December 29, 2014

FDA's 2015 Regulatory Targets in Genetic Testing: Laboratory-Derived Tests and Next-Generation Sequencing

The FDA is holding two upcoming public workshops in the next several months that consider several areas of genetic test regulation which may be the subject of upcoming FDA actions. The FDA derives authority for any proposed oversight of genetic testing from its general mandate to regulate medical devices; one category of device is the in vitro diagnostic (IVD), a term that generally captures tests and assays that are used in the diagnosis (or treatment) of disease, including genetic tests. The ongoing issue of whether laboratory-derived tests (LDT) should be directly regulated by the agency continues to be unresolved. Because LDTs constitute the majority of commercially available genetic tests in the U.S., the absence of regulation regarding the utility and/or validity of these tests means that most of the genetic tests in the U.S. are not subject to FDA oversight (however, general certification of laboratories does occur under the Clinical Laboratory Improvement Amendments (CLIA). The FDA published its Framework for Regulatory Oversight of Laboratory Developed Tests last fall, and generally proposed a risk-based classification and regulatory structure for LDTs. The agency’s rationale for increasing its involvement in this genetic testing sector was provided: 
LDT’s are important to the continued development of personalized medicine, but it is important that in vitro diagnostics are accurate so that patients and health care providers do not seek unnecessary treatments, delay needed treatments, or become exposed to inappropriate therapies.The FDA has generally not enforced premarket review and other applicable FDA requirements because LDTs were relatively simple lab tests and generally available on a limited basis. But, due to advances in technology and business models, LDTs have evolved and proliferated significantly since the FDA first obtained comprehensive authority to regulate all in vitro diagnostics as devices in 1976.
The public workshop for discussion of the LDT framework will be held on January 8-9, 2015; public comments to the online document can still be filed until until February 2, 2015.

The FDA is also considering how it might interface with the field of next generation sequencing (NGS), a term applied to high-throughput methods for generating multiple DNA sequences in parallel; such methods can produce whole-genome or exome-only DNA sequences efficiently and quickly. Typically, the sequencing operation does not start with a particular clinical goal in mind or a particular gene or mutation of interest; the approach is clinically neutral and aims to produce genome-wide DNA sequences. NGS sequencing therefore creates high-volume data that requires serious computational analysis in order to create meaningful, useful results for clinical application. NGS can generate data that reveals rare and previously unknown genetic variants. Because of the broad-brush nature of whole-genome sequencing, it has the potential to reveal incidental (undirected) findings; the ethical management of such information by medical personnel has been the subject of bioethical and academic debate. The FDA has issued a discussion paper which highlights specific concerns and possible standardization for NGS technologies: 
NGS tests are unique among existing IVDs in the amount of data that can be generated, the lack of an a priori definition of what will be detected, and the number of clinical interpretations that can be made from a single patient sample. In order to continue to support the development of useful medical information, FDA believes the most efficient possible approaches to regulating NGS tests should be considered. Among the possibilities, a standards-based approach to analytical performance of NGS tests and the use of centralized curated databases containing up-to-date evidence to support clinical performance are under discussion.
The public workshop on NGS regulation will be held on February 20, 2015; the agency will  receive comments until March 20, 2015.

December 22, 2014

Myriad Genetics Loses Latest Round of BRCA Genetic Testing Litigation at the Federal Circuit

In 2013, the Supreme Court considered whether isolated genes qualified as patentable subject matter in AMP v. Myriad (see here for analysis). That case centered on Myriad Genetics' patent claims to isolated BRCA1 and BRCA2 genes which are used to provide genetic testing to detect an increased genetic susceptibility to developing breast and/or ovarian cancer. The Court rejected the patent claims to the isolated genes, noting that:
[S]eparating that gene from its surrounding genetic material is not an act of invention. 
After the Court’s opinion was issued, several genetic testing companies immediately moved into the marketplace, offering diagnostic genetic testing for mutations in the BRCA1 and BRCA2 genes (Ambry Genetics and others, see here). At that time, Myriad still held other patent claims that had not been challenged in the earlier litigation. Therefore, following the Supreme Court decision, Myriad promptly filed suit against the new entrants, asserting remaining patent claims to DNA primers (short sequences used to amplify/copy a BRCA1/2 sequence) and to testing methods. Myriad sought a preliminary injunction against Ambry Genetics. In University of Utah Research Foundation et al. v. Ambry Genetics, issued earlier this year, a federal district court denied a preliminary injunction to Myriad, basing its decision on a conclusion that Myriad could not show a reasonable likelihood of success on the merits of the litigation because the asserted patent claims were likely not patentable subject matter. Now, on appeal, the Federal Circuit has upheld the denial of the preliminary injunction, in In re BRCA1-And BRCA2-Based Hereditary Cancer Test Patent Litigation, issued last week. With respect to the patent claims to the primers (short DNA strands that initiate the synthesis of a longer DNA molecule, such as a gene) the court stated: 
The primers before us are not distinguishable from the isolated DNA found patent-ineligible in Myriad and are not similar to the cDNA found to be patent-eligible. Primers necessarily contain the identical sequence of the BRCA sequence directly opposite to the strand to which they are designed to bind. They are structurally identical to the ends of DNA strands found in nature. 
In this recent litigation, Myriad had also asserted several method claims that captured the basic process of comparing the sequence of a patient’s BRCA1 or BRCA2 genes with a wild-type (normal) DNA sequence of the relevant gene. In its analysis of these claims, the Federal Circuit rejected the claims, not because of a natural phenomenon or law of nature, but rather relying on the “abstract idea” exception to patentable subject matter (this exception most recently discussed by the Supreme Court in Alice Corp. v. CLS earlier this year):
Here, under our earlier decision, the comparisons described in the first paragraphs of claims 7 and 8 are directed to the patent-ineligible abstract idea of comparing BRCA sequences and determining the existence of alterations. The methods, directed to identification of alterations of the gene, require merely comparing the patient’s gene with the wild-type and identifying any differences that arise. 
In this second round of litigation over the DNA primers, the Federal Circuit relied on the Supreme Court’s reasoning regarding isolated genes to invalidate the DNA primer claims (the Federal Circuit had initially upheld the patent claims to isolated genes in 2012, only to be reversed by the Supreme Court). With respect to the method claims, the Federal Circuit relied on the abstract ideas exception as it had in its rejection of similar method claims in its 2012 decision preceding the Supreme Court case. This decision is the latest round in Myriad’s attempts to restrict competition in the BRCA1 and BRCA2 genetic testing field through assertion of patent claims, and Myriad has now lost on patent claims to isolated genes, DNA primers, and basic genetic testing methods (only claims to cDNAs were upheld). Ambry hailed the Federal Circuit's decision. Also last week, the United States Patent and Trademark Office (PTO) has issued its 2014 Interim Guidance on Patent Subject Matter Eligibility. This updated guidance follows an unusually high number of Supreme Court cases to examine patentable subject matter in life science, business method and software patents over the last 6-7 years, and the PTO has been publishing its evolving thinking on these issues. The PTO is seeking public comment on the Interim Guidance until March 16, 2015, and it will hold a public forum on these issues in January 2015.