June 30, 2015

Congress Weighs In on CRISPR Gene-Editing Technology with Hearings and Proposed Legislation

On two separate fronts, Congress has now engaged with the controversy over the use of genome-editing technology, particularly the CRISPR/CAs9 (CRISPR) protocol. Last week, the House Research & Technology Subcommittee of the Committee on Science, Space and Technology held a hearing, The Science and Ethics of Genetically Engineered Human DNA. The use of CRISPR for editing of the human germline was suddenly a public concern when Chinese scientists published a set of gene-editing human embryo experiments (see here). At the hearing, several scientists testified on the current level of CRISPR development and possible applications. One presenter, Dr. Jennifer Doudna, is one of the developers of the CRISPR technology, and was part of a scientific ad hoc group that published a call for caution in the use of the technology, particularly as applied to reproductive purposes, such as genetic engineering of the human germline (see here). Several themes emerged during the testimony and subsequent questioning by Congressional panel members (the webcast of the House hearing is available here). The application of CRISPR to actual clinical/medical uses is still a work in progress, although panelists agreed that the pace of development is swift, as the relative ease of use and efficiency of the CRISPR technology has excited the scientific community. In the questioning from the House members, some dominant concerns emerged: would potential regulation apply to privately funded research as well as government-sponsored; how would a U.S. based regulatory regimen have any effect on international scientific efforts; is the U.S. at the forefront of technology development in these life science sectors. The hearing was clearly exploratory and a way for concerned representatives to weigh in on an emerging scientific debate. All participants noted that the National Academy of Sciences and National Academy of Medicine will be holding an international summit on gene-editing this fall in order to develop guidelines for use of the technology: 
The committee will consider and recommend standards, guidelines, and practices governing the use of gene-editing technologies in biomedical research and medicine. 
The second intersection of Congress and gene-editing technology comes in the form of an amendment introduced into the current appropriations bill under consideration by the House that would prohibit the FDA from reviewing any application for clinical trials on the use of genome editing in embryos or gametes. It's not clear if this provision could make its way into the final bill, but more importantly, it is likely a shot across the bow to the private sector, creating a roadblock for any commercial endeavors of germline gene-editing in reproduction, as any such government-funded research is already blocked by existing laws that prohibit most embryo-based research.

June 26, 2015

Federal Court Establishes Broad Scope of Genetic Privacy Under Genetic Information Nondiscrimination Act (GINA)

In a first of its kind case involving the scope of genetic privacy afforded by federal law, a federal court has ruled that an employer violated the Genetic Information Nondiscrimination Act (GINA) when it requested DNA samples from two employees for an internal investigation. In Lowe v. Atlas Logistics Group Retail Services (N.D. Ga) a grocery distributor in Atlanta, Georgia (Atlas) was confronted with several instances where it appeared that an employee had defecated on a grocery warehouse floor. In order to determine the culprit, Atlas requested DNA samples from two employees suspected of committing these acts. The employees provided saliva for the DNA testing, but were excluded as suspects. However, the employees went on to sue the company for violating GINA, the federal law which prohibits employers from using genetic information they may acquire to discriminate in hiring, promotion or firing decisions. Employers are also barred from requesting genetic information of employees except in very limited circumstances. Until this case, there was almost no contemplation of scenarios where an employer might request genetic information for a forensic purpose in the context of actual employment (most allegations of GINA violations concern employer access to medical genetic information). However, the plaintiffs alleged that the Atlas request, albeit for non-medical purpose, violated a general GINA prohibition on employer access to genetic information. Atlas contended that the requested genetic information was not covered by GINA, and that the statute was intended to apply only to the gathering of disease-related medical information. The federal judge disagreed and sided with the plaintiffs, finding that Atlas had indeed violated GINA:
If all the Court considers is the language of GINA, the undisputed evidence in the record establishes that the DNA analysis at issue here clearly falls within the definition of “genetic test.”
Now, a federal jury has awarded $500,000 in compensatory damages and $1.75 million in punitive damages to the two plaintiffs. This case is likely to remain somewhat idiosyncratic in its facts, but it signals a broad interpretation for the protection afforded to employees by GINA, which should insulate them from any attempt by employers to use genetic information for general retainment purposes, even when the DNA information is non-medical in nature. Of course, the plaintiffs alleged that the acquisition of their genetic information for arguably limited purposes still allowed an employer the possibility of testing that DNA sample for other medically-related information, or to keep the sample for such purposes later; one could imagine scenarios where an employer might try to obscure the purpose for testing by hiding behind a forensic pretext. This case makes that less likely. Thus, the case is notable as the first GINA case in federal court to interpret the scope of subject matter encompassed by the statute; its conclusion that GINA is to be read broadly sets a genetic privacy baseline. To date, GINA has been largely been invoked not in private litigation, but in complaints submitted to the Equal Employment Opportunity Commission (EEOC) (see here).

June 15, 2015

Federal Circuit Invalidates Patent Claims to Methods for Noninvasive Prenatal Testing of Fetal DNA

The recognition that fetal DNA could be recovered from maternal serum launched the development of non-invasive prenatal testing (NIPT) using cell free fetal DNA (“cffDNA”). 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, Inc. holds the rights to the foundational U.S. Patent No. 6,258,540 Sequenom sued Ariosa Diagnostics, Inc. (formerly Aria) and several other genetic testing companies for infringement of the patent based on their offerings of NIPT tests. Claim 1 of the patent is as follows: 
1. A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample. 
In Sequenom v. Ariosa (2015), the Federal Circuit has just ruled that the patent claims to methods for detecting and recovering the fetal DNA are invalid for lack of patentable subject matter (35 U.S.C. § 101). This patent case follows 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 mater. At the trial court in 2013, the judge had granted summary judgment to Ariosa, ruling that the patent claims impermissibly claimed a natural phenomenon and thereby preempted other uses of the natural subject matter, an outcome in conflict with Supreme Court dictates. The Federal Circuit has just affirmed that lower court decision, relying on the analytic framework from Mayo to dissect the patent claims. The court summarized the Mayo test: 
First, we determine whether the claims at issue are directed to a patent-ineligible concept. If the answer is yes, then we next consider the elements of each claim both individually and “as an ordered combination” to determine whether additional elements “transform the nature of the claim” into a patent-eligible application. 
The court notes that the presence of fetal DNA in maternal serum is a patent-ineligible natural phenomenon (step 1) and then goes on to step 2, where it considers whether the other elements of the patent claim (detecting, amplifying) operate to transform the unpatentable natural phenomenon, deciding that they do not:
Thus, in this case, appending routine, conventional steps to a natural phenomenon, specified at a high level of generality, is not enough to supply an inventive concept. Where claims of a method patent are directed to an application that starts and ends with a naturally occurring phenomenon, the patent fails to disclose patent eligible subject matter if the methods themselves are conventional, routine and well understood applications in the art. The claims of the ’540 patent at issue in this appeal are not directed to patent eligible subject matter and are therefore, invalid. 
Judge Linn filed a concurrence, but made it clear that he did so because Mayo demanded the application of a fairly unforgiving test, and without that standard, he did regard the Sequenom method claim to be patentable: 
But for the sweeping language in the Supreme Court’s Mayo opinion, I see no reason, in policy or statute, why this breakthrough invention should be deemed patent ineligible. 
Thus, the Federal Circuit has reinforced an analytic approach to the patentable subject matter question of method claims that applies the Mayo framework. Mayo requires that if a patent claim reads on a natural phenomenon, all of the surrounding elements of the claim are analyzed separately to determine if they supply an “inventive concept.” This claim dissection does appear to conflict with a well-known maxim from Diamond v. Diehr (1981), and antecedent to Mayo, that patent claims need to be evaluated as a whole, not as set of constituent parts:
In determining the eligibility of respondents' claimed process for patent protection under § 101, their claims must be considered as a whole.
Ariosa can be added to a line of life science patent cases that are struggling with several issues: how to precisely identify when a natural phenomenon or law of nature is present in a patent claim; and how to evaluate the eligibility of a patent claim that embeds natural subject matter but does not preempt that use.

June 3, 2015

Federal Judge Upholds Oregon County Ban on Planting of GMO Crops Despite Right to Farm Statute

A federal judge in Oregon has rejected an initial challenge to the ban on the planting of genetically engineered/modified (GMO) crops in Jackson County, Oregon. Jackson County Ordinance 635 was a ballot initiative put to a vote in May, 2014 and it passed by a 2-1 margin. In Schultz Family Farms, LLC v. Jackson County, (D. Ore. 2015) a group of local alfalfa farmers challenged the ban, due to go into effect later this year, citing Oregon’s Right to Farm Act. Right to farm laws have generally insulated existing farming activities from later-enacted prohibitions that would declare farming activities to be a nuisance or trespass. The plaintiffs claimed that they would be required to remove about 300 acres of herbicide-resistant “Roundup Ready” alfalfa in order to comply with the ordinance. The plaintiffs also claimed that the ordinance was prohibited by a recently enacted state law, Senate Bill 863 (the Seed Bill), that preempted any local bans on the planting of GMO crops. However, in the ruling, the judge stated: 
It is clear from the text and context of the Seed Bill that the Oregon legislature meant to preempt counties and other local  governments from enacting laws banning the use of GE seeds so that the GMO issue could be addressed on a state-wide, uniform basis.In  other words, the Seed Bill preempts laws precisely like the Ordinance. However, it is equally clear that the legislature meant to carve out a specific exception authorizing Jackson County Ordinance 635. 
Thus, the judge denied summary judgment for the farmers, finding that the challenged ban had specifically survived the statewide prohibition on local ordinance banning the planting of GMO crops, and Jackson County can continue with enforcement of the ordinance. The judge agreed, however, that Oregon now has a statewide preemption against any other similar ordinances. The order notes that Ordinance 635 contemplates possible interference with farming activities because of the planting of GMO crops, thus inadvertently aligning with the purpose of the more traditional right to farm laws: 
Section 2 of the Ordinance states the "findings" and gives the primary purposes of the Ordinance, one of which is to protect local farmers from "significant economic harm to organic farmers and to other farmers who choose to grow non-genetically engineered crops" that can be caused by "genetic drift" from GE crops. 
There are a few other jurisdictions with bans on the cultivation of GMO crops. Several California counties have bans in place, including Marin, Santa Cruz, Mendocino, Trinity, and Humboldt. Last year, a federal judge in Hawaii ruled that an ordinance banning cultivation of GMO crops in Kauai County was preempted by state law. Efforts continue to enact GMO crops bans in some jurisdictions; however, just last month, a ballot initiative banning GMO cultivation in Benton County, Oregon, was defeated by an over 2-1 margin. It is possible that the plaintiffs could pursue a regulatory taking challenge now to Ordinance 635, if they can demonstrate loss of all economic value of their property (Lucas v. South Carolina Coastal Council) or meet the demanding requirements of a balancing test derived from Penn Central Transportation Co. v. New York City. However, for now, this ruling is significant for its determination that a ban on GMO planting can coexist with a right to farm statute.

May 26, 2015

White House Weighs In on Use of CRISPR Gene-Editing Technology for Human Germline Modification

The rapid dissemination of the publication reporting the use of CRISPR/Cas9 gene-editing technology by Chinese scientists in an attempt at human germline modification has generated quick responses from several official quarters. The National Academy of Sciences (NAS) has announced its upcoming involvement in the scientific, ethical, and policy debate over the use of the CRISPR technology in germline applications: 
The National Academy of Sciences and the National Academy of Medicine are launching a major initiative to guide decision making about controversial new research involving human gene editing. Human gene-editing technologies, such as CRISPR-Cas9, may lead to promising new treatments for disease. However, recent experiments to attempt to edit human genes also have raised important questions about the potential risks and ethical concerns of altering the human germline. Future advances are likely to raise new questions. 

Our initiative will include an international summit this fall to convene researchers and other experts to explore the scientific, ethical, and policy issues associated with human gene-editing research. In addition, we will appoint a multidisciplinary, international committee to begin a comprehensive study of the scientific underpinnings and clinical, ethical, legal, and social implications of human gene editing. The committee will consider and recommend standards, guidelines, and practices governing the use of gene-editing technologies in biomedical research and medicine. An advisory group to steer the overall initiative will soon be announced.
The NAS initiative has now generated an official reaction from the Obama administration. It is evident that the administration would like to see the scientific community get out ahead of lawmakers in considering how to responsibly handle the potential of CRISPR in reproductive applications. In the White House statement:
The scientific community has a good record of establishing and adhering to ethical principles in genetic technology. In the 1970s, scientists called for a temporary moratorium on gene-splicing technology until the implications and policies could be sorted out. Similarly, this year scientists called for a moratorium on germline-editing research until the safety and ethical issues could be explored by the community. 
The advances in health technology over the past century - vaccines, antibiotics, early disease diagnostics, and treatment for countless health conditions - have reduced infant mortality, extended life expectancy, and alleviated suffering for millions. But new technology also brings risks and ethical challenges that require careful consideration. For example, researchers in China recently conducted genome-editing experiments in human embryos of a kind not able to develop into a fetus or a person. 

Research along these lines raises serious and urgent questions about the potential implications for clinical applications that could lead to genetically altered humans. The full implications of such a step could not be known until a number of generations had inherited the genetic changes made — and choices made in one country could affect all of us. 

It is important that the NAS’ international summit fully explore the implications of germline editing for the current generation and generations to come across the globe, as well as the potential for alternative technologies that do not require germline alteration to deliver similar medical promise. The Administration looks forward to seeing the results of the scientific community’s discussion.
The quiet alarm that underlies these relatively rapid reponses highlights how the use of CRISPR technology application in human reproduction is not just another clinical application, but it goes right to the heart of human potential and scientific power, as well as not insignificantly raising fears of eugenic intent.
In the U.S., we lack a formal regulatory body devoted to oversight of reproductive technologies (unlike, e.g., the UK Human Fertilization and Embryology Authority) so we see a more ad hoc display of responses. The reminder by the National Institutes of Health that no federal funding would be available for gene-editing experiments on the human germline is a kind of de facto ban, since many U.S. scientists rely on federal support.