November 16, 2015

Federal Circuit Considers Rehearing on Denial of Patent to Noninvasive Prenatal Testing of Fetal DNA

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
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.
Sequenom then described the future impact of the decision as "an existential threat:" 
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.

November 6, 2015

ASHG Recommends State Licensure of Genetic Counselors

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.

October 31, 2015

PTO Issues AIA-Mandated Report on Genetic Testing and Gene Patents

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.

October 28, 2015

High Court of Australia Rejects Myriad Genetics BRCA1 Gene Patents

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.

September 30, 2015

CRISPR Gene-Editing Technology: UK Application Filed, More Official Statements, International Summit

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.