The Federal Circuit denied a petition for an en banc rehearing of Ariosa v. Sequenom (Fed. Cir 2015). This case tests the patent eligibility of a method to detect fetal DNA in maternal blood in order to perform prenatal testing. This case is set against a lingering unrest over the recent Supreme Court decision in Mayo v. Prometheus (2012), invalidating a method of drug dosaging as the improper patenting of a natural phenomenon. Claim 1 of the Sequenom patent is as follows:
A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.
The denial was accompanied by two concurring opinions (Judges Lourie and Moore, Judge Dyk) and one dissent (Judge Newman). The concurrences both thought that Ariosa was wrongly decided as a policy matter, but that their court was bound by the Mayo decision. In Mayo, a 2-part test which required the identification of any "patent-ineligible concept" and if found, a patent claim would then need an "inventive concept" to make the claim patentable.
Application of the Mayo test in the panel decision of the Federal Circuit identified a natural phenomenon (the presence of the fetal DNA in maternal serum) in Claim 1 that was appended to conventional laboratory techniques (not to an inventive concept) and that result did not present a patentable invention. The recent petition for a rehearing and the accompanying amici involvement indicate continued discomfort with Mayo’s demand for the addition of an inventive concept to any discovered natural phenomeon before patenting is permitted. An “inventive concept” is not identified, nor is that requirement demanded by the statute or even explicitly required by the earlier 35 U.S.C. 101 landmark cases of the high Court (while also suggesting a consideration of prior art as well). It should be noted that the current debate is particularly centered on method claims, especially those with either diagnostic or therapeutic application. Will the Mayo test not only invalidate many diagnostic patent claims but challenge the eligibility of standard pharmaceutical treatment claims, for example, if the underlying metabolic processes are simply natural phenomena? Judge Dyk suggested that the Mayo framework may overlook a form of creativity that can emerge from discovery-based effort:
But, as I see it, there is a problem with Mayo insofar as it concludes that inventive concept cannot come from discovering something new in nature — e.g. , identification of a previously unknown natural relationship or property. In my view, Mayo did not fully take into account the fact that an inventive concept can come not just from creative and unconventional application of a natural law, but also from the creativity and novelty of the discovery of the law itself. This is especially true in the life sciences, where development of useful new diagnostic and therapeutic methods is driven by investigation of complex biological systems.
Thus, until the Supreme Court returns to consider whether Mayo has imposed a rigid, inflexible test with inapposite and/or ambiguous requirements, many argue that diagnostic and therapeutic innovation is at risk. Alternatively, however, more attention to embedding unambiguously detailed and physical manipulation into patent claims may overcome some of the concerns with breadth and scope underlying the preemption rationale for exclusion of the type of claim seen in the Sequenom patent. A petition for certiorari to the Supreme Court can be expected; 2016 could see the Court return to the issue of life science patent eligibility.
The International Summit on Human Gene Editing, hosted by the National Academies of Science and Medicine (NAS, NAM) and international partners, has just concluded a 3-day meeting (archived webcast available here). This summit was called following the rapid dissemination of human gene editing research using the CRISPR/Cas 9 technology (see earlier posts here and here). The impact of this technology cannot be understated:
The rapid development and widespread adoption of easy-to-use, inexpensive and effective genome-editing methodologies has changed the landscape of biology. The simplicity of the CRISPR–Cas9 system allows researchers and students to make precise changes to genomes, thereby enabling many experiments that were previously difficult or impossible to conduct.
Widespread concern over possible attempts to engineer the human germline (perform gene editing on embryos or gametes for reproductive purposes) led to calls for caution or even a research moratorium (see here). At the conference this week, panels discussed the current technical state of human gene editing, existing and potential governance structures, international perspectives, and social consequences of the technology. The most controversial application of human gene editing – germline editing creating heritable genetic changes – was central to many of the discussions, and the conference oscillated between considering the legitimacy of germline editing and considering the arguably more mundane regulatory control of somatic gene editing. The conference coordinating committee has released a consensus statement that endorses further research on both somatic and germ-line gene editing, subject to existing regulations and oversight mechanisms. The full statement is here. I reproduce the portion of that statement that focuses on the hotly contested issue of germline gene editing:
3. Clinical Use: Germline. Gene editing might also be used, in principle, to make genetic alterations in gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool. Examples that have been proposed range from avoidance of severe inherited diseases to ‘enhancement’ of human capabilities. Such modifications of human genomes might include the introduction of naturally occurring variants or totally novel genetic changes thought to be beneficial.
As reported by David Baltimore, chair of the conference committee, the members did not recommend either a ban or a moratorium on research into germline gene editing, but they state that any use of gene editing in reproduction at this time would be "irresponsible." In the U.S., the NIH has already ruled out federal funding for such research:
Germline editing poses many important issues, including: (i) the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism); (ii) the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment; (iii) the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations; (iv) the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country; (v) the possibility that permanent genetic ‘enhancements’ to subsets of the population could exacerbate social inequities or be used coercively; and (vi) the moral and ethical considerations in purposefully altering human evolution using this technology.
It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application. Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.
However, NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed.
The NAS contemplates ongoing public engagement with the controversies raised by human gene editing, in the form of an upcoming formal NAS study and the establishment of a publicly accessible forum to continue the discussion. More analysis of the conference and the effects on the current research climate will be posted here.
The FDA has issued an approval for the marketing of genetically engineered (GE) Atlantic salmon, capping a long regulatory review (see here). The product, AquaAdvantage, made by Aqua Bounty, Inc., has been under agency review for years. This Atlantic salmon has been genetically engineered to add the growth hormone gene from the Chinook salmon, which causes the fish to reach market weight in about half the time. The FDA regulates GE animals under the new animal drug provisions of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) because recombinant DNA introduced into an animal is treated as a drug. From the FDA statement:
Based on a comprehensive analysis of the scientific evidence, the FDA determined that AquAdvantage Salmon meets the statutory requirements for safety and effectiveness under the Federal Food, Drug, and Cosmetic Act. Among the requirements the sponsor had to meet are that food from the fish is safe to eat; the rDNA construct (the piece of DNA that makes the salmon grow faster) is safe for the fish itself; and the AquAdvantage Salmon meets the sponsor’s claim about faster growth. In addition, the FDA determined that food from AquAdvantage Salmon is as safe to eat and as nutritious as food from other non-GE Atlantic salmon and that there are no biologically relevant differences in the nutritional profile of AquAdvantage Salmon compared to that of other farm-raised Atlantic salmon.
The agency will not require the GE salmon to be labeled:
The AquAdvantage Salmon may be raised only in land-based, contained hatchery tanks in two specific facilities in Canada and Panama. The approval does not allow AquAdvantage Salmon to be bred or raised in the United States. In fact, under this approval, no other facilities or locations, in the United States or elsewhere, are authorized for breeding or raising AquAdvantage Salmon that are intended for marketing as food to U.S. consumers. As required by the National Environmental Policy Act, the FDA completed an environmental assessment to determine whether approval of the application would result in significant effects on the quality of the human environment in the United States. The FDA has determined that the approval of the AquAdvantage Salmon application would not have a significant environmental impact because of the multiple and redundant measures being taken to contain the fish and prevent their escape and establishment in the environment.
Based on our assessments of food derived from the AquAdvantage Salmon, we have determined that the term “Atlantic salmon” is the appropriate common or usual name for such food within the meaning of section 403(i) of the FD&C Act because AquAdvantage Salmon meets FDA’s regulatory standard for Atlantic salmon (Ref. 10) and the composition and basic nature of food from AquAdvantage Salmon does not significantly differ from its non-GE counterpart—non-GE farm-raised Atlantic salmon. In addition, we have determined that food derived from AquAdvantage Salmon is as safe and nutritious as food from other farm-raised Atlantic salmon. For these reasons, we have concluded that there is no material difference between food derived from AquAdvantage Salmon and food derived from other non-GE, farm-raised Atlantic salmon that is required to be disclosed in the labeling of food derived from AquAdvantage Salmon under the relevant provisions of the FD&C Act, as explained above. See 21 U.S.C. 321(n) & 343(a).
Senator Lisa Murkowski (R-AK) has been an outspoken opponent of FDA approval of the GE salmon (in line with general statewide opposition), and has been attempting to pass legislation requiring the labeling of the GE salmon if the agency approval cannot be overturned:
The FDA has said there will be draft guidance on voluntary labeling indicating whether food has or has not been derived from GE Atlantic salmon. So, basically, if you want to put a label on that says this is a fake fish, a fake salmon, you can go ahead, but you don't have to. It is only voluntary. That is not good enough for this mom. That is not good enough for most who care about what their families are eating. So we are going to continue to press for mandatory labeling if the FDA is going to approve--wrongheadedly, in my mind--this genetically engineered fake fish for human consumption. They darn well better agree that labeling will be required because I am not going to eat it.
Public sentiment against approval of the GE salmon was well-registered with the FDA; over 1.5 million public comments were posted against agency approval; the agency decision not to require labeling has generated more opposition and the FDA's safety evaluation has been challenged as cursory. The marketplace could well determine whether GE salmon actually becomes part of the American food supply; many retailers and restaurants are on record stating that they will not sell the product. Upcoming developments to watch will be the ongoing pressure to require labeling (as well as the Senate prospects for the federal anti-GE labeling bill discussed here earlier). Furthermore, the fate of future GE seafood products (about 35, by one count) that come before the FDA remains uncertain. Lastly, a lawsuit has been filed in Canada opposing the AquaBounty production of the GE salmon eggs in Canada as a potential environmental threat to wild salmon stocks.
Non-invasive prenatal testing (NIPT) is an alternative to the invasive techniques of amniocentesis or chorionic villi sampling used in reproductive medicine, both of which carry some risk to the fetus. The research demonstrating that fetal DNA could be recovered from maternal serum prompted the development of testing techniques that could simply rely on maternal blood testing in order to recover fetal DNA and perform genetic analysis. The scientists were awarded U.S. Patent No. 6,258,540. Claim 1 of the patent:
A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.
Sequenom, Inc. holds the rights to the patent. It sued Ariosa Diagnostics and several other genetic testing companies for infringement of the patent. In Ariosa Diagnostics, Inc. v. Sequenom, Inc., issued in June, the Federal Circuit ruled that the patent claims to methods for detecting and recovering the fetal DNA from a maternal sample were invalid for lack of patentable subject matter (35 U.S.C. § 101) (see here). That decision followed a sequence of recent Supreme Court cases, AMP v. Myriad (2013) (Myriad) and Mayo v. Prometheus (2012) (Mayo) that each invalidated patent claims in the life sciences for a lack of patentable subject matter. The Federal Circuit relied on the analytic framework from Mayo to dissect the patent claims, summarizing the test as follows:
First, we determine whether the claims at issue are directed to a patent-ineligible concept. If the answer is yes, then we next consider the elements of each claim both individually and “as an ordered combination” to determine whether additional elements “transform the nature of the claim” into a patent-eligible application.
The court noted that the presence of fetal DNA in maternal serum was a patent- ineligible natural phenomenon (step 1) and then proceeded to step 2, where it considered whether any other elements of the patent claim (detecting, amplifying) operated to transform the unpatentable natural phenomenon:
Thus, in this case, appending routine, conventional steps to a natural phenomenon, specified at a high level of generality, is not enough to supply an inventive concept. Where claims of a method patent are directed to an application that starts and ends with a naturally occurring phenomenon, the patent fails to disclose patent eligible subject matter if the methods themselves are conventional, routine and well understood applications in the art. The claims of the ’540 patent at issue in this appeal are not directed to patent eligible subject matter and are therefore, invalid.
Judge Linn filed a concurrence, but made it clear that he did so because Mayo demanded the application of a fairly unforgiving test that led to an incorrect result in this case. In August, Sequenom filed a petition with the Federal Circuit requesting a rehearing en banc, contending that the panel’s decision wrongly applied the Mayo framework to find a groundbreaking invention unpatentable (see here):
To avoid this absurd result, all the Court must do is reaffirm—as did the Supreme
Sequenom then described the future impact of the decision as "an existential threat:"
Court in Mayo—that a combination of known steps that incorporates or is motivated by an unpatentable natural phenomenon is nonetheless patentable if that combination “considered as a whole” was not routine before the patent disclosed it.
The full Court's intervention is particularly necessary because, if this Court does not step in and draw this line, the panel's rule threatens to swallow many more meritorious inventions along with this one.
Ariosa has recently filed its response to the Sequenom petition. Ariosa argues that the Federal Circuit’s decision properly utilized the Mayo-based framework as an analytic device:
Appellants’ only legal argument (as opposed to their dire policy-based prognostications) in favor of rehearing en banc is that Mayo, Myriad and Diehr must be read as teaching that “a combination of known steps that incorporates or is motivated by an unpatentable natural phenomenon is nonetheless patentable if that combination ‘considered as a whole’ was not routine before the patent disclosed it.” Yet Appellants’ misreading of those precedents amounts to nothing short of a wholesale revision of the Supreme Court’s two-part test for determining whether a claim recites patent-eligible subject matter.
The contrasting arguments of the parties frame a question for the Federal Circuit regarding whether a patent claim embedding a natural phenomenon requires a holistic interpretation (Sequenom) or should be subject to a more splintered analysis (Ariosa). A decision from the Federal Circuit on the petition for rehearing is likely to issue in the next several months; if they do not accept it, the decision could then be appealed to the Supreme Court, which has issued two life science decisions on patentable subject matter in the last three years.
The medical specialty of genetic counseling is high in demand these days as genetically-informed medical care (genomic medicine, precision medicine) becomes the dominant paradigm in heath care. The National Society of Genetic Counselors (NSGC) provides the following definition of the field:
Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates:
Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.
Education about inheritance, testing, management, prevention, resources and research.
Counseling to promote informed choices and adaptation to the risk or condition.
To date, about 20 states require genetic counselors to be licensed for practice (here is the Pennsylvania licensing law). The U.S. has a generally state-based model of professional licensure for medical occupations (M.D.s included). Now, the American Society of Human Genetics (ASHG), a primary professional organization in clinical genetics, has called for state licensure of genetic counselors across the U.S. From the ASHG statement:
Healthcare reform and the rapidly expanding role of genomics in many healthcare decisions will increase the demand for qualified genetics professionals. State licensure of certified counselors will help to ensure that the healthcare system has a qualified workforce to provide genetic and genomic services for the growing number of patients and families who need them.
Many health plans recognize genetic counselors as important members of the healthcare team and depend on them to help ensure provision of state-of-the art genetic services, including the ordering of appropriate genetic/genomic tests and the attendant pre-and post-test counseling and education. Licensure also provides genetic counselors with the credentials many hospitals need to approve billing and reimbursement for services.
ASHG supports licensure already enacted by more than twenty states and encourages the remaining states to license certified genetic counselors as one way to increase access to high-quality genetic/genomic services across the country.
The NSGC has published model legislation for licensure. The ASHG’s recent recommendation in favor of state licensure signals the increasing need for standardized professional services, albeit with state variations (e.g., see earlier post on Virgina's licensure statute). At least five states have licensing legislation pending. A parallel observation on the trend toward genetic counseling licensure is to note that the services of such professionals are often incorporated into patient management by referral from treating physicians; however, some studies suggest that genetic counselors are actually underutilized in some sectors of genetic testing (see here and here), with the consequence that patients undergoing such testing may not receive optimal education and guidance about their test results.
In the debates over the legitimacy of gene patents, one of the central concerns over the impact of gene patenting was whether patients could access second-opinion (confirmatory) genetic testing of positive test results. This circumstance was most acutely illustrated in the BRCA1 and BRCA2 breast cancer gene testing field, where the patents on these genes were held by Myriad Genetics, Inc.. Unlike some other gene patent holders, Myriad did not license other genetic testing laboratories to offer commcercial clinical testing, with the result that almost all BRCA1/2 genetic tests in the U.S. were performed by Myriad. Of relevance here, this meant that patients lacked opportunities for independent assessment of test results that indicated the presence of a mutation in either gene which significantly increased risk of developing breast and/or ovarian cancer. As is well-known now, the Myriad patents were invalidated in the landmark case of Association for Molecular Pathology v. Myriad Genetics in 2013. However, several years earlier, as part of the America Invents Act of 2011 (AIA), Congress instructed the U.S. Patent and Trademark Office (PTO) to conduct a study on the impact of gene patents on the availability of confirmatory genetic diagnosis. The AIA required the PTO to assess the following:
(1) The impact that the current lack of independent second opinion testing has had on the ability to provide the highest level of medical care to patients and recipients of genetic diagnostic testing, and on inhibiting innovation to existing testing and diagnoses.
(2) The effect that providing independent second opinion genetic diagnostic testing would have on the existing patent and license holders of an exclusive genetic test.
(3) The impact that current exclusive licensing and patents on genetic testing activity has on the practice of medicine, including but not limited to: the interpretation of testing results and performance of testing procedures.
(4) The role that cost and insurance coverage have on access to and provision of genetic diagnostic tests.
Although behind schedule, the PTO report has now issued. No doubt, assessing the climate of genetic testing against a backdrop of gene patenting has been significantly altered by AMP v. Myriad; it could be argued that the PTO’s report is somewhat obsolete now. However, the agency acknowledges the changes in the field since 2011, and simply advances some modest conclusions and recommendations about the availability of genetic testing in general. From the report:
Although the evidence on each of these points was limited in its scope and mixed in its implications, recent Supreme Court decisions make it unlikely that exclusive provision of a diagnostic test, whether for an original diagnosis or to confirm the original result, will be possible based on patenting and licensing behavior. Patients seeking independent confirmation of diagnostic results will almost certainly be able to find it as long as the demand level for the test (or research interest in the particular gene or condition) supports a market for multiple test providers. For this reason, much of the USPTO’s factual findings may now be superseded by intervening judicial decisions. In view of the altered legal landscape, the USPTO’s recommendations to Congress are limited in scope.
The first recommendation is to proceed cautiously, monitoring changes in the actual availability of gene-based diagnostic tests from multiple providers. The second recommendation is to consider creating mechanisms to facilitate sharing data on diagnostic correlations in order to build robust databases of the relationships between genetic mutations and the presence, absence, or likelihood of acquiring the relevant medical condition. Data sharing of this kind would promote the most rapid advances in the diagnostic accuracy of individual tests. The third recommendation is to consider the role of cost and insurance. However, because the USPTO does not have the institutional expertise to make specific recommendations regarding insurance coverage for gene-related diagnostic tests, this report can only emphasize that insurance coverage does appear to play significant a role in access to testing and should be taken into consideration when issues of access are examined.
It was always a jurisdictional stretch to require the PTO to undertake this kind of analysis; the fact that such a mandate emerged from the AIA illustrates the high level of controversy over the validity of gene patents, an issue that was unresolved at the time of the law’s enactment. The PTO in general is not charged with considering the impact of patenting on market access or health care. However, its observations on the need for data-sharing of genetic correlations to clinical findings is on target. With respect to the BRCA1 and BRCA2 genetic mutations correlated with increased cancer risk, one of the consequences of the Myriad dominance of the testing market through its patents was that the company maintained the repository of most test results for these genes (important gene mutations), and was under no obligation to share them. Loss of its gene patents did not alter the fact that it had established significant genetic databases of clinically relevant mutations in the breast cancer genes. However, resistance to the establishment of proprietary genetic databases of critical genetic mutations has emerged through such initiatives such as Free the Data, and later, with the international genetic data-sharing efforts underway through the Global Alliance for Genomics and Health. Notably, the federally-funded ClinVar was established in 2013, which is an open-access public database of clinically relevant genetic data. However, the PTO report is correct in identifying this phenomenon as a determinant of whether patients are able to receive state of the art interpretations of mutational significance as the basis for medical decision-making. Furthermore, issues of cost and insurance access remain as determinants for consumers, and the patent structure of a genetic testing market will affect cost, but - apart from the notice in this PTO report - ongoing evaluations of patent validity in biotechnology do not consider such issues directly; they are collateral to decisions that are made with reference to the strictures of patent law. However, this report does sketch out an accurate field-wide portrayal of the access determinants that are indirectly influenced by patent rights.
In 2013, the U.S. Supreme Court invalidated patent claims to isolated BRCA1 and BRCA2 breast cancer genes in the case of Association for Molecular Pathology v. Myriad Genetics, on the basis that genes are not patentable subject matter (see here). Now, the High Court of Australia (HCA) has issued a decision in a case that challenged the legitimacy of patent claims to isolated genes. This month, in the case of D’Arcy v. Myriad Genetics, Inc., the HCA invalidated similar Myriad patent claims on the isolated BRCA1 gene. In contrast to the U.S. patent, the Australian claims were confined to mutated or polymorphic BRCA1 genes that are indicative of cancer risk, but which are central to a patenting strategy that would control much of current BRCA1 genetic testing. The Court’s summary:
Today the High Court unanimously allowed an appeal from a decision of the Full Court of the Federal Court of Australia. The High Court held that an isolated nucleic acid, coding for a BRCA1 protein, with specific variations from the norm that are indicative of susceptibility to breast cancer and ovarian cancer, was not a "patentable invention" within the meaning of s 18(1)(a) of the Patents Act 1990 (Cth) ("the Act").
The term "nucleic acid" includes two kinds of molecules, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), which are found inside a human cell. A gene is a functional unit of DNA which encodes a particular protein produced by the cell. The protein produced depends on the sequence of nucleotides. The BRCA1 gene codes for the production of a protein called BRCA1.
The first respondent filed a patent which contained 30 claims. Relevantly, Claims 1 to 3 concerned a nucleic acid coding for a BRCA1 protein, and with one or more specified variations from the norm in its nucleotide sequence, isolated from its cellular environment. Those specified variations, characterised as mutations or polymorphisms, are indicative of susceptibility to breast cancer and ovarian cancer.
Section 18(1)(a) of the Act requires that, for an invention to be patentable, it must be "a manner of manufacture" within the meaning of s 6 of the Statute of Monopolies. The appellant commenced proceedings in the Federal Court of Australia challenging the validity of Claims 1 to 3 on the basis that the invention claimed did not meet the requirement of s 18(1)(a).
The primary judge dismissed the appellant's challenge, holding that the invention fell within the concept of a "manner of manufacture”. The Full Court dismissed an appeal from that decision. The Full Court held that an isolated nucleic acid was chemically, structurally and functionally different from a nucleic acid inside a human cell. The invention was a manner of manufacture because an isolated nucleic acid with the characteristics specified in Claims 1 to 3 resulted in an artificially created state of affairs for economic benefit.
By grant of special leave, the appellant appealed to the High Court. The Court unanimously allowed the appeal, holding that the invention claimed did not fall within the concept of a manner of manufacture. The Court held that, having regard to the relevant factors, an isolated nucleic acid, coding for the BRCA1 protein, with specified variations, is not a manner of manufacture. While the invention claimed might be, in a formal sense, a product of human action, it was the existence of the information stored in the relevant sequences that was an essential element of the invention as claimed. A plurality of the Court considered that to attribute patentability to the invention as claimed would involve an extension of the concept of a manner of manufacture which was not appropriate for judicial determination.
In the reasoning behind the Australian decision, the Court invoked some similar themes from the U.S. 2013 decision, such as favoring an interpretation of the claims as drawn to information rather than a chemical:
It follows that in reality the claim in suit is no more expressed in terms of a chemical formula than was the claim in respect of the BRCA1 gene simpliciter which was rejected in the United States.
The scope of the claims were also cited as concerns:
Myriad acknowledges that a sample taken from a patient will infringe claim 1 if one or more of the specific mutations and polymorphisms identified in the claim are present, even if the testing is not directed at the BRCA1 gene or the identified mutations and polymorphisms. That is a problem.
Another international challenge to gene patenting (both product and method claims) remains on deck from Canada, in a case filed by the Children’s Hospital of Eastern Ontario (CHEO) against the University of Utah Research Foundation, Genzyme Genetics and Yale University over the patents covering five genes related to Long QT syndrome, a cardiac disorder. That case is also noteworthy in presenting a patent challenge from a government health provider (CHEO), reflecting the government-centered structure of Canada's healthcare system, where provincial governments assume responsibility in this sector.
Over the last year, several ad hoc and professional organizations have continued to weigh in on whether the CRISPR/Cas9 gene-editing technology should be subject to any pauses in its adoption as a method of genome alteration or correction (see here). The advent of CRISPR/Cas9 technologies, beginning with the first publication in 2012, has accelerated scientific interest in gene editing because the technique has offered a more efficient approach than previous genome-altering methodologies. Here is an overview of the directions such research can take:
Genome editing has tremendous value as a tool to address fundamental questions of human and non-human animal biology and their similarities and differences. There are at least four categories of basic research involving genome editing technology that can be distinguished: 1) research to understand and improve the technique of genome editing itself; 2) genome editing used as a tool to address fundamental questions of human and nonhuman animal biology; 3) research to generate preliminary development of human somatic applications; and 4) research to inform the plausibility of developing safe human reproductive applications.
However, the CRISPR age is encountering fits and starts. Most controversially, the specter of CRISPR becoming a novel reproductive technology to perform gene editing on a human embryo has raised the most attention and concern. Earlier, this year, two groups of American scientists issued cautionary statements (see earlier post here); the NIH then reiterated its ban on any federal funding of research on gene-editing in embryos. More recently, other international bodies are weighing in. The U.K. Wellcome Trust has now issued a statement:
Research using genome editing tools holds the potential to significantly progress our understanding of many key processes in biology, health and disease and for this reason we believe that responsibly conducted research of this type, which is scientifically and ethically rigorous and in line with current legal and regulatory frameworks, should be allowed to proceed. We will continue to support the use of genome editing in preclinical biomedical research as well as studies that progress and refine these technologies. Within the UK, this research may involve the use of somatic (non-reproductive) or germ cells, including human embryos up to 14 days old - within the confines of the HFE Act 2008 - where appropriately justified and supported by rigorous scientific and ethical review.
Against that backdrop, a U.K. developmental biologist has applied to the Human Fertilisation and Embryology Authority (HFEA), for permission to edit the genome of a human embryo (there is no such agency in the U.S). The goal of the proposed research is to identify what genes in the developing embryo are active in the early post-fertilization stages; the research would use surplus embryos from IVF clinics where permission has been granted for such use. The license may be granted:
The Human Fertilisation and Embryology Authority (HFEA) has yet to review her application, but is expected to grant a licence under existing laws that permit experiments on embryos provided they are destroyed within 14 days. In Britain, research on embryos can only go ahead under a licence from an HFEA panel that deems the experiments to be justified.
In a separate development, The Hinxton Group, an international consortium centered on stem cell issues, published a statement calling for caution in possible reproductive applications, but not a moratorium:
Oversight structures must be in place prior to any attempts to use genome editing in human reproduction. Effective oversight requires the development of appropriate standards for preclinical data (e.g., What are acceptable thresholds for off-target events and mosaicism? What are appropriate methods for determining the impact of off-target events?). Initial attempts should be conducted only in the context of formal clinical research or trials. In addition, the health and well-being of participants, developing fetuses, and pregnancy outcomes should be monitored carefully. The health and well-being of those born should also be monitored in long-term follow-up and research, albeit with a mind toward the burdens this would impose.
Finally, in an event that will likely feature a spectrum of viewpoints, the Chinese Academy of Sciences (CAS) and the Royal Society (the science academy of the U.K.) are joining the U.S. National Academy of Sciences (NAS) to hold a highly anticipated international summit on human gene-editing on December 3, 2015 in Washington, D.C. A preliminary meeting (and webcast) to organize the summit will be held next week on October 5, 2015; details here.
In an unusual foray into advocacy involving the pharmaceutical marketplace, a coalition of oncologists has published a call to action in the Mayo Clinic Proceedings regarding the high price of cancer drugs; the physicians advocate for a number of regulatory and legislative measures to reduce the cost of cancer drugs, increase market competition, and ultimately improve patient access. It has been evident for a while that while molecular research has resulted in the development of new therapeutic approaches to cancer – especially targeted biotech drugs – the price of some of these drugs has well exceeded both patient and physician expectations; hence, the term "financial toxicity." In just one example, the Amgen drug Blincyto, an immunotherapy for leukemia, can cost about $178,000 for a course of treatment. The recent attention to funding research on "precision medicine" from the NIH and the White House focused on how cancer treatment (new drugs) is one of the chief beneficiaries of these efforts. In the published commentary, the oncologists make several points:
In 2014, all new US Food and Drug Administration (FDA) approved cancer drugs were priced above $120,000 per year of use.
For a patient with cancer who needs one cancer drug that costs $120,000 per year, the out-of-pocket expenses could be as high as $25,000 to $30,000—more than half the average household income and possibly more than the median take-home pay for a year. Patients with cancer then have to make difficult choices between spending their incomes (and liquidating assets) on potentially lifesaving therapies or foregoing treatment to provide for family necessities (food, housing, education).
The commentary specifically calls for the following measures:
(1) Creating a post-FDA drug approval review mechanism to propose a fair price for new treatments, based on the value to patients and heath care.
A number of the suggested measures are familiar tactics, although not all in force. For example, the patent recommendations overlap with ongoing efforts to improve either patent quality or forestall dubious attempts to extend the term of lucrative patents (the “evergreening” phenomenon, for example, has been countered using patent law theories of double patenting). The phenomenon of “pay for delay” in which brand name companies pay would-be generic competitors to stay out of the market has encountered the Supreme Court’s Federal Trade Commission (FTC) v. Actavis decision in 2013 which endorsed antitrust inquiries into such arrangements; the Federal Trade Commission actively monitors such agreements. The call for the FDA to incorporate a pricing determinant in the drug approval process runs counter to any agency mandate to consider such questions in its regulatory work. Federal legislation to allow patients to import prescription drugs from Canada has been introduced, but not enacted. The call for the government to allow Medicare to negotiate bulk pricing with drug companies has been a political football for more than a decade since the enactment of Medicare Part D prohibited that option; the Obama administration has endorsed such negotiations, but the realities of Congress today make that unlikely. With respect for the calls to professional organization, the American Society for Clinical Oncology (ASCO) is actively pursuing methods for drug valuation that incorporate pricing. Despite these particulars, the Mayo commentary lines up with other public acts of priced-based resistance from the oncology community, such prescribing refusals based on cost (e.g., Sloan-Kettering oncologist practices) or cost-consciousness in prescribing practices. The article further endorses a consumer petition drive which seeks patient support for these efforts. A critical mass of attention is developing to the high pricing of new biotech cancer drugs; the British medical journal Lancet published a recent editorial:
(2) Allowing Medicare to negotiate drug prices.
(3) Allowing the Patient-Centered Outcomes Research Institute, created through the Affordable Care Act initiatives to evaluate the benefits of new treatments, and similar organizations to include drug prices in their assessments of the treatment value.
(4) Allowing importation of cancer drugs across borders for personal use (e.g., prices in Canada are about half of prices in the United States).
(5) Passing legislation to prevent drug companies from delaying access to generic drugs (pay-for-delay).
(6) Reforming the patent system to make it more difficult to prolong product exclusivity unnecessarily (patent “evergreening”).
(7) Encouraging organizations that represent cancer specialists and patients (e.g., American Society of Clinical Oncology, American Society of Hematology, American Association for Cancer Research, American Cancer Society, National Comprehensive Cancer Network) to consider the overall value of drugs and treatments in formulating treatment guidelines.
It therefore seems depressingly clear that industry's inflated pricing of new cancer drugs is contributing to a failure of health systems to offer promising new therapies to the very people for whom the drugs are created—cancer patients worldwide.
It should be noted that despite the Lancet's pessimism, the U.K. did actually establish a Cancer Drugs Fund under the National Health Service to target assistance to those needing expensive cancer drugs; however, as just announced, the fund is over-budget and now restricting which drugs will be covered.
The first biosimilar drug has entered the U.S. market, with the launch of the Sandoz product Zarxio, which is a biosimilar of the Amgen reference product Neupogen; it received the first FDA approval for a biosimilar drug earlier this year (following expert panel approval). The biologic drug Neupogen, used to restore white blood cell function for cancer patients undergoing chemotherapy, has been one of the most successful biotech drugs of the biotechnology industry. In general, biologics are produced from living systems, such as microorganisms or cells, rather than from direct chemical synthesis; a biosimilar is a product that is "similar" to the originally approved biologic. Under the biosimilar drug approval pathway established under the Biologics Price Competition and Innovation Act of 2009 (enacted as part of the Affordable Care Act), the FDA was empowered to receive applications from companies wishing to offer a biosimilar drug that could replace and/or compete with the reference product. Importantly, a distinction is made between “biosimilar” and “interchangeable.” The FDA explains:
A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.
An interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional standards for interchangeability. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product.
FDA requires licensed biosimilar and interchangeable biological products to meet the Agency’s rigorous standards of safety and efficacy. That means patients and health care professionals will be able to rely upon the safety and effectiveness of the biosimilar or interchangeable product, just as they would the reference product.
To date, the FDA has not established the formal guidelines for a biosimilar to earn the designation of “interchangeable;” Sandoz, among others, has called for such action. As a result, the full market scope of market competition contemplated for an age of “biotech generics” awaits further regulatory developments from the FDA. This contrasts with the fate of Zarxio in the European Union, where the biosimilar has been approved since 2009 and where an approval by the the European Medicines Agency (EMA) means that a physician could decide that a biosimilar is interchangeable as a function of professional judgment, rather than regulatory designation.
The entry of Zarxio into the U.S. market has been accompanied by a patent-related dispute between Sandoz and Amgen regarding what level of information exchange between biosimilar applicant and reference product sponsor is required by the BCPIA (the so-called "patent dance"). In 2014, Sandoz provided notice to Amgen that it had filed a Biologics License Application (BLA) with the FDA to produce a biosimilar of Neupogen. A legal scuffle followed this notice, with Amgen claiming that Sandoz did not provide the actual BLA application as required by the BCPIA. The district court agreed with Sandoz that the statute did not require the application to be provided, but it did recognize an obligation of the application to provide notice of commercial marketing to the sponsor after FDA approval. In July of this year, the Federal Circuit subsequently sided with Sandoz and did not require it to provide the application to Amgen, and interpreted the BCPIA to establish that the notice to Amgen triggered a 180-day delay of marketing for Sandoz, which is why Zarxio has just entered the market now despite its approval in March.The growing pains for the age of biotech generics continue on another front, as the FDA has just released proposed naming guidelines to distinguish follow-on products from the original reference drug.
The ongoing legal battles over the scope of reproductive rights protected by the 14th Amendment – with claims of constitutionally protected values of liberty and privacy invoked – continue, going back to the signature case of Roe v. Wade in 1973 and furthered tailored by Planned Parenthood v. Casey (1992), among other cases. Other arguments for the protection of reproductive autonomy are grounded in gender equality. Fast forwarding to the rapidly developing technological landscape of genetic testing, reproductive medicine has steadily refined the options available for prenatal testing to provide prospective parents with ever more accurate – and earlier obtained – medical information. The most dramatic development has been the availability of non-invasive prenatal diagnosis (NIPD) that relies on obtaining fetal DNA (cell-free detal DNA, cffDNA) from maternal blood as early as 4 weeks into gestation and to test for a number of genetic/chromosomal disorders, including Down syndrome (attributed to the presence of an extra chromosome 21, leading to a trisomy). NIPD has reduced the need for invasive procedures, such as chorionic villi sampling and/or amniocentesis. As prenatal testing becomes more sophisticated, an ongoing political battle rages over whether abortion rights should be restricted based on the intent or rationale of the mother for seeking the procedure. This has led to both state and federal efforts to restrict abortion when it is sought on the basis of gender, race or genetic anomaly (e.g., Down syndrome). Currently, a bill, HB 135, is pending in Ohio that would ban any abortion that is sought sought because prenatal testing reveals Down syndrome. North Dakota enacted a similar bill in 2013 (that same bill would have prohibited abortions about as early as 6 weeks; that portion was struck down by the Eighth Circuit in July of this year). To date, there are no reports of enforcement of these selective bans on abortion. Yet they raise not only the most obvious legal issue of whether such laws impinge on the constitutional right enshrined by Roe (or present the “undue burden” prohibited in Casey). They raise a novel issue of whether the legal rights accorded to the mother can vary according to genetic status of a fetus. Beyond that, express litigation over the constitutional concerns of the fetus itself would lead into the legal personhood legal battles that have been fought already (and overwhelmingly seen the defeat of attempted personhood ballot initiatives and legislation) (see earlier posts here and here). Thus, an indirect genetically-determined legal climate of maternal rights emerges if these laws work as intended – with the twist that the relevant genetic information is derived from the fetus. While is appears that these laws are unworkable as a practical matter, these bills can formally require the provider to question the mother about her motives and can impose felony charges on a physician violating the ban. The Ohio bill is likely to pass, and join the North Dakota bill alone in targeting maternal rights on the basis of a fetal genetic anomaly. Proponents of these bills have argued that, for example, the current climate of genetic testing only encourages the elimination of offspring with detectable genetic abnormalities, with the result that Down syndrome births become increasingly uncommon, and they invoke a kind of disability discrimination argument in support of these measures (however, that leads back to the fetal personhood debate). Opponents argue that the Roe-based constitutional right to seek an abortion – while certainly cabined by many modern legislative limitations – is not conditioned on maternal motive or the genetic status of the fetus, but is simply motivated by a desire to limit women's reproductive choices.
In June, the Federal Circuit ruled that a prenatal testing method for detecting fetal DNA in maternal serum was not patentable, violating the prohibition against the patenting of natural phenomena (see here). In the case, Ariosa Diagnostics, Inc. v. Sequenom Inc. (2015), a representative claim from U.S. Patent No. 6,258,540 is as follows:
1. A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.
In the invalidity challenge asserted by Ariosa when the company was sued for patent infringement by Sequenom, Ariosa argued that the method claim effectively covered (or preempted) all uses of the newly observed natural phenomenon - namely, the presence of fetal DNA in maternal blood. The method is centered on that discovery - detect the fetal DNA and perform genetic assessments on that sample, thereby avoiding more risky invasive prenatal procedures. The trial court, and then the Federal Circuit, concluded that the method patent claims were invalid, that they did attempt to patent a natural phenomenon, not an actual invention. As the Federal Circuit stated:
Thus, in this case, appending routine, conventional steps to a natural phenomenon, specified at a high level of generality, is not enough to supply an inventive concept. Where claims of a method patent are directed to an application that starts and ends with a naturally occurring phenomenon, the patent fails to disclose patent eligible subject matter if the methods themselves are conventional, routine and well understood applications in the art.
Now, Sequenom has filed a petition at the Federal Circuit, asking for an en banc review of the court's panel decision in June. Sequenom challenges the panel's application of a test for patent eligibility derived from the Supreme Court's 2012 decision in Mayo v. Prometheus. Further, Sequenom argues that the impact of the patent denial on future method patent claims that center on a newly discovered natural phenomena is devastating to future innovation:
The full Court’s intervention is particularly necessary because, if this Court does not step in and draw this line, the panel’s rule threatens to swallow many more meritorious inventions along with this one. The core of nearly every major innovation is the discovery of a fact about the natural world that motivates inventors to combine existing techniques to achieve new practical results. Accordingly, the panel’s test would threaten an invention implementing the discovery that a certain form of Ebola virus provokes an immune response that prevents infection (to take just one timely example). Nearly all vaccines have this problem: The hard part is determining the natural law that a given attenuated virus creates lasting immunity; once you know that, the rest is “routine.” The same goes for future holy-grail discoveries like simple, non-invasive methods of detecting early-stage cancer— ironically, the cheaper and simpler the method discovered, the less patentable it will be. In truth, the problem goes well beyond diagnostics or even medicine: If combining conventional techniques in an unconventional fashion, motivated by a discovery about nature’s laws, is unpatentable subject matter, it is hard to see how any process claim can survive.
The Ariosa decision particularly impacts method claims, not composition of matter claims (which were already severely impacted by AMP v. Myriad in 2013). Whether the Federal Circuit decides to accept the petition and rehear the case en banc is unknown; what is known, however, is that the Ariosa decision does jeopardize the validity of similar method claims to the detection of many biochemical or molecular relationships, just at a time when much of modern biotech research is devoted to uncovering exactly that kind of information.
The Equal Employment Opportunity Commission (EEOC) has filed a federal complaint against a Virginia employer, Bedford Weaving, Inc., alleging that the company illegally sought medical information from a job applicant, and used that information to deny her a job. The lawsuit relies on the Americans with Disabilities Act (ADA) and the Genetic Information Nondiscrimination Act (GINA), both of which are enforced by the EEOC. The ADA, enacted in 1992, prohibits an employer from taking any adverse position against an applicant or an employee based on a real or perceived disability. GINA, enacted in 2008, prohibits inquiries regarding family or personal medical history; such inquiries might reveal genetic disorders or susceptibilities that an employer might use in hiring, retaining or promoting employees. Title II of GINA prevents employers from requesting genetic information or making employment decisions based on genetic information:
Under Title II of GINA, it is illegal to discriminate against employees or applicants because of genetic information. Title II of GINA prohibits the use of genetic information in making employment decisions, restricts employers and other entities covered by Title II (employment agencies, labor organizations and joint labor-management training and apprenticeship programs - referred to as "covered entities") from requesting, requiring or purchasing genetic information, and strictly limits the disclosure of genetic information.
More background from the EEOC:
Bedford Weaving operates a weaving manufacturing facility in Bedford, Va. According to the complaint, Bedford Weaving's employment application asked applicants questions about their family medical history, solicited disability-related information, and contained questions about applicants' personal medical history.
Pamela Hedrick applied for work at the facility in August 2013 and filled out an application at that time. Hedrick suffers from chronic obstructive pulmonary disease and asthma, which she disclosed on her application in response to Bedford Weaving's illegal medical questions. EEOC's complaint stated that Bedford Weaving told Hedrick it had no vacant positions, while in fact it had at least two vacant positions for which Hedrick was qualified. EEOC charged that Bedford Weaving failed to hire Hedrick because of her disability, which Bedford Weaving became aware of because Hedrick disclosed disability-related information on her application.
The questions asked on the employment application and the alleged failure to hire due to the information disclosed, violate the Americans with Disabilities Act which prohibits employers from making disability-related inquiries of an applicant before a job offer, and from refusing to hire an individual due to a real or perceived disability. The questions also violate the Genetic Information Nondiscrimination Act (GINA), the federal law that prohibits employers from requesting genetic information, including family medical history, or using that information in the hiring process.
The EEOC seeks back pay, compensatory damages and punitive damages as well as injunctive relief.
In 2014, the EEOC settled a class action enforcement action against an employer that violated GINA by making prohibited pre-employment medical inquiries (see here). As illustrated by the new EEOC filing, while GINA is centrally concerned with prohibiting discriminatory practices in the workforce that are based on the genetic status of applicants or employees, it includes strong prohibitions against employer acquisition of such genetic information, whether directly (genetic testing) or indirectly (family history). An academic study published earlier this year found that the general public is largely unaware of GINA or the legal protections against genetic discrimination. That conclusion is noteworthy, as a major impetus for GINA's passage was to alleviate fears by employees that genetic test results sought in medical care might lead to adverse action by an employer. However, most employees in the U.S. are not aware of these legal protections; nonetheless, the use of genetic testing in medical care today continues to increase.
As genetic engineering emerged from laboratories in the 1970’s into the biotechnology industry in the 1980’s, the possibility of government regulation arose, with a central question of whether a drug, for example, produced by genetic engineering rather than conventional chemical synthesis, required a distinct regulatory response. In another version of that same question: did a genetically modified plant require a distinct biotechnology regulatory treatment or could the plant fit into established oversight routes for plants produced through convention breeding techniques? In its most generic form, the debate that began in the 1980's wrestled with whether biotechnology processes produce inherently distinct products that demanded novel regulatory responses. According to the Coordinated Framework for the Regulation of Biotechnology announced by White House Office of Science and Technology Policy (OSTP) in 1986, the answer was generally no; a product or an engineered organism could be evaluated by the traditional agencies and laws that already existed to identify and manage risk. The
coordinated framework thus divided the primary regulation of
biotechnology products among three agencies – the Department of
Agriculture’s Animal and Plant Health Inspection Service (APHIS), the Environmental Protection Agency (EPA), and the Food and Drug
Administration (FDA). That scheme was updated in 1992, and that document continued to be the last word in regulatory design. Now the White House OSTP has announced that it will initiate a modernization of the 1992 policy. In a just-published memorandum to the three federal agencies, the OSTP first provides a definition of “biotechnology products” that will be the targets of the review:
For the purpose of this memo, “biotechnology products” refers to products developed through genetic engineering or the targeted or in vitro manipulation of genetic information of organisms, including plants, animals, and microbes. It also covers some of the products produced by such plants, animals, and microbes or their derived products as determined by existing statutes and regulations. Products such as human drugs and medical devices are not the focus of the activities described in this memo.
In a briefing document on its blog, the OSTP has described the process ahead:
The goal of the effort is to ensure public confidence in the regulatory system and improve the transparency, predictability, coordination, and, ultimately, efficiency of the biotechnology regulatory system. Here is a bit more detail about the effort’s three components:
A modernized jurisdictional design could address some overlap between the responsible agencies, while also considering newer technologies and their placement into the scheme. For example, new organisms or products from the more recent field of synthetic biology might not fit the traditional category of “genetically engineered” which contemplated a small number of discrete and planned changes into an existing organism. A recent study from the Venter Institute on the regulatory challenges raised by synthetic biology endorsed the basic earlier principle that a product should be evaluated for its own discrete risk profile even when produced through synthetic biology; however, the study notes that specific jurisdictional boundaries between the three federal agencies and specific legal authorities need to be updated to account for an expanding portfolio of genetic engineering modalities that will produce even more novel organisms than the first wave of genetic engineering.
First, the Administration will update the Coordinated Framework, after public input, by clarifying the current roles and responsibilities of the EPA, USDA, and FDA in the regulatory process. This update will help clarify which biotechnology product areas are within the authority and responsibility of each agency and outline how the agencies work together to regulate products that may fall under the authorities of multiple agencies.
Second, the Administration will develop a long-term strategy, after public input, to ensure that the Federal regulatory system is well-equipped to assess efficiently any risks associated with the future products of biotechnology. This will include performing periodic horizon-scanning of new biotech products, coordinating support for the science that informs regulatory activities, developing tools to assist small businesses as they navigate the regulatory system, and creating user-friendly digital tools for presenting the agencies’ authorities, practices, and basis for decision-making.
Third, the Administration will commission an outside, independent analysis of the future landscape of the products of biotechnology. The Administration has already asked the National Academies of Sciences, Engineering, and Medicine to conduct such an analysis.