June 30, 2014

PTO Reacts to Supreme Court Cases on Patentable Subject Matter in Biotechnology and Software

New developments in the question of what subject matter is eligible for patenting illustrate how this seemingly foundational question for the high-tech fields of biotechnology and software remains unsettled, even decades after these industries entered the commercial sector. Patenting for these technologies must not run afoul of the long-standing prohibition on patenting natural phenoma, laws of nature and abstract ideas. Recent years have seen the landmark cases of AMP v. Myriad (2013) and Mayo v. Prometheus (2012) issue from the Supreme Court and impact the life science sector. Myriad took on the eligibility of product claims that derived from natural substances or chemicals (e.g., genes/isolated DNA) and found them invalid. Mayo considered the eligibility of method claims where a natural correlation or relationship was embedded in the claim, therefore risking the possibility that the patent claim “preempts” the use of the natural correlation, and invalidated a method claim for optimizing drug dosage because it violated the prohibition on patenting laws of nature. Following these cases, the U.S. Patent and Trademark Office (PTO) issued new subject matter guidance for patent examiners in applying these holdings to the examination of new patent applications. This guidance document was discussed in an open forum in May of this year, and the PTO has extended the deadline for public comments to July 31, 2014.  Last week, at the annual BIO convention in San Diego, the PTO presented a set of model patent claims derived from the discovery of a protein antibiotic and written post-Myriad, and invited further comments. So the question of how life science patenting steers clear of capturing natural, uninvented subject matter continues. In the field of software patenting, a different question continues to be debated. The patenting of computer-based  technologies, which allow all manner of operations and processes to be carried out through digitization/computer code, must not cross over into the patenting of abstract ideas. Until this month, the most recent precedent on this point, Bilski v Kappos (2010), disallowed the patenting of a computer-implemented scheme for hedging against the risk of price changes because the Court declared that it was no more than an abstract idea. Just two weeks ago, the Supreme Court issued Alice Corporation Pty. Ltd. v. CLS Bank International, in which patent claims to a computer-implemented scheme for mitigating settlement risk in transactions. The Court declared the patent claims also invalid as they improperly claimed an abstract idea, which is not patentable. The PTO has issued new preliminary examination instructions that apply Alice Corp. to patent examination practice. Both lines of cases (life science and computer-related) reiterate existing precepts of patentable subject matter, but the interpretation of these cases remains unsettled. With the comment process now underway at the PTO on the post-Myriad/Mayo guidelines that extend the logic of the ruling on isolated genes to many other natural substances and products will be revisited, but it's possible that full development of the scope of this exception will again require judicial review.

June 29, 2014

FDA and 23andMe Restart the Regulatory Process for Oversight of Genetic Testing Services

The need for regulation of genetic testing offered by genomics companies has been debated for years, accompanied by mixed signals from the FDA over its role in such efforts. The bulk of genetic testing services offered by private companies are offered as laboratory-derived tests (LDTs) that are purchased from the test developer. Laboratories providing LDTs are regulated under the Clinical Laboratory Improvement Amendments (CLIA), administered by the Centers for Medicare and Medicaid Services (CMS), which requires that laboratories meet specified standards, and that individual tests are scientifically accurate, but which does not evaluate the clinical validity or clinical utility of LDTs. In addition, direct to consumer (DTC) genetic tests are offered directly to the public and do not require a medical intermediary; results are provided to the client. The industry has long argued that its services were simply LDTs that did not require formal review as medical devices, but simply had to meet the general CLIA standards for clinical laboratories. However, the FDA has recognized that genetic testing may pose special concerns that warrant specific attention and reacted accordingly. In 2010, the FDA sent warning letters to a number of genetic testing companies, including 23andMe, advising them that their genetic services, although direct to consumer, met the classification of a device that required FDA approval as medical devices. A Government Accountability Office (GAO) investigation in 2010 found that several companies provided inconsistent results to undercover consumers, and that the information provided also did not line up with the consumer’s actual clinical status. The Federal Trade Commission, publishes consumer alerts stating that DTC genetic tests may not be reliable and warning that consumers may be deceived by marketing claims. 

23andMe has offered several kinds of genetic testing, ranging from tests assessing risk for an individual disease or condition to aggregate testing for hundreds of DNA variants across an individual’s genome. A consumer receives information regarding possibly significant DNA variants identified in her genome, as well as a health report from the company assessing medical risk based on the genetic data. The FDA was most concerned about the company health report because it could form the basis for consumer medical decision-making using possibly weak or non-credible information. In 2012, 23andMe announced that it had filed a premarket notification submission to the FDA for its $99.00 Saliva Collection Kit and Personal Genome Service (PGS), a service offered since 2008. However, the company did not properly respond to the FDA’s inquiries and comments in the period that followed. As a result, in November 2013, the FDA ordered 23andMe to cease offering the (PGS) test product; the company complied and announced that its health reports would be discontinued (only providing "uninterpreted raw genetic data"). Now, the company has announced the filing of a premarket submission for a genetic test for Bloom’s syndrome – indicating a restart to its regulatory path with the FDA and even optimism: 
Once cleared, it will help 23andMe, and the FDA, establish the parameters for future submissions. More importantly, for our customers, it marks a baseline on the accuracy and validity of the information we report back to them. The submission includes robust validation data covering major components of our product such as the genotyping chip, software and saliva kit. 
As the contours of the regulatory process traveled by 23andMe for its services becomes clear, other personal genetic testing companies are likely to follow suit and the FDA could begin to offer an orderly oversight structure for the products and services offered by this industry. Given the status of 23andMe as a flagship genomics company, and the hesitant moves by the FDA over these several years, the outcome of this submission and review will sketch out a regulatory path for the industry. However, reaction to FDA involvement is mixed; critics contest the level of consumer harm created by these products and argue that consumers should have the right to obtain their genetic data without government interference, noting the First Amendment right to receive information. Future consumers might contest excessive regulation on that basis.

June 21, 2014

NIH: Recombinant DNA Advisory Committee Review No Longer Necessary for Gene Therapy Trials

In a move that signals the maturity of the gene therapy field, the National Institutes of Health (NIH) has announced that it will no longer subject all applications for gene therapy trials to automatic review by the Recombinant DNA Advisory Committee (RAC). Gene therapy is defined as: 
the transfer of genetic material into humans with the goal of replacing or compensating for the function of abnormal genes, or to enhance the immune system’s ability to attack cancer cells.
RAC occupies a singular place in the history of government oversight of new technologies. The committee was established in 1974, following increasing concern by scientists in the then-emerging field of molecular biology as the techniques involving recombinant DNA were developed and disseminated. The Asilomar conference of 1975 originated with scientIsts, and led to the publication of physical and biological containment strategies to limit the risk of working with recombinant organisms (e.g., bacteria, viruses). RAC issued the first Recombinant DNA Research Guidelines in 1976, and these were the precursor to later guidelines for the gene therapy applications that were first submitted to RAC in the late 1980's. Now, following a study from the Institute of Medicine that called for streamlining the review process for gene therapy (removing redundancies in the review process), the NIH has acceded to their recommendation that RAC reviews of gene therapy be reserved for exceptional cases where both of these conditions exist: 
1. The protocol review could not be adequately performed by other regulatory and oversight processes (for example, the institutional review boards, institutional biosafety committees, and the FDA).

2. One or more of the following criteria are satisfied: 

Protocol uses a new vector, genetic material, or delivery method that represents a first-in-human experience, thus representing unknown risk.

Protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value.

Proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for local and federal regulatory bodies to evaluate the protocol rigorously.
In reviewing the history of RAC oversight for the gene therapy field, the IOM stated
When recombinant DNA technology was new, and the many risks concerning individual clinical trial protocols were uncertain, the public, scientists, and policy makers raised important questions about potential dangers—such as whether this technology could harm patients, create new infectious organisms, or make genetic alterations that could be passed down to future human generations. In its report, the IOM committee finds that the major concerns about recombinant DNA from 40 years ago do not raise the same level of concern today, as hundreds of gene therapy clinical trials have evaluated the technique’s safety and effectiveness. 
The RAC committee stands as a model of a technology-specific review body set up to augment existing regulatory processes in the case where a novel technology has emerged with potential risks to health and safety. This recent move now becomes a model for partial deregulation of a maturing technology. Gene therapy protocols will continue to be reviewed by the FDA and institutional oversight panels. The IOM report recognizes that this model of regulatory layering still has relevance for current emerging technologies, and specifically cites the field of nanotechnology as a candidate for a future RAC-like review body to consider its specific applications in medicine.

June 6, 2014

Eve of Destruction? World Health Organization Defers Setting Date for Destruction of Smallpox Virus

The public health campaign to eradicate smallpox, a highly contagious viral disease with significant mortality, was one of the public health success stories of the 20th century. Following decades of vaccination against the variola major virus, the causative agent of smallpox, the World Health Organization (WHO) declared the eradication of smallpox in 1980 (the last case in the U.S. occurred in 1949, and the last global case was in Somalia in 1977). With this goal achieved, a long-standing concern for international public health authorities has been how to limit and manage the remaining stocks of the smallpox virus. With eradication achieved, should variola virus be retained in laboratories, in view of its characterization as a dual-use microbe – a source of legitimate research interest as a viral pathogen as well as a potential bioweapon? In 1983, by international agreement, a decision was made to retain variola virus stocks at two WHO Collaborating Center laboratories: the State Research Centre for Virology and Biotechnology in Koltsovo, Russia, and in the U.S. at the Centers for Disease Control and Prevention in Atlanta, Georgia. Speculation has continued, however, over whether unaccounted virus stocks exist in other places. The World Health Assembly (WHA), the decision-making conference of the WHO, supported the policy of setting limits on access to variola virus, and, by 1994, endorsed the eventual destruction of the remaining virus stocks. Over the years, WHO surveyed whether consensus research goals required continued maintenance of virus stocks. In 2011, the WHA reaffirmed the eventual destruction of the virus stocks, but deferred the setting of an actual date to the WHA conference in May of this year. Within WHO, the two advisory committees that considered the issue reached different conclusions. At this recent conference, it was decided that the virus stocks will continue to be maintained, because research goals dependent on access to the virus remain unfinished. These goals include the further development of antivirals (smallpox vaccines exist and are maintained in national and international stockpiles). Dissension among the WHO advisory committees contributed to the decision to delay the setting of a date for destruction of the stocks. Not surprisingly, a divergence of views on the merits of retaining variola virus stocks exists in the scientific community (support for maintaining virus stocks for future research versus calls for destroying the virus stocks) as well as among the WHO member states (with U.S. favoring retention while less-developed countries have favored destruction). A further wrinkle in the debate is the emergence of new technical capabilities (e.g., synthetic biology techniques) that could allow artificial reconstruction of the smallpox genome; such a possibility focuses policy concerns away from access to viral stocks and instead on access to genomic and technical information (actual publication). Of course, concerns about informational access have surfaced recently with research reporting the development of highly pathogenic H5N1 influenza viruses (see here and here). The still-unresolved smallpox (variola) virus retention issue illustrates how dual-use research concerns can originate from existing natural pathogens, as well as newly engineered or synthesized pathogens.