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Cancer, Genetics, Medicine and Society, Science, Science Policy

A closer look at Supreme Court’s decision on gene patenting

A closer look at Supreme Court's decision on gene patenting

As previously discussed here and elsewhere, the Supreme Court today issued its opinion in the gene patenting case Association for Molecular Pathology vs. Myriad Genetics, Inc. In a unanimous decision (.pdf) authored by Justice Thomas, the Court declared that isolated genomic DNA was not eligible for patent protection, but that cDNA – “cloned” or “complementary DNA” – could be patented. This was largely the outcome some predicted after oral argument. And while the actual business and research effects of the decision remain to be seen, this does bring to a close the longstanding practice of patenting isolated portions of the human genome in its native state.

This likely brings to a close Myriad Genetics’ saga of aggressively enforcing its patents directed to BRCA1 and BRCA2 testing

The Court’s decision was relatively simple. It began with a largely accurate, and lengthy, recitation of the molecular biology behind transcription and translation. This factored significantly into the Court’s discussion of the differences between isolated genomic DNA and cDNA, particularly the absence of introns from cDNA molecules. It then assessed the patents’ claims at issue, which were generally directed to “an isolated DNA” of varying lengths and sequences. The opinion noted that, “Myriad’s patents would, if valid, give it the exclusive right to isolate an individual’s BRCA1 and BRCA2 genes… by breaking the covalent bonds that connect the DNA to the rest of the individual’s genome.” And the Court concluded its opinion by declaring that claims directed to molecules of isolated genomic DNA, themselves, were unpatentable “products of nature” because Myriad did not “alter any of the genetic information encoded in the BRCA1 and BRCA2 genes,” nor did the isolated genomic DNA possess “markedly different characteristics from any found in nature.”

The Court rejected Myriad’s claim that it created a new chemical entity because, in isolating the genes from their surrounding chromosomes, Myriad necessarily cleaved the chemical bonds of the chromosomes’ phosphate backbones. This was irrelevant because “Myriad’s claims are simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA.”

As for Myriad’s cDNA claims, however, the Court – in a single, short paragraph – declared them eligible for patent protection because the “non-coding regions have been removed,” thus creating a new molecule not found in nature. Interestingly, the Court recognized the possibility of retrovirii potentially creating identical DNA transcripts to the cDNAs at issue, but dismissed this concern in a footnote: “The possibility that an unusual and rare phenomenon might randomly create a molecule similar to one created synthetically through human ingenuity does not render a composition of matter nonpatentable.”

Bizarrely, Justice Scalia joined the Court’s opinion in its entirety except for its preliminary scientific discussion. In a separate concurrence, Justice Scalia wrote: “I am unable to affirm those details on my own knowledge or even my own belief.” Typically, Justice Scalia does not qualify the factual portions of opinions he joins, even where they involve science. And notably, in the Court’s recent decision in Maryland v. King involving the constitutionality of warrantless DNA tests for arrestees, Justice Scalia’s dissent is replete with the factual differences between DNA and fingerprint testing.

This likely brings to a close Myriad Genetics’ saga of aggressively enforcing its patents directed to BRCA1 and BRCA2 testing. Myriad will continue to offer its BRACAnalysis product, which, because of its trade secret mutational database, is likely still the most robust BRCA test on the market. And competitors will be able to enter the BRCA testing market and make use of Myriad’s methods, although they will have to do so without the benefit of certain cDNA molecules or Myriad’s clinical data.

But the decision leaves a number of legal questions unanswered: What about other patents directed to “isolated and purified” natural products? Are cDNAs nonetheless obvious, and therefore unpatentable for that reason? And, considering the Court’s mention of retrovirii, how “unusual and rare” must a “natural phenomena” be to still be patent eligible if synthetically created? These are issues that the lower courts are likely to struggle with going forward, and issues that may, one day, be back in the hands of the Supreme Court.

Jake Sherkow, JD, is a fellow at Stanford Law School’s Center for Law and the Biosciences. His current research focuses on the intersection of patent law, biotechnology, and agency regulation.

Previously: Supreme Court rules on Myriad’s “gene patenting” case and Are genes patentable? A summary of the Supreme Court case

Cancer, Genetics, In the News, Medicine and Society, Science, Science Policy

Supreme Court rules on Myriad’s “gene patenting” case

Supreme Court rules on Myriad's "gene patenting" case

This morning, the U.S. Supreme Court issued their anxiously awaited decision in the case of the Association for Molecular Pathology vs. Myriad Genetics, Inc. Often called the gene patenting case, the case raises the issue of whether companies like Salt Lake City-based Myriad Genetics, Inc. can patent genes, in this case, the BRCA1 and BRCA2 genes. Mutations in these genes confer a substantially higher risk of breast or ovarian cancer.

The Court ruled that naturally isolated DNA is not patentable, but that synthetic DNA (such as the cDNA for the BRCA1 and 2 genes) is patentable. The decision was unanimous. From the decision:

A naturally occurring DNA segment is a product of nature and not patent eligible merely becauseit has been isolated, but cDNA is patent eligible because it is not naturally occurring.

cDNA is not a “product of nature,” so it is patent eligible under §101. cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments. Its creation results in an exons-only molecule, which is not naturally occurring. Its order of the exons may be dictated by nature, but the lab technician unquestionably creates something new when introns are removed from a DNA sequence to make cDNA.

We’ll have a longer comment about the decision later today or tomorrow from Jacob Sherkow, JD, a fellow at Stanford Law School’s Center for Law and the Biosciences. Sherkow recently wrote a wonderful blog post for us summarizing the oral arguments in the case, which took place in April. And the SCOTUS blog carried a great, ‘made simple’ synopsis of the issue earlier this year for readers who want to quickly get up to speed.

The decision is likely to have far-reaching implications for the many other gene patents granted by the U.S. Patent and Trademark Office since the first gene (chorionic somatomammotropin) was patented by the University of California, Berkeley, in the early 1980s. The National Society of Genetic Counselors now estimate that around 20 percent of all human genes are patented.

Previously: Are genes patentable? A summary of the Supreme Court case, At Stanford event, cancer advocate Susan Love talks about “A future with no breast cancer” and BRCA patients use Stanford-developed online tool to better understand treatment options
Photo by Mark Fischer

Ethics, NIH, Patient Care, Pediatrics, Research, Science Policy

Bioethicists say criticisms of preemie oxygen study could have “chilling effect” on clinical research

Bioethicists say criticisms of preemie oxygen study could have “chilling effect” on clinical research

Thanks to a public outcry that included objections from bioethics experts from across the country, the federal Office for Human Research Protections (OHRP) has decided to suspend sanctions it imposed earlier this year on a study of blood oxygen levels used to treat premature infants. The OHRP’s sanctions, issued in March, sharply criticized the study’s leaders for not providing the infants’ parents with adequate information about the risks of the trial. But many bioethics experts disagreed with the OHRP’s assessment of the situation.

Last week, a group of more than 40 of the country’s top bioethicists, including two at Stanford, sent a letter to OHRP stating that the sanctions could have a chilling effect on much-needed clinical research. In a highly unusual action, Francis Collins, MD, PhD, the director of the National Institutes of Health, worked with two colleagues to write a similarly critical letter that said, in part:

This controversy has alarmed some of the parents of infants who were in the study, confused the biomedical research community, and befuddled IRBs. Several other studies seeking new insights to improve care for these vulnerable infants have been put on hold as the field tries to understand the OHRP findings.

The two letters appear online today in the New England Journal of Medicine (NEJM), and constitute a remarkably intense criticism of the OHRP, the agency within the U.S. Department of Health and Human Services responsible for overseeing the safety and well-being of human research subjects.

I’ve been following the developing story with the help of Stanford bioethicist David Magnus, PhD, who was one of the writers of the bioethicists’ letter. Last week, before the agency revised its stance, Magnus summarized what the bioethics community found objectionable about the OHRP’s sanctions: “They believe in an absolute interpretation of risk,” he said. The agency’s risk assessment was based “not [on] what kids who are actually sick would be exposed to, but what a healthy child would be exposed to.” Healthy babies born at term face much lower risks of severe eye disease, neurological damage and death than the babies in the study – but the tiny preemies in the study weren’t healthy term infants, and were not placed at additional risk, the bioethicists assert, because of their participation in the study.

The tussle has a complex back story that involves 1,300 fragile premature infants, their parents, 23 academic medical centers and an important piece of paperwork.

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NIH, Research, Science, Science Policy

Shortfall of physician-scientists: “A national concern”

Shortfall of physician-scientists: "A national concern"

The importance of the physician-scientist is the focus of a new Perspective piece in the New England Journal of Medicine. Writing that an increasing number of MDs have moved away from the laboratory and into clinical practice, and calling the shortfall of new physician-researchers a “national, if not global, concern,” Michael M. Gottesman, MD, outlines how the National Institutes of Health is working to reverse the trend. And he notes that the awarding of the 2012 Nobel Prize in Chemistry (which went to Robert Lefkowitz, MD, and Stanford’s Brian Kobilka, MD, both trained in cardiology) “should remind us of the critical role that clinician-scientists have played in formulating the seminal concepts that govern modern biomedical science.”

Previously: Funding basic science leads to clinical discoveries, eventually, Why basic research is the venture capital of the biomedical world, At press conference, Nobel Laureate Brian Kobilka discusses his research and “irrational optimism” and Stanford’s Brian Kobilka wins 2012 Nobel Prize in Chemistry

Genetics, In the News, Medicine and Society, Science, Science Policy

Are genes patentable? A summary of the Supreme Court case

Are genes patentable? A summary of the Supreme Court case

As you likely heard, the Supreme Court heard oral arguments yesterday in a case that’s of interest to many biomedical researchers. That case, widely known as the “gene patenting case,” has a single question presented: “Are human genes patentable?” It may irk some researchers and clinicians that the answer isn’t a straightforward “no.” But the issues are surprisingly complex: How does one define a “gene,” and a “human” vs. a “synthetic” one at that? What about primers, probes, and cDNA? And what does one mean by “patentable”?

First, a brief lay of the legal landscape. Typically, an inventor cannot patent a “product of nature.” But ever since a 1911 appellate decision (.pdf), a natural product can be patented if it’s “isolated and purified” from its surrounding environment. Thus, the chemical compound adrenaline was itself patented because it was isolated and purified from adrenal glands. Shockingly, the Supreme Court has never directly reviewed this isolated and purified doctrine, even after 102 years.

This all raises the question of whether human genes should be allowed to be patented as a matter of policy, if not law.

And so, on this basis, isolated human genes have long been patented. In 1994, researchers at the University of Utah finally located and sequenced (.pdf) the BRCA-1 and BRCA-2 genes, variants of which put women at astonishingly high risk for early onset breast and ovarian cancer. Those researchers obtained patents on both the isolated sequences and cDNA variants of those, and assigned them to Myriad Genetics, a diagnostic testing company.

Arguments at the Supreme Court - and the justices themselves – grappled with the distinctions between isolated genomic DNA and cDNA. Lower court opinions had made a significant case out of the fact that because the covalent bonds of isolated genomic DNA were cleaved from the surrounding chromosome, an isolated gene was, in fact, a new chemical entity. Similarly, several justices suggested that because cDNA was not found in nature, it too, was patentable – even if it was simply the product of reverse transcribing an mRNA sequence. (For a further breakdown on the oral arguments themselves, see Stanford’s Center for Law and the Biosciences’ oral argument recap.)

But it seems that at least five justices – and thus, a majority – believe that patents on isolated DNA are not eligible for patent protection. They don’t seem to buy the argument that simple covalent cleavage renders something a new chemical entity. The Court and lawyers deployed various analogies to make this point: gold from ore, a piece of wood from a tree, a liver from a patient, etc. It seems less clear, however, whether a majority will similarly rule cDNA to be patent ineligible.

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Media, NIH, Research, Science Policy

NIH deputy director discusses blogging and science policy

NIH deputy director discusses blogging and science policy

Rock Talk, a National Institutes of Health (NIH) blog on extramural research policy, debuted two years ago as a way to enhance transparency about how the federal agency develops policies and present data that influence such decisions.

In a commentary published yesterday in Nature, Sally Rockey, PhD, deputy director for extramural research at the NIH, discusses her motivation for launching the blog and how it has increased dialogue with constituents about science policy. She writes:

We learned a lot about our constituents’ interests and needs through the blog, and we have been able to highlight behind-the-scenes data, actively engage the community in policy-making and provide insight into our decisions. Without public input, effective and impactful policy cannot be created. My blogging experience has convinced me that using social-media platforms is one effective way for science-funding agencies to successfully support research.

The blog is not the official vehicle for communicating policy changes. We have the NIH Guide for Grants and Contracts for that. And we have official channels for soliciting public feedback — through requests for information in the NIH Guide, for example. But the blog allows me to extend that conversation to people worldwide, many of whom I would not be able to reach in other ways. People are sometimes concerned that offering a dissenting opinion to NIH officials might affect their chances of getting funding. Although that is absolutely not the case, one advantage the blog does have over some other channels is that it allows people to remain anonymous if they wish.

In addition to fostering conversations on policy, Rockey offers examples of how the blog has allowed her team to provide real-time updates during national emergencies, such as Hurricane Sandy, and debunk urban myths about NIH-supported research.

Previously: Veteran blogger offers tips for starting a science blog

Aging, Cancer, Clinical Trials, Dermatology, Research, Science, Science Policy, Stanford News

Funding basic science leads to clinical discoveries, eventually

Funding basic science leads to clinical discoveries, eventually

When I first interviewed Brian Kobilka, MD, winner of the 2012 Nobel Prize for Chemistry in October, I was struck by an off-hand comment about his motivation for his near-obsessive two-decades long research quest to uncover the workings of GPCRs, or G-protein-coupled receptors, which serve as one of the main methods of molecular communication within the body.

The research, which it’s believed will lead to the creation of new drugs for clinical care, was not originally done for this purpose. It was motivated by simple scientific curiosity – the kind that often leads to amazing discoveries that help cure suffering or save lives. Initially, Kobilka just really wanted to know how it worked.

In a story published in today’s Inside Stanford Medicine,  I describe the success of research based on scientific curiosity in leading to clinical care breakthroughs. The story describes the 30-year history of scientific breakthroughs that led to the approval of a new drug called vismodegib that is used to treat inoperable basal cell carcinomas, and how the drug helped save the eyesight of 101-year-old Winnie Bazurto of San Mateo, Calif. It’s a story that begins with a similar motivation – basic scientific interest – and ends with discoveries that help patients in a very practical way. As Jean Tang, MD, PhD, Bazurto’s dermatologist and vismodegib researcher, says in the article:

If a patient only knew the whole story — how the happenstance of science led to their treatment… If they could go back to when this molecular pathway was first discovered in fruit flies, they’d be amazed. It’s not until the dots are connected 30 years later that it begins to make sense.

Stanford’s Matthew Scott, PhD, one of the key players in this basic-science success story, commented to me in an e-mail just how essential it is for future clinical discoveries that basic science continues to be funded. He expressed concern about a current trend toward conservatism in funding that requires much quicker results that lead to treatment options for patients saying, “Current conservatism in funding asks for translational work that gives cures in a few years (which never happens). Far-sighted funding of basic science … pays off big time.”

The vismodegib story illustrates just how essential basic science is to the future of clinical discoveries:

For many of the basic scientists involved in this research, the clinical use of hedgehog-inhibiting drugs to treat patients like Bazurto — while not the original goal of their research — is the ultimate success.

Previously: Why basic research is the venture capital of the biomedical world, Future of medical research is at risk, says Stanford medical school dean and The economic benefits of publicly funded medical research
Photo by Norbert von der Groeben

Ethics, In the News, Science Policy, Stem Cells

Supreme Court decision on human embryonic stem cell case ends research uncertainty

Supreme Court decision on human embryonic stem cell case ends research uncertainty

Yesterday, the Supreme Court declined to hear the case of Shirley vs. Seblius, which challenged the federal government’s right to fund research on human embryonic stem cells. This is good news for stem cell researchers. I asked Stanford law professor and bioethicist Hank Greely, JD, about the verdict, and he told me this morning:

At last, it’s over!  To call Sherley v. Sebelius our long national nightmare is a bit of an overstatement, except as to those keenly interested in pluripotent stem cell research.  This case, filed in August 2009, should have been thrown out by October 2009.  (Ironically, the district court judge did try to throw it out then, but used what the appellate court considered the wrong approach.)   But, at long last, after 41 months of uncertainty, leavened with occasional shock and panic, the case is dead.  The Supreme Court has, not surprisingly, denied review of the decision by the Court of Appeals for the District of Columbia Circuit, which upheld the district court’s summary judgment in favor of the plaintiffs.

And so it is finally established that, no, Congress did not, in the Dickey-Wicker Amendment, as re-passed every year since 1996, try to outlaw the positions taken by the Clinton, Bush, and Obama Administration.  Funding human embryonic stem cell research does not violate the NIH appropriations provisions.  It does, however, still rest within the discretion of the sitting President.  That seems safe for the next four years; it would be good if Congress could pass legislation expressly supporting such research for the four, and eight, and twelve, years beyond that.

Greely has been outspoken about the ongoing case on the Center for Law and the Biosciences‘ blog. You can read more about the legal background of the case here and in subsequent entries.

Previously: Judge Lamberth dismisses stem cell lawsuit, Stanford law professor on embryonic stem cell ruling and Stem cell funding injunction overturned by federal court

 

Health Policy, In the News, Pediatrics, Public Health, Research, Science Policy

Gun safety addressed by editorials in three JAMA journals

Gun safety addressed by editorials in three JAMA journals

In the wake of last week’s tragic school shooting in Connecticut, three Journal of the American Medical Association publications are running editorials today about gun safety. All three are free online and worth reading. Archives of Internal Medicine‘s piece advocates for tighter restrictions on the sale of guns and ammunition, while the editorial in Archives of Pediatric & Adolescent Medicine describes the legal battle in Florida to defeat a law that would muzzle pediatricians’ first-amendment right to talk with their patients’ parents about gun safety in the home.

The piece that I found most powerful, however, was JAMA‘s Silencing the Science on Gun Research, in which the authors describe how Congress has systematically stripped all Department of Health and Human Services agencies of the ability to fund research into the epidemiology of gun injuries:

In 1996, pro-gun members of Congress mounted an all-out effort to eliminate the National Center for Injury Prevention and Control at the Centers for Disease Control and Prevention (CDC). Although they failed to defund the center, the House of Representatives removed $2.6 million from the CDC’s budget—precisely the amount the agency had spent on firearm injury research the previous year. Funding was restored in joint conference committee, but the money was earmarked for traumatic brain injury. The effect was sharply reduced support for firearm injury research.

To ensure that the CDC and its grantees got the message, the following language was added to the final appropriation: “none of the funds made available for injury prevention and control at the Centers for Disease Control and Prevention may be used to advocate or promote gun control.”

Congress later expanded this restrictive language to all DHHS agencies, including the National Institutes of Health, the authors explain. They conclude:

Health researchers are ethically bound to conduct, analyze, and report studies as objectively as possible and communicate the findings in a transparent manner. Policy makers, health care practitioners, and the public have the final decision regarding whether they will accept, much less act on, those data. Criticizing research is fair game; suppressing research by targeting its sources of funding is not.

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Events, Media, Medicine and Society, Neuroscience, Research, Science Policy

Stanford scientist sets sail on new publishing model with launch of open-access, embargo-free journal

Stanford scientist sets sail on new publishing model with launch of open-access, embargo-free journal

A new study from Stanford molecular and cellular physiologist Axel Brunger, PhD, and colleagues clears up a controversy in the neuroscience community by pinpointing a critical feature of the mechanism by which our nerve cells manage to talk to one another in something approaching real time. If that conversation were stuck in slo-mo, the distinction between brain and blob would vanish.

While the study is noteworthy in itself, the fact that its findings appear in the first issue of eLife, a newly launched open-access journal, rather than Science or Nature is also significant. As a Howard Hughes Medical Institute investigator with close to 250 peer-reviewed publications under his belt, Brunger is hardly hard-up for high-rated scientific outlets. But his experience, he tells me, has made it clear that “our peer-reviewed publication system is in a state of crisis.”

It seems other scientists feel the same. A University of Montreal study published in November concluded that the most prestigious journals were publishing fewer and fewer of the most frequently cited articles.

“For many ‘high-impact factor’ journals, initial triaging and final decisions aren’t made by active scientists,” says Brunger. “That’s not to say that these journals don’t publish excellent work, but the criteria for acceptance seem rather arbitrary and random.”

The brainchild of three heavyweight research-funding entities – HHMI, the Max Planck Society, and Wellcome Trust – eLife is not only open-access, but publication-immediately-upon-acceptance and embargo-free. (Not to mention just plain free, for both authors and readers.) Brunger’s is one of a score or so of research papers selected for eLife’s first issue, which published today.

Photo by mikebaird

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