April 25, 2013

Avian Influenza A(H7N9): Full Genetic Sequence Publicly Available

The avian influenza A(H7N9) virus (official name) has emerged in China since February, and human cases of infection have increased steadily and spread to Taiwan. Of 112 cases reported, there are 22 deaths; China Daily updates; map of cases here. Just yesterday, the World Health Organization (WHO) issued this characterization: “This is an unusually dangerous virus for humans," said Keiji Fukuda, assistant director-general for health security of WHO. The true pathogenicity of the virus in humans is unclear; some reports state a mortality rate of 20% (deaths/cases); however, this is inexact because there may be mild disease that is not detected, and the actual lethality may be lower. The virus is avian in origin, a triple reassortant (mixture) of three avian viruses. Initial assessments are that humans are acquiring infection through contact with infected birds; the unanswered question is whether human-to-human transmission is occurring (a precursor to a true pandemic). H7N9 has been sequenced and genetic analysis reported by two groups, one from China and one an international collaboration, which noted: “These viruses possess several characteristic features of mammalian influenza viruses, which are likely to contribute to their ability to infect humans and raise concerns regarding their pandemic potential.” Since the outbreak originates from China, the level of transparency from this country is critical and so far, reports are positive. WHO has reported that it receives case notifications from Chinese public health officials, and that China has sent virus samples to all 5 international collaborating centers for influenza (which includes the U.S. Centers for Disease Control (CDC)).The virus genetic sequences (sequences of the coding regions of all eight viral genes) were deposited in the influenza sequence database maintained by the Global Initiative on Sharing All Influenza Data (GISAID). This is a global consortium that was started after the 2004-5 influenza A(H5N1) outbreaks, amid concerns that virus sequences were not being shared, due to concerns about asymmetry between virus sharing and access to antivirals and vaccines, particularly from developing countries (e.g., Indonesia withheld H5N1 viruses). Claims for patent rights surfaced in the H5N1 pandemic, including a patent application filed by the CDC (see here for my article on the set of patent rights relevant to influenza pandemics). Despite the fact that patent rights have been sought for H5N1 virus sequences and H1N1 virus sequences, the sensibility of GISAID is to encourage unrestricted access: 
Influenza viruses have not been subject to intellectual property rights historically. This tradition has been important because the required changes in influenza viruses contained in human influenza virus vaccines to match those viruses circulating currently in the field must occur at a speed far in excess of the legal process associated with the attainment of commercial protection. In order to allow rapid development of products such as vaccines and other interventions on an equitable basis by all countries and other interested parties, the convention has been for human health professionals to share virus specimens and data openly without creating barriers of exclusivity such as the filing of patents. 
Already, this public health crisis illustrates a strikingly different posture by China in contrast to its reaction to the emergence of SARS (Severe Acute Respiratory Syndrome) in 2003, most notably in transparency. During that period, China was not initially forthcoming with the details of the epidemic, and the absence of information impeded public health surveillance. When SARS appeared, the causative agent was not immediately known and it was finally identified as a novel coronavirus. In addition to the difficulties on obtaining actual epidemiological data during the crisis, the SARS crisis was also encumbered by the efforts of leading research groups to file patent applications on the SARS virus sequence. With respect to influenza viruses in general, progress in linking the sharing of virus genetic sequences to access to countermeasures (overcoming some of obstacles in the H5N1 pandemic) has occurred with the establishment in 2011 of the Pandemic Influenza Preparedness Framework Framework for the Sharing of Influenza Viruses and Access to Vaccines and Other Benefits (PIP) by WHO, which applies to influenza viruses with pandemic potential. PIP thus encourages the dissemination of virus samples and research results; it also provides for transparency in virus sequence tracing by contributing laboratories, and it embeds norms which discourage seeking intellectual property rights (but this is not legally binding). As PIP is recently enacted, it has yet to be tested in a declared pandemic, and it is not clear that the current H7N9 outbreaks will amplify into an official pandemic. 

One other aspect of H7N9 is notable at present: the virus genetic sequence has two mutations linked to increased human-to-human transmission which were identified in the H5N1 research papers that were subject to debate in late 2011 as possible sources of dual-use information (the debate centered on whether the data should be published). For background, see here and here. The question: what does the observation of these mutations mean for the viability (and scientific merit) of the earlier dual-use experiments? Has their utility been increased as a result of what is being learned about H7N9? 

April 16, 2013

Supreme Court Oral Argument on Gene Patents in AMP v. Myriad

Yesterday, the Supreme Court heard oral arguments in Association for Molecular Pathology v. Myriad Genetics, in which a coalition of patients, physicians and researchers challenged the validity of Myriad’s patents on the BRCA1 and BRCA2 genes (see here and here). The challenge is based on 35 U.S.C. 101 (patentable subject matter), and it asserts that isolated human genes are natural products which cannot be patented because U.S. patent law denies patents for products or laws of nature. That prohibition is grounded in the Court’s own jurisprudence, which distinguishes “between products of nature, whether living or not, and human-made inventions” (Diamond v. Chakrabarty, 1980). I attended the oral argument, having filed an amicus brief, and here is an initial overview. Counsel for the Petitioners, AMP et al., advanced the importance of the product of nature doctrine in disqualifying patents on genes, and responded to questions on multiple issues: how could DNA patenting could be distinguished from other kinds of drug patents, would a biotech company have an incentive to isolate genes if patents are not available, and whether cDNA, which Justice Kennedy labeled an “economy-class gene,” differed enough from a native gene to be patentable. In an ongoing attempt to frame gene patenting in a more familiar context, the Justices utilized several analogies to genes during the session, from an Amazon plant-derived drug, to a baseball bat excised from a tree, to the ingredients in chocolate chip cookies. The U.S. government, represented by the Solicitor General, emphasized that the product of nature doctrine was essential to maintain a boundary between freely available, unpatented scientific phenomena, and inventive efforts that can be patented, and argued that patents on genes violate that doctrine. He reiterated the government’s view that cDNAs, as “artificial DNA” were patent-eligible, while unmodified genomic DNA was not. The appearance from the executive branch highlights the split on the issue of gene patenting between the Justice Department and the Patent and Trademark Office (PTO), which has granted gene patents for several decades. 

Counsel for the Respondent, Myriad, confronted questions regarding how an isolated gene differs from a native gene, and a query from Justice Kagan that probed the limits of patent eligibility: “Do you think that the first person who isolated chromosomes could have gotten a patent on that?  Counsel conceded that “it would pass through the Section 101 gate.” Justice Breyer responded to that hypothetical: “Everything is inside something else. Plants, rocks, whatever you want. And so everything will involve your vast taking something out of some other thing where it is, if only the environment. And it's at that point that I look for some other test than just that it was found within some other thing.” Breyer indicated, therefore, that mere extraction alone could not provide a meaningful test for eligibility, and it produced an open-ended 35 U.S.C. 101 with no limits: “[W]e are reducing, then, 101 to anything under the sun, and -- and that, it seems to me, we've rejected more often than we've followed it.” Breyer could certainly been referring to Mayo v. Prometheus (2012), in which the Court invalidated a patent on methods of optimizing drug dosage (in an opinion that he authored). Although respondents raised the issue of industry reliance on gene patents, and urged deference to PTO guidelines that implement the policy of granting patents on genes, Justice Ginsburg noted the disapproval of the PTO's view within the executive branch (“even though the Government has disavowed it”) and she concluded that “the strength of the presumption" of deference would be diluted. Several recurring themes emerged. Questions regarding the eligibility of cDNA comprised a good part of the session, with several Justices seeking to answer how a decision that invalidated isolated genes, but upheld cDNAs would be received by the biotech industry. The focus on cDNA indicates that the Court is trying to define the scope of its decision, and it could indicate that the Court is not struggling over the central issue of the patent eligibility of the isolated gene. On another point, the Justices were concerned with whether and how patents for the methods attendant to the discovery of a new natural molecule (e.g., method of isolation, method of tagging, method of use) might provide enough incentives for investment even if a patent on the molecule could not be obtained. It did not appear that the Court was persuaded that enough differences exist between native genes and isolated genes to survive the prohibition on patenting products of nature. It did appear that the Court might be receptive to the respondents’ and the government’s argument that enough structural and functional differences between native genes and cDNA molecules exist to render the latter patentable, and a decision upholding only the cDNA patent claims might appeal to the Court. Importantly, such an outcome would still affirm the product of nature doctrine. However, if the Court can further clarify the legal analysis for that doctrine, it would be useful for biotechnology in general, as this case presents a rare opportunity for the Court to do so.

April 7, 2013

Alaska Continues Statewide Opposition to FDA Approval of Genetically Engineered Salmon

At state and federal levels, Alaska continues to display its opposition to the introduction of a genetically engineered (GE) food product - specifically, to the potential entry of GE salmon into the U.S. marketplace (see here). To date, the product, AquAdvantage salmon, made by AquaBounty Technologies (ABT) has not received market approval from the FDA. 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. According to ABT, the addition of the growth hormone gene “provides the fish with the potential to grow to market size in half the time of conventional salmon.” At the end of 2012, pursuant to the National Environmental Policy Act (NEPA), the FDA released a draft Environmental Assessment (EA) in support of its Finding of No Significant Impact (FONSI) for AquAdvantage salmon. The FONSI determination, if prevailing, means that the FDA will not be required to prepare the more rigorous environmental impact statement (EIS) for GE salmon; this determination has been criticized by consumer advocates. The FDA has extended the period for public comments on the draft EA until April 26, 2013. Both state and federal legislators from Alaska have been active in opposing the introduction of the fish, voicing concerns about potential mating between the GE salmon and the native Alaska salmon, with the potential for irreversible genetic contamination of the wild-type stock. According to ABT, the selected fish would be female and sterile and could not breed with the wild salmon. But assuming less than 100% ability to properly screen and control the stocks, even a minute number of GE fish that could breed into the wild population could initiate the genetic contamination of the wild-type stock. The Alaska legislature has now passed a bipartisan resolution opposing the introduction of the GE salmon
Opposing the United States Food and Drug Administration's preliminary finding relating to genetically engineered salmon; urging further examination of genetically engineered salmon; opposing AquaBounty's petition to produce genetically engineered salmon; and proposing, if AquaBounty's petition is approved, that its product should be labeled as "genetically modified.” 
The regulatory paradigm for the review of the ABT salmon is that the added gene is reviewed as a veterinary drug: "the rDNA construct in the resulting GE animal is thus a regulated article that meets the drug definition" - hence the oversight by the FDA's Center for Veterinary Medicine (CVM). In 2010, an earlier CVM report stated that there were no significant safety or environmental issues raised by the ABT salmon. A food additive petition was filed at the FDA by food safety advocates in 2012, requesting that the addition of the growth hormone gene to the fish trigger a food additive review, bringing the GE salmon under the purview of a more conventional food safety review process. In addition, current FDA policy will not require the GE salmon to be labeled (nor any other GE food). Several supermarket chains have announced that they will not carry the GE salmon product. Just last month, Sen. Mark Begich (D-AK) succeeded in introducing an amendment to the continuing resolution passed in March (temporary budget agreement) that would establish a reserve fund for the labeling of GE fish. Begich also introduced two bills in the Senate; a prohibition on approval of GE salmon (the bill cites “escapement”) and, if GE salmon is approved, a requirement for food labeling (that would a first at the federal level). Regarding the strength of the opposition in Alaska, there is no comparable statewide cohesion to date targeting a specific GE food product. More generally, future litigation is likely to challenge both the FDA’s regulatory paradigm for GE salmon as well as the merits of the FONSI determination for the food product by the agency.

April 1, 2013

India's Supreme Court Validates Anti-Evergreening Patent Law in Denying Novartis Gleevec Patent

The Supreme Court of India issued a landmark patent ruling today regarding the patentability of a form of the Novartis biotechnology drug, Gleevec (Imatinib, a monoclonal antibody), used to treat leukemias. India is home to a significant generic drug industry that has supplied low-cost drugs worldwide. Prior to 2005, India's patent law did not allow patents on drug products (only on processes to produce them) and as a result, its generic industry was not constrained by any existing product patents in the country, and India became a generic powerhouse. As a result of India’s signing on to the TRIPS treaty in 1994 (Trade-Related Aspects of Intellectual Property, intended to achieve international patent harmonization), India was required to bring its patent law into compliance with respect to TRIPS patentable subject matter requirements (what can be patented). So as of 2005, pharmaceutical product patents became available. However, in drafting the new patent law extending protection to drug products, India, mindful of its position as a leading supplier of drugs around the world, decided to confront the potential for patent owners to conduct an “evergreening” of patent rights. Evergreening is a strategy whereby companies holding patents on brand name drugs, faced with the expiration of patent rights, apply for patents on new formulations of the active ingredient or on minor chemical variations in an effort to extend patent protection and frustrate generic competitors. The net effect can be to allow a company to obtain new patent rights on essentially the same drug, and to delay generic entry. In the 2005 redrafting of India's Patents Act, an anti-evergreening Section 3(d) was added:
The mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant. Explanation: For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy. 
The plaintiffs (India’s Cancer Patients Aid Association, among others) argued that Novartis's application for a patent on a beta crystalline form of Gleevec could not meet the laws’s requirement that new form of a known substance (here, Gleevec) must be shown to have increased efficacy (therapeutic effectiveness). In a lengthy consideration of the various chemical properties that were changed in the beta form (such as bioavailability), the court nonetheless concluded that these properties had not been shown by Novartis to result in the increased efficacy ("the beta crystalline form of Imatinib Mesylate certainly cannot be said to possess enhanced efficacy over Imatinib Mesylate"). The pharmaceutical patent was denied for lack of invention (not new), inventive step (non-obvious), and failure to meet the specific standard set by Section 3(d) for a new form of a known substance. As a result, no patent can issue. The impact of this ruling will be to curtail attempts to evergreen patents on brand name pharmaceuticals in India as a means of blocking generic competition (e.g, India's Cipla and Natro can sell generic Glivec at about one-tenth the cost of the brand name Gleevec in India.)  Because India is a leading international supplier of low-cost pharmaceuticals, the decision is likely to confine holders of brand name patents in India to exploitation of the initial term of patent, without the likelihood that extensions can be easily procured. The generics can enter the market more quickly. Although U.S. patent law does not have a specific "anti-evergreening" standard for drug patents, existing legal standards do prevent the patenting of obvious variations of known subject matter (35 U.S.C. Section 103) as well as a prohibition against double patenting when a successive and obvious patent application originates from the same inventive entity holding patent rights to dominant subject matter, a concept that is often applied in the context of drug patent litigation.