDS patients. In its response to that petition, stating that “NIH believes that the issue of drug pricing is one that would be more appropriately addressed by Congress,” the agency denied the request. Here, the petition argues the necessity for a march-in for a number of reasons, primary focusing on an excessive price in the U.S. relative to similarly economically situated countries, but it further invokes an ADA-related argument on behalf of AIDS patients and cites adverse consequences for U.S. businesses seeking to be globally competitive. The current petition attempts to provide a metric for ascertaining when a cost would not be “reasonable” – suggesting a comparative study of U.S. prices vs. those in other income-equivalent countries. In addition to the specific relief requested, the petition asks NIH to formulate a policy that would include conditions warranting a use of the march-in mechanism, specifically where the U.S. price is higher than that charged in countries with similar income levels, and where the patent rights are frustrating the use of a dependent technology, e.g., a combination drug product. There is no reason to believe that NIH will be more receptive to this march-in request than to any of the previous filings, but the petition does attempt to quantify when the activities of a patent owner who controls a patented invention derived from federally funded research do not result in a “reasonable” satisfaction of health needs. As the agency did in 2004, NIH is likely to suggest that Congress is the appropriate venue to address any drug price standardization (federally funded research or not) and that the Federal Trade Commission is the appropriate venue for focusing on anticompetitive behavior. Notwithstanding the confounding variable of dissimilar national health care systems, this effort does prod the NIH to provide some definition for what reasonable implementation of a patented invention entails; to date, there has been no development of a march-in standard from NIH, and this dormant statutory authority has little definition.
A preview of the biotechnology-related election issues on the November 6 ballot illustrates both direct and indirect implications of the upcoming vote. Two areas of biotechnology and the law will be clearly impacted by the results of state and national elections - the partial regulation of genetically engineered food through labeling, and the federal funding of embryonic stem cell research. The most directly consequential measure (yes/no) is in California. There is a state ballot initiative to require the labeling of genetically engineered (GE) foods in California, Prop 37; if adopted, it would be the first such state mandate to be imposed (see here). Thus, on November 7th, California could be looking at implementing a regime of mandatory labeling for GE foods, and we could expect legal challenges to follow with likely First Amendment challenges to the labeling, where the contours of the commercial speech doctrine would be at issue (e.g., somewhat analogous to International Dairy Foods Association v. Amestoy (2nd. Cir. 1996), where the 2nd Circuit invalidated a Vermont measure requiring hormone-related labeling of dairy products).
It is also foreseeable that the outcome of the Presidential election will indirectly (but seriously) affect the status of stem cell research in the U.S. – specifically the ongoing controversy over the federal funding of embryonic stem cell research (see here). In 2009, President Obama reversed the Bush-era policy of disallowing the use of federal funds for the derivation of new embryonic stem cell lines; as a result, the National Institutes of Health (NIH) is allowed to award grants for such research. The Romney website contains a policy on stem cell research; while not directly addressing the use of federal funds for embryonic stem cell research, the statement is written to focus on alternatives: “Adult stem cell research and alternative methods to derive pluripotent stem cells, such as altered nuclear transfer and direct reprogramming, are scientific paths that carry much promise and avoid raising ethical concerns.” Governor Romney vetoed a Massachusetts bill in 2005 that would have allowed “therapeutic cloning” – the creation of a cloned embryo to derive genetically compatible embryonic stem cells (this debate was extant in federal legislative battles at that time, with Democrats and Republicans having opposing positions). The 2012 campaign site contains this statement: “When confronted with the issue of stem cell research as governor of Massachusetts, Mitt Romney chose to support life by vetoing a bill that would have allowed the cloning of human embryos.” Actually, this is a veto more grounded in a rejection of deliberate embryo creation rather than the stem cell research itself. Thus, this statement does not address whether Romney would allow the funding to derive embryonic stem cells from leftover or discarded embryos that were created not for research, but in the process of assisted reproductive technologies (e.g., at fertility clinics). However, from all available evidence, it can be inferred that the Romney position will be to undo the Obama policy of federal funding for new stem cell lines from unused embryos. Thus, on November 7th, the stem cell community wil either encounter the status quo (Obama) or the possible elimination of federal funds for embryonic stem cell research (Romney); a Romney win would also obviate the current legal challenges to the Obama policy. On a final note, the larger specter of federal support for scientific research is implicated in the national race, particularly as questions of government scope and resources have factored in so highly. A group of 68 Nobel Prize winners endorsed President Obama recently, largely based on their view that Obama “delivered on his promise to renew our faith in science-based decision making and has championed investment in science and technology,” while concluding that Romney would “devastate a long tradition of support for public research and investment in science.”
There is an update on the lawsuits brought by a coalition of food safety and environmental advocates to challenge the U.S. Fish and Wildlife Service (FWS) for their practice of granting permission for the planting of genetically engineered (GE) soybeans and corn in the national wildlife refuges (see here). The national wildlife refuges are a "national network of lands and waters for the conservation, management, and where appropriate, restoration of the fish, wildlife, and plant resources." The legal actions were filed on a regional basis and alleged that FWS has allowed the planting of GE crops in refuges without conducting an Environmental Impact Statement (EIS) as required by the National Environmental Policy Act (NEPA). These plantings are part of a FWS program that designates a portion of a refuge for agricultural purposes. One of the concerns is that many of the GE crops are Roundup Ready crops, engineered for herbicide-resistance, and GE crop plantings result in more introduction of herbicides into the natural habitat. Thus, the plaintiffs have alleged two forms of harm to a refuge from GE crops: genetic contamination of natural species and chemical harms from the herbicides. NEPA, passed in 1970, requires that any action undertaken by a federal agency that may have environmental consequences be thoroughly evaluated by conducting a rigorous environmental review (the EIS) of possible impacts and consideration of alternatives. NEPA effectively allows for citizen challenges to a broad range of federal actions that pose environmental risk through the use of a procedural objection, as exemplified by these lawsuits.
To date, the plaintiffs' coalition has won rulings in earlier challenges to the planting of GE crops in the national refuges, where the courts have ordered FWS to conduct the requisite EIS (e.g., the Northeast region). In two recent rulings that illustrate the regionally-specific analyses, Judge Boasberg in D.C. District Court upheld the challenge to the Southeast region plantings, ruling that an FWS phaseout in 2013 was not an adequate response to an allegation of incomplete environmental review. In a parallel challenge to GE crop planting in the Midwest region, Judge Boasberg ruled that FWS had made an adequate environmental assessment in view of its stated objective). One might guess that the FWS would decide as a matter of national policy to prepare an EIS for any proposed designation of refuge property for GE plantings. The FWS, however, has been unwilling to establish such a national policy that would routinely institutionalize EIS preparation - instead, has contended with individual lawsuits seeking to get an EIS prepared or to get an environmental assessment evaluated. On balance, it is likely that national wildlife refuge policy is evolving to conclude that the planting of any GE crop on land that is designed to house and maintain natural habitats is no longer compatible with the introduction of GE crops. Certainly, the widespread use of GE crops in general practice undermines any need for a national refuge to be a repository for such species.
The Presidential Commission for the Study of Bioethical Issues (PCSBI) has issued a report on one of the intersections between genetic testing and privacy. The PCSBI was established by President Obama; to date, their only other report focused on the regulatory landscape for synthetic biology (more here). Now, the Commission has published Privacy and Progress in Whole Genome Sequencing, which examines how the increasing availability of whole genome sequencing (WGS, where the full DNA sequence of a genome is obtained) in both clinical and research settings has to be matched with an attention to how such data is used in a manner that protects the privacy of the patient and/or research subject. The report illustrates the legal complexity of privacy in American law generally – a very mixed portfolio of (sectoral) protections. The legal concerns with the widespread introduction of genetic information into science and medicine are several and concern whether an individual has control of when genetic testing occurs, when genetic information can be disclosed, and how genetic information can be used. With respect to genetic information, much of the legal attention has focused on the issue of genetic discrimination, which concerns use, and has not focused on genetic privacy. Most simply, privacy is concerned with disclosure, while discrimination is concerned with misuse. Can the privacy of “genetic information” be protected with existing law? Is a genomic DNA sequence a category of "personally identifiable information" (PII), meriting special protection from unauthorized disclosure? In general, medical information generated during patient care is protected by the Health Insurance Portability and Accountability Act (HIPAA), which makes a provider accountable for maintaining both patient confidentiality and privacy of medical records. But, as the commission notes, it is not clear whether genetic or genomic information is always included in the protected health information that HIPAA addresses. Since 2008, the U.S. has the Genetic Information Nondiscrimination Act (GINA), which protect individuals from discrimination based on the use of their genetic information in employment and health insurance. Notably, it does not extend to the provision of life, long-term care or disability insurance.
The PCSBI report particularly focuses on how genetic information derived in the research setting will be protected from unauthorized disclosure, a project that not only requires the cooperation of researchers and health institutions, but auxiliary participants, such as database managers. Very generally, the U.S. does have norms for the protection of human subjects generally, most notably the Common Rule, which establishes standards to protect human research subjects and is applicable to all federally-funded research. While a patient can rely on HIPAA for some medical privacy, the research subject needs to be protected against the unauthorized disclosure of personally identifiable genetic information outside the medical care setting. One of its most significant recommendations is that no WGS be conducted without the consent of the individual. While that may sound straightforward and sensible, this point is relevant to the uses of surreptitious genetic testing that occur in criminal law, for example, but could be performed in other contexts (e.g., this issue addressed with the pending California bill on genetic privacy, SB 1267, which would “prohibit any person, as defined, from obtaining, analyzing, or disclosing genetic information without the written authorization of the individual to whom the information pertains”). The report notes a very uneven set of protections against unauthorized genetic testing and disclosure across the states. In total, the report calls attention to the wide array of entities that are involved in the processing of genetic information – not only scientific and medical, but third party data handlers – and calls for standardization of informed consent procedures to protect individual choice regarding genetic testing and its disclosure. It asks funders of such research to monitor privacy protections as a part of their review. While the report did focus on the ethical introduction of WGS into wider use, its recommendations are relevant to all types of genetic information and might serve to incorporate privacy safeguards as a routine dimension of genetically-based medical care and research.
A petition for certiorari has been filed in Sherley v. Sebelius, the ongoing challenge to the NIH Guidelines for the federal funding of embryonic stem cell research funding (previous coverage). The recent decision from the Court of Appeals for the D.C. Circuit rejected the claim of the plaintiffs that the funding violates the Dickey-Wicker amendment, which prohibits the use of federal funds for any research in which an embryo is harmed or destroyed. That provision was interpreted by the court to not cover the process for deriving embryonic stem cells from embryos, thus not placing the NIH stem cell policy in violation of the funding ban. The challenging researchers continue to claim that such an interpretation is erroneous. In the D.C. Circuit decision, the concurring opinions acknowledged the murky legal climate for federal funding of embryonic stem cell research, noting the automatic attachment of the Dickey-Wicker amendment to HHS funding bills without much new deliberation since 1996. Judge Brown wrote: "Given the weighty interests at stake in this encounter between science and ethics, relying on an increasingly Delphic, decade-old single paragraph rider on an appropriations bill hardly seems adequate." The petition advances several procedural arguments against the D.C. Circuit’s decision; one alleges a violation of the Administrative Procedure Act (alleging the 2009 Obama Executive Order unlawfully relieved NIH from completion of its formal rule-making obligations) and a misinterpretation of the law of the case doctrine (does it include decisions made at the preliminary injunction stage?). The petitioners cite a conflict among the circuits over the law of the case doctrine, trying to entice the Court into a review. Before we hear from the Court on this petition, the upcoming election will intervene – and the contrasting positions of Obama and Romney will either uphold or dismantle the current NIH policy. There has been very little federal litigation on embryonic stem cell research, but we now have more than a decade’s worth of political instability over the issue, with another indirect political referendum on November 6th. It should be noted that the recent attempts at personhood legislation (also at the federal level) are contemporary initiatives to ban embryonic stem cell research, as they would codify the legal status of the embryo as a fully constitutionally-protected individual; that would likely outlaw embryonic stem cell research. A Romney victory could be expected to reverse the NIH policy and render this litigation moot; an Obama victory would not.
In a case that presents a novel question regarding the scope of patent rights in a biotechnology invention, the Supreme Court has agreed to hear the appeal in Bowman v. Monsanto (Fed. Cir. 2011). Here, Monsanto sued an Indiana farmer, Vernon Hugh Bowman, for patent infringement for his use of patented seed for the growth of second-generation genetically engineered (GE) soybeans. The patented crop is the Monsanto Roundup Ready soybeans, which contain a gene that encodes EPSPS, a glyphosate-tolerant enzyme. The genetically modified plants express the enzyme and thus and exhibit resistance to the herbicide glyphosate– specifically, to the application of the Monsanto product, glyphosate, sold as Roundup. The purpose is to create a crop through genetic engineering that can withstand the application of the herbicide (weed-killer). Bowman was accused of patent infringement by buying GE commodity seed from a grain elevator which he then used for replanting (replication), which Monsanto characterized as an unauthorized use of a patented invention. The doctrine of patent exhaustion in patent law generally operates to limit the control that an inventor holds over the life of a lawfully sold patented article – the first sale of a patented invention is authorized, and then exhausts the control that the patent holder retains over subsequent uses (absent some valid conditional sale agreement that accompanies the sale). Would that doctrine extend to a claim that a later sale of originally-patented GE seed to Bowman and his use in planting became an act of patent infringement because the seed replicates and he “made” an infringing article? In 2011, the Federal Circuit ruled that Bowman’s planting of the GE seed he purchased created an act of patent infringement, rejecting an interpretation of the exhaustion doctrine that would recognize the special attributes of seeds, which embody the property of replication and “manufacture” of an originally-patented invention. Did the company’s patent rights extend to this later series of events, or did they exhaust upon the first sale of the patented seed? In his petition, Mr. Bowman presented the following question to the Supreme Court:
Whether the Federal Circuit erred by (1) refusing to find patent exhaustion in patented seeds even after an authorized sale and by (2) creating an exception to the doctrine of patent exhaustion for self-replicating technologies?
The Supreme Court has provided some recent guidance on patent exhaustion in Quanta v. LG (2008), where they held that a sale that “substantially embodies” the patented invention exhausts the patent rights. Interestingly, the U.S., as amicus curiae, urged the Court not to take the case, warning that “if this Court granted certiorari, however, its decision could also affect the enforcement of patents for man-made cell lines, DNA molecules, nanotechnologies, organic computers, and other technologies that involve self-replicating features.” The Court did take the case, however, and it signals that it does wish to consider the prospect that the inherent property of self-replication in some biotech-related inventions does not demand unexhausted patent rights.
The plaintiffs have filed a petition for certiorari with the Supreme Court in the ongoing gene patent challenge, Association for Molecular Pathology v. U.S. Patent and Trademark Office et al. (AMP v. USPTO). The litigation
centers on whether genes and methods for their use qualify as patentable
subject matter. The doctrine of patentable subject matter asks whether a
patent fits into the kinds of inventions that are eligible for
patenting or whether it goes too far and extends into the impermissible
categories of "abstract ideas, natural phenomena and laws of nature;"
more background here. The Supreme Court had previously been asked to hear the case, but then remanded the case back to the Federal Circuit in view of the Mayo v. Prometheus (a patent to a method of drug treatment) decision that they had just handed down. In their decision this summer, the Federal Circuit upheld the patent claims to genes, rejecting arguments that such patents covered products or laws of nature. In the opinion authored by Judge Lourie, the court relied on the chemical differences between native and isolated DNA to find enough structural differences to confer patent eligibility. In her concurrence, Judge Moore also
cited the reliance interests held by existing patentees and the
biotechnology industry as a reason for not undoing decades of patenting. The new petition argues that Supreme Court precedent supports their view that the function of a molecule is paramount in the analysis comparing native to isolated; they argue that the isolated gene maintains the functions of native DNA and therefore cannot not be patentable. The petition also advances a First Amendment basis for not patenting genes (the patent interfering with a right to use information) and revives another source of dispute in this case, which is over which parties in this complex coalition of plaintiffs have the standing to sue. We could get a decision on whether the Supreme Court will take the case in the next few months. The Court has not heard a patentable subject matter case that involves molecular genetics since Diamond v. Chakrabarty in 1980. However, that case involved a genetically engineered organism (a bacterium), while this case centers on isolated genetic molecules - the genes.
The recent release of 30 research papers, collectively describing the results from the ENCODE project, prompted headlines around the country characterizing this as a milestone in genetic research. As a follow-on project to the release of the original Human Genome Project sequence (which focused on the genes), the ENCODE project attempts to identify what the rest of the DNA in our genome – the so-called “junk” – is doing. It’s already known that only about 1% of the human genome actually contains the genes. What are the rest of the 3 billion bases for? “Junk DNA” was never an accurate or worthy title for it – it simply revealed the state of ignorance about the human genome. Now, the ENCODE consortium reports its further annotation of human DNA – they were able to “assign biochemical functions for 80% of the genome.” They “systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification.” This work begins to detail the underlying genetic switching mechanisms that operate behind the scenes in the genome and "regulate" how genes are expressed. No one doubts that nature is likely to have retained much of the DNA in our genome because of its usefulness. However, it's not clear that the ENCODE project, in cataloguing the signals from any biochemical event to describe "function," has yet produced a map with high genetic resolution. The Human Genome project - writ large - continues to unfold. However, the legal system has made use of DNA identification technologies that were developed from current genetic knowlege. If we look for any impact on the uses of DNA sequence information in the law, several consequences of the ENCODE research emerge. First, in using DNA as a forensic tool – relying on individuality in sequence to create a personally distinguishable identifier – criminal (and other) law has come to rely on a consensus use of a set of DNA sites (the STR (short tandem repeat) loci, retained in the FBI CODIS database) that were chosen because they offered variation but minimal biological information. Thus, these DNA sites could be used for forensic comparison while revealing very little about an actual person; that fact minimized any privacy invasion from use of these markers. In theory, they capture genotype differences without revealing critical phenotypic information. It was already known, for example, that some of the STR sites were found in an intragenic region – e.g., CSF1P0 maps to an intron – but these sites were not considered informative for any particular trait or condition. Could these STR sites now now be recharacterized as informative – and could they reveal more about the phenotype of an individual? My colleague, David Kaye, has more thoughts on ENCODE and "junk DNA." Practically, might the STR loci now be susceptible to a more critical look when a 4th Amendment-based privacy interest in invoked to challenge a government DNA database?
A key question emerges: does the ENCODE research meaningfully reclassify the STR loci for 4th Amendment purposes? This is not an abstract inquiry; already, the ENCODE data has been invoked in the rehearing of Haskell v. Harris by the 9th Circuit en banc in California. This case is a 4th Amendment challenge to the state’s practice of collecting DNA from arrestees (9th Circuit panel upheld; see earlier story). The Electronic Frontier Foundation, as amicus, has asked the court to reconsider the privacy interest advanced by the challenger in view of the ENCODE findings. A precise ENCODE-derived analysis of the STR loci is not available; the EFF letter simply states that “ENCODE has determined that “junk” DNA plays a critical role in determining a person’s susceptibility to disease and physical traits like height” (citing to the New York Times article on ENCODE) and that it is "highly likely that the genetic markers contained in each Appellant's DNA profile reveal much more information than just his or her identity." That's speculation which lacks any precision with respect to the STR loci that underlie the legal challenge. It’s true that ENCODE has certainly opened the door to a reunderstanding of purpose in much of the human genome (actually, that is its goal); it is not known whether the STR loci, however, are individually tracked to real phenotypic expression, and whether STR loci variations contribute to a more complex DNA profile for an individual than was previously thought. In general, the constitutional analysis now confronts an evolving scientific portrait of the human genome, but at this point, it has not been shown that the precise STR loci at the center of the DNA database challenges have been reconceptualized by ENCODE in a manner that undermines their genetically inert status. What's noteworthy about this period in DNA database litigation is that Haskell v Harris and the recent King v. Maryland (likely to be heard by the Supreme Court) are advancing the constitutional issues of DNA collection from arrestees in the nation's leading courts at a time where the underlying science is more in flux than usual.
Several items regarding the federal funding of life science research are worth noting because they illustrate the tensions over how the government funds science and what the public may or may not receive in the form of benefit. As a general matter, the federal government allocates approximately 10% of its discretionary funding to research and development, a percentage that has declined from about 25% in the mid-1990's. One point of contention in science funding debates is that the government funds useless research that appears to have no link to human improvement. That charge resonates with some of the parameters of basic research in molecular biology, where by definition, scientists have used seemingly obscure organisms as models (e.g., fuitfly, yeast, nematode, fish) for studying molecular processes, and the argument for such research has been that such work reveals universal biological processes that apply to humans. Now, in recognition of the fact that wild-card research observations could have great relevance for human benefit (including health), a Golden Goose Award has been established by a coalition of universities, think tanks, and businesseses for the purpose of “highlighting examples of seemingly obscure studies that have led to major breakthroughs and resulted in significant societal impact.” In a ceremony this week, one of the awards was for the research on the green fluorescent protein from jellyfish - which first explained why some jellyfish glow - but then the isolation of the gene allowed it to be used as a portable flashlight attached to genetic switching molecules, providing a means to track how gene expression occurs in any cell; such a technique has been used in HIV and cancer research. Other awards this week recognized analogous work in radiation physics and material science. So that is all to the good, but such efforts occur against real funding instability for federal science research. In a related but unfortunate linkage, the ongoing federal budget politics have produced a sequestration deal that ended the budget standoff last August but then embedded automatic cuts in federal spending that occur in January 2013. There's no progress in Washington on avoiding such an outcome. As a result, the current projection is for an 8.2 percent cut in federal science funding, with a specific loss of at least $2.5 billion for NIH alone. That would (and already has) greatly impact existing grant programs and plans for upcoming research in biomedicine; e.g., see a Mayo Clinic analysis. All of this is worth remembering as the political season produces a lot of verbiage regarding the criticality of American science, but a peek behind the words reveals mathematical truths that will undermine how much research can get done.
Science and technology policy has been recognized as an integral component of the Presidential election cycle for the past several elections. The organization Sciencedebate.org has managed to place a set of science policy questions before the presidential candidates in 2008 and again this year; President Obama and Governor Romney have answered the questions here. It’s clear that the major political parties, based on ideological and process preferences, differ on how the (federal) government should be involved in the operation of American science operates and in how its emerging technologies should be regulated by government. One policy lever is fiscal: the decision to authorize spending on “big science” (e.g., space exploration or the Human Genome Project) or to calibrate annual funding levels for the major federal research agencies (in the case of life sciences, the National Institutes of Health and the National Science Foundation are closely watched). Those decisions are on the input side. On the output side, what happens to the technologies produced with the help of federal monies? Here are such critical issues of regulation as those governing genetically engineered food and crops, genetic testing, nanotechnologies, and stem cell research. Although Obama and Romney provide general remarks to the set of general question, there is an absence of any details regarding some critical and pressing issues in the biotech-related life sciences:, e.g., authorization of (embryonic) stem cell research, labeling of genetically engineered (GE) food, or how the government manages dual-use research and disclosure with bioterrorist potential For example, the 2008 questionnaire specifically asked about genetics research and embryonic stem cell research. Obama's policies are evident from his record (e.g., yes to embryonic stem cell research, no to regulation or mandatory labeling of GE food). The current set of questions did not require either candidate to be specific on those issues. In general, with respect to the formation of government policy for the life sciences, the president has an Office of Science and Technology Policy (since 1976), and the last several presidents have created their own bioethics-related advisory panels (Obama's is here) to study current controversies. Despite that, this election-year project to focus the (major) presidential candidates on the role of science in today’s government portfolio is useful, but more explicit questioning on the actual issues confronting regulatory agencies and legislatures would place the very real policy differences between the candidates in sharper focus.
