A declaration of intent to conduct “gain-of function” experiments on the novel avian influenza A(H7N9) virus has been published by scientists who wish to alter the genetic composition of the viruses to determine what genetic changes/mutations correlate with altered function. Gain of function (GOF) experiments on pathogens alter existing properties and can result in the creation of more dangerous pathogens; the goal is to gain insights into the relationship between genetics (structure) and function. The H7N9 virus emerged earlier this year in China, and to date the World Health Organization reports 135 human cases, with 44 fatalities. This new effort to study H7N9 is proposed by a consortium of scientists, including Ron Fouchier and Yoshihiro Kawaoka, who were the principal investigators for the experiments on HPAI H5N1 viruses that produced viruses with potentially increased human to human transmissibility. Those earlier experiments raised such an alarm that publication of the research was halted in the U.S. while the NSABB federal advisory committee evaluated the risk of publication (both were eventually published). The proposed experiments fall into the category of DURC (dual research of concern), defined as such:
Dual use research of concern(DURC) is a subset of dual use research defined as life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security.
The declaration of intent by the scientists is presumably an attempt to increase transparency and invite deliberation at the front end of the process and avoid the panicked reaction that followed the announcements of the earlier H5N1 experiments in 2011. The authors also include materials outlining the biosafety precautions that would accompany the experiments. Early official reaction from the CDC and NIH declares that such experiments will receive extra scrutiny before U.S. government funding will be made available, according to recently issued federal guidelines for DURC issued earlier this year. The CDC has also issued specific biosafety guidelines for working with the H7N9 virus. The following kinds of gain-of-function experiments were announced in the letter:
•Immunogenicity. To develop more effective vaccines and determine whether genetic changes that confer altered virulence, host range or transmissibility also change antigenicity.
•Adaptation. To assist with risk assessment of the pandemic potential of field strains and evaluate the potential of A(H7N9) viruses to become better adapted to mammals, including determining the ability of these viruses to reassort with other circulating influenza strains.
•Drug resistance. To assess the potential for drug resistance to emerge in circulating viruses, evaluate the genetic stability of mutations conferring drug resistance, and evaluate the efficacy of combination therapy with antiviral therapeutics. Also, to determine whether A(H7N9) viruses could become resistant to available antiviral drugs, and to identify potential resistance mutations that should be monitored during antiviral treatment.
•Transmission. To assess the pandemic potential of circulating strains and perform transmission studies to identify mutations and gene combinations that confer enhanced transmissibility in mammalian models (such as ferrets and guinea pigs).
•Pathogenicity. To aid risk assessment and identify mechanisms, including reassortment and changes to the haemagglutinin cleavage site, that would enable circulating A(H7N9) viruses to become more pathogenic.
These proposed experiments – altering the critical variables of spread and virulence for the viruses, changing drug resistance and vaccine susceptibility – will likely produce viruses that are potentially more dangerous than those we currently know about. The stated goal of such work is to learn which mutations alter the risk profile of a virus – confer pandemic potential – and use that knowledge to design vaccines or discover antivirals that can respond to these viruses. Further, it is argued that ongoing surveillance efforts can be focused on identifying virus isolates that display such mutations and pose an elevated public health risk, although this point is contested by other scientists. It’s not clear whether the NSABB will be involved at this early stage – to date, it has not advised on the merits of funding specific experiments which can be characterized as DURC. The recent tightening of federal review of such research will be put to the test with these proposed experiments as the investigators seek U.S. funds. With respect to the publication of results, the influenza researchers anticipate the possible fallout:
To advance A(H7N9) virus research, findings should be shared in refereed publications. Investigators agree to adhere to guidelines for responsible communication of results and every effort will be made to put the results in context and reduce sensationalism.
The questions that were raised by the H5N1 influenza controversy - what criteria are to be used when evaluating the funding for DURC or what conditions need to attach to such funding – will now surface with this H7N9 research declaration – and their resolution might establish a template for future research proposals.
Several developments have followed last month's Supreme Court decision that invalidated Myriad Genetics patent claims to isolated genes; (AMP v. Myriad opinion). Within hours of the Court’s decision, several competitors announced plans to offer BRCA1 and BRCA2 genetic tests. Myriad has recently filed patent infringement suits against Ambry Genetics (California) and Gene by Gene (Texas), based on the assertion of patent claims from ten patents it holds to BRCA1 and BRCA2 related genetic materials and methods (including some with contested claims in the Supreme Court). The complaint against Ambry is here; the complaint against Gene by Gene complaint is here. The suits, filed in Utah federal court, could be an opening play to fully litigate these other patents or a maneuver to create licensing structures for these patented materials and methods. A strategy by Myriad to obtain a preliminary injunction against these companies would have to contend with the more rigorous scrutiny for such requests after eBay v. MercExchange (2006), where the Supreme Court reaffirmed the need to consider "public interest" in the award of injunctions, and the current climate might lend support for such an argument against any injunction. Ambry has indicated that it will “vigorously defend” its right to offer testing services.The Court’s invalidation of some of Myriad’s patent portfolio related to BRCA1/2 testing has clearly led to altered expectations regarding the state of the genetic testing marketplace. Evidence of this is the response from Senator Patrick Leahy, Chair of the Senate Judiciary Committee, to Myriad’s lawsuit, calling for the National Institutes of Health (NIH) to exercise “march-in” rights that it holds pursuant to the Bayh-Dole Act of 1980. That option applies to patents for which NIH provided federal funding (or other federal agencies). Apart from the march-in authority, the U.S. government retains a default mechanism, a compulsory license that allows it to use any patented invention (or authorize 3rd parties to do so) under the statutory authority of 28 U.S.C. 1498, which requires “reasonable and entire compensation for such use and manufacture.” Since the march-in authority has never been exercised by the NIH (see here), it is unlikely to respond to Leahy’s call. Nor is it likely that the government would regard the BRCA1/2 genetic testing controversies as critical enough to trigger the compulsory license mechanism. These disputes are likely to be settled more informally, and more quickly, as the high visibility of these tests will retain public attention and maintain pressure on Myriad to support the expansion of genetic testing options.
Connecticut and Maine have become the first states to pass laws mandating the labeling of foods with genetically engineered (GE) ingredients (Maine law; Connecticut law). The laws, however, are conditional in that they will not take effect until a critical mass of similar laws is enacted by other states; thus, they remain pending in actual effect. The battles over the labeling of GE food have continued for years, with efforts at state and national levels (see here and here). Maine will mandate the phrase “Produced with Genetic Engineering" and the Maine law contains this synopsis:
This bill requires disclosure of genetic engineering at the point of retail sale of food and seed stock and provides that food or seed stock for which the disclosure is not made is considered to be misbranded and subject to the sanctions for misbranding. The bill provides that food or seed stock may not be labeled as natural if it has been genetically engineered. The bill exempts products produced without knowledge that the products, or items used in their production, were genetically engineered; animal products derived from an animal that was not genetically engineered but was fed genetically engineered food; and products with only a minimum content produced by genetic engineering. The bill also provides that the disclosure requirements do not apply to restaurants, alcoholic beverages or medical food.
The Maine law embeds the following trigger: it “goes into effect when five other states, or any state, or states with a total population of 20 million people, enact labeling requirements for genetically modified (GM) foods.” The Connecticut law dictates labeling “in the case of such food for retail sale contained in a package, with the clear and conspicuous words: "Produced with Genetic Engineering." Here is a similar trigger in Connecticut, activating the law in a year where the following conditions occur:
(1) Four states, not including this state, enact a mandatory labeling law for genetically-engineered foods that is consistent with the provisions of this subsection, provided one such state borders Connecticut; and (2) the aggregate population of such states located in the northeast region of the United States that have enacted a mandatory labeling law for genetically-engineered foods that is consistent with this subsection exceed twenty million based on 2010 census figures.
The northeast region defined in the Connecticut law consists of Maine, Vermont, New Hampshire, Massachusetts, Rhode Island, New York, New Jersey and Pennsylvania. It could be argued that the approach of Maine and Connecticut to a GE food labeling law – not with immediate effect, but conditional on other political developments – can recruit support from hesitant politicians because it remains aspirational. That might encourage other states to follow suit. At the federal level, the Genetically Engineered Food Right-to-Know Act, has been introduced to mandate a federal scheme for GE food labeling; such bills have been introduced for years in Congress. Prospects for federal legislation, however, remain dim.
The Supreme Court has issued its decision in Federal Trade Commission (FTC) v. Actavis, a case that presents the issue of pay for delay settlements between brand name and generic drug companies - a legal dispute at the intersection of patent, antitrust and food and drug law. Essentially, this case scrutinized a particular form of settlement practice in a patent infringement suit between a brand name drug patent holder and a generic competitor – facilitated by the intricate mechanics of the 1984 Hatch-Waxman Act, which rewired the drug approval process for generic drugs and accelerated the entry of generic drugs into the marketplace. When a generic company prepares for market entry, it may undertake actions which trigger an infringement lawsuit (most commonly in the statute's Paragraph IV certification in which the generic asserts that the brand name patent is either not infringed or is invalid) from the brand name company. In these suits, although a brand name company sues a generic competitor for patent infringement, the litigation flips and the plaintiff (brand name) might decide to pay the defendant (generic) to drop the suit and delay its entry into the market – hence, the "pay for delay" or “reverse payment” settlement. As a result, generic entry is delayed by the deal made with the brand name; in addition, potentially invalid patents are not challenged or litigated for validity. As Justice Breyer explained:
The payment in effect amounts to a purchase by the patentee of the exclusive right to sell its product, a right it already claims but would lose if the patent litigation were to continue and the patent were held invalid or not infringed by the generic product.
These reverse payment settlements have been controversial – so much so that the FTC tracks these settlements, under Congressional mandate (40 reported in 2012). Are these settlements anticompetitive, potentially violating the antitrust laws? The FTC thought so and challenged one of these in FTC v. Actavis (as violating Section 5a of the Federal Trade Commission Act), which made its way to the 11th Circuit – there, the appellate court said that the FTC could not challenge the settlement on antitrust grounds, because the patent holder was not exceeding the effective rights granted by the patent – that is, to exclude competitors. This standard was known as the “scope of the patent” analytic framework – and it’s clearly deferential to reverse payments. Other courts disagreed, notably the 3rd Circuit in the In Re: K-Dur Antitrust Litigation in 2012, which characterized these settlements as presumptively illegal ("prima facie evidence of an unreasonable restraint of trade"). A classic Circuit split developed over the the antitrust analysis applicable to these settlements. The question presented:
Whether reverse-payment agreements are per se lawful unless the underlying patent litigation was a sham or the patent was obtained by fraud (as the court below held), or instead are presumptively anticompetitive and unlawful (as the Third Circuit has held).
The FTC urged the Court to adopt a presumptive illegality standard (relying on Section 1 of the Sherman Act) – but the Court has now rejected that in favor of the “rule of reason” analysis under antitrust law – essentially, a contextual inquiry that will study the market, product, parties, etc., to analyze the anticompetitive effects of a particular settlement. This is more of a victory than a loss for the FTC and consumers – because the Court has said that reverse payment settlements are not immune to antitrust scrutiny and any distinct allegations of anticompetitive effect must be considered – albeit against the background of a patent-generated dispute. The FTC reacted accordingly:
The Supreme Court’s decision is a significant victory for American consumers, American taxpayers, and free markets. The Court has made it clear that pay-for-delay agreements between brand and generic drug companies are subject to antitrust scrutiny, and it has rejected the attempt by branded and generic companies to effectively immunize these agreements from the antitrust laws. With this finding, the Court has taken a big step toward addressing a problem that has cost Americans $3.5 billion a year in higher drug prices.
The lower courts will have to sort out how to assess an antitrust claim apart from a fully litigated patent infringement suit – and Justice Breyer did not provide much of roadmap to do so (now an antitrust analysis must be performed that need not be dependent on litigating the merits of the underlying patent lawsuit, which may be difficult):
We therefore leave to the lower courts the structuring of the present rule-of-reason antitrust litigation.
Because reverse payment deals delay the entry of generics, it’s been argued that they contravene the spirit of Hatch-Waxman – and now, the Court has authorized the validity of an antitrust inquiry into these settlements. More litigation will follow, and it’s likely that some of these deals will be deemed anticompetitive – and illegal. The result will likely be that brand names will lose a handy mechanism to buy off generic competition. Because generic competition lower drugs prices significantly, consumers are likely to encounter more competitive drug pricing. The Court’s decision may also mean that the appetite for these deals is decreased, as brand name companies consider whether to risk an antitrust challenge to any of these settlements. Alternatively, the deals offered to the generics may not be as lucrative, to avoid triggering the antitrust scrutiny that the Court will now allow.
Within a day of the Supreme Court’s decision in AMP v. Myriad, invalidating patent claims to isolated genes (see here), the genetic testing environment for the BRCA1 and BRCA2 genes has shifted noticeably. Before elaborating on that, it’s worth noting some of the characterizations of the decision from the mainstream press, which reveals public perception of the issues and/or significance of the case. Soon after the opinion was released, the Drudge Report shouted “You Can Keep Your Genes” – a type of headline that appeared in other forms around the country – a mistaken impression that patent rights in human genes translated to any ownership of anyone’s person or bodily materials. But in the sense that the “in vitro” BRCA1 and BRCA2 genes could not be used without permission of the patent holder, the headline had some accuracy. Other news accounts noted the bifurcated nature of the decision, invalidating patents on isolated genes, while upholding patent claims to semi-synthetic cDNA molecules, creating a mixed picture for biotech companies, depending on business models (e.g., genetic testing for single genes or producing recombinant proteins?).
Several companies have announced their intention to offer BRCA1 and BRCA2 testing: in the day since the ruling, DNA Traits has already posted “Proud to Bring BRCA1 and BRCA2 Testing to You” on their website; other go-aheads include Quest Diagnostics, Ambry Genetics and GeneDx, which announced “its intention to launch a suite of comprehensive genetic tests for inherited cancers including BRCA1 and BRCA2 genes, given the Supreme Court's ruling in the Association for Molecular Pathology vs. Myriad Genetics case.” Academic researchers are also gearing up, notably Dr. Mary-Claire King of the University of Washington (see here) and Dr. Wayne Grody of UCLA, who noted that his laboratory would also offer tests on other genetic diseases covered by gene patents, such congenital hearing loss, spinocerebellar ataxia and various muscular dystrophies. Reaction from professional organizations that had participated in the case was enthusiastic. From the Association for Molecular Pathology (AMP), lead plaintiff:
AMP is very pleased with the Supreme Court’s decision in the case. The Court’s decision that human genes are not patentable is a great step forward for the field of molecular pathology, for genomic science, and most important for our patients. We look forward to exciting future advancements in diagnostic testing and therapeutics that will accrue to the benefit of our patients and our field.
The American Medical Association (AMA), which filed an amicus brief) reacted:
The AMA is pleased that the justices saw through the flawed premise that resulted in Myriad’s exclusive patent awards and affirmed that human genes are products of nature and not patent eligible. Removing the patents on the building blocks of life ensures that scientific discovery and medical care based on insights into human DNA will remain freely accessible and widely disseminated, not hidden behind a vast thicket of exclusive rights.
The
College of American Pathologists (CAP) noted the significance for advances in genetic testing:
Genomic medicine has the
potential to be a cornerstone of medical testing, treatment, and
clinical integration, but the question of ‘who owns your genes’ needed a
definitive answer. Now we have it.
International reaction includes efforts to push for the amendment of the Patent Act in Australia to prohibit gene patents, following a February court decision in that country that had upheld Myriad patent claims against a patentable subject matter-type challenge from Cancer Voices Australia. Testing access is not the only issue at stake in the gene patent controversy. Myriad Genetics, in establishing itself as the central provider and repository for U.S. genetic testing for the BRCA1 and BRCA2 genes, did not maintain a reliable, accessible database of all the mutations in these genes that it had collected over the years. The Sharing Clinical Reports Project, a public effort to get patients and physicians to report genetic mutations to a public database, was announced in April, 2013. The loss for Myriad of its gene patent claims will certainly accelerate the efforts to establish a credible, dynamic BRCA1 and BRCA2 database which is critical for identifying the sites of genetic mutations, their frequency, and the associations between mutations and diagnosis or prognosis. It’s fair to say, at this point, that the BRCA1 and BRCA2 field is now supercharged as a result of yesterday’s decision, and will rapidly correct for the lag and underdevelopment that it has experienced in the nearly 20 years since the first Myriad patents issued.
