June 30, 2016

Supreme Court Denies Certiorari in Sequenom v. Ariosa

The Supreme Court has denied certiorari for the appeal in Sequenom v. Ariosa (Fed. Cir. 2015). There has been widespread interest in this case, which invalidated patent claims to a method of performing prenatal diagnosis using cell-free fetal DNA (cffDNA) collected from a maternal blood sample (see earlier post here). The method has been critical to the development of non-invasive prenatal testing (NIPT). NIPT testing can be used to identify chromosomal abnormalities or other genetic aberrations, and it offers an alternative to the invasive techniques of amniocentesis or chorionic villi sampling, both of which carry some risk to the fetus. Sequenom would have followed a sequence of recent Supreme Court decisions, AMP v. Myriad (2013) and Mayo v. Prometheus (2012) (Mayo) that each invalidated patent claims in the life sciences for a lack of patentable subject matter. The most controversy has followed the Mayo decision, which was then followed by a software-related patent case, Alice v. CLS (2014). The Mayo/Alice pair has distilled an analytic framework for determining when method patent claims impermissibly read on a law of nature or a natural phenomenon. The framework has been criticized for being overly broad, and for having a deleterious impact on the viability of method patent claims in the life sciences, particularly in the diagnostic testing sector. In the Federal Circuit decision in Sequenom last year, the concurrence by Judge Linn also took direct issue with the Court’s recent dictates in these method patent cases. But the Court did not take the invitation to focus on its own recently developed test. So in deciding not to take the case, the Court will not - for now - review its Mayo/Alice roadmap. One example of continuing influence of the Court's current paradigm is Cleveland Clinic v. True Health Diagnostics (N.D. Ohio 2016), invalidating the method patent claims on a method of detecting cardiovascular disease by detecting the elevation of specific enzyme levels (see earlier post here).

June 22, 2016

RAC Approves First Use of CRISPR Gene-Editing Protocol in Humans

Yesterday, the Recombinant DNA Advisory Committee (RAC), a federal advisory committee to the NIH, held a public meeting to consider the first submission for approval to use a CRISPR/Cas9-based (CRISPR) study protocol with human patients. CRISPR is a technique that allows genes to be edited; it has swept through biomedical science in the last few years as a breakthrough technology. The RAC committee has provided oversight for the field of gene transfer therapies for decades (and supplements FDA and local institutional oversight by IRBs and IBCs). As an advisory committee to NIH, first constituted in 1974, RAC's regulatory portfolio for human experiments began with reviewing gene transfer studies pursuant to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. The field of "gene therapy" has largely been comprised of studies involving gene transfer into patients to correct, replace, or diminish gene activity relevant to various clinical conditions; to date, several thousand gene therapy clinical trials worldwide have been conducted. RAC's jurisdiction extends to the use of gene-editing protocols, as well as other gene-altering technologies such as RNA interference. Now, a collaborative effort from the University of Pennsylvania (Penn), M.D. Anderson Cancer Center, and the University of California, San Francisco produced a proposed study protocol involving CRISPR gene-editing that was discussed and evaluated by the RAC this week at its meeting. The protocol involves an ex vivo technology where T cells of cancer patients will be removed and subject to gene-editing to alter several cell receptors before the cells are infused back into the patient. The goal is to engineer the T cells of the immune system so that they target and destroy cancer cells; this initial study is to identify any safety issues that might emerge. The recruited patients have either myeloma, melanoma, or sarcomas and would be those for which conventional therapies are not available or effective. During the meeting, questions were raised about potential conflicts of interest due to financial interests of some investigators, as well as the involvement of Penn, as it was the site of the now well-known 1999 gene therapy trial that resulted in the death of Jesse Gelsinger; that trial had notable flaws involving the transparency of preclinical testing and of competing financial interests. After public review and discussion of the protocol, the committee voted to approve the protocol. Yesterday's approval marks the first RAC-sanctioned use of CRISPR technology in human patients.

This is the first study protocol submitted to RAC that uses CRISPR in humans, but it is not the first gene-editing human protocol that RAC has considered. Sangamo BioSciences received approval to use its zinc-finger gene-editing technology (ZFN) in two different human trials: an ex vivo protocol approved in 2007, and an in vivo protocol approved in 2015. In what appeared to be a coincidence, yesterday's meeting also considered the first proposed gene therapy trial to treat Ornithine Transcarbamylase (OTC) Deficiency since the 1999 Gelsinger trial. Several discussants referenced the Gelsinger incident in their comments. The committee held a discussion of whether preclinical trials for the gene transfer method in non-human primates were necessary before approval (only mice studies were provided); RAC then voted an approval with stipulated conditions

As gene transfer studies have become more routine over the last several decades, the scope and need for continued RAC oversight has been questioned. A recent study of RAC that was conducted by the Institute of Medicine examined whether gene transfer oversight by RAC continued to be necessary; the report concluded that only new protocols presenting novel vectors or technical approaches needed to be evaluated by RAC. However, the IOM committee explored whether the RAC model of a public advisory committee could be utilized more generically for other emerging biotechnologies. including, for example, protocols from the field of nanobiotechnology or synthetic biology, for example. The IOM report endorsed consideration of an expanded scope for RAC or an advisory committee with similar attributes to provide the kind of oversight for new technologies as RAC has provided for decades in the field of gene therapy.

June 15, 2016

National Academy of Sciences Report on Controversial Gene Drive Technology Endorses Further Research, Controlled Field Trials

The National Academies of Sciences, Engineering, and Medicine (NAS) has issued a report on gene drive technology, Gene Drive Research in Non-Human Organisms: Recommendations for Responsible Conduct. A gene drive is a method by which specific genetic mutations (or alleles) are preferentially inherited, and over time, the effect is to eliminate other competing alleles. This has population-wide consequences for an organism, and can permanently alter (or reduce) the genetic diversity of a species. The phenomenon of a gene drive occurs in nature, and has been observed in many organisms
In nature, certain genes ‘drive’ themselves through populations by increasing the odds that they will be inherited.
Now, however, advances in gene-editing technology have facilitated the development of deliberately engineered gene drives. From the report summary:
A wide variety of gene drives occur in nature. Researchers have been studying these natural mechanisms throughout the 20th century but, until the advent of CRISPR/Casfor gene editing, have not been able to develop a gene drive. Since early 2015, laboratory scientists have published four proofs-of-concept showing that a CRISPR/Cas9-based gene drive could spread a targeted gene through nearly 100% of a population of yeast, fruit flies, or mosquitos.
In other words, use of gene drive technology can impose a specific genetic allele (variant) on a population and eliminate all other forms of the gene. Effectively, the population is now homozygous for the preferred variant. That is both the attraction and the concern regarding the use of this technique. Genetic traits could be eliminated, and at its most extreme, whole populations could be "driven" out of existence. It is simple to imagine particular uses of the technology that would eliminate undesirable traits in a target population, such as the ability of mosquitos to spread malaria, or very currently, the ability of the Aedes aegypti mosquito to transmit the Zika virus. The report summarizes possible applications and the requirement for a deliberative approach to use of the technique:
Gene-drive modified organisms hold promise for addressing difficult-to-solve challenges, such as the eradication of insect-borne infectious diseases and the conservation of threatened and endangered species. However, proof-of-concept in a few laboratory studies to date is not sufficient to support a decision to release gene-drive modified organisms into the environment. The potential for gene drives to cause irreversible effects on organisms and ecosystems calls for a robust method to assess risks. A phased approach to testing, engagement of stakeholders and publics, and clarified regulatory over-sight can facilitate a precautionary, step-by-step approach to research on gene drives without hindering the development of new knowledge.
The report did not recommend a moratorium on research, despite noting the potential for adverse consequences. Instead, it endorsed continued research on the technology with some limited field evaluations:
Although there is insufficient evidence available at this time to support the release of gene-drive modified organisms into the environment, the likely benefits of gene drives for basic and applied research are significant and justify proceeding with laboratory research and highly-controlled field trials.
The current regulatory landscape for gene drive applications is summarized:
In the United States, regulation of gene-drive modified organisms will most likely fall under the Coordinated Framework for the Regulation of Biotechnology, which includes the U.S. Food and Drug Administration, the U.S. Department of Agriculture, and the U.S. Environmental Protection Agency. However, the diversity of potential gene-drive modified organisms and contexts in which they might be used reveals a number of regulatory overlaps and gaps. The U.S. government will need to clarify the assignment of regulatory responsibilities for field releases of gene-drive modified organisms, including the roles of relevant agencies.
At the present time, the patchwork structure for biotechnology regulation is currently under formal review by the Obama administration (see earlier post for more background). In general, as the new products of genetic engineering have been developed over the years, they encounter oversight from any one (or more) of three agencies: the FDA, EPA, or USDA. As the regulatory framework is redesigned, we could expect that various applications of gene drive technology will face an approval process customized to the particular goal and purpose of the technology. The report states:
It is important to note that a one-size-fits-all approach to governance is not likely to be appropriate. Each phase of research activity—from developing a research plan to post-release surveillance—raises different levels of concern depending on the organism being modified and the type of gene drive being developed.
The NAS report has received criticism from opponents of field testing, who noted that precise control of such experiments is not possible, and wider, possiblly uncontrolled spread of altered organisms could occur. Other criticisms suggest that the scope of the report is too limited, and does not adequately address possible dual-use concerns (malevolent uses of the technology). The report has some conceptual overlap with efforts of the World Health Organization (WHO) has previously released a guidance framework for how to introduce genetically engineered mosquitoes that are reproductively disabled, thus reducing the population of a malaria vector. In summary, the NAS panel has cautiously endorsed further gene drive research in the U.S., and contemplates eventual field trials of engineered organisms.