April 7, 2016

Major Overhaul of Federal Biotechnology Regulation is Underway; National Academy of Sciences Invites Public Participation

The federal regulation of biotechnology products is grounded in a design that was first announced in 1986 as the Coordinated Framework (CF) for the Regulation of Biotechnology, later updated in 1992. Those documents have largely shaped the the federal regulatory regime for biotechnology. A key concept in this original framework was that products produced through genetic engineering (or recombinant DNA) techniques would not receive special oversight because of the processes used to produce them. Instead, a risk-based approach was instituted that focused on the characteristics of actual products, not underlying production techniques. In 2015, the White House, through its Office of Science and Technology (OSTP), announced that it would launch an overhaul of the 1992 policy. In the memorandum, the OSTP provided a definition of “biotechnology products” to be included in the review: 
For the purpose of this memo, “biotechnology products” refers to products developed through genetic engineering or the targeted or in vitro manipulation of genetic information of organisms, including plants, animals, and microbes. It also covers some of the products produced by such plants, animals, and microbes or their derived products as determined by existing statutes and regulations. Products such as human drugs and medical devices are not the focus of the activities described in this memorandum. 
Since the 1980’s, the existing coordinated framework has divided the primary regulation of biotechnology products among three agencies: the U.S. Environmental Protection Agency (EPA), the U.S. Department of Agriculture (USDA), and the U.S. Food and Drug Administration (FDA). The OSTP is involved in a more general role as overseer of the regulatory design, rather than as a formal regulatory body. In the memorandum sent to the heads of the EPA, FDA and USDA, the OSTP alludes to the regulatory overlap, redundancy and confusion that has arisen with the multi-agency design: 
Each of the Federal regulatory agencies with jurisdiction over the products of biotechnology has developed regulations and guidance documents to implement its authority under existing laws, resulting in a complex system for assessing and managing health and environmental risks of the products of biotechnology. While the current regulatory system for the products of  biotechnology effectively protects health and the environment, in some cases unnecessary costs and burdens associated with uncertainty about agency jurisdiction, lack of predictability of time frames for review, and other processes have arisen.
As part of the modernization initiative, the Administration held 3 meetings organized by the relevant agencies to receive feedback on the proposed overhaul. Two documents were issued that are helpful to understanding the current climate that is precipitating calls for redesign: a table of current agency responsibilities, and a series of case studies illustrating how a singular GE product can be subject to multi-agency review. Pursuant to the OSTP charge, a committee formed by the National Academy of Sciences, Medicine and Engineering was commissioned to conduct a formal study, “Future Biotechnology Products and Opportunities to Enhance Capabilities of the Biotechnology Regulatory System.” This committee has set the following objectives:
Describe the major advances and the potential new types of biotechnology products likely to emerge over the next 5-10 years. 
Describe the existing risk analysis system for biotechnology products including, but perhaps not limited to, risk analyses developed and used by EPA, USDA, and FDA, and describe each agency’s authorities as they pertain to the products of biotechnology. 
Determine whether potential future products could pose different types of risks relative to existing products and organisms. Where appropriate, identify areas in which the risks or lack of risks relating to the products of biotechnology are well understood. 
Indicate what scientific capabilities, tools, and expertise may be useful to the regulatory agencies to support oversight of potential future products of biotechnology. 
The first public meeting of the NAS committee will be held on April 18, 2016. The agenda for the meeting is posted here.

March 31, 2016

Lawsuit Challenges FDA Approval of Genetically Engineered Salmon

This week, a coalition of environmental, food safety and consumer groups has filed suit against the FDA for its 2015 approval of a genetically engineered (GE) salmon product in 2015 (following several decades of review). The product is AquaAdvantage, made by Aqua Bounty, Inc.  This is the first transgenic animal to be approved by the FDA for food consumption. 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. The production plans submitted to the FDA describe the preparation of the GE fish eggs in Canada, and the actual production of the fish in Panama (with eventual location in the U.S. as well). Following the approval, Alaska Sen. Lisa Murkowski, an opponent of the FDA's actions (see here), inserted a legislative provision into the 2015 omnibus spending bill, requiring the FDA to develop a labeling scheme for the GE salmon before they enter the market. As a result of that maneuver, the FDA is in the process of complying with that mandate, and the GE salmon is not yet commercially available.

In their press release, the plaintiffs assert several grounds on which the agency’s action does not comply with existing federal law: 
The lawsuit challenges FDA’s claim that it has authority to approve and regulate GE animals as “animal drugs” under the 1938 Federal Food, Drug, and Cosmetic Act. Those provisions were meant to ensure the safety of veterinary drugs administered to treat disease in livestock and were not intended to address entirely new GE animals that can pass along their altered genes to the next generation. The approval of the GE salmon opens the door to other genetically engineered fish and shellfish, as well as chickens, cows, sheep, goats, rabbits and pigs that are reportedly in development. 
The lawsuit also highlights FDA’s failure to protect the environment and consult wildlife agencies in its review process, as required by federal law. U.S. Atlantic salmon, and many populations of Pacific salmon, are protected by the Endangered Species Act and in danger of extinction. Salmon is a keystone species and unique runs have been treasured by residents for thousands of years. Diverse salmon runs today sustain thousands of American fishing families, and are highly valued in domestic markets as a healthy, domestic, “green” food.
The lawsuit was filed in the Northern District of California. The suit could directly test the applicability of the FDA's determination that the insertion of new genetic material amounts to a kind of "veterinary  drug" and thus applications for approval of food from GE animals require a new drug application under the Federal Food, Drug, and Cosmetic Act. According to the FDA: 
FDA regulates GE animals under the new animal drug provisions of the law, and the agency must approve them before they are allowed on the market. Food and animal feed from GE animals will undergo FDA review before the food or feed can be marketed. The Federal Food, Drug, and Cosmetic Act defines a drug as "an article (other than food) intended to affect the structure or any function of the body of man or other animals." Therefore, the rDNA construct intended to change the structure or function of the body of the GE animal is a drug.
The suit also challenges the legitimacy of the FDA's determination that the GE salmon posed no environmental risk, based on an Environmental Assessment; the plaintiffs argue that the FDA is required to perform the more rigorous Environemntal Impact Statement (EIS). The food and restaurant industries had earlier indicated some resistance to selling the GE salmon; Red Lobster and Costco have already announced that the product will not be carried.

March 30, 2016

Vermont Law Requiring Labeling of Genetically Engineered Foods Set to Take Effect as Congressional Opposition Fails

Vermont is on track to implement the nation’s first law requiring the labeling of foods with genetically engineered (GE) ingredients, whether raw or processed. (The term "genetically modified organism" (GMO) is often seen in discussions as well). The state’s Act 120, passed in 2014, was enacted to advance several objectives related to “public health and food safety, environmental impacts” and avoidance of “consumer confusion and deception.” The law states: 
[F]ood offered for sale by a retailer after July 1, 2016 shall be labeled as produced entirely or in part from genetic engineering if it is a product:
(1) offered for retail sale in Vermont; and 
(2) entirely or partially produced with genetic engineering. 
The law further describes the labeling: 
[I]n the case of any processed food that contains a product or products of genetic engineering, the manufacturer shall label the package in which the processed food is offered for sale with the words: “partially produced with genetic engineering;" “may be produced with genetic engineering;" or “produced with genetic engineering.” 
In the two years since its passage, there have been several efforts in Congress to enact a federal law that would reassert federal jurisdiction over the labeling issue and preempt any state labeling laws. The House considered bills in 2015, and the Senate just this month considered its own version. Although a House bill passed, the attempts to establish a federal counterweight to state labeling efforts failed as a similar bill was defeated in the Senate. Efforts to mandate the labeling of GE food products at the national level have consistently failed in Congress, and the FDA has resisted all calls for a national mandate on labeling. Now, as Vermont’s law will take effect on July 1, 2016, preparations for compliance are evident on a number of fronts. The Attorney General has issued a memorandum detailing its enforcement strategy which states: 
Our Office expects that most GE foods on Vermont grocery store shelves will be properly labeled by July 1, 2016. Out of recognition that some food products have longer shelf lives, CP (Consumer Protection Rule) 121 creates a six-month “safe harbor” for foods distributed before July 1, 2016, and offered for retail sale through December 31, 2016. During this six-month period, unless there is evidence that a manufacturer distributed a mislabeled product after July 1, 2016, we will not bring an enforcement action or seek fines for those products. 
Beyond these developments in Vermont, Connecticut and Maine have also passed mandatory GE labeling laws; however, their implementation will only be triggered when a number of states join the effort (see here). On the commercial front, with the Vermont mandate looming, major food manufacturers are releasing plans to add labeling labeling regarding the “genetically engineered” attributes of their food products. General Mills issued a statement
As the discussions continue in Washington, one thing is very clear: Vermont state law requires us to start labeling certain grocery store food packages that contain GMO ingredients or face significant fines. We can’t label our products for only one state without significantly driving up costs for our consumers and we simply will not do that. The result: consumers all over the U.S. will soon begin seeing words legislated by the state of Vermont on the labels of many of their favorite General Mills products. 
Other major companies following suit include Kellogg’s, ConAgra Foods, and Campbell’s Foods. In a departure from other manufacturers, Campbell’s has called for a federally mandated labeling system to systematize labeling, and the company formally withdrew from food industry efforts to oppose GE food labeling laws and initiatives. The effect of the Vermont law is now being realized across the food industry; however, a lawsuit filed against Vermont's law by the Grocery Manufacturers Association (GMA) is still working through the federal courts: the trial judge denied summary judgment and a preliminary injunction for GMA; an appeal of the district court's injunction ruling is on appeal at the Second Circuit.

March 26, 2016

Sequenom Petitions Supreme Court to Review Denial of Prenatal DNA Testing Patent

In the closely-watched patent law case with significant implications for the patenting of diagnostic and other methods in biomedicine, Ariosa v. Sequenom (Fed. Cir. 2015), new developments could result in the case finally reaching the Supreme Court. Sequenom (the assignee of the patent) has now filed a petition for certiorari at the Supreme Court, seeking to overturn the ruling of the Federal Circuit that invalidated its patent to a method of performing prenatal diagnosis using cell-free fetal DNA (cffDNA) collected from a maternal blood sample (see here). Here is Claim 1 of U.S. Patent No. 6,258,540: 
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 Federal Circuit applied a two-part test from  Mayo v. Prometheus (2011) and found a lack of patentable subject matter: 
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. 
The petitioners argue that earlier Supreme Court case law does not mandate the result that the Federal Circuit arrived at. Citing the landmark case of Diamond v. Diehr (1981), concerning whether a patent claim to a rubber-curing method preempted the use of a mathematical formula, the petition notes that Diehr stated that “[i]n determining the eligibility of respondents’ claim[s]...under §101, their claims must be considered as a whole.” The petition further notes that the recent Mayo test is not rooted in the central imperative for excluding certain subject matter from patenting, which is a preemption of fundamental knowledge that becomes an obstacle to scientific progress. They characterize the Mayo test as a rote application of a two-step formula that avoids an actual analysis of whether a patent claim “preempts” further use of fundamental subject matter in the field. The petitioners argue that no preemption occurs here: 
Demonstrated methods show that cffDNA may be used without practicing each of the patent’s core steps: One need not fractionate the sample; one may forego  amplification; and one can use cffDNA without distinguishing paternally inherited sequences at all. These non-preempted innovations are conclusive evidence that petitioner’s patent does not claim the natural phenomenon itself —instead claiming merely one set of applications then  known only to the inventors. 
The petition further develops the impact of the Ariosa (and Mayo) decisions on a wide swath of method patents in the life sciences: 
[T]he decision below threatens to destroy the predictability and certainty the patent system needs to do its job. At a minimum, the biomedical community is now adrift in determining whether or not patents will ever be available in these or related fields. And that’s essentially the ballgame, because once you must seriously question the availability of patent protection, you cannot: (1) confidently invest in research; (2) confidently invest in clinical validation and commercialization of existing patents; or (3) confidently predict that it is better to disclose your discoveries through the patent system than it is to keep them a trade secret. 
In the denial for rehearing en banc, several judges of the Federal Circuit noted their disagreement with an outcome mandated by the Mayo test, but not commanded by the overall objectives of the patentable subject matter doctrine. This case is well-positioned to provide the Court with an opportunity to investigate the method (diagnostic, therapeutic, etc.) claims in biotechnology and consider whether the Mayo test has imposed a rigid formula that short-circuits case-by-case consideration of preemption. For that reason, the Court may respond to the appeal for clarification and review and accept the case; if so, this case would add to an unprecedented involvement by the Court in this patent law doctrine (5 cases in 6 years).

March 15, 2016

More Diagnostic Method Patent Claims Found Invalid Under Mayo/Alice Framework

Some instability in the interpretation of allowable subject matter in biotechnology patent law continues, as the life science sector contends with recent Supreme Court decisions affecting both composition of matter and method claims. For composition of matter claims, the AMP v. Myriad (2013) Supreme Court case established that an isolated gene was not patentable because it is a product or law of nature, while synthetic non-natural DNA sequences (cDNA) were patentable. The method claims in that case (largely directed to methods to identify mutations in the BRCA1 and BRCA2 genes) were held to be invalid, on the basis that such claims were directed to abstract ideas. Two other cases from the Court established a test for method claims in order to differentiate between impermissible claims to abstract ideas, laws of nature, natural phenomena, and permissible claims to applications or inventive manipulation of such subject matter. The test from Mayo v. Prometheus (2011) (a case with patent claims to method of drug optimization using metabolite testing) was 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. 
Later, in the software-based Alice v. CLS (2014), the Court reaffirmed this test. In the last several years, lower court cases have contended with applying this test to challenged life science method claims. Most notably, in Ariosa v. Sequenom (Fed. Cir. 2015), using the Mayo test, the Federal Circuit decided that methods for the detection of fetal DNA in maternal serum were invalid as directed to natural laws (see here). That case is likely to be appealed to the Supreme Court.  A recent district court case illustrates the ongoing impact of all of these decisions on patent claims to diagnostic methods iin biotechnology. In Cleveland Clinic v. True Health Diagnostics (N.D. Ohio 2016), the court considered a defendant’s invalidity challenge on its motion to dismiss under Rule 12(b)6. A representative claim from one of the patents in suit is as follows: 
14. A method of assessing a test subject's risk of developing a complication of atherosclerotic cardiovascular disease, comprising: 
determining levels of myeloperoxidase (MPO) activity, myeloperoxidase (MPO) mass,or both in a bodily sample of the test subject, said bodily sample being blood,serum, plasma, blood leukocytes selected from the group consisting of neutrophils and monocytes, or any combination thereof; 
wherein elevated levels of MPO activity or MPO mass or both in the subject's bodily sample as compared to levels of MPO activity, MPO mass or both, respectively,in comparable bodily samples obtained from control subjects diagnosed as not having the disease indicates that the test subject is at risk of developing a complication of atherosclerotic cardiovascular disease. 
Effectively, the method utilizes the observation that levels of the enzyme MPO correlate with blood vessel inflammation, and can thus be indicative of an elevated risk of a cardiovascular event. The patent claim is somewhat similar to the method claim in Mayo, where the observation of a metabolite level was indicative of pharmaceutical effectiveness (or toxicity). On a motion to dismiss by the defendant, the district court applied the Alice/Mayo test and decided that the correlation between MPO and cardiovascular risk was a law of nature, and that the addition of claim steps to “determining” and “comparing” only supplied routine and conventional processes that did not constitute an “inventive concept.” The court noted its standard that it would only “grant the motion only if defendant is able to show invalidity by clear and convincing evidence,” which it found here. The Cleveland Clinic decision (and other similar opinions) reflect the continuing influence of the Mayo/Alice test on life science method claims despite judicial criticism; the field awaits a possible return by the Supreme Court to these issues if Sequenom files a petition for certiorari this year and the Court accepts review.