It may not be widely known that the federal government retains a specific legal authority to expand the use of a patented invention that was developed using federal research grants, under a federal statute that was enacted in 1980 to remedy the underutilization of American inventive efforts. The Bayh-Dole Act accelerated the transfer of federally funded research into practical real world use; toward that end, the law allows federal grantees (such as universities) to pursue patent rights for any inventions developed in the course of the federally funded work. In addition, a little-known provision in the Bayh-Dole Act gave authority to any federal agency that funds research, such as the National Institutes of Health (NIH) (the major source of federal biomedical funding), to order a “march-in” of patent rights (35 U.S.C. 203) where the funding agency determines such action is necessary to achieve the goals of the statute. This authority is held by any federal granting agency/department (e.g., NASA, DOE, DOD). Effectively, then, NIH (or others) can compel a patent owner to allow third parties to make and use the patented invention. The patent owner is to be reasonably compensated for the use. According to the statute, march-in authority is justified when "action is necessary to alleviate health or safety needs which are not reasonably satisfied by the contractor, assignee, or their licensees" or "action is necessary to meet requirements for public use." To date, the NIH has refused to exercise this authority; five requests have been submitted since 1980. Most recently, in 2012, NIH was asked by Knowledge Ecology International (KEI) to use march-in rights for the AIDS drug Norvir due to excessive price raises (Abbott Pharmaceuticals held the patents); a previous KEI petition on Norvir had been filed in 2004. The NIH declined both requests (see earlier post). In its 2012 rejection, the NIH rejected the contention that price disparities between the price of drugs in the U.S. drugs compared to other high-income justified a march-in maneuver:
The NIH continues to agree with the public testimony in 2004 that the extraordinary remedy of march-in is not an appropriate means of controlling prices of drugs broadly available to physicians and patients.
In 2010, the NIH also declined to implement a march-in when a KEI petition was filed to remedy the manufacturing shortage of Fabryzyme by Genzyme, Inc. Now, KEI has filed a march-in petition with NIH over the high pricing of the prostate cancer drug Xtandi (patents granted to the University of California; now assigned to Astellas Pharma):
This letter is a request that the U.S. federal government use its rights in patents for the prostate cancer drug (enzalutamide), marketed under the brand name of Xtandi by Japan-based Astellas Pharma. This is a product that has an average wholesale price (AWP) of $129,269 per year, and which is far more expensive in the United States than in other countries. Specifically, we ask the Department of Health and Human Services (DHHS), National Institutes of Health (NIH), and/or the Department of Defense (DoD) to use its royalty free rights in the relevant patents, or to grant this request for march in rights. The relevant patents include, but are not limited to, the three patents listed in the FDA Orange Book for Xtandi (7,709,517, 8,183,274, and 9,126,941), all of which were granted to the Regents of the University of California, a public institution. All three inventions were made with the support of the United States government under National Institutes of Health SP ORE grant number 5P50CA092131 and Department of Defense (Army) grant number W81XWH0410129.
What can be expected with this most recent march-in petition to the NIH? In an environment where drug pricing is high on the radar screen for patients and for physicians (see earlier post on "financial toxicity"), and where the U.S. generally does not subscribe to price controls in health care, the high cost of drugs – especially new, targeted drugs – is causing politicians and bureaucrats to pay more attention. In January, prior to the filing of the new KEI petition, 50 members of Congress wrote a letter to NIH, asking that the agency set true guidelines for when the exercise of march-in rights would be reasonable. Then, in a hearing in the House Ways and Means Committee last week, Department of Health and Human Services (HHS) Secretary Burwell stated that HHS would consider the request for march-in guidance from the legislators. In the current campaign season, efforts to control drug prices are already part of political platforms and discourse (see here, for example). But with respect to the dormant march-in authority granted to the federal government, it may be that HHS and/or NIH are more willing to consider all measures and now actually welcome the existence of a statutory authority long ignored. At the least, NIH could begin to clarify how the march-in provisions are to be interpreted. However, that is not to say that march-in rights are a wholesale solution to drug pricing (see here for one study on the limits of such authority). For example, the ability of the federal government to negotiate drug prices for Medicare is often proposed as a leavening force; Congress has explicitly banned that option but it could be rescinded (or possibly by executive order?). Because some of the new “precision medicine” drugs are the most expensive (especially cancer drugs), the disconnect between the promise of genetically-informed medical care and actual access to biotech drugs is growing. That asymmetry will only add to the pressure on both legislative and executive branches to incorporate drug pricing realities into the overarching project of health care access as exemplified by the Affordable Care Act (Obamacare).
In 2016, the National Science Advisory Board for Biosecurity (NSABB) has returned to reconsider the issues regarding the approval, funding and oversight of experiments on pathogens that are engineered to contain mutations conferring elevated transmissibility in mammals and/or enhanced pathogenicity (virulence). This line of research has been called gain-of-function research (GOF). Such pathogens are studied to determine which genetic changes in a virus or bacterium confer attributes which create a more dangerous pathogen. Knowledge that a specific genetic mutation could confer a higher risk profile could theoretically allow more precise and knowledgeable public health surveillance of naturally occurring mutations. In addition, therapeutic countermeasures could be developed in advance of an actual strain appearing in the population. Nonetheless, these experiments could produce what have been called potentially pandemic pathogens (PPP) and are therefore controversial because of the possible release of a dangerous microbe, either by accident (biosafety) or design (biosecurity). The NSABB is charged with advising the federal government on bioterrorism-related scientific matters, the panel being created post-9/11. In the wake of controversial experiments published in 2011 and 2012 describing the creation of GOF H5N1 influenza viruses with enhanced transmissibility in humans, the NSABB has been working on formalizing a risk-benefit framework for determining whether certain experiments should be restricted or their funding limited. In 2014, a federal moratorium on the funding of GOF studies was imposed following a series of biosafety incidents at federal laboratories (some GOF studies have been allowed to resume, involving Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza). The NSABB is now conducting public meetings as the next stage in the deliberative process it outlined in 2015. The NSABB commissioned a formal risk and benefit assessment (RBA) from an outside contractor to provide the board with qualitative and quantitative information about the risks and benefits of conducting certain scientific studies. The NSABB also commissioned a formal study of the ethical frameworks that could be relevant to the formulation of official policy. In addition, a working group of the NSABB has published their review of the current issues. Their findings are as follows:
Key Finding 1: There are many types of GOF studies and not all of them have the same level of risks. Only a small subset of GOF studies - GOF studies of concern - entail risks that are potentially significant enough to warrant additional oversight.
Last month, the NSABB held an public committee meeting to review all of these recently commissioned reports, with the purpose of making progress in developing a formal roadmap for the federal government to use in deciding whether and/or how to support GOF experiments. The NSABB also invited public comments on the studies cited above. Criticism from other scientists include critiques of the GOF definition itself, objections to the comparatives used in the RBA assessment (e.g., 1918 pandemic influenza virus), a call for more clinician involvement in the process, as well as general objections to a lack of avenues for more public participation in the debate. As this deliberative process plays out over the next several months, the fate of the government-imposed moratorium will also be a consequence of the NSABB conclusions. The deliberative process continues: the second public National Academies of Sciences Symposium on GOF research will be held on March 10 & 11, 2016 and will include a discussion of the RBA study as well as NSABB’s preliminary findings and draft recommendations (the first symposium was held in 2014, see here). There will be an opportunity for the public to participate in the event as well as to submit questions online.
Key Finding 2. The U.S. government has effective policy frameworks in place for managing risks associated with life sciences research. There are several points throughout the research life cycle where, if the policies are implemented effectively, risks can be managed and oversight of GOF studies could be applied.
Key Finding 3. Oversight policies vary in scope and applicability, therefore, current oversight is not sufficient for all GOF studies that raise concern.
Key Finding 4. There are life sciences research studies that should not be conducted on ethical or public health grounds if the potential risks associated with the study are not justified by the potential benefits. Decisions about whether GOF studies of concern should be permitted will entail an assessment of the potential risks and anticipated benefits associated with the individual experiment in question. The scientific merit of a study is a central consideration during the review of proposed studies but other considerations and values are also important.
Key Finding 5. The biosafety and biosecurity issues associated with GOF studies are similar to those issues associated with all high containment research, but a small subset of GOF studies have the potential to generate strains with high and potentially unknown risks (emphasis added). Managing risks associated with all high containment research requires Federal-level oversight, institutional awareness and compliance, and a commitment by all stakeholders to safety and security. Biosafety and biosecurity are international issues requiring global engagement.
The powerful gene editing technology, CRISPR/Cas9, is now the subject of debate over its uses and applications (see here), and whether any limits should be set on possible applications in reproductive medicine (see here). However, a wholly separate controversy has been circulating in the field, involving a messy patent dispute between two of the main players in the development of the technology. A patent application on the technology was filed by Jennifer Doudna and her colleagues (Doudna) (assigned to UC Berkeley). In the same time frame, CRISPR-related patent applications were also filed by Feng Zhang and his colleagues (Zhang) (assigned to MIT and its Broad Institute). Doudna filed in May, 2012, while Zhang filed in December, 2012. Doudna's application is still pending, while Zhang has a number of issued patents to date (e.g., U.S. Patent No. 8,607,359); Zhang requested an accelerated patent examination and thus received the earliest issued patents. U.S. patent law underwent a significant change in 2013 when the America Invents Act (AIA) came into force, establishing a first-inventor-to-file standard in the law. Until then, the U.S. required that a patent be awarded to the first inventor (in time); that individual might or might not be the first to file a patent application on the invention. U.S. patent law has had a mechanism for identifying the first inventor where two separate applicants file for a patent on overlapping subject matter, known as an interference proceeding. The U.S. Patent and Trademark Office (PTO) has issued a Declaration of interference between Doudna and Zhang, based on the sequence of the Doudna/Zhang patent filings, which both claim overlapping subject matter (since both were filed before the AIA took effect, the conflict will be settled under the old first-to-invent standard). The Administrative Patent Judge has issued a "count," which is a fictional claim that encompasses the conflicting subject matter:
A method, in a eukaryotic cell, of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded thereon, the method comprising:
Although this is an oversimplification, a key dispute centers on whether Doudna is only entitled to patent rights on an in vitro CRISPR/Cas9 component system, while Zhang is entitled to patent rights on the use of CRISPR in eukaryotic cells (the most valuable application of the technology). In an interference, the first filer (Doudna) is deemed the senior party, while the second filer (Zhang) is the junior party, and thus has the burden of proof to establish an earlier date of invention. Invention requires conception of the inventive idea, as well as either actual or constructive reduction to practice (meaning actual work on the invention or the actual filing of a patent application). A judge from the PTO’s Patent Trial and Appeal Board (PTAB) will conduct the proceeding. The interference could be expected to take several years, at least. The parties could settle along the way, with priority conceded and possible licensing options established. Since U.S. patent interferences are phasing out of American law due to the changes instituted by the AIA, it is no small irony that one of the most high-profile interferences will occur 3 years after the statute took effect. In addition, the patent rights to one of the most important advances in biotechnology will be sorted out according to the now-discarded first inventor paradigm of U.S. patent law. The patent rights at stake are immensely valuable, and even with an uncertain IP landscape, gene editing startups are proliferating as well as investments from established pharmaeutical companies in gene editing ventures.
contacting, in a eukaryotic cell, a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly lnterspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) system comprising:
a) a DNA-targeting RNA comprising
i) a targeter-RNA or guide sequence that hybridizes with the target sequence, and
ii) an activator-RNA or tracr sequence that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment, and
b) a Cas9 protein,
wherein the DNA-targeting RNA forms a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said target DNA molecule is cleaved or edited or transcription of at least one gene encoded by the target DNA molecule is modulated.
The rapid adoption of the CRISPR/Cas9 gene editing technology is evident in the explosion of papers describing the use of the technique for possible use in a variety of applications (e.g., retinitis pigmentosa, Duchenne's muscular dystrophy, HIV infection). As described in earlier posts here, the use of gene editing falls into two broad categories: altering genes in somatic cells (non-reproductive) to treat disease in individuals or altering the germline DNA in embryos to preemptively treat or minimize later-developing disease. It is the latter application that has led to many calls for an official moratorium, a ban on funding, and the convening of a wide public discussion on whether scientists should be able to edit germline DNA, which would create heritable genetic changes passed on to later generations. As reported here earlier, a development biologist in the U.K. applied to the Human Fertilisation and Embryology Authority (HFEA) for permission to use gene editing to study early embryonic development. That application has now been approved:
Our Licence Committee has approved an application from Dr Kathy Niakan of the Francis Crick Institute to renew her laboratory’s research licence to include gene editing of embryos. The committee has added a condition to the licence that no research using gene editing may take place until the research has received research ethics approval. As with all embryos used in research, it is illegal to transfer them to a woman for treatment.
The goal of Dr. Nakian's research is described:
To provide further fundamental insights into early human development we are proposing to test the function of genes using gene editing and transfection approaches that are currently permitted under the HFE Act 2008. We also propose to use new methods based on CRIPSR/Cas9, which allows very specific alterations to be made to the genome. By applying more precise and efficient methods in our research we hope to require fewer embryos and be more successful than the other methods currently used. Importantly, in line with HFEA regulations, any donated embryos would be used for research purposes only. These embryos would be donated by informed consent and surplus to IVF treatment.
The HFEA approval in the U.K. is without precedent and represents the first officially sanctioned use of gene editing on germline DNA. The 2015 publication of a gene editing experiments on non-viable embryos by Chinese scientists was widely condemned and it accelerated the urgency of considering ethical and regulatory aspects of this research as soon as possible. As described here earlier, a recent National Academy of Sciences (NAS) international summit on gene editing technologies had concluded with a consensus statement that it would be "irresponsible" to use gene editing for the purpose of altering germline DNA in the creation of embryos for reproduction. This research does not do that, explicitly. It will use gene editing to study how genetic changes affect embryonic development as its end goal. With regard to the U.S., there is already an NIH-imposed ban on any federal funding for gene editing on human embryos; in addition, the U.S. has no regulatory equivalent of the U.K. HFEA to consider any possible requests for the approval of non-reproductive embryonic developmental studies like the one approved here. The ongoing NAS study committee will convene another public meeting next week (February 11) to consider more impacts of gene editing technologies; details here.