In a move that signals the maturity of the gene therapy field, the National Institutes of Health (NIH) has announced that it will no longer subject all applications for gene therapy trials to automatic review by the Recombinant DNA Advisory Committee (RAC). Gene therapy is defined as:
the transfer of genetic material into humans with the goal of replacing or compensating for the function of abnormal genes, or to enhance the immune system’s ability to attack cancer cells.
RAC occupies a singular place in the history of government oversight of new technologies. The committee was established in 1974, following increasing concern by scientists in the then-emerging field of molecular biology as the techniques involving recombinant DNA were developed and disseminated. The Asilomar conference of 1975 originated with scientIsts, and led to the publication of physical and biological containment strategies to limit the risk of working with recombinant organisms (e.g., bacteria, viruses). RAC issued the first Recombinant DNA Research Guidelines in 1976, and these were the precursor to later guidelines for the gene therapy applications that were first submitted to RAC in the late 1980's. Now, following a study from the Institute of Medicine that called for streamlining the review process for gene therapy (removing redundancies in the review process), the NIH has acceded to their recommendation that RAC reviews of gene therapy be reserved for exceptional cases where both of these conditions exist:
1. The protocol review could not be adequately performed by other regulatory and oversight processes (for example, the institutional review boards, institutional biosafety committees, and the FDA).
2. One or more of the following criteria are satisfied:
Protocol uses a new vector, genetic material, or delivery method that represents a first-in-human experience, thus representing unknown risk.
Protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value.
Proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for local and federal regulatory bodies to evaluate the protocol rigorously.
In reviewing the history of RAC oversight for the gene therapy field, the IOM stated:
When recombinant DNA technology was new, and the many risks concerning individual clinical trial protocols were uncertain, the public, scientists, and policy makers raised important questions about potential dangers—such as whether this technology could harm patients, create new infectious organisms, or make genetic alterations that could be passed down to future human generations. In its report, the IOM committee finds that the major concerns about recombinant DNA from 40 years ago do not raise the same level of concern today, as hundreds of gene therapy clinical trials have evaluated the technique’s safety and effectiveness.
The RAC committee stands as a model of a technology-specific review body set up to augment existing regulatory processes in the case where a novel technology has emerged with potential risks to health and safety. This recent move now becomes a model for partial deregulation of a maturing technology. Gene therapy protocols will continue to be reviewed by the FDA and institutional oversight panels. The IOM report recognizes that this model of regulatory layering still has relevance for current emerging technologies, and specifically cites the field of nanotechnology as a candidate for a future RAC-like review body to consider its specific applications in medicine.
The public health campaign to eradicate smallpox, a highly contagious viral disease with significant mortality, was one of the public health success stories of the 20th century. Following decades of vaccination against the variola major virus, the causative agent of smallpox, the World Health Organization (WHO) declared the eradication of smallpox in 1980 (the last case in the U.S. occurred in 1949, and the last global case was in Somalia in 1977). With this goal achieved, a long-standing concern for international public health authorities has been how to limit and manage the remaining stocks of the smallpox virus. With eradication achieved, should variola virus be retained in laboratories, in view of its characterization as a dual-use microbe – a source of legitimate research interest as a viral pathogen as well as a potential bioweapon? In 1983, by international agreement, a decision was made to retain variola virus stocks at two WHO Collaborating Center laboratories: the State Research Centre for Virology and Biotechnology in Koltsovo, Russia, and in the U.S. at the Centers for Disease Control and Prevention in Atlanta, Georgia. Speculation has continued, however, over whether unaccounted virus stocks exist in other places. The World Health Assembly (WHA), the decision-making conference of the WHO, supported the policy of setting limits on access to variola virus, and, by 1994, endorsed the eventual destruction of the remaining virus stocks. Over the years, WHO surveyed whether consensus research goals required continued maintenance of virus stocks. In 2011, the WHA reaffirmed the eventual destruction of the virus stocks, but deferred the setting of an actual date to the WHA conference in May of this year. Within WHO, the two advisory committees that considered the issue reached different conclusions. At this recent conference, it was decided that the virus stocks will continue to be maintained, because research goals dependent on access to the virus remain unfinished. These goals include the further development of antivirals (smallpox vaccines exist and are maintained in national and international stockpiles). Dissension among the WHO advisory committees contributed to the decision to delay the setting of a date for destruction of the stocks. Not surprisingly, a divergence of views on the merits of retaining variola virus stocks exists in the scientific community (support for maintaining virus stocks for future research versus calls for destroying the virus stocks) as well as among the WHO member states (with U.S. favoring retention while less-developed countries have favored destruction). A further wrinkle in the debate is the emergence of new technical capabilities (e.g., synthetic biology techniques) that could allow artificial reconstruction of the smallpox genome; such a possibility focuses policy concerns away from access to viral stocks and instead on access to genomic and technical information (actual publication). Of course, concerns about informational access have surfaced recently with research reporting the development of highly pathogenic H5N1 influenza viruses (see here and here). The still-unresolved smallpox (variola) virus retention issue illustrates how dual-use research concerns can originate from existing natural pathogens, as well as newly engineered or synthesized pathogens.
Two counties in Oregon recently passed bans on the planting of genetically engineered (GE) crops; the Jackson and Josephine County measures passed handily. The Jackson County ordinance:
It is a county violation for any person or entity to propagate, cultivate, raise or grow genetically engineered plants in Jackson County.
These efforts began in Jackson County where proponents of the ban (local farmers) gathered enough signatures in 2013 to put a local GE ban on the ballot in the spring of 2014. That effort stirred opposition from seed companies and other parties, which reacted by pushing for a legislative fix to preempt such local agricultural governance. The result is that both of these newly-enacted county bans exist against the backdrop of a recently enacted state law that prohibits local counties from interfering with agricultural choice:
A local government may not enact or enforce a local law or measure, including but not limited to an ordinance, regulation, control area or quarantine, to inhibit or prevent the production or use of agricultural seed, flower seed, nursery seed or vegetable seed or products of agricultural seed, flower seed, nursery seed or vegetable seed.
The Oregon county measures are in line with other counties around the country that have enacted such bans (e.g., in Washington, Hawaii, California). In Oregon and the other states with such bans, the rationales advanced for the ban on GE crops include the avoidance of genetic contamination of non-GE crops by neighboring GE crops (e.g., pollen drift). (Several years ago, an apparent genetic contamination of the wheat crop in eastern Oregon elevated concerns about other potential instances of genetic contamination). A further motivation for a GE ban arises from the nature of the engineering itself – these crops are generally engineered for herbicide resistance (Monsanto's Roundup Ready technology) – meaning that the crops can withstand widespread application of these weed-killers. As a result, heavy use of potentially dangerous herbicides is encouraged by the planting of these GE crops, and proponents of such a ban point to the potential environmental and health complications from widespread use of the herbicide. The Oregon counties also have significant numbers of organic farming operations which could face exposure to GE materials or herbicides, scenarios that conflict with established principles of organic farming.
An apparent clash between the new county ordinances (at least for Josephine County) and the state’s new preemption statute looms, lodged against a backdrop of the significant home rule environment for localities that is found in Oregon; Jackson County was granted a waiver from the state law because the ballot initiative had been established before the law was passed. A similar legal showdown could emerge in Hawaii, which has passed a state preemption statute following the enactment of local GE crop bans. The shifting legal landscape between assertions of local governance and reactive preemption is also occurring with respect to state mandates for the labeling of GE food and pending federal preemption efforts to nullify such laws (see earlier post here). In a further sign of Oregon's attention to the legal issues raised by GE crops and GE food, a citizens' effort is underway to get a mandatory GE food labeling law on the ballot for November, 2014.
In its first law enforcement action in the personalized genomics sector, the Federal Trade Commission (FTC) has entered a final consent order against several personal genomics companies for engaging in business practices that deceived consumers. In general, personalized genomics companies follow several business models. A company may offer genetic testing services in which a consumer pays to have her DNA analyzed for mutations that, in the company's claim, are alleged to correlate with various medical conditions or susceptibilities. In another model, genomics companies provide genetic testing and also offer products which are alleged to treat or alleviate the medical conditions identified by the DNA testing. GeneLink, Inc. and its former subsidiary, foru International Corporation, followed the second model and offered what were claimed to be “genetically guided personalization of nutrient and skin care formulations” as part of a general anti-aging portfolio of services and products. The FTC filed a complaint against GeneLink and foru for statements and practices that violate the Federal Trade Commission Act, which prohibits false advertising and “unfair or deceptive trade practices.” The FTC complaint recited promotional materials from GeneLink:
[B]y analyzing and understanding your unique genetic strengths and weaknesses, you can eliminate the guesswork and “genetically guide” the optimal nutritional supplement or skincare formulation to match your LifeMap Healthy Aging Assessment®.
The FTC cited the scope of the claims made by GeneLink:
According to ads and other promotional materials, the supplements could treat serious conditions like diabetes, heart disease, arthritis, and insomnia. Claims for the skin serum cited a “double blind, randomized and controlled study” and promised the product would “compensate for particular deficiencies in areas of skin aging, wrinkling, collagen breakdown, irritation, and the skin’s ability to defend against environmental stress.”
The violation of the FTC Act was recited in the complaint:
12. Through the means described in Paragraph 11, respondents have represented, expressly or by implication, that genetic disadvantages identified through respondents’ DNA Assessments are scientifically proven to be mitigated or compensated for with nutritional supplementation.
13. In truth and in fact, genetic disadvantages identified through respondents’ DNA Assessments are not scientifically proven to be mitigated or compensated for with nutritional supplementation. Therefore, the representation set forth in Paragraph 12 was, and is, false or misleading.
Following a period of public comment, a final consent order was entered to settle the charges brought against the companies. The companies are now prohibited from offering products for purposes not supported by credible scientific data and the level of scientific support required for health-related claims is specified:
“[C]ompetent and reliable scientific evidence” shall consist of at least two adequate and well-controlled human clinical studies.
This FTC action no doubt puts the personalized genomics sector on notice that dubious claims for genetic “treatments” will be subject to FTC monitoring and enforcement actions. This action also exemplifies how the FTC, as the federal consumer protection agency, employs its broad mandate to capture many potentially deceptive business practices in a high-technology areas: the companies were also charged with inadequate data security practices with respect to the collection of consumer information, and the consent order further requires the companies to institute appropriate data security measures for any future data collection. More generally for the genomics sector, the FTC action follows the Food and Drug Administration's (FDA) 2013 warning to 23andme, one of the leading providers of personalized DNA testing, that its services constituted the marketing of an unapproved medical device in violation of the Federal Food, Drug and Cosmetic Act; the company then took corrective actions in removing certain health-related reporting from its products.
Last week, the Federal Circuit issued an opinion, In re Roslin Institute (Edinburgh), that addressed the eligibility of patent claims to a cloned mammal. The Roslin Institute in Scotland accomplished the cloning of the sheep, Dolly, in 1997. This feat was the first reported cloning of a mammal accomplished by the technique of somatic cell nuclear transfer (SCNT). Subsequently, Roslin received U.S. Patent No. 7,514,258 in 2009 directed to the SCNT cloning method. Claim 1:
1. A method for producing a mammalian cultured inner cell mass cell by nuclear transfer comprising:
(i) inserting a nucleus of a quiescent mammalian differentiated cell into an enucleated mammalian oocyte of the same species to reconstruct an embryo;
(ii) culturing the reconstructed embryo; and
(iii) isolating and culturing inner cell mass cells obtained from said cultured, reconstructed embryo to obtain a cultured inner cell mass cell.
The current patenting dispute arose from Roslin’s attempt to patent the actual clones derived from SCNT. These are product claims; here is representative Claim 155:
155. A live-born clone of a pre-existing, nonembryonic, donor mammal, wherein the mammal is selected from cattle, sheep, pigs, and goats.
The Patent Trial and Appeal Board (Board) rejected the proposed claims for failure to satisfy 35 U.S.C. § 101 (patentable subject matter) 35 U.S.C. § 102 (novelty) and 35 U.S.C. § 103 (nonobviousness). With respect to the patentable subject matter issue, the Board described the claims as directed to a natural phenomenon, which is not patentable. Roslin attempted to distinguish the clones from the naturally occurring animals by noting environmentally-induced phenotypic differences in a clone and by noting that the SCNT technique creates a clone with mitochonodrial DNA contributed by a donated egg. These arguments were not successful. The Federal Circuit discounted any patentable difference afforded by the presence of new phenotypic differences from the natural animal or by the presence of unrelated mitochondrial DNA – Roslin arguing for some functional difference in phenotypic divergence and for a structural/functional difference with the mitochondrial DNA. In both cases, these alleged differences were unclaimed and the Federal Circuit therefore discounted these arguments. The legal relevance of the differences between a natural organism and a scientifically altered one dates back to the beginning of the era of patenting the products and techniques in biotechnology (and even earlier). Genetically engineered animals and organisms are eligible for patenting, as established by the Supreme Court in Diamond v. Chakrabarty (1980). In that opinion, a bacterium genetically engineered to degrade oil was deemed to be an invention:
Here, by contrast, the patentee has produced a new bacterium with markedly different characteristics from any found in nature and one having the potential for significant utility. His discovery is not nature's handiwork, but his own; accordingly it is patentable subject matter under § 101.
Here, the Federal Circuit found no invention in the existence of the clone, even while noting technical achievement:
[R]oslin’s chief innovation was the preservation of the donor DNA such that the clone is an exact copy of the mammal from which the somatic cell was taken. Such a copy is not eligible for patent protection.
The court reaffirmed the relevance of the Chakrabarty standard:
Roslin argues that such copies are either compositions of matter or manufactures within the scope of § 101. However, Dolly herself is an exact genetic replica of another sheep and does not possess “markedly different characteristics from any [farm animals] found in nature.” (citing Chakrabarty).
The recent 2013 Supreme Court decision on the patenting of isolated genes, Association for Molecular Pathology v. Myriad Genetics, was also cited for its analysis of the fault line between natural products and inventive-level human alteration:
In Myriad, the Court concluded that “isolated,” naturally occurring DNA strands are not eligible for patent protection. 133 S. Ct. at 2111. Here, as in Myriad, Roslin “did not create or alter any of the genetic information” of its claimed clones, “[n]or did [Roslin] create or alter the genetic structure of [the] DNA” used to make its clones. Myriad, 133 S. Ct. at 2116.
The Federal Circuit did acknowledge that strict nuclear genetic identity might not be fatal:
To be clear, having the same nuclear DNA as the donor mammal may not necessarily result in patent ineligibility in every case. Here, however, the claims do not describe clones that have markedly different characteristics from the donor animals of which they are copies.
Further work remains to be done on clarifying the relative roles of structure and function in the elucidation of “differences” because these very different attributes can be conflated in patent eligibility analysis. The Roslin decision’s reliance on “marked differences” leaves more of that work to be done. Roslin still holds valuable patent rights in the use of the SCNT technique itself, which can be used for reproductive cloning (as here) or therapeutic cloning (see recent post on SCNT-derived human stem cells).
