February 4, 2016

U.K. Approves First Application for Use of CRISPR Gene Editing In Embryo Research

The rapid adoption of the CRISPR/Cas9 gene editing technology is evident in the explosion of papers describing the use of the technique for possible use in a variety of applications (e.g., retinitis pigmentosa, Duchenne's muscular dystrophy, HIV infection). As described in earlier posts here, the use of gene editing falls into two broad categories: altering genes in somatic cells (non-reproductive) to treat disease in individuals or altering the germline DNA in embryos to preemptively treat or minimize later-developing disease. It is the latter application that has led to many calls for an official moratorium, a ban on funding, and the convening of a wide public discussion on whether scientists should be able to edit germline DNA, which would create heritable genetic changes passed on to later generations. As reported here earlier, a development biologist in the U.K. applied to the Human Fertilisation and Embryology Authority (HFEA) for permission to use gene editing to study early embryonic development. That application has now been approved
Our Licence Committee has approved an application from Dr Kathy Niakan of the Francis Crick Institute to renew her laboratory’s research licence to include gene editing of embryos. The committee has added a condition to the licence that no research using gene editing may take place until the research has received research ethics approval. As with all embryos used in research, it is illegal to transfer them to a woman for treatment.
The goal of Dr. Nakian's research is described:
To provide further fundamental insights into early human development we are proposing to test the function of genes using gene editing and transfection approaches that are currently permitted under the HFE Act 2008. We also propose to use new methods based on CRIPSR/Cas9, which allows very specific alterations to be made to the genome. By applying more precise and efficient methods in our research we hope to require fewer embryos and be more successful than the other methods currently used. Importantly, in line with HFEA regulations, any donated embryos would be used for research purposes only. These embryos would be donated by informed consent and surplus to IVF treatment.
The HFEA approval in the U.K. is without precedent and represents the first officially sanctioned use of gene editing on germline DNA. The 2015 publication of a gene editing experiments on non-viable embryos by Chinese scientists was widely condemned and it accelerated the urgency of considering ethical and regulatory aspects of this research as soon as possible. As described here earlier, a recent National Academy of Sciences (NAS) international summit on gene editing technologies had concluded with a consensus statement that it would be "irresponsible" to use gene editing for the purpose of altering germline DNA in the creation of embryos for reproduction. This research does not do that, explicitly. It will use gene editing to study how genetic changes affect embryonic development as its end goal. With regard to the U.S., there is already an NIH-imposed ban on any federal funding for gene editing on human embryos; in addition, the U.S. has no regulatory equivalent of the U.K. HFEA to consider any possible requests for the approval of non-reproductive embryonic developmental studies like the one approved here. The ongoing NAS study committee will convene another public meeting next week (February 11) to consider more impacts of gene editing technologies; details here.

December 21, 2015

Federal Circuit Denial of Rehearing for Prenatal DNA Testing Patent: Supreme Court Review?

The Federal Circuit denied a petition for an en banc rehearing of Ariosa v. Sequenom (Fed. Cir 2014). This case tests the patent eligibility of a method to detect fetal DNA in maternal blood in order to perform prenatal testing. This case is set against a lingering unrest over the recent Supreme Court decision in Mayo v. Prometheus (2012), invalidating a method of drug dosaging as the improper patenting of a natural phenomenon. Claim 1 of the Sequenom patent is as follows: 
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. 
The denial was accompanied by two concurring opinions (Judges Lourie and Moore, Judge Dyk) and one dissent (Judge Newman). The concurrences both thought that Ariosa was wrongly decided as a policy matter, but that their court was bound by the Mayo decision. In Mayo, a 2-part test which required the identification of any "patent-ineligible concept" and if found, a patent claim would then need an "inventive concept" to make the claim patentable.

Application of the Mayo test in the panel decision of the Federal Circuit identified a natural phenomenon (the presence of the fetal DNA in maternal serum) in Claim 1 that was appended to conventional laboratory techniques (not to an inventive concept) and that result did not present a patentable invention. The recent petition for a rehearing and the accompanying amici involvement indicate continued discomfort with Mayo’s demand for the addition of an inventive concept to any discovered natural phenomeon before patenting is permitted. An “inventive concept” is not identified, nor is that requirement demanded by the statute or even explicitly required by the earlier 35 U.S.C. 101 landmark cases of the high Court (while also suggesting a consideration of prior art as well). It should be noted that the current debate is particularly centered on method claims, especially those with either diagnostic or therapeutic application. Will the Mayo test not only invalidate many diagnostic patent claims but challenge the eligibility of standard pharmaceutical treatment claims, for example, if the underlying metabolic processes are simply natural phenomena? Judge Dyk suggested that the Mayo framework may overlook a form of creativity that can emerge from discovery-based effort: 

But, as I see it, there is a problem with Mayo insofar as it concludes  that  inventive concept cannot come from  discovering something new in nature — e.g. , identification  of a previously  unknown natural relationship or property. In my view, Mayo did not fully take into account the fact that an inventive concept can come not just from creative and unconventional application of a natural law, but also from the creativity and novelty of the discovery of the law itself. This is especially true in the life sciences, where development of useful new diagnostic and therapeutic methods is driven by investigation of complex biological systems.
Thus, until the Supreme Court returns to consider whether Mayo has imposed a rigid, inflexible test with inapposite and/or ambiguous requirements, many argue that diagnostic and therapeutic innovation is at risk. Alternatively, however, more attention to embedding unambiguously detailed and physical manipulation into patent claims may overcome some of the concerns with breadth and scope underlying the preemption rationale for exclusion of the type of claim seen in the Sequenom patent. A petition for certiorari to the Supreme Court can be expected; 2016 could see the Court return to the issue of life science patent eligibility.

December 3, 2015

International Summit on Human Gene Editing: No Recommendation for Ban or Moratorium on Germline Gene Editing Research

The International Summit on Human Gene Editing, hosted by the National Academies of Science and Medicine (NAS, NAM) and international partners, has just concluded a 3-day meeting (archived webcast available here). This summit was called following the rapid dissemination of human gene editing research using the CRISPR/Cas 9 technology (see earlier posts here and here). The impact of this technology cannot be understated: 
The rapid development and widespread adoption of easy-to-use, inexpensive and effective genome-editing methodologies has changed the landscape of biology. The simplicity of the CRISPR–Cas9 system allows researchers and students to make precise changes to genomes, thereby enabling many experiments that were previously difficult or impossible to conduct.
Widespread concern over possible attempts to engineer the human germline (perform gene editing on embryos or gametes for reproductive purposes) led to calls for caution or even a research moratorium (see here). At the conference this week, panels discussed the current technical state of human gene editing, existing and potential governance structures, international perspectives, and social consequences of the technology. The most controversial application of human gene editing – germline editing creating heritable genetic changes – was central to many of the discussions, and the conference oscillated between considering the legitimacy of germline editing and considering the arguably more mundane regulatory control of somatic gene editing. The conference coordinating committee has released a consensus statement that endorses further research on both somatic and germ-line gene editing, subject to existing regulations and oversight mechanisms. The full statement is here. I reproduce the portion of that statement that focuses on the hotly contested issue of germline gene editing:
3. Clinical Use: Germline. Gene editing might also be used, in principle, to make genetic alterations in gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool. Examples that have been proposed range from avoidance of severe inherited diseases to ‘enhancement’ of human capabilities. Such modifications of human genomes might include the introduction of naturally occurring variants or totally novel genetic changes thought to be beneficial.

Germline editing poses many important issues, including: (i) the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism); (ii) the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment; (iii) the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations; (iv) the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country; (v) the possibility that permanent genetic ‘enhancements’ to subsets of the population could exacerbate social inequities or be used coercively; and (vi) the moral and ethical considerations in purposefully altering human evolution using this technology.

It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application. Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.
 As reported by David Baltimore, chair of the conference committee, the members did not recommend either a ban or a moratorium on research into germline gene editing, but they state that any use of gene editing in reproduction at this time would be "irresponsible."  In the U.S., the NIH has already ruled out federal funding for such research:
However, NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed. 
The NAS contemplates ongoing public engagement with the controversies raised by human gene editing, in the form of an upcoming formal NAS study and the establishment of a publicly accessible forum to continue the discussion. More analysis of the conference and the effects on the current research climate will be posted here.

November 30, 2015

FDA Approves Genetically Engineered Salmon for Market; No Labeling Required

The FDA has issued an approval for the marketing of genetically engineered (GE) Atlantic salmon, capping a long regulatory review (see here). The product, AquaAdvantage, made by Aqua Bounty, Inc., has been under agency review for years. This Atlantic salmon has been genetically engineered to add the growth hormone gene from the Chinook salmon, which causes the fish to reach market weight in about half the time. The FDA regulates GE animals under the new animal drug provisions of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) because recombinant DNA introduced into an animal is treated as a drug. From the FDA statement
Based on a comprehensive analysis of the scientific evidence, the FDA determined that AquAdvantage Salmon meets the statutory requirements for safety and effectiveness under the Federal Food, Drug, and Cosmetic Act. Among the requirements the sponsor had to meet are that food from the fish is safe to eat; the rDNA construct (the piece of DNA that makes the salmon grow faster) is safe for the fish itself; and the AquAdvantage Salmon meets the sponsor’s claim about faster growth. In addition, the FDA determined that food from AquAdvantage Salmon is as safe to eat and as nutritious as food from other non-GE Atlantic salmon and that there are no biologically relevant differences in the nutritional profile of AquAdvantage Salmon compared to that of other farm-raised Atlantic salmon.

The AquAdvantage Salmon may be raised only in land-based, contained hatchery tanks in two specific facilities in Canada and Panama. The approval does not allow AquAdvantage Salmon to be bred or raised in the United States. In fact, under this approval, no other facilities or locations, in the United States or elsewhere, are authorized for breeding or raising AquAdvantage Salmon that are intended for marketing as food to U.S. consumers. As required by the National Environmental Policy Act, the FDA completed an environmental assessment to determine whether approval of the application would result in significant effects on the quality of the human environment in the United States. The FDA has determined that the approval of the AquAdvantage Salmon application would not have a significant environmental impact because of the multiple and redundant measures being taken to contain the fish and prevent their escape and establishment in the environment.
The agency will not require the GE salmon to be labeled:
Based on our assessments of food derived from the AquAdvantage Salmon, we have determined that the term “Atlantic salmon” is the appropriate common or usual name for such food within the meaning of section 403(i) of the FD&C Act because AquAdvantage Salmon meets FDA’s regulatory standard for Atlantic salmon (Ref. 10) and the composition and basic nature of food from AquAdvantage Salmon does not significantly differ from its non-GE counterpart—non-GE farm-raised Atlantic salmon. In addition, we have determined that food derived from AquAdvantage Salmon is as safe and nutritious as food from other farm-raised Atlantic salmon. For these reasons, we have concluded that there is no material difference between food derived from AquAdvantage Salmon and food derived from other non-GE, farm-raised Atlantic salmon that is required to be disclosed in the labeling of food derived from AquAdvantage Salmon under the relevant provisions of the FD&C Act, as explained above. See 21 U.S.C. 321(n) & 343(a).
Senator Lisa Murkowski (R-AK) has been an outspoken opponent of FDA approval of the GE salmon (in line with general statewide opposition), and has been attempting to pass legislation requiring the labeling of the GE salmon if the agency approval cannot be overturned:
The FDA has said there will be draft guidance on voluntary labeling indicating whether food has or has not been derived from GE Atlantic salmon. So, basically, if you want to put a label on that says this is a fake fish, a fake salmon, you can go ahead, but you don't have to. It is only voluntary. That is not good enough for this mom. That is not good enough for most who care about what their families are eating. So we are going to continue to press for mandatory labeling if the FDA is going to approve--wrongheadedly, in my mind--this genetically engineered fake fish for human consumption. They darn well better agree that labeling will be required because I am not going to eat it. 
Public sentiment against approval of the GE salmon was well-registered with the FDA; over 1.5 million public comments were posted against agency approval; the agency decision not to require labeling has generated more opposition and the FDA's safety evaluation has been challenged as cursory. The marketplace could well determine whether GE salmon actually becomes part of the American food supply; many retailers and restaurants are on record stating that they will not sell the product. Upcoming developments to watch will be the ongoing pressure to require labeling (as well as the Senate prospects for the federal anti-GE labeling bill discussed here earlier). Furthermore, the fate of future GE seafood products (about 35, by one count) that come before the FDA remains uncertain. Lastly, a lawsuit has been filed in Canada opposing the AquaBounty production of the GE salmon eggs in Canada as a potential environmental threat to wild salmon stocks.

November 16, 2015

Federal Circuit Considers Rehearing on Denial of Patent to Noninvasive Prenatal Testing of Fetal DNA

Non-invasive prenatal testing (NIPT) is an alternative to the invasive techniques of amniocentesis or chorionic villi sampling used in reproductive medicine, both of which carry some risk to the fetus. The research demonstrating that fetal DNA could be recovered from maternal serum prompted the development of testing techniques that could simply rely on maternal blood testing in order to recover fetal DNA and perform genetic analysis. The scientists were awarded U.S. Patent No. 6,258,540. Claim 1 of the patent: 
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. 
Sequenom, Inc. holds the rights to the patent. It sued Ariosa Diagnostics and several other genetic testing companies for infringement of the patent. In Ariosa Diagnostics, Inc. v. Sequenom, Inc., issued in June, the Federal Circuit ruled that the patent claims to methods for detecting and recovering the fetal DNA from a maternal sample were invalid for lack of patentable subject matter (35 U.S.C. § 101) (see here). That decision followed a sequence of recent Supreme Court cases, AMP v. Myriad (2013) (Myriad) and Mayo v. Prometheus (2012) (Mayo) that each invalidated patent claims in the life sciences for a lack of patentable subject matter. The Federal Circuit relied on the analytic framework from Mayo to dissect the patent claims, summarizing the test as follows: 
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 noted that the presence of fetal DNA in maternal serum was a patent- ineligible natural phenomenon (step 1) and then proceeded to step 2, where it considered whether any other elements of the patent claim (detecting, amplifying) operated to transform the unpatentable natural phenomenon: 
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 that led to an incorrect result in this case. In August, Sequenom filed a petition with the Federal Circuit requesting a rehearing en banc, contending that the panel’s decision wrongly applied the Mayo framework to find a groundbreaking invention unpatentable (see here): 
To avoid this absurd result, all the Court must do is reaffirm—as did the Supreme
Court in Mayo—that a combination of known steps that incorporates or is motivated by an unpatentable natural phenomenon is nonetheless patentable if that combination “considered as a whole” was not routine before the patent disclosed it.
Sequenom then described the future impact of the decision as "an existential threat:" 
The full Court's intervention is particularly necessary because, if this Court does not step in and draw this line, the panel's rule threatens to swallow many more meritorious inventions along with this one. 
Ariosa has recently filed its response to the Sequenom petition. Ariosa argues that the Federal Circuit’s decision properly utilized the Mayo-based framework as an analytic device:   
Appellants’ only legal argument (as opposed to their dire policy-based prognostications) in favor of rehearing en banc is that Mayo, Myriad and Diehr must be read as teaching that “a combination of known steps that incorporates or is motivated by an unpatentable natural phenomenon is nonetheless patentable if that combination ‘considered as a whole’ was not routine before the patent disclosed it.” Yet Appellants’ misreading of those precedents amounts to nothing short of a wholesale revision of the Supreme Court’s two-part test for determining whether a claim recites patent-eligible subject matter.   
The contrasting arguments of the parties frame a question for the Federal Circuit regarding whether a patent claim embedding a natural phenomenon requires a holistic interpretation (Sequenom) or should be subject to a more splintered analysis (Ariosa). A decision from the Federal Circuit on the petition for rehearing is likely to issue in the next several months; if they do not accept it, the decision could then be appealed to the Supreme Court, which has issued two life science decisions on patentable subject matter in the last three years.