GeneWatch Vol. 23 No. 5-6 by Council for Responsible Genetics

VOLUME 23 NUMBER 5-6 OCTOBER-DECEMBER 2010 SPECIAL DOUBLE ISSUE

THE MAGAZINE OF THE COUNCIL FOR RESPONSIBLE GENETICS | ADVANCING THE PUBLIC INTEREST IN BIOTECHNOLOGY SINCE 1983

FEATURES

ISSN 0740-9737

Genes, Patents, Common Sense and the Law / James Evans Interviews: The ACLU, Public Patent Foundation, and Myriad Genetics Special topic: Assisted Reproductive Technology

Special Topic: Gene Patents

All that glitters is not necessarily patentable (p. 6)

Dedication: Paul Steven Miller JEREMY GRUBER

Genes, Patents, Common Sense and the Law JAMES EVANS

When the Grass Eats the Cows JOHN CONLEY AND DAN VORHAUS

The Plantiffs 10 AN INTERVIEW WITH SANDRA PARK OF THE ACLU The Defendants 12 AN INTERVIEW WITH RICHARD MARSH OF MYRIAD

It’s time for a rational approach to the gene patent mess (p. 8)

GENETICS Both sides of the BRCA case speak to GeneWatch (p 10 and 12)

Protecting the Intellectual Foundations of 16 Genetic Science EILEEN M. KANE The Danger of the Broad Brush 18 CHRISTOPHER M. HOLMAN The Overstated Case 20 ROBERT COOK-DEEGAN

Can gene patents coexist with a preserve of open knowledge? (p 16)

The Sky Is Not Falling 22 AN INTERVIEW WITH DANIEL RAVICHER OF THE PUBLIC PATENT FOUNDATION Why Banning Patents Would Hurt Patients 24 SHARON TERRY The Physical Embodiment of Information 26 MAGDALINA GUGUCHEVA A Return to Judging 28 MICHELE GOODWIN The President of Genetic Alliance defends the utility of gene patents (p 24)

Why Genes Must Remain Eligible for 30 Patenting KEVIN NOONAN Naturally Occurring Genes and the 32 Commons by Necessity DAVID KOEPSELL The problem with gene patents goes beyond the practical - it’s also a matter of property rights (p 32)

2 GENEWATCH

OCTOBER-DECEMBER 2010

Despite the legal challenges to gene patents, patents on organisms are still very much accepted (p. 38)

The Salzberg Screen AN INTERVIEW WITH STEVEN SALZBERG

In Defense of a Working Good PAUL BILLINGS

Freedom of Genes DEBRA GREENFIELD

Patents on Genes, Organisms - and Human(oid)s? STUART NEWMAN

Synthetic Biology: The Next Wave of Patents on Life ERIC HOFFMAN AND JAYDEE HANSON

****

Diane Beeson, Hedva Eyal and Kathleen Sloan write on the critical issues of assisted reproductive technologies (p 42, 45 and 47)

EEOC Issues Strong Final Rule Implementing GINA JEREMY GRUBER

Dangerous Harvest DIANE BEESON

Reproductive Trafficking HEDVA EYAL

Film Review: Eggsploitation KATHLEEN SLOAN

Topic Updates: DNA Alarms, Mandatory Sickle Cell Testing, and GM Mosquitoes

Is Government Getting Out of the Ethics Business? JEREMY GRUBER

Endnotes

Yes, you are reading this sign correctly (p 48)

VOLUME 23 NUMBER 5-6

GENEWATCH 3

GENEWATCH OCTOBER-DECEMBER 2010 VOLUME 23 NUMBERS 5 & 6 & DESIGNER Samuel Anderson

EDITOR

EDITORIAL COMMITTEE

Ruth Hubbard Sheldon Krimsky Jeremy Gruber GENEWATCH is published by the Council for Responsible Genetics (CRG), a national, nonprofit, tax-exempt organization. Founded in 1983, CRG’s mission is to foster public debate on the social, ethical, and environmental implications of new genetic technologies. The views expressed herein do not necessarily represent the views of the staff or the CRG Board of Directors.

ADDRESS 5 Upland Road, Suite 3 Cambridge, MA 02140 PHONE 617.868.0870 FAX 617.491.5344 NET www.councilforresponsiblegenetics.org BOARD OF DIRECTORS SHELDON KRIMSKY, PhD, Board Chair Tufts University PETER SHORETT, MPP Treasurer The Chartis Group EVAN BALABAN, PhD McGill University PAUL BILLINGS, MD, PhD, University of California, Berkeley SUJATHA BYRAVAN, PhD Centre for Development Finance, India ROBERT DESALLE, PhD American Museum of Natural History ROBERT GREEN, MD, MPH Boston University JEREMY GRUBER, JD Council for Responsible Genetics RAYNA RAPP, PhD New York University PATRICIA WILLIAMS, JD Columbia University STAFF Jeremy Gruber, President and Executive Director Sheila Sinclair, Manager of Operations Samuel Anderson, Editor of GeneWatch Kathleen Sloan, Program Coordinator Andrew Thibedeau, Senior Fellow Magdalina Gugucheva, Fellow

4 GENEWATCH

Editor’s Note BY SAMUEL ANDERSON You are reading the largest issue—by far—in GeneWatch’s 27-year history, and the majority of the articles and interviews herein focus on the topic of gene patents. It might have been more difficult to fill the better part of 52 pages with discussion of a single topic if everyone wasn’t already talking about it. Now, you might as well know upfront that the Council for Responsible Genetics’ official position on gene patents is more than a little critical … which is to say, some of CRG’s board and staff have put in a good deal of work to support a ban of gene patents. However, GeneWatch is not in the business of simply lining up a powwow of agreement. Some of the voices represented in this issue fall on the other end of the spectrum, supporting the logic and utility of allowing patents on genes. David Koepsell (p. 32) and Kevin Noonan (p. 30) have butted heads over the issue in other venues; James Evans (p. 6) coauthored a key report criticizing the gene patent system, and Paul Billings (p. 35) co-authored the dissent; and Sandra Park of the ACLU (p. 10) and Daniel Ravicher of the Public Patent Foundation (p. 22) are plaintiffs in the suit against Myriad Genetics, for which Richard Marsh (p. 12) is General Counsel. That case—in which a district court ruled several of Myriad Genetics’ patents on genes related to breast cancer invalid—is referenced often in the following pages. Association for Molecular Pathology et al. v US Patent and Trademark Office et al. (or, for short, AMP v. USPTO, or AMP, or ‘the Myriad case,’ or ‘the BRCA case’) has drawn national media attention, and with it, the kind of hyperbole made for sound bites. Some opponents of gene patents don’t mind suggesting that by patenting human genes, a company or scientist literally owns us; while some pro-patent advocates seem to believe that the biotech industry, and the entire country

with it, is on its way to utter ruin if gene patents are invalidated. Yet in a debate so rife with hyperbole, there is a wide gulf of gray area. Even if the Myriad case—currently under appeal—must ultimately fall one direction or the other, it has stirred up a wider discussion with plenty of room for nuance. Both the hyperbole and the nuance were apparent in the various responses to a Department of Justice amicus brief pertaining to the Myriad case. The brief held that human genes are, as products of nature, unpatentable, and that when a DNA molecule is isolated it is “no less a product of nature … than are cotton fibers that have been separated from cotton seeds or coal that has been extracted from the earth.” Many anti-gene patent advocates celebrated the brief as a victory, even though, as Magdalina Gugucheva (p. 26) points out, the brief ’s actual position actually falls well short of endorsing a ban on gene patents. Meanwhile, patent lawyer Harold C. Wegner summed up his thoughts in an email newsletter: “Eric Holder Hijacks the Patent System, Flunks Patents 101.” Exaggeration is interesting, which is why I am a bit sorry to tell you that the following pages are chock full of intelligent, level-headed discussion. Then again, depending on where you stand, you may find some of it not quite so enlightened. At any rate, I can guarantee you this much: you won’t agree with everyone. Wouldn’t that be boring?

What do you think? GeneWatch welcomes all comments and letters to the editor. Please email anderson@gene-watch.org if you would like to submit a letter (400 words or less, please) or with any other comments or queries.

Featured artist Sarah Kim is a graduate of Massachusetts College of Art and Design who enjoys working on any and all kinds of illusration. You can see more of her work at www.skimilkart.com. This is Sarah’s fifth GeneWatch cover. OCTOBER-DECEMBER 2010

Dedication: Paul Steven Miller BY JEREMY GRUBER This special issue of GeneWatch magazine is dedicated to the memory of Paul Steven Miller (1961-2010), who recently passed away from cancer at the young age of 49. Paul was a friend and advisor to the Council for Responsible Genetics, a tireless advocate for disability rights and a great humanitarian. During the course of an extraordinary and highly successful career, Paul fought against those who judge people on how they look or their gender, race, age, or nationality. Paul was born in Flushing, NY with the genetic condition achondroplasia, a type of dwarfism. Paul never let his condition define him or his accomplishments, though. He went on to graduate at the top of his class at the University of Pennsylvania and then Harvard Law School. Despite his academic achievements, he received 45 rejection letters from small-minded law firms before finding a position with Manatt Phelps in Los Angeles (Paul's work at the firm would become the inspiration for the character Hamilton Schuyler on the series L.A. Law). Paul went on to become Director of Litigation for the Western Law Center for Disability Rights, a leader of Little People of America, and then Deputy Director of the U.S. Office of Consumer Affairs. An appointment as White House liaison to the disability community followed, a position Paul held under both the Clinton and Obama administrations, and which he used to help recruit individuals with disabilities to take positions all over both administrations. "I felt compelled to do something more meaningful with my career that would have an impact," he said in a 2004 interview. And have an impact he did. Paul was instrumental in helping write the Americans with Disabilities Act, the landmark civil rights law which marked its 20th anniversary several months ago. In his own words: I think the reality for students with disabilities, for professionals with disabilities, is dramatically different today than it was a scant 15,18 years ago â&#x20AC;Ś I think that's attributable to the ADA, to an education process that employers have begun to journey down â&#x20AC;Ś It has made America stronger, because it forces employers to focus more on people's qualifications than on stereotypes about that individual's disability. In 1994 President Clinton appointed

VOLUME 23 NUMBER 5-6

Paul to be a commissioner of the Equal Employment Opportunity Commission where he worked for ten years, becoming one of the longest serving Commissioners in the history of the Commission. As Commissioner, Paul spent much of his time on developing ADA enforcement. He successfully spearheaded efforts to improve the agency's legendary backlog through mediation and became the agency's most visible spokesperson against all types of discrimination, particularly on behalf of people with disabilities, reaching out to people all over the United States and the world, educating them, encouraging them to use the system, and as a result improving the lives of millions. Paul was a member of the HHS Secretary's Advisory Committee on Genetics, Health and Society. Noting gaps in the ADA, Paul became an early champion of genetic nondiscrimination legislation and frequently wrote on the topic. It was in this vein that I came to know Paul as we worked together for over 15 years on the successful passage of what would become the Genetic Information Nondiscrimination Act. Paul was a true genius on disability and employment discrimination law and a force of nature on any issue he worked on. He helped settle the EEOC's first court action against genetic testing in the workplace and led the drafting of the Presidential Executive Order on Genetic Discrimination and Privacy which created the first legal protections against genetic discrimination for Federal employees. That same year, in testimony before the U.S. Senate, Paul declared: In this country, people should be judged based upon their abilities, and not based upon fears, myths, or stereotypes. Yet, with the expansion of genetic information available to employers, there is a risk that employers will misinterpret and misuse genetic test results to weed out persons according to their perceived health risks based on genetic information. Furthermore, people may refuse to take genetic tests, a potentially lifesaving measure, out of fear that employers may discriminate against them. For these reasons, genetic information does not belong in the workplace. Paul left the EEOC in 2004 to become the Henry M. Jackson Professor of Law at the University of Washington School of Law

from which he took a temporary leave to serve as Special Assistant to the President in the first year of the Obama administration where he managed Presidential appointments and nominations. In his final years he focused on tensions between disability rights and genetic science. In a paper titled "Avoiding Genetic Genocide," Paul criticized scientists for what he saw as their eagerness to use genetics to produce "perfect" humans. He wrote: Good health is not the absence of a disability. Scientists caught up in the excitement of genetic discovery can forget that life with a disability can still be a rich and fulfilling life. As his wife, Jenni, recounted at his recent memorial service in Washington D.C., Paul had the "golden rolodex." But unlike most well connected persons, Paul built friendships from the most distinguished of colleagues to the least and everyone in between. Moreover he went out of his way to give of his time to everyone he knew. And he did it all with an incredible wit and sense of humor. In his final year, when cancer treatments required his arm to be amputated, Paul joked that he was the only one-armed Jewish dwarf to ever serve in the White House. In a statement released shortly after his passing, President Obama declared about Paul Miller: More important than any title or position was the work that drove him. He dedicated his life to a world more fair and more equal, and an America where all are free to pursue their full measure of happiness, and all of us are better off for it. Paul was a giant to everyone who knew him and he will be sorely missed. Our best wishes go out to his wife Jenni and daughters Naomi and Delia. Jeremy Gruber is President and Executive Director of CRG.

GENEWATCH 5

Genes, Patents, Common Sense and the Law Eliminating patents on naturally occurring phenomena is both logical and in our best interest

The Secretary's Advisory Committee on Genetics, Health, and Society no longer exists, having been allowed to sunset in late 2010. The committee was active on many fronts, having weighed in on the issue of genetic discrimination, direct to consumer genetic testing, and the regulation of laboratory testing, among others. One of its most high profile legacies may be the work that it did with regard to gene patenting. In early 2010 SACGHS made a set of formal recommendations to the Secretary of Health and Human Services advocating that legislative actions be pursued to create an exemption from infringement for those who use patented genes in diagnostic tests as well as to create a broad research exemption for those who use patented genes in the pursuit of research. The report also advocated against the granting and enforcement of "association patents" in which a simple association

6 GENEWATCH

between genotype and phenotype is claimed as patentable. The recommendations of SACGHS were lauded by some and reviled by others. In light of events since issuance of that report, the recommendations may seem less extreme to those who objected to them. Notably, in the spring of 2010, Judge Roberts Sweet issued a ruling in the Federal District Court for the Southern District of New York which, while tangibly of minimal effect, served to dramatically focus attention on the issue of gene patents and make a high profile court case even more dramatic (Association for Molecular Pathology et al. v. US Patent and Trademark Office et al.). In short, Judge Sweet ruled in summary judgment that the plaintiffs were correct and that genes were not legitimately patentable material. His argument was novel and, at least to this geneticist, persuasive. In short, Judge Sweet argued that

the natural function of a gene is to encode information and thus the mere isolation of a gene (or for that matter its manipulation into another form which does not substantially affect the nature of that information) does not qualitatively change the material in any legitimate intrinsic sense and therefore cannot be patented. The next surprising development was the filing of an amicus brief by the Department of Justice which argued largely in support of the plaintiffs, agreeing that naturally occurring genes are not patentable material. The case is being appealed, and while conventional wisdom holds that Judge Sweet's decision will be overturned, if there is one thing we should have learned from the recent history of gene patents and the courts it is that making predictions is a rather hazardous endeavor. Taking the (perhaps na誰ve) view that logic should play a role in the decisions of courts, it seems to me that the way forward is clear. The information content of any given gene has evolved over millions of years and human genes existed within us long before we began to dissect our own genomes. Patenting the information contained in human genes (by either patenting a naturally occurring gene or a modified version of that gene which imparts essentially the same information) is extremely hard to justify while maintaining a straight face. The law has always held that we cannot patent gold, sunshine or an unmodified field mouse. It is therefore difficult to envision just how we could legitimately sanction the patenting of naturally occurring genes or the information contained therein. One is, of course, perfectly free to patent novel and inventive methods for purifying an element like gold or silver, as well as new means of capturing sunlight to accomplish a particular purpose like powering an electrical grid. One is also free to patent a new type of mouse that has never existed before. In the same vein, if one modifies the information in a gene in a

OCTOBER-DECEMBER 2010

Images: Wikimedia Commons (modified)

BY JAMES EVANS

way that is novel, non-obvious, and useful, it is eminently reasonable to expect patent protection on such an invention. The creation of new DNA sequences that perform novel feats and convey novel information should be patentable–but merely isolating a naturally occurring gene and distilling its information (for example in a cDNA), no matter how difficult, ingenious or useful, renders that gene no more patentable than silver would be should I invent a new method for its purification. In the furor over gene patents it is often forgotten just why the patent system exists in the first place. Patents were enshrined in the US Constitution in order to "promote the progress of science and useful arts." Thus the primary intent of the patent system is a broad social goal–not the creation of profit. Certainly the harnessing of self interest is a significant means by which the patent system exerts its power, but we should not forget that stimulation of commerce is only the means by which we hope to achieve the beneficial effects of the patenting system. If the primary intent of the patent system was merely the stimulation of commerce then we would, as the DOJ brief pointed

conditions are met–conditions which have not been met by those who hold current gene patents. Moreover, the claims that the commercial scientific infrastructure of the country will topple if gene patents are found to be unenforceable are silly. Indeed, the evidence suggests that far from precipitating catastrophe, the elimination of gene patents would be a boon to commercial activity. The SACGHS report, based on empiric studies of the

Those few companies that have staked their business model on insuring no competition through the enforcement of gene patents will suffer should genes be rendered unpatentable ... but both the broad market and the public will benefit.

out, allow the patenting of far more things than we do. The hyperbole found on both sides of this debate can reach remarkable levels. On one hand, I see no inherent metaphysical objection of the patenting of genes or life forms as long as they are truly novel, useful and non-obvious. Indeed, should human ingenuity prove able to best evolution by creating novel DNA sequences which impart new information in order to treat disease and ease human suffering, this seems a worthy (and patentable) pursuit. On the other hand, patenting is not a right. It is a privilege granted when certain specific

VOLUME 23 NUMBER 5-6

gene patenting landscape, is particularly informative with regard to this issue. About 20% of the human genome is patented, which means that some disease-relevant genes are under patent while some are unconstrained by exclusivity. In work commissioned by SACGHS, a study of this landscape revealed that for genes which happen not to be under exclusive constraint (such as cystic fibrosis and Huntington's disease) a thriving market place exists where dozens of laboratories –both private and public–vie to outcompete one another on the basis of innovation, quality and service. However, for those genes controlled

by patent-enabled exclusivity, where only a single laboratory is permitted to analyze them, what one sees is a striking lack of any meaningful competition, undermining access, quality and innovation. To be sure, those few companies that have staked their business model on insuring no competition through the enforcement of gene patents will suffer should genes be rendered unpatentable–but both the broad market and the public will benefit. Finally, the SACGHS report advocated that a broad exemption be made for those who use patented genes in the pursuit of research. Nothing could be more in keeping with the intent of the patent system itself. Indeed, restricting research with patents is antithetical to the very purpose of the patent system: instead of promoting progress, it squelches progress and innovation at the most proximal conceivable point. Thoughtfully granted patents are an undeniable boon to progress and human well being, but inappropriately granted patents can just as surely suffocate innovation. Eliminating patents on naturally occurring phenomenon such as the information contained in genes is not only logical but will stimulate progress and productivity. The elimination of toll gates at the extreme upstream position of the gene will harness self interest and human ingenuity to the benefit of all. James P. Evans, PhD, MD, directs the Clinical Cancer Genetics Services at the University of North Carolina School of Medicine and was a member of the Secretary's Advisory Committee on Genetics, Health, and Society.

GENEWATCH 7

When the Grass Eats the Cows The gene patent mess calls for a rational solution BY JOHN CONLEY AND DAN VORHAUS

and the single court decision to consider it even obliquelyâ&#x20AC;&#x201C;the Federal Circuit's 1991 decision in Amgen v. Chugaiâ&#x20AC;&#x201C;had dismissed it in a footnote. Chemistry triumphed over information, and the semantics of patent claiming seemed to have foreclosed a potentially fundamental issue. Then came Judge Sweet's Myriad (Association for Molecular Pathology v. USPTO) district court opinion invalidating Myriad's isolated gene patents and, at least for a moment, the world turned upside down (the title of the song that Cornwallis' band played during the surrender at Yorktown: "If ponies rode men and if grass ate the cows"). Judge Sweet adopted the information-first argument, deriding the gene-in-isolation distinction as "a patent lawyer's trick." Roberte and I were simultaneously gratified and horrified that our thought experiment had become (at least ephemeral) legal reality. As we await the Federal Circuit's decision in Myriad, there's very little new to say about the case. Reactions have been

predictable. Disinterested legal commentators have almost universally predicted that the Federal Circuit will reverse or at least significantly limit the scope of the district court's rulingâ&#x20AC;&#x201C;it's just too doctrinally radical to stand, posing too much risk to the biotechnology industry. Advocates have performed their expected roles: Big Biotech sees signs of the apocalypse, while public domain enthusiasts see a new golden age of genetic research unencumbered by patents. Most of this attention, however, has been focused on what might be the less important part of the case: the gene patents. Technology and other principles of patent law may be conspiring to reduce the practical significance of single-gene patents. On the technology side, more efficient (and much cheaper) wholegenome sequencing may permit new applications to avoid "using" protected single genes in isolation. (The Patent Act prohibits making, using, or selling the patented invention exactly as it's claimed in the patent.) Nonetheless, at least in the short to medium term, single-gene

Image: Samuel Anderson

Back in 2003, patent lawyer Roberte Makowski and I published an article in the Journal of the Patent & Trademark Office Society in which we argued that litigants and courts should revisit whether patents on genes, as conventionally drafted, violated the prohibition on patenting products of nature. We noted that claims on "isolated" (removed from their natural environment in the body) or "purified" (often, with non-coding regions removed, as with cDNA) genes evaded this prohibition by putting the focus entirely on chemical differences between such genes and their naturally occurring precursors. We then asked whether this exclusive focus made sense, given that people are interested in patenting genes because of their information-carrying capacity, which is the same in the natural and patented versions. We also noted that neither the United States Patent Office nor the courts had ever squarely addressed the product of nature argument. The USPTO had brushed it aside with references to novelty and utility, which are separate statutory questions,

8 GENEWATCH

OCTOBER-DECEMBER 2010

patents are likely to impede the development of gene-based diagnostic techniques (especially "multiplex" techniques that use multiple genes). On the legal front, note that Myriad is about only one aspect of patentability: whether the claimed invention is patentable subject matter. To say, as Judge Sweet did, that an isolated gene is a product of nature is to say that it does not fall within the realm of patentable subject

of methods generally is up in the air. The Supreme Court had a chance to clarify things this past summer in Bilski v. Kappos, which involved a simple business method, but its fractured opinions only confused things further. All we know for sure is that the Federal Circuit's machineor-transformation test (which requires that a method be tied to a particular machine, or transform something into a different state) cannot be the sole test. We await the Federal Circuit's further (remand) decision in Both sets of extreme reactions to Bilski, as well in Prometheus v. Judge Sweet’s Myriad decision are Mayo, which involves another almost certainly wrong: it is not the simple method, this time for adjusting the dose of medicaend of the world for commercial tion after measuring its level in biotechnology, nor is it the best the body. The Federal Circuit's possible outcome for science and decision in these two cases (assuming they come first) will medicine and their constituents. presumably shed some light on the likely fate of the Myriad matter. But in a 2009 case called In re method claims, and on medical associaKubin, the Federal Circuit made it much tion and diagnostic patents more easier to defeat single-gene patents on generally. Amidst all this legal uncertainty, it is obviousness ground. Reversing its own 1995 precedent, the court held that a gene worth stepping back and taking a practi(in cDNA form) was obvious when a lot cal look at the whole situation. Both sets was known about the protein it encodes of extreme reactions to Judge Sweet's and the method for sequencing it was also Myriad decision are almost certainly well-known-in other words, when it was wrong: it is not the end of the world for "obvious to try" to sequence that gene. commercial biotechnology, nor is it the This reinterpreted obviousness require- best possible outcome for science and ment may prove to be an insurmountable medicine and their constituents-that is, barrier to many, if not most, single-gene us. Gene patents themselves are not evil. On the contrary, they–and their prompatents in the future. The less-discussed but potentially ise of monopoly rents–have played an more significant patents at issue in Myr- essential role in financing the biotechnoliad are the company's method patents. ogy industry. The problem is not with These cover methods of making sense of gene patents per se, but with the way that gene test results and using them to make they can be used as barriers to research diagnostic predictions. They are extraor- and innovation. If Myriad had made difdinarily broad, allowing Myriad to ferent business judgments, its patents monopolize just about any diagnostic use would probably not be under attack. of the breast cancer genes, regardless of Would the ACLU have targeted Myriad if, for example, it permitted second-opinthe patents on the genes themselves. The patentable subject matter status ion testing by independent labs at

patient-friendly prices? Or if it had announced a broad, royalty-free research license for its genes? The complexity of the gene patent landscape–keep in mind that there are patents on an estimated 20% of human genes–along with the actions of certain patent holders, including Myriad, have combined to produce a dense gene patent "thicket" that threatens biotechnology innovation, particularly in the area of multiplex diagnostic technologies. The public disaffection with gene patents that Judge Sweet's opinion expresses so clearly will only get worse if the gene patent thicket begins to materially impair the development of these technologies. It's time for the biotechnology to move toward the kind of patent pooling that has facilitated the advance of so many other technologies, from sewing machines to jet engines. Innovators should have a place for one-stop shopping at reasonable prices, rather than facing individual patent-holders bent on monopolization and stacked gene patent royalties that threaten to exceed 100% of their revenues. Some biotech players might have short-term reasons for opposing this approach, but the current legal mess ought to be a wake-up call: if the industry doesn't move in this direction of a rational economic solution, courts and legislators will likely impose something far worse.

John M. Conley, PhD, JD, University of North Carolina School of Law; Of Counsel, Robinson, Bradshaw & Hinson, Charlotte, NC; Contributor, Genomics Law Report. Dan Vorhaus, JD, Robinson, Bradshaw & Hinson, Editor of Genomics Law Report.

The Council for Responsible Genetics has launched a new blog: Genetic Watchdog. Watch for regular news and commentary as recorded by CRG staff, board members, and friends, and join the discussion by leaving your own comments. You don’t have to wait for the next GeneWatch to keep up with the latest events in biotechnology and ethics! The blog can be found at: http://www.councilforresponsiblegenetics.org/Blog.

VOLUME 23 NUMBER 5-6

GENEWATCH 9

The Plaintiffs An interview with Sandra Park of the ACLU

Was the gene patents suit something that has been in the works for quite a while, or was it Myriad's more recent behavior that really spurred it? The case was developed over a significant period of time, but by the time it was taking shape, Myriad had already owned its patents for a long time, so we knew how they were enforcing their patents. When they obtained their patents, they immediately sent out cease and desist letters to labs, including a lab right by two of our clients. They immediately took action to enforce their patents in such a way as to prevent other labs from conducting clinical testing. Have you seen differences in the way that people are viewing gene patents since beginning work on this case? When patents on genes were first being issued back in the 1990s, there was advocacy organized to try to oppose those patents at the time, and it came largely from the scientific community and allied groups. At the time, though, I don't think that there were legal arguments for why these sorts of patents were invalid, and I think the case has really brought those legal issues-that these patents are for products of nature and therefore should not have been granted in the first place-to the fore. With the lawsuit and the accompanying media attention, there certainly has been greater awareness about the fact that genes are being patented. I think that the scientists who have been concerned about gene patents were on some level not sure how to do any further advocacy on the issue, and I'd say that there wasn't really that much advocacy being done on the issue until the lawsuit came around. There has been a lot of renewed interest in trying to stop these patents from interfering with clinical practice and research. Do you see that activism still gaining momentum, even after the initial explosion of media coverage around the District Court's ruling? Well, media coverage tends to focus on

10 GENEWATCH

specific events, so when the court decision came out, there was a lot of attention-partially because those in the patent world and in biotech were very surprised by the decision. But I wouldn't say the advocacy has died down, and I think that as the case continues through the appellate process, the media will be following it closely. The education that needs to be done on this issue should not just focus on the case. Whatever happens with the case-and I totally expect it to be successful-there are other fronts where people should continue to confront this issue. You know, media ebbs and flows, and the case has been a galvanizing force for media attention thus far, but other advocacy efforts are being organized. There was the SACGHS report which did get some media attention when it came out in February, making recommendations as to why gene patents should not be enforced, and in Australia there has been a lot of attention on the issue more generally and there have been ongoing advocacy efforts, both through a governmental investigation and a lawsuit that was brought there. So aside from this case, it's an issue that continues to receive a lot of attention. What kind of patterns do you see, if any, in terms of who lines up for and against gene patents? The plaintiffs in the case are scientific organizations, physicians, geneticists, researchers, patients, and breast cancer and women's health advocacy organizations; and I think that the amici and our side have really represented the entire medical and scientific community. We have also had some expert declarations, most notably from Joseph Stiglitz, on the economics of patents and why a patent incentive is not necessary and in fact impedes both economic progress and scientific progress on these issues. On the other side it has been, for the most part, biotechâ&#x20AC;&#x201C;but a particular segment of biotech. I think part of the reason is that these patents have been issued by the Patent Office for a period of time, and so, from an industry perspective, there's a level of comfort with the status quo,

regardless of the merits of the issue. Our position has always been that we actually think these patents impede the kind of research that I think a lot of biotech companies want to do in terms of development of products, and there are new technologies that are being developed that will actually be impeded if you need to go out and get licenses and permissions from patent holders on genes. My take on it is really that those who have come out against the suit are either patent holders themselves or part of the industry, and are just more comfortable with the status quo; but that in fact, if these patents were lifted, it would actually help their industry because there would no longer be impediments to the kind of research and product development that they want to do. If the plaintiffs win this case, how close does it come to closing the book on the issue? Will there still be a need to draw attention to gene patents? If the case is successful, it will be setting precedent for many, many gene patents; so while the case is being brought against particular patents, a ruling finding that isolated DNA cannot be patented will affect the other gene patents that are out there. I don't think public education on this issue should be focused on the case so much as on the fact that the Patent Office has been issuing these sorts of patents, and really looking, policy-wise, at why these patents don't serve our health and science policy. I think the case has been a galvanizing point in terms of how to bring this issue to the public and to the media, but I'd like the discussion to be much broader than simply the legal arguments that are being made. Are there any specific misconceptions you hear repeated a lot, other than just legal arguments, that you would like to

OCTOBER-DECEMBER 2010

Images: ACLU

Sandra Park, JD, is an attorney at the ACLU Womenâ&#x20AC;&#x2122;s Rights Project.

clear up? One argument we've heard is that this case will be the downfall of the biotech industry, and I just don't think that's at all the case. Our goal here is really to lift the monopoly on genes, the central thing needed for research and development to occur, so that's one of the spins on the case I think is wrong. In terms of public perception, when people first hear about it, I think their immediate assumption is that we're talking about patents on genetic tests, so we've really tried to make clear to people that the patents here are on DNA itself and not on particular tests. The way I think that is made especially clear is the fact that when Myriad obtained its patents on the DNA, they were able to send cease and desist letters to labs that were using different tests than the ones that Myriad uses. It is because their patents are on the actual DNA that they were able to stop labs from using different testing methods to analyze those particular genes. The other thing is just letting people know that this isn't a new issueâ&#x20AC;&#x201C;the scientific community has been concerned about it for a long time. It's new in the sense that this is the first lawsuit that has been brought to challenge it, but it's been an

VOLUME 23 NUMBER 5-6

ongoing problem. We have learned what the problems are from years of these patents being put in place and being enforced. Because we have had those bad experiences, seeing how these patents affect clinical practice and patient care, it has become even more clear to us that these patents should be challenged.

argument that I have heard, and a lot of the research that has been done on that issue show that patents are not at all necessary in terms of creating genetic tests. Other than that, the legal arguments have really not been compelling at all to me. It is true that each side sees it in their own way, but what I have found most strik-

While working on this issue, I've noticed that certain people on either side of the debate seem to think that no reasonable person could agree with their opponents. So: is there any argument in favor of gene patents where you think reasonable people could disagree? I understand why patent holders want to protect these patents, but I really haven't seen the arguments to back it up. The thing that I've heard most, and that Myriad has said most in their papers, is that they had to have the patent protection in order to commercialize the patents and spend many millions of dollars advertising the product and educating doctors about the test. I do think it's important for that kind of education to happen, so I certainly agree that it's an important function they have played; but I don't think at all that a patent is necessary for that to happen. Really, that has been the main

This isnâ&#x20AC;&#x2122;t a new issueâ&#x20AC;&#x201C;the scientific community has been concerned about it for a long time. ing is that the other side really does not want to acknowledge that the Supreme Court has recognized limits on what is patentable subject matter, regardless of whether it is new or useful. There are still limits to what can be patented, even if you are identifying something for the first time or even if you are identifying something useful. When Einstein gave us E=mc2, it was new and useful, but it could not be patented. That's what has been most striking to me, the rejection of that legal principle.

GENEWATCH 11

The Defendants An interview with Richard Marsh of Myriad Genetics

jobs and revenue. To take a position against all of that is rather surprising and troubling.

The Department of Justice recently released a friend-of-the-court brief agreeing with Myriad on some points, but holding that isolated DNA molecules are a product of nature and therefore not patentable. Would you count yourself among the many people who were surprised by this position? Yes, absolutely we were surprised. Particularly when you look at the past 30 years of practice of both the courts and the Patent and Trademark Office, which has now issued literally thousands and thousands of isolated DNA patents for human, plant and animal application … to see this shift now was very surprising. A curious note is that David Kappos, the director of the Patent and Trademark Office has said that at the PTO, they're continuing business as usual, that they're not following the position of the Department of Justice.

That's one of the common arguments in favor of gene patenting, that they incentivize capital investment to fund research; but there are also plenty of people who argue that gene patents actually inhibit research. Is there anything you can point to that convinces you that gene patents incentivize rather than stifle research? I would absolutely refute those allegations. They were postured in the lawsuit to try to influence Judge Sweet's decision making. As to Myriad specifically, they're absolutely false. How can you say that Myriad has ever, just once, told anyone not to do research? Not once. In fact there have been over seven or eight thousand articles which have been published on the BRCA1 and BRCA2 genes. Over 18,000 different authors have been researching this. It's just mind boggling to think that anyone would make that premise. As to the BRCA patent, specifically, it's just not supported by the record whatsoever. And it's very curious … you'll notice that halfway into the litigation, once Myriad proffered all the proof and showed how widespread this has been researched and published, the ACLU attorneys started changing their posture and saying, "Well, patents do give you the right to prohibit research." And they're right, they technically do, but nobody so utilizes them. One of the best things you can do is to read the amicus brief filed by Chris Holman and Robert Cook-Deegan. It wasn't filed in support of a specific party, but it does contain a very appropriate listing of various reports that were done, all of which concluded that there was no evidence that patents hinder research, that patents drive prices up or result in more expensive testing. It's easy for me to say all of these things–I do have a biased opinion–but if you go look at that evidence, put forth by a third party unaffiliated with Myriad who felt it was so important that they took the time to address that of all of these perceived evils, none of this is taking place. There's no evidence to suggest that these things actually happened.

Did you get the sense that the PTO had not exactly signed onto this position? Clearly, as far as the brief, they did not sign on, they did not participate. The best that we can tell at this point is that the PTO does not agree with this position. I think what we find kind of curious–but maybe not too surprising, given the current administration and the things they have been trying to implement–is that here you have the PTO, 30 years of practice, and ten years they've had these guidelines which were put in place after public notice, public hearings, public comments; and now you have this shift in position which was done overnight, behind closed doors, with no public comment and no notice, which runs against 30 years of established industry practice. The other thing which is troubling is recognizing that all we have because of the birth and growth of the biotech industry, which is now $30 billion in R&D spent in 2008 alone … a tremendous industry has sprung up, all of which is now in jeopardy; that in today's economic times, when we're trying to find jobs and stimulate the economy, the current administration would take a position which will result in a loss of

12 GENEWATCH

Does that mean you would support a law or precedent that would continue to allow patents on isolated DNA molecules but would prevent patent holders from prohibiting research on those genes? Myriad would have no problem with that position. In fact, there are a few instances in which Congress has already said that you cannot enforce a certain patent against medical practitioners if it's necessary in connection with human treatments. Congress clearly can do that, and we'd be fine with it. If you think about it, for practical purposes, for a diagnostic company, you need research done. When we first developed the BRCA test, none of the doctors would do the testing. The medical societies which dictate the guidelines about what doctors should and should not do–the American Congress of Obstetricians and Gynecologists, the American Society of Clinical Oncology–we needed them to publish guidelines to advise doctors to recommend our tests. The only way guidelines get published is if people do research and talk about this, so we're out there paying people and giving them samples, telling them to do more research. In the health care industry, the last thing any medical diagnostic provider would do is tell someone "don't do that research." So that certainly would be a very appropriate suggestion, and I think some people have suggested it before, that there ought to be a research exemption. We would support that. So if research isn't a threat, when does Myriad have the motivation to enforce patents? There must be some situations when these patents need to be enforcedthat's why they're important, right? Well, it's difficult to say. There has been a lot of use of the patents out there in the world. The only two instances when we've done anything were ten years ago, when

OCTOBER-DECEMBER 2010

Images: Myriad Genetics

Richard Marsh, JD, is Executive Vice President, General Counsel and Secretary of Myriad Genetics.

two professors at a University of Pennsylvania lab started doing commercial level testing. Our belief back then was that we have spent all this time and effort, we were spending hundreds of millions of dollars to make the investment to commercialize the test and have a gold standard test, and that was an instance where we thought it was inappropriate for them to ride our coattails, if you will. We had raised that issue with them, and the University asked them to stop doing the testing. Since then, you've raised a good question: When will we enforce the patents? Well, I would like to think that Myriad has now become the gold standard, and because of the quality and turnaround time of our tests, that's why people come to us. There hasn't been a need to enforce the patents, just because, I think, people have come to seek us out not just because of our patents, but more so because of the quality of the test we're providing. If that's the case-that it's less about the patents on the specific gene than the quality of the actual diagnostic test-why not tell the Penn professors, "You can't use the same test that we do, but you can come up with some other test that still involves the BRCA gene?" If you think about it, this is the bedrock of the patent system: In exchange for this limited period of exclusivity, you are required to disclose your invention, talk about your discovery, and indicate how it can be practiced, in order to spur innovation, so people can design around it. People can come up with alternative manners and mechanisms by which they can come up with a predictive test. That all would be outside the scope of our patent, we would not have the ability to prohibit that. That's why it spurs innovation: if you make disclosures, others can design around it and improve upon it. The problem is that, if patent protection not in place, the original incentive to spend the dollars and effort to make the

VOLUME 23 NUMBER 5-6

inventions doesn't happen. Secondly, instead of disclosing inventions, they are kept as trade secrets and not disclosed, so people don't learn about the advancements in science. Although it seems like if you had a secret way of coming up with a diagnostic test, people would be pretty reluctant to buy the test if they don't know how the results are being determined. So you have to explain it to the medical society, you have to show why your gene panel test really will be predictive of the outcome. That's my point: Myriad, for example, never would have spent the over $500 million we now have spent-it took us over ten years to even recoup our investment-but we did it because we knew we had patent protection. If we didn't have that, we would not have spent the money. This is why I say that without gene patents, we would have less innovation, we would

that work just to have someone come in behind us and start doing the same test. Couldn't it actually benefit Myriad in some projects not to have to deal with intellectual property issues? The investment just wouldn't happen, because there's no guarantee that we'll be able to get a return on our investment. The last company I worked for was Iomega–remember, they made zip drives–but this is not like that, a product which you can just develop and immediately put it on the market place. You have to validate it, you have to prove that the gene panel works. We're looking a lot more like a pharmaceutical product in the regulatory approval that takes place. Nobody will spend the three to five years of development if there's no patent protection. Look at the pharmaceuticals: they won't launch a product unless there's patent protection to do it.

I think lots of people get lost in this idea that the gene would have been discovered anyway. That’s absolutely right. But with the discovery of the gene, you’re just getting out of the starting block. have less personalized medicine testing coming on the market, because people would just not spend the money to develop it. Does Myriad conduct any research or commercialize any products using genes on which it does not own the patents-or, for that matter, genes which have been patented by somebody else? No, we don't. We now have eight different molecular diagnostic products. Half of them are predictive medicine, where we'll look at genes and try to determine if there are mutations; some of them are personalized medicine, where we'll try to decide, based on biomarkers in the body, whether someone is getting an effective dose of a drug. But every time we look at a test, one of the first questions we ask is: What is the intellectual property position on this? Can we get a license to it? For instance, some of the work for a pancreatic test we're doing was developed at Johns Hopkins, and we got a license from them to go ahead and do this test. We will not do a product unless we know there's intellectual property protection, because we know it will take years to publish it, to teach doctors about it, and we're not going to do all

But how much of all that money is really involved in locating and isolating the gene, as opposed to the cost of actual commercialization? That's a very important question. I think lots of people get lost in this idea that the gene would have been discovered anyway. That's absolutely right. But with the discovery of the gene, you're just getting out of the starting block. In 1996, when we launched our test, if you took a female patient who walked into some OBGYN clinic and said, "Hey doctor, I'm concerned about my family breast cancer history," the doctor would just give them a mammogram. Nobody knew about cancer predisposition risk, and this is what we've been doing, taking the time to help sponsor research and educate medical societies and the insurance industry. And who does that? You've got to have a company, you've got to have a medical department, an accounting department, a legal department … I mean, we're a 1,000 employee company. The discovery alone just barely starts the process. It's discovery plus commercialization that actually benefits society.

GENEWATCH 13

It does seem that the initial research to isolate the BRCA genes would have happened anyway. We can all speculate. We have to take a step back and consider the big picture here: If we're wondering whether the patent system works, we shouldn't let a single isolated case rule what's most appropriate. In this case, yes, there were other groups looking for it, and I presume they would have found it. But that gets to my point before: discovery alone doesn't commercialize and promote the science, all it does is result in discovery. There have been lots of discoveries that have never made it to the market for a variety of reasons. But you're right, there were other groups looking for the BRCA gene, and I presume would have found it … but Myriad found it first. Myriad recently offered to surrender one of its gene patents in Australia. I've seen various speculation as to why … can you clear up the reasoning behind that decision? It's always comical to sit back and listen to the speculation, when if they would just call and ask we could enlighten them. In Australia, we actually don't have the commercialization rights. Ten years ago, we gave that to a company called Genetic Technologies. They have the exclusive

lions and millions of dollars when this is not an issue? You're free to practice it, the patent is not being enforced." So, to try to underscore that point, we said, "Look, we'll even surrender the actual patent, because it makes no difference." Right now we're still in the process of telling them it's nonsensical–why are we having litigation over patents that aren't being enforced? Go find someone who is enforcing patents if you want a real live case. That's the only reason we offered to surrender the patent-because it wasn't being enforced. And do you know whether that licensee in Australia, Genetic Technologies, is getting by financially without the BRCA patent? I don't know much about that. They're not like Myriad, where it's a substantial part of our business. They do a variety of other types of testing, so for them the BRCA analysis testing is not a main product.

Is that difference the reason it's worthwhile for Myriad to spend millions in legal fees for the case in the U.S. instead of just surrendering the patent and relying on the quality of its testing? Let me give a little color to that … this case is not about Myriad. They only sued us on 15 claims of seven patents, and we have 23 This lawsuit will not have an impact patents that cover BRCA on Myriad. It’s going to have a much analysis. If we were to lose all greater impact on the biotechnology 15 claims, we'd still have all 23 patents. Patents don't just industry as a whole. go away because you lose a claim here or a claim there. rights to commercialize BRCA testing This lawsuit will not have an impact on there. As a matter of their commercial- Myriad. Our intellectual property position ization strategy, they had earlier made a will remain strong. It's going to have a "gift" of the patents. They can't make a gift much greater impact on the biotechnology of the actual patents, but they told the Aus- industry as a whole. Actually, it did cross tralian people, "We are not going to enforce our minds: Why even bother to appeal these patents against anyone." In other this? It's just Judge Sweet, it's not a bindwords: "We'll compete with anyone else ing decision, this case is not impactful on Myriad … why spend all the money and the just on the quality of our testing." So, when this lawsuit came, it was kind effort? And the reason is, this is an imporof a copycat of the U.S. case-the nonprofit tant issue to the biotechnology sector. We bringing the case picked Myriad since clearly believe that the patent system that's what they did in the U.S. Well, when works. We believe we are a poster child of we got sued, we said, "Wait a minute-the the success of how public science has been patents aren't being enforced against any- promoted because of the patents granted body. Everyone's free to practice the on the genes. We firmly believe that socipatents. There's no issue here." The prob- ety as a whole has benefited. I clearly lem is we're now being forced to spend appreciate that there will always be a few the patent litigation costs, literally millions anecdotal stories, there will always be a and millions of dollars, and our initial handful of individuals who because of their response was, "Why would we spend mil- personal circumstances may be negatively

14 GENEWATCH

affected. I don't want to minimize that-it is a real issue for someone who has a family history and can't afford the test. Myriad specifically provides free testing for those who fall below a certain welfare level. Having said that, if you take society as a whole, clearly society has been benefited by the patenting of the BRCA genes and all the biotech patents out there. Look at all the personalized medicine products out there today. And remember, in a few short years our patent is going to expire, and this benefit goes back to the public as a whole. If losing this case isn't going to have a big impact on Myriad in terms of business, are you saying that Myriad is footing the bill on behalf of the entire biotech industry? We clearly are being forced to respond to this lawsuit. We would love it if the ACLU would find someone else who is enforcing their patents against people. We'd be happy if they would go find some company that has a patent on toe fungus. But obviously they picked Myriad because we have the breast cancer gene, because women's health is a very high profile and emotional area. Let's all recognize what this is–that's the only reason they picked us. It's not necessarily because we have isolated DNA–there are tens of thousands of isolated DNAs out there, so why didn't they go pick on DuPont or Monsanto or Eli Lilly or anyone else? They picked us because they knew they could sensationalize and get a lot of emotion behind this area. And we acknowledge that it's a very important issue. But that's why they call these things test cases, we're having to bear the burden, if you will, of going forward. Now, I know that as of Friday there are 15 or so amicus briefs who have either filed in support of us or posturing a position in support of patents. So we're the named party, but we're not alone in this. I know Myriad is not alone in its position, but this appeal must cost a significant amount of money. It seems there was an option not to appeal the decision, and if it's not important to Myriad's business, why take on all the court costs? Or am I wrong-is anyone helping out with the costs? Nope, it's just us, there's no one sponsoring us or supporting us. We're footing the bill entirely on our own. It's just a fact of life when you're in the business world. You hope to avoid it, and you try to avoid it when you can, but that's just litigation.

OCTOBER-DECEMBER 2010

The Council for Responsible Geneticsâ&#x20AC;&#x2122; Genetic Privacy Manual Understanding the Threats - Understanding Your Rights Senator Edward Kennedy once said that the mapping of the human genome will "affect the 21st century as profoundly as the invention of the computer or the splitting of the atom affected the 20th century." Indeed, it's already hard to keep up with the rush of information and opinion coming out as the result of the rapid growth in genetic research and technology today. Even without our fully realizing it, genetic technology is entering almost every area of our lives, from human health and reproductive technologies to the criminal justice system. Genetic testing is becoming mainstream and the opportunities to reveal genetic information are multiplying. An individual's genetic information has incredible value in a host of areas where invasions of privacy and potential discrimination are present; it is both highly identifiable and provides a window into your health and even the health of your family members. Most consumers lack a proper under-

VOLUME 23 NUMBER 5-6

standing of genetics and it isn't hard to understand why. To the degree that the public has any background in genetics, it is often distorted by everything from popular culture to consumer advertising. The media regularly covers the latest genetic "breakthrough" and widely distributes exaggerated claims. The Internet offers little clarity; even consumers who want to seek a basic understanding of genetics and "Google" DNA will find approximately 143 million and growing sources of information, along with 10 million for "genetic engineering" and almost 2 million for "DNA and altering." The consumer has even less understanding of the privacy threats involved in releasing their DNA or other forms of genetic information from issues of accessibility to storage of genetic information and their associated risks. The extremely varied legal and regulatory framework of protections in areas where genetic information is acquired poses significant additional barriers to consumer under-

standing. The consumer is highly unlikely to fully appreciate the value of their genetic information and make informed decisions about its use. As a result, millions of people's privacy is regularly and often unknowingly compromised. The Council for Responsible Genetics' Genetic Privacy Manual: Understanding the Threats- Understanding Your Rights is a comprehensive, electronic source of information for the consumer on these issues. The manual consists of five major sections: 1. Understanding the Threat 2. Understanding the Science 3. Genetic Privacy and the Law 4. Tips for Protecting Your Genetic Privacy 5. Additional Resources The Council for Responsible Genetics' Genetic Privacy Manual: Understanding the Threats - Understanding Your Rights can be accessed at: www.councilforresponsiblegenetics.org/geneticprivacy.

GENEWATCH 15

Protecting the Intellectual Foundations of Genetic Science Concerns about patents accompanied genetic research long before the gene patent system got its day in court BY EILEEN M. KANE Can the discoveries from genetic science be patented? There is a tension between the incentives created by the patent system–rewarding the disclosure of new knowledge with exclusive rights–and the norms of scientific research–disclosing new knowledge for further scholarly investigation. The intellectual force of reductionism in the life sciences, deepening the investigation of molecules and relationships that explain biological phenomena, generates direct conflicts with patent law's exclusion of basic knowledge from patenting. For emerging fields of science and technology, this tension surfaces immediately: the scholarly imperative to dive in and work on an unfettered intellectual landscape may clash with new possibilities for commercial development. The result is that a new scientific field may emerge that is immediately dotted with fences and boundaries-the patents that structure how its knowledge can be used. Genetic science has not been immune to this conflict. The era of genes and genetic testing has proceeded alongside concerns that patenting efforts, in some instances, have unnecessarily reduced access for researchers, clinicians and patients to medical significant genes and methods for their use. That outcome is troubling because genetic medicine represents a paradigm shift in which disease is explained and treated according to genetically-dictated biochemical mechanisms. Genetic testing can be used to identify disease susceptibility, to establish diagnostic status, and to design personalized therapeutic regimens in medical care. Adverse patenting not only limits scientific research; it also impacts patient care. We are now approaching the resolution of two separate challenges in genetic patenting. Can genes themselves be patented? Can the scientific correlation between a gene mutation and disease susceptibility be captured as a patented method of genetic analysis? Not everything can be patented. The Supreme Court has been quite clear that "laws of nature, natural phenomena, and abstract ideas" are not patentable, although the interpretation of this maxim has been difficult.1 Yet the underlying rationale is that

16 GENEWATCH

scientific advances depend on an available substrate of basic knowledge, and that, therefore, patenting the intellectual foundations of a field has an adverse effect on its progress.2 The patentable subject matter doctrine in patent law, patent eligibility, performs this necessary gatekeeping function.3 The patent eligibility of genes and genetic methods can be decided by comparing these claimed inventions against the established exclusions of "laws of nature, natural phenomena, and abstract ideas" from patenting. There is a paradoxical element to the public debate over patents pertaining to genetic science. While patent eligibility for inventions in genetic science has generated significant public controversy for years, until recently, it had yet to receive the formal legal review by the courts that could resolve the issue. Many stakeholders who were concerned about gene patenting lacked any formal standing to raise the issue in the courts. Thus, it is no surprise that the recent court cases impacting the patent eligibility of genes and genetic correlations would generate intense interest. The Genes In Association for Molecular Pathology v. United States Patent and Trademark Office4 a coalition of professional medical organizations, medical providers, researchers and patients challenged the eligibility of "isolated DNA" patent claims on the purified BRCA1 and BRCA2 genes, alleging that genes are both "products of nature" and "manifestations of laws of nature" for which patents may not be obtained.5 The judge accepted the arguments of the plaintiffs that the patenting of genes violates prohibitions against patenting products of nature or manifestations of the laws of nature, and ruled that the challenged patent claims were invalid.6 The argument of the defendants–that the purified gene is not a product of nature, but a product of invention–failed. The debate continues: does purification of a gene create a new product or does it simply allow the DNA to be used for its natural function? Must a product of nature be structurally or functional identical to its natural counterpart? If purified DNA is reenacting

its natural performance in the cell, then is "isolated DNA" really any different than the natural form? Moreover, is the function of DNA particularly special? All of these overtones are apparent in the AMP case, and the eligibility of DNA can be analyzed utilizing patent law standards, without recourse to non-legal genetic exceptionalism. The purified gene is often claimed as an isolated complementary DNA, or cDNA, the abbreviated, message-bearing form of the gene, a result of laboratory manipulation, reflecting divergence from the physical genomic form.7 However, all of that structural investment is done to preserve the natural informational content of the gene: the maintenance of its functional identity. Thus, we must ask what the product of nature doctrine is trying to accomplish by prohibiting the patenting of natural products. The underlying goal appears to be preserving access to natural products and knowledge where no truly inventive alteration has taken place. It is obvious that the purified gene is valuable precisely because it reprises its natural behavior outside the cell. The purified gene is surely the clone of its cellular self, and a product of nature that cannot be patented. However, there is more complexity. DNA is not like other biomolecules. It is important to understand the complex set of attributes that distinguish DNA from other molecules-its identity as both chemical and template-and how these attributes impact the patenting analysis. The discovery of the structure of DNA ended the most impassioned search in the history of biological science: to identify where genetic information was encapsulated and how it was transmitted. The gene emerged as the molecular repository of an embedded codethe genetic code, a long-sought law of nature.8 This code was deciphered in order to establish how DNA instructs the execution of proteins.9 The Human Genome Project began to assemble the set of specific embodiments–the genes–that account for human form and function.10 Genes are nature's exemplars of the genetic code; as such, they embody this law of nature.11 It has long been established that "manifestations of laws of nature [are] free to all men

OCTOBER-DECEMBER 2010

molecules, the mechanism of pharmaceutical metabolism, or the cause and effect relationship between genotype and phenotype. While the universe of biological molecules may be finite, the set of relationships and interactions that define human metabolism are likely to be vast. Therefore, it is essential to establish whether every observation of molecular performance can be converted into a patent claim. It is fair to conclude that the animating rationale for excluding natural phenomena from patenting would apply to exclude these types of patent claims. For genetic science, this would translate as a prohibition against patenting the fundamental genotype/phenotype correlations that underlie genetic medicine.

and reserved exclusively to none."12 Following from the Supreme Court's dictate that the laws of nature are not patentable, it can be concluded that the patenting of genes effectively preempts the genetic code, and is therefore not allowable.13 This becomes a separate analytic basis for concluding that genes are ineligible for patenting.

Image: Wikimedia Commons (modified)

The Genetic Correlations The patenting controversies in genetic science continue. Can one patent the observation that a mutation in a gene, such as BRCA1, is associated with a higher susceptibility to early-onset breast and ovarian cancer? Can this scientific correlation be captured in a patented method without running into the exclusion of "laws of nature, natural phenomena, and abstract ideas" from patenting? Maybe not. The AMP litigation also presented this issue, asking whether patenting the method of utilizing the relationship between a mutation in the BRCA1 gene and a higher cancer risk was, in effect, the patenting of a natural phenomenon. Again, the judge sided with the plaintiffs, although the reasoning employed a legal test that has now been discarded by the Supreme Court in the business method patent case, Bilski v. Kappos.14 Other recent cases in the life sciences focus on whether scientific correlations can form the basis for a patented method: LabCorp v. Metabolite15 (a diagnostic method for detecting a vitamin deficiency using the quantitative correlation

VOLUME 23 NUMBER 5-6

between the level of the amino acid homocysteine and several B vitamins), Prometheus v. Mayo16 (a treatment method using the correlation between a metabolite level and drug toxicity to more precisely tailor pharmaceutical dosage), and Classen v. Biogen17 (a method for optimizing an immunization regimen utilizing the correlation between administration and effect). Prometheus, Classen and AMP will now be recalibrated in the post-Bilski framework; the Federal Circuit will have an opportunity to revisit the eligibility of scientific correlations as patent method claims using the law of nature/natural phenomena analysis. As a result of the fact that these important patent cases involving method claims have been litigated without directly reaching the public domain questions embedded in the patentable subject matter doctrine, the field awaits more definitive guidelines for how the detailed investigation of biological mechanism can coexist with patent law's prohibition on patenting basic and essential knowledge. The significance of determining whether scientific correlations are subject to patenting cannot be overstated. Beyond the identification of the molecules that perform biochemical tasks, modern biological research focuses on determining dynamic intermolecular relationships and biochemical causation. The contested method claims in biochemical or genetic testing are heterogeneous, where a patent claim may cover, for example, quantitative relationships between

Conclusion The article concludes that genes and genotype/phenotype correlations form the intellectual foundations of the genomic era in science, and are the kind of basic knowledge tools that fall within the exclusions from patentable subject matter. In the near future, AMP will present the Federal Circuit, and possibly the Supreme Court, with the opportunity to settle these critical eligibility questions for patent law. Resolution of the eligibility controversies in genetic patenting is important for genetic medicine and also has larger theoretical implications. The life sciences await a definitive and modern interpretation of the product of nature doctrine and its scope, and a contemporaneous analysis of whether and how correlations in the life sciences are regarded as natural phenomena or laws of nature. Other scientific sectors are also impacted by any judicial reaffirmation that basic knowledge cannot be patented, such as nanotechnology and other fields in the physical sciences. The patenting of applied research and true invention can coexist alongside the preserve of open and available knowledge. More narrowly tailored patent claims in genetic science can be imagined, including therapeutic applications of genes engineered into specific molecular constructs and the use of scientific correlations embedded within specific genetic testing protocols. Such inventive precision will allow creative applications of fundamental knowledge to emerge and legitimately solicit legal protection, while the intellectual substrates for genetic science remain unowned. That is an optimal balance. Eileen M. Kane, PhD, JD, is Professor of Law at Penn State Dickinson School of Law.

GENEWATCH 17

The Danger of the Broad Brush The ACLU attack on gene patents threatens unintended consequences for biotechnology and next-generation genetic testing. BY CHRISTOPHER M. HOLMAN In considering the policy implications of Association for Molecular Pathology v. United States Patent and Trademark Office (the Myriad decision),1 it is important to bear in mind that much more is at stake than the specific patents targeted for invalidation by the plaintiffs in the case (the ACLU and Public Patent Foundation, referred to collectively herein as the ACLU). The ACLU has garnered compelling emotional capital by stressing the alleged detrimental impact of the challenged BRCA patents on patients suffering from, or at risk of developing, breast cancer. More particularly, much of the criticism has focused on the alleged overly aggressive patent enforcement practices of the patent owner Myriad Genetics. But instead of mounting a legal challenge to these particular patents, or to Myriad's patent enforcement practices, the ACLU has launched a broadside attack that threatens to render a huge swath of biotechnology inventions ineligible for patent protection, particularly inventions relating to genetic discoveries. If the Federal Circuit affirms the Myriad decision on appeal, it could cause substantial collateral damage to future innovation in genetic diagnostic testing, personalized medicine, and biotechnology in general. Because of the potential for substantial unintended negative consequences, Robert Cook-Deegan and I have submitted an amici curiae brief with the Federal Circuit that supports neither party, but urges the Federal Circuit to reverse the lower court's decision finding the claims at issue patent ineligible.2 Dr. Cook-Deegan directs the Center for Public Genomics at Duke University, which conducted eight case studies of the impact of so-called "gene patents" on genetic diagnostic testing that were commissioned by the U.S. Secretary's Committee for Genetics, Health and Society and published in April 2010. We have both devoted much of our scholarship to the study of human gene patents and their role in biotechnology and genetic testing. Dr. Cook-Deegan and I do not always see eye

18 GENEWATCH

to eye when it comes to questions of gene patent policyâ&#x20AC;&#x201C;he is generally more skeptical of the value of gene patents in the context of genetic testing, and more apprehensive about the potential negative impact of gene patents on future availability of genetic diagnostic testing. Nonetheless, we both agree that the approach taken by the ACLU and the district court could substantially harm innovation in biotechnology by broadly rendering genetic and biopharmaceutical inventions ineligible for patent protection, regardless of their usefulness and nonobviousness, and thought it important to voice our concerns to the Federal Circuit. In this article, I summarize some of the points made in our brief. The Role of Gene Patents in Incentivizing Investment in Biotechnology The U.S. Patent and Trademark Office has a long-standing policy of permitting gene patents, and has issued thousands over a period extending back more than 30 years. The biotechnology industry has benefited greatly from this policy, and gene patents have played a critical role in incentivizing the sizable investment necessary to develop and secure marketing approval for life-saving biotechnology products, as noted in two authoritative reports from the Congressional Office of Technology Assessment published in 1984 and 1991.3 Although the current controversy involves genetic diagnostic testing, historically the most important role of gene patents has been their use in providing protection for biologic drugs. For various reasons, it can be difficult to effectively patent a recombinant protein itself, and biologic innovators have relied heavily on patents directed towards the genetic sequences used in the production of human protein therapeutics. In effect, biotechnology gene patents play a role analogous to that of drug patents in the traditional pharmaceutical industry. Indeed, a 2009 report issued by the Federal Trade Commission concluded that

gene patents have provided the "fuel" for the "R&D engine" bringing biologic drugs to patients.4 Gene patents have been more controversial in Europe, but there too the debate has been resolved in favor of gene patents. Indeed, Myriad's European patents directed towards the BRCA genes were found valid after being challenged in opposition proceedings in the European patent office. Ironically, many of these issued European patent claims would appear to be patent ineligible under the district court's decision. If affirmed on appeal, the Myriad decision would cause U.S. patent law to diverge from European law with respect to this important class of patents. Insufficient Evidence of Harm That Would Justify Broad, Subject Matterbased Invalidation of Gene Patents Initially, much of the concern over gene patents was based on a fear that they would create a "patent thicket" that would impede biomedical research. However, after more than a decade it is becoming increasingly apparent that the feared patent thicket for the most part failed to materialize, at least in noncommercial, academic research. DNA hybridization array technologies, as exemplified by the Affymetrix gene chip and Illumina bead arrays, were thought to be particularly threatened by the human gene patent thicket. After all, these products can involve the use of DNA molecules representing many thousands of genes in a single array, and it was assumed that with so many issued gene patents it would be prohibitively burdensome to obtain licenses or patent clearance to make or use the arrays. In fact, however, it appears that hybridization array technology has never been the subject of a patent infringement lawsuit involving a gene patent (although they have generated copious patent litigation involving non-gene patents). Today, most of the angst over gene patent centers around the potential negative effect on genetic diagnostic testing. The recently released Revised Draft Report

OCTOBER-DECEMBER 2010

on Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests (the SACGHS Report),5 for example, identifies a potential for a substantial negative impact of gene patents on genetic diagnostic testing, but concludes that there is currently no conclusive evidence establishing that gene patents have had a net negative effect on the availability of genetic testing services. Critics of gene patents, and Myriad's BRCA patents in particular, have alleged that gene patents unduly raise the cost of genetic diagnostic testing. However, SACGHS looked for evidence that patentbased exclusivity resulted in higher costs for genetic testing services and was unable to document any consistent effect. In fact, the SACGHS Report states that one "surprising finding from the case studies" was that the price of Myriad's BRCA test is "actually quite comparable to the price of other full-sequence tests done â&#x20AC;Ś at both nonprofit and for-profit testing laboratories." More Targeted Approaches for Dealing with Problematic Gene Patents and Patent Enforcement Practices The ACLU could have chosen a more targeted approach to address the perceived problems with the Myriad patent claims. For example, they argue that at the time Myriad identified and characterized the BRCA genes their existence was wellknown, and it was inevitable that one of the multiple laboratories actively engaged in efforts to isolate and sequence the genes would have succeeded. In effect, they are arguing that the claimed inventions are obvious. But if that is the case, then the appropriate avenue for challenging the claims is the doctrine of nonobviousness, as set forth in Section 103 of the Patent Statute.6 The ACLU further alleges that the challenged patent claims are overly broad, completely blocking the ability of others to perform any sort of genetic testing, or to perform research, and even preventing doctors from communicating with their patients. In fact, this is probably a gross overstatement of the actual scope of coverage that would be afforded these claims if Myriad ever sought to enforce them in court. If a court were to interpret the claims as broadly as the ACLU suggests, there is good reason to believe at least some of the claims could be invalidated for lack of novelty or obviousness. More generally, the enablement and writ-

VOLUME 23 NUMBER 5-6

ten description requirements as set forth in Section 112 are the appropriate doctrinal tools for challenging overly broad patent claims.7 Unfortunately, instead of using these more targeted approaches to challenge Myriad's patent claims, the ACLU has chosen to argue for a novel interpretation of the doctrine of patent eligibility which if embraced by the courts would not only invalidate the challenged claims, but would likely substantially restrict or even eliminate effective patent protection for gene-based inventions in general. Dr. Cook-Deegan and I argue in our brief that public policy would be better served by employing more conventional doctrines of patentability to challenge gene patent claims that appear overly broad, or which are directed towards allegedly obvious subject matter, thereby preserving the ability of true innovators to obtain patent claims of reasonable scope directed towards useful and nonobvious genebased inventions. Much of the concern relating to gene patents has more to do with the enforcement and business practices of gene patent owners than with the patents themselves. For example, there has been little criticism of gene patent owners who enforce their patents to protect an innovative biologic drug produced through recombinant expression of the patented gene. Given the high cost and risk associated with bringing a biologic to market, most would consider enforcement of gene patents in this context legitimate. In contrast, Myriad's use of gene patents to maintain market exclusivity over BRCA testing in the U.S. has been highly controversial. However, if society determines that the business and enforcement practices of certain gene patent owners is problematic in some contexts, it would be more appropriate to consider alternatives that more directly address these concerns, rather than the ACLU approach which would broadly preclude effective patent protection for DNA-based inventions in general. For example, since the real concern with gene patents is the potential for restrictions on research and genetic testing, a more targeted approach could involve the creation of some sort of exclusion from infringement liability for those using patented genetic technology in research or genetic testing. This is the approach recommended in the SACGHS report, and could be accomplished by simply expanding the scope of a provision that

already exists in the patent statute which shields healthcare providers from liability for acts of patent infringement occurring during the performance of "medical activities." Alternatively, if deemed necessary, other approaches such as compulsory licensing, invocation of march-in rights, and assertion of state sovereign immunity could be considered.8 Potential Unintended Negative Consequences for Biotechnology Looking forward, companies focused on the development of pharmacogenetics and personalized medicineâ&#x20AC;&#x201C;technologies widely viewed as critical to the future of pharmaceutical development of healthcareâ&#x20AC;&#x201C;point to gene patents as critical for securing the funding necessary to bring these products to market. If the Federal Circuit affirms the Myriad decision, it could dramatically reduce the private incentive for investment in innovation in these and related fields. It could also undermine incentives for the development of new biologics, an increasingly important class of life-saving drugs. Some would argue that gene patents are not required to promote innovation in genetic diagnostic testing, and this might be true with respect to patents on genes for Mendelian medical conditions, such as the BRCA genes. It does not follow, however, that publicly funded research will suffice to discover and develop the next generation of genetic testing technologies, particularly those involving more complex patterns of genetic variation involving a large number of genes dispersed throughout the genome, or identification of complex gene expression patterns. It also appears likely that at some point the FDA would take a more active role in regulating genetic diagnostic testing, and require a submission of data to demonstrate safety and efficacy, which could substantially increase the cost of commercializing new genetic diagnostic tests. These developments could render the availability of effective patent protection critical for incentivizing the necessary private investment to bring these technologies to fruition. Christopher M. Holman, PhD, JD, is Associate Professor of Law at the University of Missouri-Kansas City School of Law.

GENEWATCH 19

The Overstated Case Unduly broad claims are the problem, not DNA patents themselves BY ROBERT COOK-DEEGAN Robert Cook-Deegan co-authored an amicus brief in the Myriad case with the author of the preceeding article, Christopher M. Holman. Professor Holman and I found common ground because we are both concerned about the implications of eliminating all patents on DNA-based inventions. To my eyes, the business model pursued by Myriad Genetics is problematic, and I would like to see many of Myriad's broad claims invalidated and the scope of the patents narrowed considerably–probably more so that Prof. Holman–but I share his concern that the logic of Judge Robert Sweet's March 29, 2010, ruling pushes in the direction of eliminating the possibility of patents on DNA molecules. Is DNA Patentable Subject Matter or Not? The intuition that Judge Sweet captured is that DNA is an embodiment of biological information, and one of its key properties is self-replication. This feature of DNA is the reason that Watson and Crick became household names. Judge Sweet recognized DNA's unique role as the storage and transmission medium for genetic information. It does not follow, however, that nothing made of DNA can be patented. DNA can also be engineered, and forms of it can be discovered, even in unaltered form, that have value in altering biology and possibly treating disease. If the higher courts agree with Judge Sweet, then the problems associated with gene patents in diagnostics will indeed be gone, but some good things will be gone with them. Moreover, there is another way to get the same result without the secondary consequences of eliminating all DNA patents. The Department of Justice amicus curie brief argues that Judge Sweet has been too broad, and that some DNA molecules should be patentable-those that have been engi-

20 GENEWATCH

neered or altered–but that DNA sequences found in nature should not be patentable subject matter. I am sympathetic to this view, but I do worry that it will be difficult to hold that line. Some things that could create social benefit if patentable would be swept away, and I suspect courts will be sympathetic to conferring the patent incentive for such products and services. I am thinking in particular of DNA vaccines, small interfering RNAs and DNAs, and other objects that may be found in nature but might also be molecules of therapeutic value in and of themselves. If so, they will be expensive to develop into biologic therapeutics, in which case the patent incentive would serve the same role it plays in small molecule drugs and protein therapeutics (including some "gene patents" underlying those products). The problem with Judge Sweeet's logic, and probably even the Department of Justice position, is collateral damage to socially valuable patents underlying therapeutics, and possibly also to future diagnostics that will be expensive to develop. That risk would be much less if traditional doctrines of patent law–such as novelty, obviousness, enablement, and adequate written description–were used to root out destructively broad patent claims on BRCA and other genes relevant to diagnosis, instead of a sweeping rule about whether DNA is patentable subject matter. "Discoveries" Are Sometimes Patentable in U.S. Law One argument marshaled against "gene patents" is that they are discoveries and not inventions. Genes associated with disease (or biological function) are indeed discoveries that are not invented by their discoverers, but so are many other patentable things such as antibiotics, vaccines, and hormones which are items found in nature. Social benefit arises from patenting such inventions when they require substantial investment to develop into marketable products or services. Genetic diagnostics have generally not required that kind of investment, but future diagnostics might, and some DNA-based inventions clearly will if they prove therapeutically useful. Examples include DNA vaccines

(including perhaps even naked purified DNA derived from natural pathogens), inhibitory RNAs and DNAs, or naturally occurring genes that may eventually become treatments through gene transfer. If so, they will have to be clinically tested in expensive trials, and the patent system is one way (admittedly not the only way) to induce investment in such clinical studies. Much of the argument about the BRCA patents claiming DNA molecules centers on what it means to "isolate" DNA; but DNA sequencing by definition entails "isolating" a DNA molecule in one way or another by clever laboratory manipulation. So I agree with Judge Sweet's conviction that the words "isolated" or "purified" in patent claims are basically "a lawyer's trick," but I do not agree with his logic that this implies DNA cannot be patented. Manipulation entailed in sequencing by definition entails the hand of man, and it is therefore hard to distinguish this use of DNA from the other valuable molecules found in nature that are now and have long been patentable. I don't think his line will hold in law; I do think, however, that the traditional criteria for patentability (as opposed to patent-eligibility or patentable subject matter) if properly applied would reduce DNA inventions to the scope of what is disclosed in the patent. Applying Criteria of Patentability Can Reach the Same End If banning DNA patents were the only way to solve the problems in DNA diagnostics, I might agree with Judge Sweet's ruling and the Department of Justice position. But that is not the only remedy to problematic claims in gene patents that have been granted. Many of the broadest claims in the patents being contested could be found invalid if subject to challenge in court. Before this case, there was no case law in the diagnostic context, and courts could narrow patent claims relevant to genetic testing–particularly from the U.S. Patent and Trademark Office (which has been much more prone to granting broad patent claims than the European Patent Office). The problem is much more about overly broad patent claims than whether patents on DNA exist at all.

OCTOBER-DECEMBER 2010

My argument is that rather than eliminate DNA as patentable subject matter, it would be better to allow DNA molecules to be patentable, but then apply the doctrines of patent law rigorously to eliminate the broad claims that have been granted. Current claiming practice in gene patents allows claims covering discoveries that take years of hard work, long after the patent is granted, to reduce to practice. Those practices need to change. Case law would address the problems of diagnostic patents by limiting their scope to what "inventors" actually contribute, and not more. Two examples are directly pertinent to the BRCA case. One is about claims on DNA molecules and the other about methods for detecting DNA sequence changes. Claims 5 and 6 of the original BRCA DNA molecule patent (US patent 5,747,282) claim any 15-base pair segments of DNA that have a sequence that would encode a BRCA peptide. Only a court can decide patent claim validity, but that claim seems likely to fall afoul of two patent criteria: novelty and enablement. What is claimed is not novel because it in effect covers any DNA sequence that encodes any five amino-acid sequence in any protein that is the same as any five-amino acid sequence in BRCA1. It turns out there are a lot of DNA sequences that encode at least five amino acids that can be found in the BRCA1 peptide, and some of them were in GenBank more than a year before the patent application was filed. Moreover, while Myriad et al., did make it possible to determine those sequences, they have not found a use for the vast majority of the millions of 15-mers they claim. If they had restricted the scope of the claim to mutations they demonstrated to confer risk of breast and ovarian cancer, they would have some grounds for having enabled their invention to be useful. Claims 5 and 6 as granted are extremely broad and thus probably invalid, on grounds of novelty and enablement. If they fall, would other claims block BRCA1 diagnosis? The main independent claims (1 and 2) would not be infringed, because no one makes and sequences a full-length cDNA for diagnosis. To the degree that other claims are infringed, they might be vulnerable to the same problems of novelty and/or enablement as claims 5 and 6, unless they were restricted to the very specific mutations disclosed in the patent. And if they were so restricted, they should not confer a monopoly for genetic testing. Myriad also has method claims that are quite broad. Claim 1 of their main BRCA1

VOLUME 23 NUMBER 5-6

"method" patent is basically a very wordy and convoluted way to claim comparing a sample sequence to a reference sequence and noticing if there is a difference. The utility, however, comes from knowing which alterations are associated with disease. The claim does not restrict itself to useful comparisons described in the patent. Again, if the claim were only on a method for detecting differences that were known to confer risk and disclosed in the patent, it might be specific enough to pass muster, and be enabled by the patent disclosure. But if it were restricted to what was enabled at the time of the patent application, it would not allow Myriad to block others from testing for new mutations, and while Myriad would have earned a right to licensing royalties for the mutations they worked hard to correlate with disease risk, they would not be in position to assert a monopoly for mutations they never discovered or had not yet discovered. Others might well find new mutations, and if they patented them, Myriad would have to license them to do genetic testing. This is how PGxHealth's monopoly on testing for long-QT syndrome was broken, when GeneDx secured countervailing exclusive rights to long-QT mutations. Myriad's U.S. business model would have to change (and the United States is the only jurisdiction in which Myriad has been able to establish dominance as the sole provider of BRCA testing). Their business model is the problem, not their patents, if properly interpreted. The extraordinary breadth of the claims and the cost of pushing back against Myriad's initially aggressive patent enforcement were indeed enabled by their patents, but it is not necessarily to kill all gene patents to rein in the business model. Indeed, ACLU and the Public Patent Foundation may have already achieved much of what they desired by making clear that patent-holders trying to enforce gene patents in diagnostics may well lose, especially if claims are unduly broad. I truly believe there are serious problems in DNA diagnostics that are associated with patent rights, especially when those rights have been exclusively licensed to a single provider. But if legal doctrines of patentability were properly applied to gene patents in light of how diagnostics work in the real world, monopoly business models would not be possible. DNA Patents Are Not the Problem, but Unduly Broad Claims One virtue of gene patents in diagnostics is that they reward inventors and their

institutions for some of the value they confer through their discoveries. I believe the Universities of Michigan and Toronto deserve the royalties they have earned from uncovering the cystic fibrosis gene, for example-and other universities and inventors who found mutations later have also earned royalties from CF testing. Moreover, if the CFTR gene had proven useful for gene therapy, it is hard to see how it would have been developed into a therapeutic without exclusive patent rights in the gene.

If legal doctrines were properly applied to gene patents, monopoly business models would not be possible. So it was right to patent the CFTR gene, and Michigan has licensed it for diagnostics in a way that has not hindered innovation or clinical access. My view of the problem with the BRCA story is not that patents are the root of the problem, but that unduly broad claims were sought and granted, and then Myriad pursued a monopoly business model enabled by those mistakes. Rather than proscribe DNA patents, it seems wiser to allow them, but restrict their scope by applying criteria for patentability. This would reward universities, companies, and inventors with royalties they justly earn through their valuable contributions, but not more than what they disclose and deserve. Allowing DNA claims that meet criteria for patentability would also preserve the exclusive patent rights that may prove important in developing therapeutic molecules based on DNA that will be expensive to prove safe and effective in clinical studies. Judge Sweet and the Department of Justice have done a great service by forcing a reexamination of patent policy as it pertains to DNA diagnostics. I am sympathetic to their goals, but their means are unduly broad. Professor Holman and I thus agree that it is a mistake to stipulate that DNA is not patentable subject matter as a matter of law. It would be far better to admit DNA molecules to patent eligibility, but let the other doctrines of patent law do their work. By narrowing patent scope, we should get the same result in diagnostics, but without the collateral damage to DNA patents that may be therapeutically useful. Robert Cook-Deegan, MD, is Director of the Center for Genome Ethics, Law and Policy at the Institute for Genome Sciences & Policy, Duke University.

GENEWATCH 21

The Sky Is Not Falling An interview with Daniel Ravicher of the Public Patent Foundation Daniel Ravicher, JD, is a Lecturer in Law at Benjamin N. Cardozo School of Law at Yeshiva University and Executive Director of the Public Patent Foundation, a plaintiff in the Myriad case. How far back does the debate about life patents date? There has been a debate about what should be patent eligible subject matter for centuries. It's a constant debate. When new technology comes to the forefront, the debate then gets mapped onto that technology; so when we have biotech, or genetic sequencing, or nanotech, or software, we get all these new questions about where should patents play a role in that new field. But the issue of what should be patentable isn't a new issue whatsoever-it's as old as our country. Why do you think it has taken this long for a serious challenge to gene patents to emerge? I don't know, but maybe there haven't been parties motivated enough to actually bring the challenge, since there had not been enough financial impact yet. We brought this case not from financial motivation, but because we were motivated to serve a public good. There have been other gene patent cases, but most of the time they were between parties that both have gene patents-so neither side actually wants to allege that all gene patents are invalid, they just want to accuse the other one of having undeserved patents for obviousness or some other lack of scientific merit. At times there can be a certain 'yuck factor' in the way that gene patents are portrayed, whether purposely or not, especially when it is framed as companies owning our bodies. Do you think that thinking misses the point, or is there something to it?

22 GENEWATCH

Well, what's in our bodies or not in our bodies is not a clear demarcation. The law says you can't patent something that is effectively nature, and the only use of genes isolated from the body is that they exactly replicate the genes in our body, or else they don't tell us anything about us.

company isn't being that aggressive, there is no case or controversy that would support a lawsuit. So if a company has patents but are not asserting them against anyone, they don't have to run the risk of being sued in court like we sued Myriad. There is a legal distinction between these two categories of actors.

It seems the legal issue primarily revolves around whether an isolated DNA molecule is markedly different from its counterpart as it appears in natureThat's the legal test set forth in Chakraborty, yes.

Is there a test for that distinction, or is it another fuzzy boundary? It's a fuzzy boundary, which the Supreme Court said it prefers in this area of the law. In their Bilski decision, in their KSR decision-in many decisions they've handed down, the lower court, the Federal Circuit Court of Appeals, which handles all patent appeals, has been trying to come up with hard and fast rules, objective "true-false" statements, and the Supreme Court has said that's not the way the law should be applied. The law should be flexible and considered case by case.

Do you think that test makes the most sense? Yes, there has to be some border between what is patentable and what is not. The purpose of patents is to encourage progress, to make the world a better place-not just to patent the world as you find it. What makes something better is making a significant, substantial change, So would companies that are acting to take what God or nature has given us and actually do something with it. I think that test makes sense as a policy point Some parties have said, â&#x20AC;&#x153;If this and as a legal marker, because it's an adjective that has a little decision is upheld it will ruin the bit of fuzziness to it, which entire biotechnology industry and allows it to be custom-tailored planes will fall from the sky,â&#x20AC;? in appropriate circumstances.

and thatâ&#x20AC;&#x2122;s all just a bunch of crap.

You and others have said that most gene patents are not being enforced in a way that is harmful to the public since they are being widely licensed. Is there a legal distinction between companies that are reasonable or unreasonable in the way that they manage their patents? The difference is that if a company is aggressively asserting its patents, it can be subject to a declaratory judgment lawsuit like we filed against Myriad; if a

in a way that you might call "reasonable" have anything to worry about if the case against Myriad is successful? Even Myriad itself doesn't have anything to worry about, really, for its business model. It said to its own investors that even if it loses the case, it's not going to lose its business model or revenue. We only challenged 15 claims

OCTOBER-DECEMBER 2010

out of a total of over 100 claims. Even if we win, Myriad is still going to be in business, they're still going to be processing tests-this is everything they said to their shareholders, that this isn't a financial risk to them. And we agree with that. Some parties have come in now and said, "If this decision is upheld it will ruin the entire biotechnology industry and planes will fall from the sky," and that's all just a bunch of crap. If Myriad itself is saying that it doesn't have anything financially at risk here, I don't understand how anyone else can allege that they have anything to risk here. Patents are like snowflakes: they're each different, and they all have to be individually analyzed. Our decision may or may not have some impact on the validity of other patents. Only time will tell. If Myriad themselves are saying that they will be fine â&#x20AC;Ś are they still driving the defense of this, or has it been taken over by other actors claiming to have something at stake? No, they're still defending it, though I don't know why. But I haven't understood Myriad's behavior from day one, so that's not unusual.

patent debate that comes up often is the pragmatic end, the argument that patents have an incentivizing effect on bringing these tests to market. Patents have a greater chilling effect than incentivizing effect. Whatever you say patents can incentivize, I can say they chill. Some people say they incentivize investment; patents actually chill investment to a greater degree than they incentivize it. Some people say patents incentivize research and development; patents actually chill research and development, there's no exception for research from patent infringement. So the larger effect of most patents, which is proven by the empirical data which has been published and not refuted by the propatent side, is that patents have a negative economic effect, a drag on advancement of science.

I suppose this might be why many of the most vocal proponents of gene patents are patent lawyers. They are the people who are financially incentivized to promote their system. You have to be skeptical of the patent attorneys who say the sky is going to fall and actually talk to the scientists, look at the real people, the businesses on the ground, who say everything is going to be fine. We can have a patent system which respects individual rights and research, but which also provides the protections that are necessary to create a net incentivizing effect on research and development.

Do you think this is the case across the board, beyond gene patents? Yes, the empirical data says that in the vast majority of industries, perhaps excluding chemicals, patents have a net drag effect on development. They siphon money away from R&D into the pockets of lawyers.

One of the other aspects of the gene

25 Years of GeneWatch GeneWatch Anniversary Archive: 1983-2008 The Council for Responsible Genetics was founded in 1983 to provide commentary and public interest perspectives on social and ecological developments of biotechnology and medical genetics. For a quarter of a century, the Council has continued to publish its magazine GeneWatch with articles by leading scientists, activists, science writers, and public health advocates. The collection of GeneWatch articles provides a unique historical lens into the modern history, contested science, ethics and politics of genetic technologies. The full archive of GeneWatch has been incorporated into this special anniversary DVD that includes an index of all the authors and titles. Copies of the anniversary DVD are available for a $100 donation to: Anniversary CRG DVD Council for Responsible Genetics 5 Upland Rd., Suite 3 Cambridge, MA 02140

VOLUME 23 NUMBER 5-6

GENEWATCH 23

Why Banning Patents Would Hurt Patients A wholesale ban on gene patents would not improve patient access to diagnostic tests, and it might cause more harm than good BY SHARON TERRY Gene patenting is unquestionably controversial today, not in small part due to the ACLU's lawsuit pending against Myriad Genetics and the U.S. Patent and Trademark Office demanding a broad ban on gene patenting. Actually, however, the very term "gene patents" is misleading. Patents are not, and have never been, granted on genes found in a living body. Nor are patents granted simply on the information or code within a DNA sequence. Instead, patents are granted on isolated and purified man-made DNA molecules that do not exist in nature and require a scientist's manipulation to obtain. Simply put, without this manipulation, these isolated DNA molecules would not exist. For example, a type of isolated DNA molecule that is claimed in many patents, which is called complementary DNA (or "cDNA"), is both structurally and functionally different from genes found in nature. In fact, cDNAs do not occur in nature (nor are they simply purified from nature). Rather, they are produced by making a synthetic copy of an isolated piece of DNA that includes only parts (the protein "coding regions") of the gene found in the body. Other examples include the short segments of isolated DNA, called probes and primers, which typically consist of only a very small portion of DNA of a total gene. Because of the physical and chemical differences from genes in the body, isolated DNA molecules (such as cDNAs) can be used in numerous ways that genes cannot. For example, isolated DNA molecules can be used: (1) to produce large amounts of human protein in non-human species such as yeast, (2) to identify disease-causing mutations in diagnostic tests, (3) as medical treatments (e.g., gene therapy), and (4) as chemical reagents and research tools to enable new discoveries.

24 GENEWATCH

Many of those who oppose the patenting of isolated DNA molecules articulate serious concerns. These concerns include patient access to affordable care, coverage and reimbursement for genetic tests, the availability of second opinion testing, and the appropriate scope of basic research activities that should be beyond the purview of patent holders. We believe that these serious issues need to be addressed thoughtfully. However, a wholesale ban on gene patents, like that sought by the Myriad plaintiffs, would not alleviate these concerns. Rather, such a sweeping, broad-brush approach would cause wide-ranging disruption to research and development for innovative diagnostics and treatments to the detriment of individuals and families in need of medical breakthroughs. Not only do we believe that gene patents can and should be used in a responsible manner to accelerate medical research, tests, and treatments, we have first-hand knowledge that it can be done. When my two children were diagnosed with a genetic disease called pseudoxanthoma elasticum (PXE), my husband and I worked intensely with a team of scientists to discover the gene associated with the condition. After successfully cloning the gene, we patented its corresponding cDNA and the method for detecting it. The nonprofit organization we founded to be stewards of all that was important to PXE, PXE International, now holds the patent and licenses it for a nominal fee. Although neither I nor the other co-patent holders receive income from the patent, we deliberately chose to patent it in order to ensure (a) broad and affordable availability of the test, (b) that tests are conducted by quality

providers, and (c) all test results are added to a mutation database hosted by the National Institutes of Health. Although there is still no treatment, a reliable, accessible test alleviates the typical nine year diagnostic odyssey. The

patent on the gene associated with PXE, which enables our mandate for public disclosure of results, focuses and accelerates research and will eventually lead to an effective treatment faster than would a process devoid of the coordination and control offered by the patent. The law regarding gene patenting, despite being modified somewhat by evolving case law and regulation, has been relatively stableâ&#x20AC;&#x201C;until the current

OCTOBER-DECEMBER 2010

Myriad challenge. The U.S. Patent and Trademark Office has issued thousands of patents claiming isolated DNA molecules and their uses, and in 2001 (in its patent Examination Guidelines) confirmed explicitly that isolated DNA molecules can be patented. Isolated DNA molecules, as chemical compounds, are eligible for patent protection because they are non-naturally occurring compounds, a product of human activity, and have a distinctive name,

character, and use. Therefore, as long as the claimed invention meets all of the statutory requirements for a patent (i.e., it is useful, new, non-obvious, and described adequately in the patent application), a patent covering isolated DNA molecules can be granted. Furthermore, until Myriad, the courts have not previously questioned the patent-eligibility of isolated DNA molecules. Finally, Congress has amended the patent statutes

VOLUME 23 NUMBER 5-6

numerous times in ways that reflect its acknowledgement that patents may be granted for A ban on gene patenting would isolated DNA molecules and slow down the translational work their uses. needed to bring biomedical The biotechnology industry advances to the individuals who relies on the well-settled promise of patents covering their are waiting for new diagnostics inventions, provided, of course, and treatments. that they meet all of the legal criteria. Biotechnology companies, many of which are very small pharmaceuticals isolated from natural and very few of which are profsources. itable, rely on patents to incentivize A ban on gene patenting would slow the investment needed for research down the translational work needed to and development of their products bring biomedical advances to the indiand services. The cost of bringing viduals who are waiting for new a commercial biotech product to diagnostics and treatments. In addition, market, potentially $100 million or such a ban would not remedy the legitmore, and the reality that very few imate concerns with diagnostic tests research projects make it to marsuch as their cost and coverage by insurket, combine to make innovation ance companies. Therefore, we believe in biotechnology difficult at best. that an unprecedented, wholesale ban Given this, biotechnology compaon gene patents would not alleviate legitnies and their investors will not imate concerns and would create greater advance these new technologies problems. Let's instead put this considwithout the ability to recoup these erable energy into alleviating the costs during the limited time of coverage and reimbursement for diagpatent protection. A sudden revernostics and therapy morass that will sal of this investment-backed remain untouched by any manipulation reliance on patent protection of the gene patenting system. would be an unprecedented step which would affect not only diagCompiled with contributions from Ann nostics and treatments that rely on Waldo. these inventions, but would arguably affect a much broader cirSharon Terry, MA, is President and cle of innovative discoveries. For CEO of Genetic Alliance and President example, isolated DNA molecules of PXE International. are used: (1) to test for infectious agents, (2) to manufacture vaccines, and (3) to produce proteins used as therapeutics, and (4) in screens to identify new drugs. Isolated DNA molecules are also used in agriculture and other diverse industries. Therefore, a ban on "gene patenting" would not simply affect the companies designing genetic tests, but would damage a multitude of industries with wide-ranging products. Taken to its extreme, the arguments for why isolated DNA molecules should not be patenteligible may be applied to any isolated molecules, such as antibiotics and other GENEWATCH 25

The Physical Embodiment of Information Why the Department of Justiceâ&#x20AC;&#x2122;s Myriad brief came up short on cDNA patents BY MAGDALINA GUGUCHEVA

On October 29, the United States Department of Justice filed an amicus brief in the Myriad gene patenting case. While the brief supported neither party, it was lauded in the media as weighing on the side of plaintiffs in opposing Myriad's breast cancer gene patents. The White House recently announced its support of DOJ's position, stating that patenting isolated genes would hinder innovation, delay advances toward the "revolution of personalized medicine," and prevent the proliferation of diagnostic tests like the one at issue in this case. Unfortunately, these statements misrepresent DOJ's actual position and the consequences stemming from it, and, like much of the discussion of Myriad, inaccurately gloss over the complications of gene patenting. DOJ supported the district court's invalidation of some of the challenged Myriad patents but not others. The 15 challenged claims, covered by seven patents, roughly fall into two categories. One category of the challenged claims covers actual molecules of DNA, or "compositions of matter," while the other category is comprised of "method" claims, where Myriad has claimed the process of comparing a patient's DNA sequence to known mutations in order to determine whether she had a predisposition for breast cancer. Both categories of claims were invalidated by the district court. The DOJ supported the invalidation of the method claims, but with respect to the composition of matter claims it took a different stance. The DOJ brief drew a distinction between the patents claiming natural, isolated DNA that came from a human cell, and "synthetic" DNAs called cDNAs that are made from the gene in a test tube. The DOJ took the position that the first kind of composition claims, the isolated human DNA, was a product of nature and therefore unpatentable. The second form of composition of matter patents, however, were patentable

26 GENEWATCH

according to the DOJ. Because they were purely man-made versions of the naturally occurring gene, and because they were slightly different in structure and form, the DOJ argued these molecules were wrongly invalidated by the district court. The distinction drawn by DOJ takes too formalistic an approach to both patent law and the nature of DNA. cDNAs, while different molecules than their corresponding DNAs, are different in ways irrelevant to the intellectual property Myriad has claimed. Genes in the form of DNA in our cells, in order to make the protein they encode, are first transcribed into mRNA. The mRNA, which is a perfect complement to the gene, then has certain portions of sequence, called the introns, chopped out by an enzyme in order to create a mature mRNA that only contains the nucleotide sequences coding for the protein in question. This chopping process is called splicing. To make things more complicated, the mRNA can be spliced in many alternate ways to produce sequences coding for slightly different but related proteins. Once isolated from a human tissue sample in a test tube, these mRNAs can be converted back into complementary DNA strands with the help of a viral protein called reverse transcriptase. This is how cDNA, which stands for complementary DNA, is produced. cDNAs are essentially identical to the naturally occurring, isolated mature mRNAs, except they have a different molecular "backbone" which makes them more stable. The code-the thing that is valuable, the information that Myriad through its patents has prevented others from using in diagnosing and treating genetic predispositions to breast cancer-is almost exactly the same. Thus, while in form these are different molecules, in substance and information, they are identical. The value of gene patents, whether in

cDNA, DNA, or mRNA form, is informational content. As Judge Sweet pointed out in his opinion for the district court decision, DNA is a unique and special molecule because it is the "physical embodiment of information," and, more specifically, "the physical embodiment of laws of nature-those that define the construction of the human body." The difference between cDNA and isolated DNA is like the difference between patenting a mathematical equation (not patentable under other patent law doc-

trines) saved on a computer and that printed out in a book. Saved on a computer it is perhaps "more stable" or permanent, can be transmitted by email, can be integrated into software. Yet while the physical embodiment is different when appearing on your screen or in a printed book, the thing that one might (unsuccessfully) try to patent, in either form, is the same. It is purely informational. Importantly, by maintaining the validity of Myriad's patent on cDNAs, the DOJ's position would effectively do very little to alter the current status quo with respect to both gene patenting and the state of breast cancer diagnostics. Cur-

OCTOBER-DECEMBER 2010

rently, any commercial diagnostic test must use cDNA. Isolated DNA in its natural form is not usable for these purposes. Furthermore, any research into the BRCA1/2 genes requires the use of cDNAs. By allowing Myriad to retain patents over these cDNAs, diagnostic tests for the purposes of promoting personalized medicine would remain equally hindered, and nothing would change with respect to the market for breast cancer gene testing. DOJ has likely adopted its position with biotechnology products, rather than medical diagnostics, in mind. In order to make any transgenic organism-genetically modified crops, bacteria that produce important medicines from naturally occurring genes, and oil-eating

bacteria, etc.-cDNAs must be used. Thus, firms who discover genes with useful commercial biotechnology applications-for example, those genes inserted into crops to make them herbicide-resistant-would want to patent the cDNAs used to make those crops. This intellectual property is, especially in the initial stages of product development, the only asset that biotech startups can use to attract investors. Without this intellectual property, the claim goes, biotech innovation would be stifled. The claim that a prohibition on cDNA patents would deprive biotech startups of their only property is false, yet it highlights much of the problem with a

VOLUME 23 NUMBER 5-6

binary approach to the patentability of genes. The question we should ask is The question we should ask is not, "are not, "are genes patentable?" genes patentable?" but "at what point but "at what point from the from the location of the sequence in location of the sequence in the genome to the development of a the genome to the development of a final, marketable final, marketable product should we product should we grant grant exclusive intellectual property exclusive intellectual proprights to an inventor?" erty rights to an inventor?" Once cDNAs are made, researchers can quickly into other platforms. Patents on diagnosmake more complicated molecules, tic technology merely prevent others called vectors. Vectors integrate the from using the same exact machinerycDNA into a larger, more complicated rather than information-in testing a molecule that can be used to insert the patient for which version of the BRAC1/2 gene into other cells in order to make the gene it contains. Thus, invalidating transgenic organisms at the heart of cDNA patents may prevent Myriad from biotechnology. Myriad has patents out charging absurdly high prices for on many such vectors, and as the DOJ BRAC1/2 testing by virtue of its monopimportantly points out, plaintiffs in this oly on the gene, but will still allow the case never challenged those patents. The company to retain enough intellectual vector, unlike the cDNA itself, incorpo- property in the form of technology interates many elements that are functionally, grated with the gene to maintain its not just formally, different than what one valuable position as the leader in the can find in nature, and truly combines BRAC1/2 testing market. naturally occurring genes with non-natUnfortunately, the DOJ brief has urally occurring inventions. The vector missed an opportunity to highlight these is the starting point for all biotechnology important, consequential distinctions products arising out of gene discover- between various "kinds" of gene patents, ies. instead arguing difference where it does Myriad might counter that vectors not really exist. The DOJ position would can't be used for diagnostic tests, that do very little for women currently unable only cDNAs can, and therefore cDNAs to undergo breast cancer gene testing, must be patentable to encourage the and would fail to solve the anti-commons development of diagnostic technology. effect currently resulting from exclusively Yet the cDNA by itself cannot be used held gene patents. In order to strike the diagnostically either; it must be inte- best balance of encouraging innovation grated into a platform that will allow the and preserving public access to natural researcher to actually see if the patient's phenomena and information, patents on sample binds to and compliments the naturally occurring genetic sequences in cDNA. The cDNA needs some sort of the form of cDNA, as well as DNA and further alteration, creating an invention mRNA, should be invalidated. that does markedly differ from the naturally occurring gene in both form and Magdalina Gugucheva is a Fellow of function. Myriad's diagnostic technology CRG. integrating cDNA into a usable platform, like its vectors, are also not challenged in the current case. Not only does this diagnostic technology squarely fall within patent law, but more importantly, patents claiming it don't prevent others from working with the naturally occurring information in the genes as integrated

GENEWATCH 27

A Return to Judging Genetics and biotechnologies in the courts BY MICHELE GOODWIN

28 GENEWATCH

terrain. Yet, how judges view their roles may be very different than how the public conceptualizes their authority and obligations. In Moore v. Regents, for example, the California Supreme Court found that there is no such thing as one's ownership in his body. Moore lost on all but one count in a case involving over a dozen causes of action. Moore's critical argument was that his doctor (also a medical researcher) acquired his spleen, semen, blood, and other biologics under false pretensesessentially theft-and later capitalized and derived a patent on that which was conscripted from Moore's body. The court was not persuaded by Moore's claim although there was no dispute about his doctor's unethical conduct in acquiring Moore's cell-line and other biologics. For many years, this case has riveted law students attempting to reconcile intellectual

property law, property law, and the court's decision: how Moore's doctors could own a patent (and profit) on a cell line derived from Moore's body and yet exclude Moore. But a change may be underfoot. Most recently, a lower court delivered a stunning blow to biopharmaceutical corporations in Association for Molecular Pathology v. U.S. Patent and Trademark Office (better known as the "Myriad Case") by ruling several very high-profile patents invalid. Myriad Genetics and the University of Utah Research Foundation own the patents on BRCA1 and BRCA2 genes, which are definitively linked to hereditary breast and

Image: Mechanix Illustrated, Nov. 1959

Over sixty years ago, Judge Charles Clark wrote that the function of courts "cannot be limited to a mere blind adherence to precedent." He cautioned fellow jurists against engaging in lofty formalism. Clark warned that judges must avoid clinging to precedent simply for the sake of it and "artfully" dodging new doctrine. Clark recognized the value of judges fully exercising their mental powers and "discovering and applying" new trends in law as the technology and policies of the time demanded. Clark's pragmatic advice to his colleagues on the bench remains timeless. Beyond a doubt, the burden of crafting judicial responses to nascent technology is a formidable process. The struggle today is not the relationship between legal standards for the "old" law of horse and buggy and the "new" automobile. Rather, the challenge for the contemporary bench is determining the proper application of law and legal concepts to sexy new technologies and biotechnologies such as the ownership of genetic materials, the regulation of genetically modified foods and organisms, and the appropriate criminal and tort law standards to mishaps, fraud, and breaches of fiduciary duties. Since the Supreme Court's landmark decision in Diamond v. Chakrabarty (1980), which made patenting living organisms legal in the United States, applications for biologically derived patents have taken off at break-neck speed. With equal velocity and controversy have been claims of fraud, deception, invalidity, and unfair dealing in the relationships between patients, medical researchers, and multinational pharmaceutical companies. In cases ranging from Moore v. Regents, which involved the non-consensual taking and manipulation of a patient's genetic materials by his physician (1990), to more recent cases involving the marketing of infected human tissues, judges stand in the gap of bumpy, unpaved terrain-often without legislative guidance. For some scholars, they are the principle arbiters between David and Goliath in this new

OCTOBER-DECEMBER 2010

ovarian cancers. The patents grant Myriad the exclusive right to perform diagnostic tests on the genes and herein are the most significant problems voiced by critics. The tests cost over three thousand dollars per administration and have contributed in large part to hundreds of millions in revenue earned by the company in the last two years. But some wonder, how can a gene that is found in the human body of some women afflicted with breast cancer be owned by a corporation? The concerns over Myriad's patent involve the practical, theoretical, and conspiratorial. As with traditional property ownership rights, owners possess the power to exclude, ward off, and destroy property, and the authority to prosecute those that impose upon or trespass against your property. Understandably, this unique intellectual property status involving the BRCA mutant genes causes alarm. Among the plaintiffsâ&#x20AC;&#x2122; claims is that in order for a woman to discover whether the patented mutant genes exist in her body, she has to pay Myriad for the test to discover what

ruling in the Myriad case was interpreted by some to be a guidepost for effective judicial decision-making in the biotech age. In the past, courts not only struggled with evaluating the differences between horse/buggy and car/train in tort law, but also in contract, and even property law; but they took the leap, realizing that the bench could not fall prey to ambivalence or myopic thinking. Notably, judges defined what those assignations would mean for people harmed by the technology. Judges were not blind to the economic dynamics of technology (i.e. incentivizing industry and research) nor the political landmines associated with expanding civil remedies for individuals harmed by the

VOLUME 23 NUMBER 5-6

Michele Goodwin, JD, is Everett Fraser Professor of Law at the University of Minnesota.

Genetic Justice: DNA Data Banks, Criminal Investigations, and Civil Liberties By Sheldon Krimsky and Tania Simoncelli Columbia University Press

Contemporary biotechnologies and commercial usage of genetic knowledge converge like locomotives at train crossings without lights, whistles, or signals. is in her body. Particularly sensitive in that case is that the genes under dispute are associated with ovarian cancer (BRCA 2) and breast cancer (BRCA 1), a disease that remains incurable and afflicts 1 in 8 women in the United States. As a socio-economic matter, poor women without insurance could conceivably be "priced out" from learning whether they might be at risk for breast cancer. For African American women (who are less likely to develop breast cancer, but five times more likely than their white counterparts to die from it), the outcome of this litigation and future appeals might be particularly relevant. Myriad offers no real answer to the underlying social-justice critique voiced by critiques concerned about the corporatization of medical knowledge that could save lives. However, Judge Sweets' District Court

developing technologies. Increasingly, contemporary conflicts in biotechnology mimic their predecessors and will require an engaged, courageous, equipped judiciary. Metaphorically, contemporary biotechnologies and commercial usage of genetic knowledge converge like old locomotives on roads without guardrails and train crossings without lights, whistles, and signals. The socio-legal questions and problems emanating new technologies demand focused attention from the judiciary.

Sheldon Krimsky is a founding member of the CRG Board of Directors, Professor of urban and environmental policy and planning at Tufts University, and author of eight books and over 175 published essays and reviews. Tania Simoncelli is a former member of the CRG Board of Directors and Science Advisor at the American Civil Liberties Union. She currently works for the U.S. Food and Drug Administration.

National DNA databanks were initially established to catalogue the identities of violent criminals and sex offenders. However, since the mid-1990s, forensic DNA databanks have in some cases expanded to include people merely arrested, regardless of whether they've been charged or convicted of a crime. The public is largely unaware of these changes and the advances that biotechnology and forensic DNA science have made possible. Yet many citizens are beginning to realize that the unfettered collection of DNA profiles might compromise our basic freedoms and rights. Two leading authors on medical ethics, science policy, and civil liberties take a hard look at how the United States has balanced the use of DNA technology, particularly the use of DNA databanks in criminal justice, with the privacy rights of its citizenry. Krimsky and Simoncelli analyze the constitutional, ethical, and sociopolitical implications of expanded DNA collection in the United States and compare these findings to trends in the United Kingdom, Japan, Australia, Germany, and Italy. They explore many controversial topics, including the legal precedent for taking DNA from juveniles, the search for possible family members of suspects in DNA databases, the launch of "DNA dragnets" among local populations, and the warrantless acquisition by police of so-called abandoned DNA in the search for suspects. Most intriguing, Krimsky and Simoncelli explode the myth that DNA profiling is infallible, which has profound implications for criminal justice.

GENEWATCH 29

Why Genes Must Remain Eligible for Patenting Dispelling the myths about gene patenting BY KEVIN NOONAN In the gene patenting debate, as in war, truth has been the first casualty. Whether it's publicity campaigns by the American Civil Liberties Union with clever buttons declaring "Do not patent my genes" or hyperbolic rhetoric, polemic has quickly replaced integrity in an effort to influence public opinion (both at home and abroad). A great deal of the anti-gene patenting argument is based on faulty premises, incorrect science, and a studied lack of appreciation of patent law as it has been applied, inter alia, to patent-eligibility for natural products. Since any rational debate is only as good as the information it is based upon, it is useful to address the more flagrant inaccuracies spouted by those who oppose gene patenting. Since "the truth shall set you free," there are some fundamental truths that must be considered when discussing gene patents. These include: “Genes are a product of nature”: The facts Patents claiming genes do not claim products of nature. The simple distinction is that gene claims recite that the genes are "isolated," and this limitation on their scope (as well as the 13th Amendment to the U.S. Constitution) prohibit the scenario that a patent holder may one day ring your doorbell and ask for a royalty from you because your liver is "using" a patented gene. More importantly, no one would want to own any individual person's genes: it has been known for more than forty years that any particular copy of a gene in an individual in a population is likely to contain at least one polymorphism that does or could (under the right environmental conditions) affect its function. Recent reports from J. Craig Venter on the complete sequence of human diploid genomic DNA (his own) detected more than 4 million nucleotide variants, including an extraordinary amount of genetic variation that could affect gene expression and gene products in unpredictable ways. Moreover, and more significantly, human genes as they exist in human chromosomes are physically and chemically different from genes (really, isolated

30 GENEWATCH

nucleic acids) as claimed in the overwhelming majority of so-called "gene patents." Genes have been described, properly, as the instructions for producing proteins. A gene encodes the amino acid sequence of a protein in a linear sequence of 3-base triplet codons that correspond in linear order to the amino acid sequence of the protein. However, in humans (and almost all other multicellular organisms) almost all genes are interrupted by "junk" DNA that does not encode protein (or at least does not encode the same protein that the gene encodes). The entire gene, junk and coding sequence, is transcribed into RNA by the cell and then the junk pieces are "spliced out," leaving the coding sequence (termed a messenger RNA or mRNA) that is used to produce the protein. Scientists take advantage of this process to clone genes, by isolating the mRNA and converting it into a DNA molecule called complementary DNA (cDNA), which is what is cloned, sequenced, and patented. cDNA

There is no binding legal precedent that mandates that natural products are ineligible for patenting. does not exist in nature, and must be created by man using chemical and biological techniques. The hallmark of what the Supreme Court has declared is patent-eligible is "anything under the sun made by man." The cDNA copies of genes that form the basis for human gene patenting are "made by man" and not products of nature because they do not exist in nature prior to being synthesized in a test tube by a scientist. If we are honest in defining what are actually "products of nature," then they must by definition be produced by nature. cDNA molecules are not. “Genes are products of nature”: The law The legal argument that "products of nature" are not patent-eligible proves too much, because if genes are not patentable

then many other natural products cannot be, either. This includes for example various antibiotics, and any number of products isolated from crude oil, plants, animals, and even humans. If genes are not patent-eligible, based on the fact that they are products of nature, then the patent incentive cannot exist for these "products of nature," either. If isolated human DNA is not patent-eligible, there is no principled reason why many other "natural products," such as antibodies, antibiotics, antisense and small interfering RNAs (siRNAs), hormones, metabolites, and proteins should be. Importantly, also included in any such "natural products" patenting ban would be biologic drugs, i.e., those drugs based on "naturally-occurring" human proteins. Indeed, proteins like human Blood Clotting Factors VIII and IX, insulin, human growth hormone, erythropoietin, tissue plasminogen activator, and all monoclonal antibodies are "isolated" in substantially homogeneous form, are structurally unchanged from their sources in blood and other bodily fluids, and are less altered than the cDNAs that are the subject of the claims to isolated human DNA invalidated by the district court. These considerations are also why the distinctions drawn in the Department of Justice's brief to the Federal Circuit is bad science, bad law and bad policy, in view of the expected importance of biologic drugs in the years to come. There is no binding legal precedent that mandates that natural products are ineligible for patenting. On the contrary, the prevailing precedent, Diamond v. Chakrabarty, mandates patent eligibility to anything that is a "nonnaturally occurring manufacture or composition of matter - a product of human ingenuity," that is "not nature's handiwork, but [the inventors'] own." Isolated DNA (as well as these other examples of natural products) falls squarely within this rubric. “Genes are part of a ‘commons.’” Ironically, genes and gene patenting were originally assailed as creating a "tragedy of the anticommons," because private "ownership" thereof would impede genetic research. In fact, as has been

OCTOBER-DECEMBER 2010

shown by multiple studies over the past 10 years, gene patenting has done no such thing. Indeed, every report on the subject, whether from the United States1, Germany2, Australia3 or Japan4, has found that "patent thickets"5 or the "anticommons”6 rarely affects the research of academic scientists. In addition, the incentive for gene patenting motivated private companies, most notably Celera and Human Genome Sciences, to compete with the federally funded efforts to sequence the human genome. This competition accelerated these efforts and produced sequence information more rapidly than anyone expected. If these efforts provided genetic information that can be used to address human disease one day, one month, or one year earlier than it would have been produced otherwise, who can say the incentive is insufficient? “Gene patenting inhibits genetic research.” In fact, a very good case can be made that the opposite is true. This is due to another distinction glossed over by those opposed to gene patenting: genetic information isn't patented (despite the district court's conceit that it could distinguish claimed DNA from other biological products for being "the physical embodiment of [genetic] information"). Patent law requires that claims be supported by a written description sufficient to enable the skilled worker to make and use the invention. For genes, this has meant that the genetic sequence is disclosed in almost all gene patents. This information can be used for any number of purposes, including sequence comparisons (which can be performed without "isolating" a gene), detecting genetic polymorphisms, and a variety of other scientific endeavors both before and after a patent grants, without risk of infringement. Perhaps the best indicator that "inhibiting basic research" has not been a consequence of permitting patents on human genes is the extent to which basic research has been performed on the BRCA1 or BRCA2 genes, famously patented by the University of Utah and licensed by Myriad Genetics. The number of research reports in public databases reflecting ongoing basic scientific research in peer-reviewed scientific journals on these genes is almost 10,000: a simple database (PubMed) search of "brca1 or brca2" resulted in 7,855 publications. If either of the BRCA patents were to have had a chill-

VOLUME 23 NUMBER 5-6

ing effect on basic research, the expectation would be that the number of scientific research reports would have declined in the face of patent infringement liability. On the contrary, the number of such publications has steadily increased each year, which is precisely what would be expected if these patents had no significant effect on basic scientific research. What these patents do, of course, is prevent commercial activity–i.e., using the patented isolated human DNA or performing the patented methods for profit. This is a legitimate exercise of the patent grant. “We don't need gene patents– researchers will do it anyway.” With regard to basic genetic research, this is true–it is the corollary to the previous point, that gene patents don't inhibit genetic research. However, there is a vast gap between identifying a genetic polymorphism related to a disease, or identifying a gene that encodes a useful protein, and developing a clinically validated test or producing a commercial biologic drug product, and that is where biotechnology companies come in. Of course, without the prospect of patent protection, investors are unlikely to provide the funding needed by start-up biotechnology companies to develop commercial embodiments of these inventions. And in view of the complexities of biotechnology products, other avenues–trade secrets and regulatory data exclusivity being just two–may enable companies to keep their "monopoly" much longer than the term of a gene patent. This would produce the kind of unfettered right in (undisclosed) genetic information that opponents of gene patenting wrongly assert exists today. “Gene patenting inhibits innovation.” It is easy to forget today the basis for gene patenting in the past. Any number of biologic drugs have been developed that, according to a recent Federal Trade Commission report, "have improved medical treatments, reduced suffering, and saved the lives of many Americans." These drugs were developed by companies that isolated the genes encoding them, including erythropoietin, human growth hormone, interferon, blood clotting Factors VIII and XI, human insulin, tissue plasminogen activator, and a host of others. The patent incentive was instrumental in supporting investment in these companies and in developing a biotechnology industry in the

U.S. that has been a world leader for 25 years. As anyone who followed the debate on follow-on biologics will recognize, the need for patent protection to attract investment in what remains a fundamentally risky industry has not diminished. Patent policies abroad already permit those countries to "free-ride" on American innovation. Why should we adopt their failed policies here? And who will create the next generation of drugs based on biotechnology if we do? Unfortunately, most of these arguments misconstrue the fundamental societal benefit conferred by the patent system-not incentives to innovate, and not even incentives to commercialize, but the requirements for disclosure that are fundamental to the patent grant. The plaintiffs fatally overreached in seeking to invalidate the patents-in-suit, and the U.S. District Court's decision, if upheld by the Federal Circuit or Supreme Court, is likely to have unintended and seriously negative consequences. The patents at issue, directed to isolated human DNA encoding BRCA1 and BRCA2, represent only the beginning of an era of personalized medicine that will be characterized by understanding, and utilizing, genetic differences that impact both an individual's propensity for succumbing to diseases and disorders as well as making a determination of the best therapeutic interventions and treatments for addressing them. Patents in this area are needed to promote expeditious disclosure of the genetic bases for such diagnostic and therapeutic approaches to human disease; without them, alternative means of protecting such discoveries, for example by holding them as trade secrets, will become more attractive. Patent-eligibility of isolated human DNA promotes not only disclosure of the DNA itself (and the proteins encoded thereby) but also the best mode for making and using the isolated human DNA and related methods. Even should the basic genetic information be available elsewhere, failure to patent also means failure to require full disclosure, and the attendant suppression of information would affect the development of reliable drugs and diagnostic methods (or worse, permit private companies to hold such information indefinitely). Such an outcome would be adverse to the public interest and contrary to the sound public policy underlying the Patent Act. Kevin E. Noonan, PhD, JD, is a patent attorney and founder of patentdocs.org.

GENEWATCH 31

Naturally Occurring Genes and the Commons by Necessity Certain essential parts of the natural world - like our genes - must remain part of the public domain BY DAVID KOEPSELL

Image: Wikimedia Commons (modified)

One frequent response to various arguments against gene patents is the claim that without such patents the biotech industry will falter. There is very little evidence for this, and recently the trend has been that corporations are seeking fewer patents on unmodified genes. This trend is no doubt motivated by recent shifts in the legal landscape creating greater uncertainty about the future of gene patenting in general. The decision by Judge Sweet in the AMP v. Myriad case, the report of the SACGHS, and the Department of Justice's recent amicus brief opposing patents on unmodified, but merely "isolated" genes have necessitated greater caution in patent filings. If these trends continue, only modified sequences are likely to remain patent-eligible. The DOJ's brief sets the standard pretty low for modification, given that they conclude that cDNA is sufficiently inventive to be patent-eligible; but all of this nit-picking and dithering around the edges of patenteligibility for genes, and bargaining among parties who clearly believe that gene patents have some useful role in promoting innovation, seems odd to me. All of these arguments hinge on questions regarding the efficacy, efficiency, and role of gene patenting in encouraging innovation and economic growth. Utilitarian arguments are suspect to some of us with training in ethics, and of a particular ethical bent. Utilitarian arguments can justify all sorts of nasty things, as long as the overall good outweighs the harms caused. Utility can be a reason for doing something, but it cannot, in my estimation, ever suffice if rights are otherwise violated. Those who believe in rights (and the duties they imply) must reject the sole use of utility as an argument in favor of gene patents if they violate some particular right. In my book Who Owns You? The Corporate Gold Rush to Patent Your Genes, I considered the various utilitarian arguments proposed by gene patent proponents, but argued ultimately that these pragmatic justifications were outweighed by the fact that gene patents

32 GENEWATCH

violate certain inviolable rights. I didn't arrive at those rights in the usual way. I concluded that even with gene patents, no one really "owns" you, nor can they claim to have any control over any one of us by virtue of their patents. Even while patents on unmodified genes prevent you from gaining information about your genome without paying monopolistic rents to patent holders, it is conceivable that this will be overcome by various technical possibilities, such as do-it-yourself whole genome sequencing. This is a remote and distant possibility (anticipated and prepared for by the heroic Steven Salzberg, of the University of Maryland), but it illustrates that the sort of control over individuals posed by patent ownership falls short of violating our individual autonomy over our bodies. Patents give to the patent-holder a right to exclude others from doing something. In the case of gene patents, they give their owners rights to prevent others from replicating the patented gene. In most of the valuable instances of these patents,

that right enables a company (like Myriad) to prevent others from testing for the presence of a certain mutation of BRCA1 and 2 that causes an increased likelihood of breast and ovarian cancers. Granting such a right to exclude is not unique to intellectual property law. It also is a hallmark of real property law. The term "real property" at one time applied to all tangible goods, but now it is generally understood to mean simply "land." Many of us think that rights to ownership of land and other tangible objects is a natural right. The authors of the Declaration of Independence, taking their cue from John Locke, believed that certain rights were inalienable. Locke expressed his view that "life, liberty, and property" were among the most crucial, inalienable, natural rights that inhere in all humans. The Declaration of Independence cites "life, liberty, and the pursuit of happiness," although clearly the laws that were established in the various states and protected by the Federal Government have long Continued on page 34

OCTOBER-DECEMBER 2010

Foiling Gene Patents: The Salzberg Screen An interview with the creator and namesake of the BRCA screen that circumvents gene patents

All the legal fuss about gene patents may be for naught. Operating under the belief that “any individual should be allowed to interrogate his or her genome ... regardless of whether a private company claims to ‘own’ the rights to particular gene mutations,” Steven Salzberg, Director of the Center for Bioinformatics and Computational Biology at the University of Maryland, and colleague Mihaela Pertea created a program to screen an individual’s genome for BRCA mutations–apparently without violating Myriad’s patents on those genes. The software is available for free download, but there is a catch: you’ll need to have your genome sequence handy. Yet as the cost of whole-genome sequencing continues to drop, it will become more and more economical to circumvent specific diagnostic tests such as Myriad’s with computational screens. In other words, the Salzberg Screen just might be the harbinger of a future in which, at least in diagnostic testing, gene patents are essentially obsolete. How is the Salzberg Screen different from anything that's already out there? It's the first purely computational screen that starts with the whole genome sequence– the "shotgun sequence" as we call it–from sequencing your genome with one of the new sequencing machines, the so called "next generation" sequencer. I understand this project is a direct response to gene patents. Is it more specifically a response to the Myriad case as well? No, it predates that-we heard about that lawsuit after we had already done most of the work. We were just about to submit the paper when we heard about the lawsuit.

VOLUME 23 NUMBER 5-6

Was the main idea from the beginning to effectively circumvent patents? I think you could fairly say it was one of the main ideas. We just wanted to demonstrate that with current technology, we're now at the point where it's pretty easy to interrogate your genome for any mutation that you want to if you have the genome sequence. And you can do that computationally: once you sequence your genome, it's a one-time assay. You can sequence your genome once and test it many times-you can continue to test it computationally the rest of your life. Whenever a new mutation is discovered that you're interested in, you can just download some software and screen your genome. That's the way things will work in the future. We are a little ahead of the curve, but that's the idea: in research, we like to be ahead of the curve. We're not there yet, because people aren't routinely getting their genome sequenced, but it's going to happen, it's just a matter of time. And the limiting factor now is the price of whole genome sequencing? Yes, the price of whole genome sequencing is now under $10,000, just to do the raw sequencing … but that's all you need for our test, that raw sequence. Our test is free, the software is free, and you can run it on your computer. It would probably take all day or overnight, since there's a lot of data in a genome sequence, but you can probably do it on your desktop computer. And the cost of sequencing is still dropping fairly rapidly. The Myriad test, which I believe is one of the most expensive, costs upwards of $4,000. We're already pretty close to the same cost, and once you have your genome you can test for any mutation in any gene-so why would you pay per gene to have them tested? It doesn't make any sense economically. You have said that "the door to this new technology is already open and cannot be closed." Do you think that gene patents could get in the way of this? Patents can slow things down and they

can get in the way, but I don't think that they are going to stop progress. They certainly impede progress … but remember, the U.S. is not the only country in the world, and the patents that are being filed in the U.S. are not recognized by many other countries. So if you can't get your genes tested here, you may be able to go somewhere else-the world is a small place. Although it seems this software does not violate Myriad's patents directly, are you concerned that they might sue you for indirectly violating their patents? I'm not really concerned, but I guess you could say I have a mild concern about that. I don't think it would really benefit them to go after me. I think right now Myriad is going to be mostly interested in just keeping their patents from being completely invalidated. The current court ruling is that the patents are not valid-and if that ruling holds up, game over for them. For the very short term, you're not going to see large numbers of people getting their whole genome sequenced; but in the medium term, maybe four or five years out, I think it's going to become increasingly feasible for people to do that. If it's cheaper, people will do it. If you can get one gene sequenced and tested for $4,000 or else get your whole genome sequenced for $4,000 and then test that one gene, I think everyone would do the latter, because once you sequence your genome you can then hang onto it and test for other mutations in the futuremutations that haven't been discovered yet. Have you had any pushback, anyone telling you that making the screen available was a bad idea? No, not really. I talked to the people in my group about it, and they were all very interested in the topic. I'd say they mostly thought it was a good idea … though I'm not sure they would have all done it themselves! To download the software, visit http://cbcb.umd.edu/software/ BRCA-diagnostic

GENEWATCH 33

Continued from page 32

included rights to land and "moveables." But genes are clearly different, and patents provide a right to exclude that is different from the exclusion granted by real property law. You are still allowed to keep the genes in your body, you just have to pay fees to know about their existence if patented. Regardless of its alleged utility, does this exclusionary right violate any natural rights? I concluded that it does, and in so doing, expanded on existing theories about the nature of what lawyers and economists have long called "the commons." The notion of a "commons" in the Anglo-Saxon tradition dates back to the practice of sovereigns granting the public the right to use of certain parcels of the lands the monarch otherwise claimed ownership over. Those who had no land, but maybe had some sheep, could graze them on the commons. These were commoners. If they could erect a shelter, they could also own that enclosed shelter and live there. These ancient commons were what I call a "commons-by-choice," as they involve natural abilities of exclusivity. The sovereign could have fenced and guarded these lands, enclosing them, and excluding all others from their use. Exclusivity is a necessary feature of the rights to ownership of land and moveables. When I possess a hammer, or a house, I can physically exclude others from it. To dispossess me of these things requires violence, and the attempt to do so violates our natural rights to our property. The mixing of my labor with a parcel of land, its use, and my ability to quietly enjoy that use, are all elements of basic Lockean theory about rights to property. Intellectual property is utterly unlike real property. The exclusivity created by the laws of patent (which emerged much later than those regarding real property), is artificial, not natural. The state must grant, through some process of registration, review, and agreement, a limited period of exclusivity- a new and unnatural monopoly right. There is simply no natural way to exclude others from using ideas. But not all ideas can become the subject of patents. The courts have long recognized that laws of nature and abstract ideas, for instance, cannot be eligible for patent protection. I contend that this is not simply a good, pragmatic idea, but rather in accord with natural law. Abstract ideas and laws of nature are incapable of enclo-

34 GENEWATCH

sure or exclusivity because they belong quite clearly to what I call the "commonsby-necessity." Unlike the commons-by-choice, the commons-by-necessity includes any part of the universe that is incapable of enclosure. Laws of nature, like F=ma or E=mc2, are parts of the fabric of the natural universe, having nothing to do with human invention. It is impossible to enclose and monopolize or otherwise exclude others from participating in them, utilizing them, or knowing about them. "Abstract ideas" are likewise commons-by-necessity. The necessity here is not pragmatic but logical. There are simply some parts of the universe that cannot be enclosed, and thus that are not amenable to ownership or exclusivity of any kind. While the commons-by-choice could be owned through valid, useful possession, the commons-by-necessity can never be. Attempts by states, through patent laws or other means, to exclude anyone from utilizing commons-by-necessity, or to grant exclusive use to anyone over these sorts of commons, are unethical. This is not because of the consequences; as I mentioned above, this is not a utilitarian argument. Abstract ideas, natural phenomena, and natural laws cannot be contained, cannot be exclusively controlled, and no rights may inhere for any one individual over them. Unlike the rights that inhere over real property, there is no manner in which anyone may claim an exclusive right over the commons-bynecessity. Instead, we all necessarily share equal rights of access to these commons, not because some sovereign says we do, but because we are entitled to free, equal and open access to instrumental use of nature's parts so long as that use does not interfere with anyone else's rights. This is consistent with John Stuart Mill's "Liberty" or "Harm" principle, which defines our rights to liberty as broadly as possible, to the extent that those liberties do not interfere with anyone else's. This is a fundamental notion of modern liberal democracy. There is thus an ethical reason why the Supreme Court has specifically excluded abstract ideas, physical phenomena, and laws of nature from patent-eligibility (in the seminal cases of Diamond v. Diehr and Chakrabarty). These are all commons-bynecessity, free for use by any and all. No sovereign could contain them, nor could any individual. Unmodified DNA is, I contend, such a commons-by-necessity, just

as gaseous oxygen, the laws of gravity, the theory of relativity, and all other naturallyoccurring laws and phenomena are. The genes that patent attorneys claim are modified through isolation, and thus somehow inventive, have pre-existed human intention. Nature isolates them with promoter and stop codons, signaling the process of transcription, characterizing them as genes long before we ever developed theories about their existence, or confirmed them through modern genetics. Identifying the sequence of naturally-occurring genetic mutations, and using those discovery to help people anticipate, treat, and maybe even cure diseases is very useful, and there are frequently inventive processes and products involved, but the sequences over which companies like Myriad have claimed exclusive ownership belong not just to the "common heritage of mankind," but to an un-encloseable commons-by-necessity. If we accept that there are such things as commons-by-necessity, and that while rights to real property are grounded in natural facts, no rights can ever obtain to certain parts of the universe (like genes, laws of nature, physical phenomena, and abstract ideas), then we must reject the practice of numerous gene patents covering merely "isolated" genes as unethical. Certainly, some reject the notion that there are any ethical norms that are grounded as I claim in natural states of affairs, and for some, ethics is something entirely man-made. For those, I ask: On what basis are rights to life, liberty, or property based, and under which claims of utility would you be willing to trade away any of these basic human rights? If we are serious about our rights and recognize that some are inviolable, then we must reject laws that seek to set aside or curtail those rights for mere utility. Our mutual rights to access all commons-by-necessity, including genes, must outweigh the desires by some to monopolize them, even if their claims about practical necessity, innovation, and profit are true. Genes must remain in the public domain, and it is not only contrary to established law, but more importantly, it is unethical to allow patents on genes that evolved due to natural processes. David Koepsell, PhD, JD, is Assistant Professor of Philosophy at Delft University of Technology and author of Who Owns You? The Corporte Gold Rush to Patent Your Genes.

OCTOBER-DECEMBER 2010

In Defense of a Working Good Before it was dissolved, the Secretary’s Advisory Committee on Genetics, Health and Society issued a controversial report calling for limits on gene patenting - but it was not unanimous I have always opposed the concept that human genes and their DNA sequences could be patented. Not only did it appear to me that they were "a product of nature," but the idea that some entity might have ownership to a chemical residing in nearly every cell of my body seemed offensive and untenable. So it was apparently paradoxical and sadly ironic that I felt compelled to join the opposition to the SACGHS report on this topic that recommended various actions against gene patenting by the HHS Secretary. My opposition was distinct from that expressed by Mara Aspinall and Sheila Walcott, who cosigned the minority dissenting statement with me. My objections were primarily based on three points: 1. The patent system has spurred innovation and rapid commercialization in the life sciences and medicine that has bene-

fited many people worldwide. We should have a strong argument to disrupt a working "good." The report did not adequately reflect this fact, nor did it include any monitors or steps to preserve this effect, if it exists, in the field impacted by gene patenting. 2. The data demonstrating the harms caused by the current system of patenting that includes "gene patents" were scant and not convincing in its specificity. While some people surely have not had access to patented products, most have; and our system of health care provision and financing routinely discriminates against the poor (and many other needy groups) generally. The system needs change, but altering patenting will not do it. 3. Finally, the report called for a variety of Executive Branch actions (notably not helping the ACLU case against Myriad). I believe the courts need to clarify the

Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests Report of the Secretary’s Advisory Committee on Genetics, Health and Society

Statement of Dissent From Ms. Aspinall, Dr. Billings, and Ms. Walcoff In our current health care system, patients routinely face unequal access to medical care, including diagnostic tests. Consequently, it is our position that statutorily modifying the gene patents system, including the creation of exemptions from liability for infringement upon such patents as defined in this report and proposed in the recommendations, would be more harmful than helpful to patient access and to the quality of innovative genetic diagnostics. The basis of our position is recognition that there are a variety of financial and scientific decisions made by both government and private stakeholders throughout our health care system that impact patient access to genetic tests. We recognize the importance of supporting and encouraging discovery and, most importantly, translating those genetic discoveries into new tools to improve patient treatment and outcomes. The patent system, although debatably imperfect, offers those who invest in developing discoveries a value for the investment. We believe that facts and findings cited in this report and in other reliable scientific literature support our view that the recommended change to the patent enforcement statute and the

VOLUME 23 NUMBER 5-6

current law on biotechnology patenting. Then, if we believe this legal regime as practiced by the PTO is inadequate or inappropriate, laws to alter it should be passed by the Congress. Executive action prior to this process seemed ad hoc to me and could cause harms while curtailing important deliberations. I therefore opposed some of the recommendations and conclusions of this SACGHS Report. I do hope that this important issue will continue to be reviewed and litigated. A clear and widely acceptable result that promotes human integrity and non-commodification while providing the hope that active research and a fecund marketplace can bring to those in need would be my goal. Paul Billings, PhD, MD, is director and chief science officer of El Camino Hospital’s Genomic Medicine Institute and a member of CRG’s Board of Directors.

Bayh-Dole Act would have significant negative consequences. Many discoveries, in academic institutions or otherwise, may not be pursued or developed. Notably, the increasing complexity of development and clinical testing for genetic tests and higher evidentiary standards and regulatory hurdles such tests must meet require increasing levels of investment (measured in millions or tens of millions). Notwithstanding our position that the recommendations regarding the statutory changes to the patent system would not ameliorate the patient access concerns this Committee has identified, we do acknowledge and appreciate the importance of patient access and quality standards with respect to provision of genetic testing. However, while we agree that licensing does play some role in universal access, public health plans such as Medicaid and Medicare, as well as private payers, continue to be free to refuse coverage and payment even if every laboratory in the country offers a test. Moreover, in addition to such reimbursement policy, other factors, including practice patterns and professional talent distribution, also impact what tests are conducted in what regions of the country. Therefore, we do not support the assertion that in most cases gene patents have had a direct and overarching negative impact on the ability of a patient to obtain a test. In terms of clinical access on behalf of patients, our assessment of the data suggests that clinicians are often significantly limited by contractual and financial barriers placed on them by their organization/institution or cost containment restrictions imposed by public and private payers. The ability for every labo-

GENEWATCH 35

ratory to offer every test, in our view, is a commercial objective more than a patient access issue since clinicians can and do order genetic tests for patients every day from laboratories both across the hall and across the county. Nevertheless, we agree that the inability of certain populations to afford genetic testing is an important and valid concern and should be addressed directly as an integrated component of systemic health care reform. It is important that good intentions do not give way to negative outcomes in other parts of the health system or economy. As such, we would strongly encourage the Department of Health and Human Services to critically evaluate the criteria and requirements of all public health programs, including Medicare and Medicaid, to ensure that every beneficiary of public health funding has reasonable and timely access to genetic tests regardless of income or geographic location. In addition, we strongly encourage HHS to evaluate relevant laws, regulations and policies, such as anti-kickback, health care fraud statutes, and government reimbursement policies, that are overly burdensome or result in practical barriers on diagnostic companies who would otherwise elect to offer tests at little or no cost based on financial need. We also agree that testing, including quality standards, whether by a single laboratory or multiple laboratories, are an important factor to the public's health. Test quality has been and should continue to be appropriately addressed by the Food and Drug Administration and the Center for Medicare and Medicaid

Services. Specifically, those agencies should continue to work together to keep pace with laboratory and diagnostic innovation and identify new ways to evaluate proficiency, reliability, and reproducibility of new and innovative genetic tests. We do not believe, nor has FDA or CMS ever suggested, that there is any credible evidence that the quality of testing performed in sole source laboratories is routinely or demonstrably subpar in any way to that which is done in multiple laboratories. Nor do we believe that data indicate that modifying the gene patent system and protections it offers through exclusive licensee agreements would result in multiple laboratories performing proprietary tests with better quality than generated by current and developing oversight of quality assurance undertaken by these agencies and the laboratories themselves. Finally, we believe that the determination of patentable subject matter and the protections afforded to such patentable subject matter should remain the primary function of the US Patent and Trademark Office, Congress, and the US courts. The suspension of patent protections such as exemptions from liability for patent infringement for a restricted class of innovation (gene patents), unless they are determined to be non-patentable (for instance, a court determination that they are a â&#x20AC;&#x153;product of natureâ&#x20AC;?), is unwarranted and a risky intrusion in to a process that has delivered many key innovations to needy Americans.

Freedom of Genes The Myriad case carries often overlooked First Amendment implications BY DEBRA GREENFIELD In the reporting and coverage of the case against the United States Patent and Trademark Office and Myriad Genetics, the company holding the patents on the BRCA 1 and BRCA 2 genes, little has been written about the ACLU's involvement as counsel for the plaintiffs. Litigation regarding the rarified nexus of the science of human genetics and the law of patents appears at first glance to be different from the historic and well-established causes for which the famous advocacy group is known. When considering the issues involved in the process of patenting human genes and genetic information, however, it becomes clear that the case is thematically related to those same traditions. Constitutional rights and civil liberties are at stake: the granting of exclusionary patents to human genes and the information they embody restricts and infringes upon the guarantees of the First Amendment, freedom of speech and expression.

36 GENEWATCH

Although the decision of the lower district court in the case now under appeal at the Federal Circuit did not reach the free speech issue argued by the ACLU, the concepts involved in the argument are important for an understanding of the broader context in which the gene patent case developed. Unique and emerging technologies of the "information age" present novel questions for scholars considering the scope and meaning of the First Amendment. Yochai Benkler's description of the creation of the digital environment and its resultant expansion of intellectual property rights in information is representative of this new consideration in First Amendment jurisprudence and methodology. He asserts that the challenge of supporting traditional goals of free speech and expression, "robust democratic discourse and personal autonomy" is made more difficult by the information economy. Simply put, "To cre-

ate property rights in this economy, government must often prohibit speech." He describes the particular concern as "the enclosure movement in our information environment. In other words, our society is making a series of decisions that will subject more of the ways in which each of us uses information to someone else's exclusive control," and notes that as intellectual property, we will expect "information to be owned, and to be controlled by its owner," blinding us to "the cost that this property system imposes on our freedom to speak."1 This evolving tension between the law of intellectual property as delineated in the United States Constitution, Article 1, Â§8, clause 8 and the First Amendment has primarily been situated in the law of copyright, but a similar tension is developing between freedom of speech and the patent system, where similar 'speech costs' undermine the system's Constitutional directive of "promoting the progress of science and the

OCTOBER-DECEMBER 2010

useful arts."2 Defined by the Patent Act as a property right granted by the government, inventors are rewarded with a twenty year monopoly forbidding anyone other than the inventor from "making, using, selling, offering to sell, or importing their invention."3 These grants are no longer concerned with just artifacts of technology. Now, as commentator John R. Thomas notes, "Patent claims, cut loose from physical moorings, have grown more abstract." Examples include voter and consumer surveying techniques, marketing and sales techniques, and patented teaching methods of language, music, vocabulary acquisition, dialogue writing, and mathematics.4 Thus, these unique questions as to what the framers meant by freedom of speech are raised not only in emerging information technologies but also in the emergence of new practices in biotechnology. Descriptions of the science and language of the biotechnology involved in human DNA is frequently analogized to the science and language of computer technology; the metaphors are abundant. Similar comparisons can be made when considering how the intellectual property grant of human DNA patents results in tensions with the First Amendment. When DNA molecules and DNA sequences, DNA sequences with single nucleotide polymorphisms (SNPs), replicated human DNA sequences (cDNA), and methods and materials for determining a relationship between a particular DNA genetic sequence and the presence or absence of a genetic susceptibility are patented, speech concerns are raised. A careful consideration of the decision of the lower district court as well as the briefs being filed in the appeal by Myriad reveal the importance of the basic underlying question in the case considered within the context of gene patenting and civil rights and liberties: What exactly is the nature of the human BRCA 1 & 2 DNA molecules and genes, and how can one characterize exactly what it is that is being patented? The briefs for Myriad describe the molecule isolated from its natural environment as simply "a chemical compound," not distinctive from any other similarly patented composition. The district court found the claimed isolated DNA to be in all respects, identical to the same molecule or sequence as that found in the body, known as native DNA, and that they have identical functions, the ability to express BRCA 1 and 2 proteins. It is this structure and function that the court relied upon to

VOLUME 23 NUMBER 5-6

describe the essence of the patent claims as "embodied information," and thus distinctive from other chemical compositions. "What is being patented is the threedimensional structure of the chemical bases that, in their ordering, direct the synthesis of other molecules in the body-namely proteins."5 Thus newly characterized, the law in the case this far is following the observations and writing of social scientists remarking on the nature of DNA in the information age, where "…biology is information, and crucially, that information is both material and immaterial." This embodied information may arguably be characterized either as a "law of nature" or a scientific principle, both of which represent exceptions to the categories of patent eligible subject matter according to the statute. When these laws or principles, i.e., human DNA or a genetic sequence are patented, the grantee is given its exclusive use, the information is privatized and the public's ability to use the informational content is restricted or denied. This embodied information can simultaneously be considered to belong to both a part of a body of collective knowledge, i.e. the "human genome," as well as existing within any one individual's particular and unique genome, one's own DNA. Thus the patenting of human DNA and genetic sequences can possibly infringe both any one individual's First Amendment rights to the information in the shared human genome, as well as infringe upon that person's ability to have access to the information regarding their own genetic profile. Benkler's First Amendment concerns regarding the enclosure of information are implicated as rights inherent in the guarantees of free speech: the ability to communicate or publish "scientific speech" is infringed when the actions or information necessary for the formulation of that speech, the available precursors to speech, are unavailable. This occurs when the right to gather information necessary for the formulation of speech is restricted or denied. Real life implications arise when this knowledge is unavailable or restricted due to exclusive or high licensing costs, and the numerous policy arguments being made in the Myriad case reveal that harms to women and public health occur as a result. Innovation and progress in medical research is impeded when researchers are precluded from using and studying the BRCA 1 and 2 genes. The privatization of

the information and knowledge embodied by human genes also have "speech costs" and can be seen to threaten the core of our civil liberties. Particular types of patents which are granted on claims covering methods of using genes and genetic information for specific diagnostic purposes also implicate First Amendment guarantees to the precursors necessary for the formulation of speech. Drafted to cover the precise functions a physician might employ, these claims are often written as describing a correlation, a relationship between particular DNA or DNA genetic sequence and the presence or absence of a genetic susceptibility to a particular illness or condition. Myriad's method claims to the correlations involving the BRCA 1 and 2 genes and a susceptibility to breast and ovarian cancer are illustrative. When these exclusionary patents are granted, the ability for others to similarly consider the correlation is denied, and the First Amendment guarantee of freedom of thought, fundamental to the ability to formulate speech, is infringed. In the coming era of the much discussed "$1000 genome," using such informational tools, any person wishing to think about their own susceptibility to breast or ovarian cancer will be infringing Myriad's patents when determining if the correlation exists in their own body. The emerging science of epigenetics suggests that exposure to various environments and personal choices can suppress gene expression, thus affecting and contributing to the structure and function of our personal genomes. This science will help to diffuse the problematic political and cultural implications of our human identities, our natures being constructed or determined by our DNA, our biology at the molecular level.6 Nonetheless, our own unique genomes consist of and reveal important information about ourselves. Thus, per commentator Jonathan Kahn: "As genes play an increasingly powerful role in contemporary legal and political culture, individuals are called upon to refer to genetic information as a basis for assessing their rights and duties."7 The plaintiffs and the ACLU are to be thanked for asserting our Constitutional First Amendment rights in their case against Myriad Genetics. Debra Greenfield, JD, is Adjunct Assisstant Professor at the UCLA Center for Society & Genetics.

GENEWATCH 37

Patents on Genes, Organisms - and Human(oid)s? Life patents go far beyond genes - but just how far remains to be seen BY STUART NEWMAN mice-and soon, rats-in biomedical research, and the increasing presence of transgenic livestock in manufacturing and meat production operations. Patent protection is just one component of the drive to produce genetically engineered organisms, but it represents a strong financial motivation for (in the words of the philosopher Francis Bacon) "effecting of all things possible" in pursuit of utility and profit. The cultural currency of transgenic animals, in particular, and the prospect of more extensive manipulation in the future, threatens a number of civilizational norms and precepts. In contrast to plants, which in their natural state exhibit wide ranging environment-dependent phenotypic plasticity, animal forms and identities are relatively stable, and are icons and constants of the visual arts and literature, particularly traditional works and those meant for children. Genetic engineering and other methods of reconfiguring animal biology, such as trans-species cloning and chimerism, inevitably blur the boundaries between different kinds of organisms,

as well as between organisms and artifacts. Given the phylogenetic continuity of all animal species, this technology will inescapably come to threaten received notions of human uniqueness. While most members of contemporary societies are willing to tolerate, or ignore, the warehousing, instrumentalization and cruelty visited on animals raised for food, research, or other human utility, the privileged status of the human body, even of those individuals defined as criminals or outcasts, has long been normative across the main political and religious spectrums. However, with the rise of religion-based states and social movements that deny the human value of outsiders, official and popular adherence to a common humanity has markedly weakened over the past decade even in modernizing societies committed to classically liberal values. Justification of torture of suspects by the highest U.S. officials, for example, unwillingness to prosecute its perpetrators or those performing grievous acts against bystanders in targeted groups, and nonchalance of the public about military methods guaranteed

Image: Samuel Anderson

A lawsuit brought by the ACLU and allied groups against the U.S. Patent and Trademark Office has challenged the notion of patents on isolated native DNA sequences. The court's summary judgment in favor of the plaintiffs held that such patents covered parts of the natural world and were therefore inappropriate subject matter. The U.S. Department of Justice has now filed an amicus brief against gene patents, but in a more restricted sense than the original judgment. Specifically, manipulations as minor as producing complementary DNA from the natural sequence qualify the product as a patentable invention. What is clear from this is that patents on genetically engineered organisms, which were designated appropriate subject matter under U.S. law by the Chakrabarty Supreme Court decision of 1980, are unlikely to come under serious legal challenge. The position of such organisms within the wider culture is also unassailed given the high penetration of GM crops in the human and animal food chains, the extensive use of transgenic

38 GENEWATCH

OCTOBER-DECEMBER 2010

to kill civilians and noncombatants (in contrast, for example, to the Vietnam war era), have risen in concert with the innovations in the murderous tactics of the U.S.'s opponents. It might seem incidental that this stark change in attitude (extending across the conservative-liberal and religious-secular divides) toward the bodily integrity of those defined as "other" has come about simultaneously with the capability to genetically engineer animals, including (absent some loose and internationally nonuniform legal prohibitions) humans. But the following contemporaneous trends should also be considered by way of context: (i) an ageing population in the U.S. and elsewhere, in need of spare body parts, is creating a demand for tissues and organs the provision of which will only occur under patent protection; (ii) such repair tissues and organs will be most useful if their sources are close to human, but most patentable if they are not exactly human; (iii) "reprogenetic" technology now permits production of human, or humanoid, individuals from stem cells derived from anonymous discarded tissues rather than any parent-associated embryos; (iv) for genetically modified organisms of human origin, the precise boundary between non-human and human is no less socially constructed than is the boundary between "us" and "them" in the political realm. It is difficult to avoid the conclusion that as medicine becomes increasingly high-tech and personalized for those who can afford it, and the disparity in national wealth and income remains at its record levels in the U.S., there will be scientific and economic incentives to produce nearhumans for research and therapy. The decline in the allegiance to a notion of human social commonality, along with the rise in the scientific understanding of human biological commonality and the means to manipulate and exploit it through, among other things, patent protection of genetically modified animals, seems to be an explosive combination. Stuart A. Newman, PhD, is Professor of Cell Biology and Anatomy at New York Medical College and former member of CRGâ&#x20AC;&#x2122;s Board of Directors.

VOLUME 23 NUMBER 5-6

Synthetic Biology - The Next Wave of Patents on Life Not only can synthetically engineered organisms be patented so can the processes used to create them BY ERIC HOFFMAN AND JAYDEE HANSON Synthetic biology -the design and construction of new biological parts, devices and systems that do not exist in the natural world and the redesigning of existing biological systems to perform specific tasks-will bring the next wave of patents on living organisms. Synthetic biology not only poses new challenges to biosafety and biosecurity but also to our patent system. Discussions on gene patents must include synthesized DNA lest technology again jumps ahead of our patent system and we spend decades trying to play catch-up. Instead of inserting genes from one species into another, what is considered "traditional" genetic engineering, synthetic biologists claim that they aim to "create" life from scratch with computer-synthesized DNA or without the use of DNA entirely. Much of what is called "synthetic biology," however, does not achieve this level of change.

naturally inclined to make sense of the transplanted DNA and to turn genes on and off. In effect, the bacteria did what they have done for eons: swap DNA. Still, this was the first time much of the public had heard of synthetic biology and was a wake-up call to many that current regulations around biotechnology are already outdated. Unfortunately, while Venter's team may have only copied the genome of a goat pathogen, their intellectual tour de force includes patenting each of the steps in the process that they used to make the copy. Nobel Prize winner, John Sulston, has argued that Venter is interested primarily in patenting the process to exclude 'free research' by others. In 1980, the Supreme Court ruled in Diamond v. Chakrabarty that genetically engineered life forms could be patented. The case was referring to more traditional genetic engineering (in this case, bacterium that was engineered At stake is whether the knowledge to eat crude oil), but the court's of how life works at its most basic ruling will undoubtedly be to the products of synlevel should be a common property extended thetic biology. The ruling states of all, or whether it should be "â&#x20AC;Śthe patentee has produced a new bacterium with markedly difcontrolled by a few. ferent characteristics from any found in nature and one having Nonetheless, in May 2010 J. Craig Ven- the potential for significant utility. His dister and his team announced they had covery is not nature's handiwork, but his "created" the world's first organism with own: accordingly it is patentable subject a synthetic genome. The success of Ven- matter."[4] Venter's inclusion of additional ter's team may be more in the area of DNA to mark the synthetic genome as patents that will apply to his new tech- his own is an additional step that makes niques than in actually having "created" clear that his 'invention' does not exist in nature. synthetic life. Since then patents on naturally occurDr. David Baltimore, a leading geneticist at Caltech, described the work to the ring genes and DNA sequences have been New York Times as "a technical tour de granted, despite the Court's clear message force" but not breakthrough science, but that naturally occurring DNA is not just a matter of scale â&#x20AC;Ś He has not created patentable. Currently, over 20% of the human genome has been patented as well life, only mimicked it." The Venter team could not get the cell as thousands of plant, animal, virus, and to reproduce without placing the synthetic bacteria DNA sequences that have natugenome in a preexisting cell, which was rally evolved over billions of years but were

GENEWATCH 39

40 GENEWATCH

ism's genome, any version of that organism that could make fuels such as ethanol or hydrogen, any method of producing those fuels that uses the organism, the process of testing a gene's function by inserting other genes into the synthetic organism, and a set of non-essential genes. These patents are not restricted to any specific cell type-it currently applies to prokaryotes and eukaryotes - or size of a synthetic genome. While these patents have yet to be granted, the claim shows the extent to which some synthetic biologists are testing the limits in the battle to control the fundamental building blocks of life and

actual living organisms. While it is likely this specific patent application's scope will be limited to cover only bacterial cells, such a patent would still grant Venter and company an exclusive license to create synthetic fuel-producing bacteria and the tools to create such organisms. Conveniently, Venter's company, Synthetic Genomics, has contracts with both Exxon Mobile and BP to produce "next-generation" biofuels from synthetic cells (or at least genetically engineered cells that contain synthetic DNA sequences). Amyris Biotechnologies is a synthetic biology company that used genetically engineered yeasts that contain synthetic DNA to break down sugarcane to produce isoprenoidsâ&#x20AC;&#x201C;which are then being converted to biofuels, industrial chemicals, among other products. Patent US 7,659,097, granted to Amyris in February 2010, covers the production of many different isoprenoids created though a number of different microbes. Amyris

already has deals with major oil and chemical companies to turn Brazilian sugarcane into high-value commodities. Again, Amyris' "biosynthetic pathways" are nearcopies of metabolic pathways found in nature with some "tweaking" of the DNA pathways to allow the yeast to do some things that traditional genetic engineering could not accomplish. The novel challenge created by the emerging field of synthetic biology is that not only can natural or synthesized DNA be patented, but the processes used to synthesize DNA and create synthetic organisms can also be patented. Furthermore, the living organisms created with synthetic DNA are covered in these patents, as are the products they are engineered to produce. Take Amyris as an example again. Through their patent, they own the process of engineering microbes with their synthetic DNA, the synthetic DNA, the microbes themselves, and any products the microbes produce. If these microbes escape and contaminate wild-type relatives, their synthetic DNA could pass on and Amyris would theoretically own those new microbes that have been contaminated with synthetic DNA. There is a significant battle going on here. At stake is whether the knowledge of how life works at its most basic level should be a common property of all, or whether it should be controlled by a few. This is nothing short of intent to further own and control the building blocks of life. What must be done While it is clear to us that current court rulings would likely support the patenting of synthetic genomes as developed by Venter's lab and other researchers, Congress should prevent the patenting of DNA sequences that simply copy naturally occurring DNA. To do otherwise would in effect allow another way to patent natural occurring organisms and their DNA-just make synthetic copies of them. That is in no one's interest but the patent holdersâ&#x20AC;&#x2122;. Eric Hoffman is Biotechnology Policy Campaigner with Friends of the Earth U.S. Jaydee Hanson is Policy Director with the International Center for Technology Assessment

OCTOBER-DECEMBER 2010

Image: Mechanix Illustrated, Nov. 1959

pulled out of the commons into private hands through patents and intellectual property rights. The U.S. Patent and Trademark Office currently argues that the mere act of "isolating" DNA is an inventive step worthy of a patent. While the Department of Justice has argued in a brief to the court that merely isolating DNA is not sufficient for a patent, the Venter team's work goes beyond isolating DNA to actually writing the sequence and getting it to "boot up" (their words!). Now, with synthetic biology, mere "isolating" is not even necessary. One could theoretically upload a DNA sequence onto a computer, "print out" an exact copy of that DNA sequence, and patent the synthetic DNA sequence as an invention. Less theoretical-and with many more commercial applications-is creating copies of natural DNA and making slight tweaks to the genome as the inventive step worthy of a patent. In effect, synthetic biologists are able to "evolve" organisms through computer algorithms and create novel DNA sequences that can be then be "printed" out and inserted into an organism. Patents have already been granted on many of the processes and products involved in synthetic biology, including patents on methods for building synthetic DNA, synthetic genes and DNA sequences, synthetic pathways, synthetic proteins and amino acids, and novel nucleotides that replace the letters of DNA. For example, in 2007 the J. Craig Venter Institute applied for a frighteningly broad patent of its "minimal bacterial genome" called Mycoplasma laboratorium. This organism was an attempt to create life with the minimum number of genes by cutting out as many DNA sequences as possible without removing its ability to reproduce or survive. U.S. patent numbers US2007 0264688 and US2007 0269862 describes creation of the first-ever, entirely synthetic living organism-a novel bacterium whose entire genetic information is constructed from synthesized DNA (but whose genome is a near-replica of a naturally occurring genome). This patent claims exclusive monopoly on the genes in the minimal bacterial genome, the entire organism made from these genes, a digital version of the organ-

EEOC Issues Strong Final Rule Implementing GINA The Genetic Information Nondiscrimination Act will provide strong new protections against genetic discrimination BY JEREMY GRUBER The Equal Employment Opportunity Commission recently issued its Final Rule implementing the Genetic Information Nondiscrimination Act after being granted broad authority to interpret it by the United States Congress. In it, the EEOC laid out in detail strong protections against genetic discrimination and employer access to genetic information for every American worker. The Council for Responsible Genetics played the lead role in advocating for a strong Final Rule implementing GINA. We met multiple times with the EEOC Commissioners and formally testified before them. CRG was the lead drafter of multiple sets of written comments in conjunction with the Genetics and Public Policy Center-comments that were adopted by civil rights and patient's groups, including the Leadership Conference on Civil Rights, American Civil Liberties Union, Genetic Alliance and the Coalition for Genetic Fairness. This was a significant victory for the Council for Responsible Genetics, as virtually all our recommendations for reform were incorporated by the EEOC into the Final Rule. As a result, the EEOC's Final Rule now includes: - strong and unambiguous definitions of key terms - narrowly crafted exceptions to the rule against acquisition of genetic information - clarification of the relationship between GINA and other civil rights and consumer laws in a manner that benefits the employee/consumer. With regards to definitions, we were able to persuade the EEOC to include in the Final Rule an expanded and clarified definition of "genetic test" to ensure carrier screening for adults, newborn screening, ancestry and paternity testing etc. were formally acknowledged in the definitions. We were also able to persuade them to clarify the definition of "manifested dis-

VOLUME 23 NUMBER 5-6

ease" so that individuals whose diagnosis was principally based on genetic information would remain protected by the law and that individuals who had manifested a genetically based disease continued to have their genetic information protected. With regards to the prohibitions on "requesting, requiring, or purchasing" genetic information, the EEOC formally acknowledged our interpretation that GINA does not require that "intent" be present for a violation of GINA to occur. The EEOC also adopted our interpretation that the exceptions to this rule should be narrowly construed. For example, they agreed that employers who might start with an innocent question, such as "How are you?," could not then follow up with more probing questions that might elicit genetic information. They further adopted our suggestion that employers who request medical information generally, under any circumstance, must indicate to whomever they ask that they do not want genetic information (a formal safe haven) to limit the opportunities for receiving genetic information as part of the normal course of business. Wellness programs that include health risk assessments or require "qualification" to participate in a specific program are ripe for access to genetic information. Our adopted comments now ensure that provision of such information must be completely voluntary and that no financial incentives can be offered. Furthermore, individuals who do not wish to provide their genetic information must be allowed alternative ways to qualify for participation in tailored programs. GINA makes an exception for the acquisition of genetic information from commercially and publicly available sources, such as picking up the newspaper and reading in the obituaries that an employee's parent died of a hereditary condition. The exception specifically exempts medical databases and court records. We argued that this provision was not meant to protect someone who was

either intentionally looking for genetic information (even in open sources such as periodicals) or someone who was looking in any source that provided a heightened risk of obtaining genetic information. The EEOC agreed and included these distinctions in the Final Rule, as well as extending them to online sources. Many additional interpretations of ours were included in the Final Rule, including a clarification of the interaction between the health insurance and employment sections of GINA in a manner that benefits the employee/consumer and ensures they are implemented and enforced with consistency and clarity. Finally, our comments suggested that the Commission include specific examples throughout the Rule to illustrate its breadth. The Commission went to great pains to do so, and included several of our sample scenarios. GINA now provides strong new protections for all Americans against discrimination and access to genetic information. As a result, Americans can finally take advantage of the tremendous potential of genetic research without the fear that their own genetic information will be used against them. While there is still much to do to ensure that genetic privacy in this country is respected, we are one step closer to our goal. The Final Rule implementing GINA may be accessed in the Federal Register here: http://frwebgate2.access.gpo.gov/cgibin/PDFgate.cgi?WAISdocID=iAu91C/0/ 2/0&WAISaction=retrieve Jeremy Gruber, JD, is President and Executive Director of CRG.

GENEWATCH 41

Dangerous Harvest Egg donation includes many known short-term risks and less often discussed long-term risks

Historically, manipulation of women's bodies by others for profit has taken many forms. One such practice with a long and tragic history is the overzealous prescribing of synthetic hormones. Defined as treatments, rather than experiments, the first synthetic hormone, diethylstilbestrol (DES), and post-menopausal hormone replacement therapy were prescribed to women for decades before their deadly side effects were documented and their use finally curtailed. A current form of hormone abuse encourages financially strapped college students to "donate" their eggs by offering thousands of dollars and skillful appeals to their altruism. Now, biotech entrepreneurs are partnering with fertility clinics in hopes of acquiring eggs for research cloning, making oocytes an even more highly coveted natural resource. Are we repeating a historical pattern in which the casualties from medical misuse of hormones must reach epidemic proportions before the damage they cause is officially acknowledged? In this article I will briefly review known short-term risks and the more poorly understood long-term risks of egg donation. I will describe some of the efforts that have been made to increase the integrity of the currently empty ritual of "informed consent" by which this expanding trade is being justified. I will conclude by considering some implications of the growing trade in human eggs. A Few of the Casualties Calla Papademous answered an ad in the Stanford University newspaper promising $50,000 to a tall, athletic young woman with an SAT score over 1400.1 Thinking she had found a way to repay some of her student loans she answered the ad and was accepted. After only a few days on Lupron, commonly prescribed for egg donation but unapproved by the FDA for this purpose, she suffered a massive stroke. Today, after extensive therapy, she is rebuilding her life, but still suffers some permanent brain damage, physical disability, and is infertile. Since she failed to

42 GENEWATCH

produce the eggs she was offered only $750. Alexandra X., featured in the documentary Eggsploitation, was a graduate student in need of money to pay expenses while finishing her dissertation in biology. She was happy to receive $3,000, and thought she had successfully completed the process only to collapse in pain on the floor of a friend's house eight or nine days after the retrieval. After fertility clinic staff where her eggs had been removed repeatedly dismissed her symptoms as "normal," she was finally hospitalized with internal bleeding and rushed into surgery just in time to save her life, but only one of her ovaries. Five years later, in her early thirties, with no family history of the disease, she was diagnosed with stage 2-B breast cancer. Deaths from early-onset reproductive and other cancers have been documented in a number of former egg donors and in many women who have undergone essentially the same ovarian hyperstimulation and egg retrieval as part of their own in vitro fertilization. Consider Stanford student Jessica Wing, who was stricken with fatal colon cancer shortly after her third egg retrieval and died at age 32. Her physician mother, Jennifer Schneider, had genetic tests conducted, which ruled out any genetic susceptibility to the disease. Based on this and further research into the issue, she has challenged the adequacy of current standards of informed consent and has become an advocate for better prospective studies of egg donors.2 Just how common are tragedies such as those described above? No one knows. We cannot be sure that early onset cancers, such as Jessica Wing's, are related to earlier ovarian stimulation. Nor can we be sure they are not caused by the radical disruption of the endocrine system that characterizes typical egg harvesting protocols-no one is keeping track of egg donors once they leave the clinics. What we do know is that the American Society of Reproductive Medicine acknowledges significant risks in its pro-

fessional literature. Its Ethics Committee states that donors are "exposed to risks of morbidity and a remote risk of mortality from COS [controlled ovarian stimulation] and oocyte retrieval" and that "it is possible that fertility drugs could increase a woman's future health risks, including the risk of impaired fertility."3 We also know that an unknown number of women have died during the development and application of these practices,4 which have now been refined to the point that fatalities appear to be rare. But then again, no one is counting. How invasive is the process? In 2006, the California Institute of Regenerative Medicine asked the Institute of Medicine to convene a conference to provide information on the safety of egg donation. The conference report, â&#x20AC;&#x153;Assessing the Medical Risks of Oocyte Donation For Stem Cell Research,â&#x20AC;? draws on stud-

OCTOBER-DECEMBER 2010

Image: Wikimedia Commons (modified)

BY DIANE BEESON

ies of women undergoing ovarian stimulation to extract eggs for their own fertility treatment, and describes the process this way: The woman self-injects hormones (gonadotropins) to stimulate the growth of ovarian follicles, plus a gonadotropin-releasing hormone (GnRH) agonist to block the normal surge of lutenizing hormone (LH), which could cause the woman to ovulate before the physician retrieves the eggs. . . . A woman subsequently selfinjects the hormone human chorionic gonadotropin (hCG, similar to LH) to effect egg maturation. When the eggs are ready the woman is brought into surgery, where she receives intravenous sedation, after which a transvaginal probe is placed in her vagina. A hollow needle emerges from the probe, travels through the back of the vagina and into the ovary, where under the guidance of ultrasound technology, the eggs are aspirated.5 What are the short-term risks? The ingestion of various drugs in preparation for egg retrieval, and the egg retrieval process itself, entail a variety of physical and psychological risks, including those stemming from the use of anesthesia, and surgical complications such as infection and bleeding. The most common side effect connected with egg donation is ovarian hyperstimulation syndrome, or OHSS. This may include nausea/vomiting, pain, fluid buildup in the abdomen, shortness of breath, and in more serious cases, blood clots, severe pulmonary distress, and kidney (and/or other organ) failure.6 The IOM report cites three prospective studies on women undergoing fertility treatment that estimate the risk for OHSS to range from 2.1 to 4.7 percent.7 At the same time, it acknowledges both that "the data concerning the occurrence of ovarian hyperstimuation syndrome are not particularly good"8 and that the definition of this iatrogenic disorder has been redefined to exclude its mildest manifestations.9 More recently, a non-industry-sponsored retrospective report of 155 former egg donors found that over 30% reported some degree of OHSS, and 11.6% required hospitalization and/or paracentesis (puncturing of the belly with a needle to draw out fluid), revealing a striking discrepancy between risk rates reported by industry

VOLUME 23 NUMBER 5-6

insiders and independent researchers.10 What are the long-term risks? Less well understood, but of even greater concern to women's health advocates than the short-term effects, are the long-term risks, particularly reproductive cancers. The IOM Report dismisses evidence of increased risks for breast, endometrial, and ovarian cancers found in some studies, but acknowledges concern with regard to uterine cancer. It also acknowledges that the studies that found no increase in risk may have done so due to inadequate long-term follow-up.11 The IOM Report concludes by admitting that "one of the most striking facts" about ovarian stimulation is how little is known about its long-term effects on women: Although more than a million IVF cycles have been performed in the United States over the past 20 years â&#x20AC;Śthere are no registries that track the health of the people who have taken part. â&#x20AC;Ś[T]he studies vary quite a lot in terms of study design, the number of subjects, and outcome, so it is impossible to draw a consistent picture from them.12 In the four years since the IOM conference was held concerns regarding cancer as a potential long-term side effect continue to mount. According to Dr. Louise Brinton of the National Cancer Institute: There has been little attention focused on the long-term effects of assisted reproductive technologies, which often involve much higher exposures to gonadotrophins than were received by women in previous eras. . . . Since in-vitro techniques have become common only in the last couple of decades, it may be some time before epidemiological studies can amass the follow-up times required to fully address long-term effects.13 She also states: Although most attention has focused on effects of fertility drugs on ovarian cancer risk, more recent investigations support the need for further attention on breast and endometrial cancers. The need is supported by the recognition that ovulation-stimulating drugs are effective at increasing both oestrogen and progestin concentrations, alterations that have been linked with

both of these cancers. Further, a relationship with breast cancer would parallel findings of an increased risk of this tumor among mothers exposed to diethylstilbestrol during pregnancy.14 While Brinton links ovarian stimulation to the DES disaster, prospective egg donors are not likely to know that it took nearly three decades of exposure to this first synthetic hormone before its causal link to elevated cancer rates among both the women to whom it was prescribed and their daughters, and genital abnormalities in many of the sons was documented.15 Ironically, exposure to DES in utero is a known cause of infertility in females, thus contributing to the market for today's fertility industry. In the case of post-menopausal hormone therapy, it was only after decades of demands from women's health advocates that clinical trials belatedly were begun. These trials were stopped in 2002 when it became apparent that women taking estrogen plus progestin were having more strokes, heart disease, and breast cancer.16 The following year, when tens of thousands of women stopped taking these hormones, we witnessed an unprecedented decrease in new cases of breast cancer.17 Brinton is not the only epidemiologist with concerns about ovarian stimulation. A recent Israeli study found "an association between treatment for ovulation induction and overall risk of cancer, particularly cancer of the uterus."18 But cancers are not the only poorly documented risk. Both cerebral19 and myocardial infarction,20 for example, have been reported in women undergoing ovarian stimulation even in the absence of OHSS. Egg donors interviewed by this author report ovarian cysts, severe mood swings, uncontrollable weight gain, and numerous other life-disrupting symptoms that are ignored in the existing research and were not considered in the IOM report. The lack of adequate longitudinal data means that "informed consent" functions primarily to protect clinics and professionals from liability, but fails to meaningfully protect egg donors. Ads focusing on financial compensation and altruism, to the exclusion of any suggestion of possible risk, have created a culture on college campuses in which it is widely believed is that egg donation is well established, routine, and completely safe. Furthermore, consent forms, whatever their content, are not likely to be seen by potential donors until

GENEWATCH 43

long after they have made the decision, based on ubiquitous advertising, to sell their eggs. Alliance for Humane Biotechnology activists last year succeeded in getting support for AB 1317, a bill in the California legislature, to require that ads soliciting egg donors reference existence of medical risk, but the American Society of Reproductive Medicine insisted that the bill exempt brokers and clinics who agree to follow ASRM ethical guidelines. The result? Egg broker ads referencing health risks have yet to be spotted. Two recent studies, one of advertising and compensation for egg donors, the other a study of compliance and range of fees among egg donor and surrogacy agencies, both found that many of the egg donor agencies in the U.S. routinely violate ASRM's ethical guidelines. Compliance, to the extent it does exist, is self-reported and unverified. The guideline's primary function seems to be to support claims of self-regulation. Women having their eggs harvested for their own use in the hopes of achieving pregnancy face essentially the same risks from ovarian stimulation as egg donors. The justification for the risk in their case is the hoped-for birth of a child. However, concerns acknowledged by 2010 Nobel Laureate R.G. Edwards about safety and damage that routine IVF may cause to both infertility patients and offspring are fueling international interest in alternative fertility treatments such as minimal stimulation IVF and natural cycle IVF.21 Scientists push for easier access to eggs In discussing scientists' interest in acquiring eggs for cloning research, the author of a 2006 Nature article acknowledged that "cloning is a wildly inefficient process" and that egg donations are "an ethical quagmire."22 Long before the demand for eggs reached this point, in 2001, pro-choice women's health advocates, led by Our Bodies Ourselves, sponsored a call for a moratorium on embryo cloning primarily because of its dependence on large numbers of human eggs.23 Three years later Korean stem cell researcher Hwang Woo-suk was found to have used more than 2,200 eggs in his fraudulent effort to harvest stem cells from a cloned embryo. This resulted in 17.7 percent of the women who supplied the eggs suffering adverse health effects. Charges of coercion and human rights violations ensued.24 The large number of human eggs

44 GENEWATCH

required for cloning research was a driving concern for pro-choice feminists who opposed California's 2004 $3 billion initiative that established the California Institute of Regenerative Medicine. Alarmed at the bill's prioritization of research cloning, a process dependent on women's eggs, a group of women's health advocates, this author included, formed the ProChoice Alliance Against Proposition 71. We submitted for inclusion in the Voter's Handbook a statement arguing against the measure. Proponents of the initiative, including two prominent scientists (one a Nobel laureate), then took legal action in an unsuccessful attempt to keep us from both using the word "cloning" and from relating to voters that embryo cloning relies on a large supply of human eggs.25 Today, scientists are protected from acknowledging that egg harvesting exposes women to significant risks by the fact that the research necessary to determine the extent of the harm has yet to be done. A series of international and national declarations and regulations affirm the importance of informed consent and the prohibition of undue inducement or influence. Disregarding these principles is considered a violation of human rights. These international standards inform the National Academy of Science's guidelines recommending that "[n]o payments, cash or in kind, should be provided for donating oocytes for research purposes."26 Nevertheless, in 2009 New York became the first state to disregard the NAS guidelines. At a hearing of the state's Ethics Committee to consider the ethics of payment, physician Jennifer Schneider described her daughter's tragic premature death following her third egg donation. She challenged the committee: if it chose to ignore NAS Guidelines, would it at least recommend the establishment of a donor registry to facilitate monitoring the longterm effects of egg donation? 27 The committee made no such recommendation. In 2006, the ProChoice Alliance for Responsible Research led a successful effort to pass California law SB 1260, which tightened restrictions on compensation for eggs (beyond expenses) for non-CIRM-funded research and closed a loophole in CIRM's regulations that could have allowed the use of non-CIRM money to acquire eggs. Since then, CIRM Director Alan Trounsen has made it clear he hopes to change this.28 In June of this year

CIRM held a workshop in which legal and ethical obstacles to achieving Somatic Cell Nuclear Transfer were discussed. The public was excluded from this workshop, in what one commentator called an apparent violation of the "the spirit and probably the letter of the California State Constitution and state open meeting laws."29 Minutes of this meeting make it clear that despite acknowledging medical and ethical barriers to procuring eggs from human donors through ovarian stimulation, many scientists are intent on pursuing research using human eggs.30 And most recently a lobbyist for the American Society of Reproductive Medicine volunteered that the ASRM was considering sponsoring legislative changes to remove prohibitions on payment for eggs for research in California.31 One of the implications of the expansion of the egg trade to procure eggs for research is that, unlike the eggs sought for reproduction, the genotype of the donor is usually irrelevant. This means the market can be expected to move beyond college campuses and into the poorest communities, both in the US and around the globe, where financial inducements may be even more irresistible and social conditions may further compromise the integrity of these transactions. Alliance for Humane Biotechnology is one of several organizations attempting to alert the public and policy makers of the risks to which egg donors are being exposed. Earlier this year AHB was contacted by a young man worried about his girlfriend who, after donating eggs, suffered a seizure, mood swings, shortness of breath, and blurred vision. He wanted advice on what she should do-having no medical insurance and a denial from the clinic that her symptoms were caused by the egg harvesting. While examples of casualties abound, those profiting from the practice of egg donation continue to dismiss the accounts as anecdotal. This will likely continue until an independent national registry of women undergoing ovarian stimulation is established and adherence to ethical standards is enforced by independent oversight. Diane Beeson, PhD, is chair of the Department of Sociology and Social Services at California State University, East Bay. Acknowledgement: The author is indebted to Tina Stevens for a close reading, helpful suggestions, and generous editorial assistance.

OCTOBER-DECEMBER 2010

Reproductive Trafficking A global womenâ&#x20AC;&#x2122;s human rights issue

BY HEDVA EYAL

Women's inferior status throughout the world renders them more exposed than men to poverty, gender-based exploitation and all forms of trafficking. One of the newest forms of trafficking has emerged as a result of exponential growth in the worldwide use of new reproductive technologies. The international community faces a reality in which medical knowledge and technologies that were developed for healing purposes are used not for saving lives, but rather for allowing people with economic means to fulfill a very specific kind of parenthood that often exploits the economic distress and risks the health of certain other women. This situation causes great concern among feminists, as transnational surrogacy and the trade in human eggs have become pervasive international phenomena. Mediating agencies use various international trade routes to connect doctors, parents-to-be, and women willing to sell their eggs or rent their wombs. Ova trade: Would-be parents often travel from western countries such as the USA, Germany, the U.K and Israel to Eastern Europe, India, Cyprus and other countries where payment for ova is cheaper or not legally regulated as it is in their home countries. In countries where ova sale is prohibited, hormones may be administered in the home country to the women who are then flown to a second country where their eggs are harvested, fertilized and inserted in the receiving woman's uterus. Many significant shortterm health risks to women are incurred in the process of extracting abnormally large numbers of eggs from their ovaries per a single cycle. Long-term effects are

VOLUME 23 NUMBER 5-6

less well understood but are known to include infertility and possibly reproductive and other cancers. Inadequate long term research has been conducted on these health risks. (See the accompanying article in this issue by Diane Beeson for more detail.) Surrogacy trade: Fertilized eggs often travel across international borders, sometimes arriving from one country while the sperm arrives from another country. The fertilized eggs may be passed to a third country where the woman who will become the surrogate mother resides and where the procedure of the insertion into the uterus is performed. Great concern regarding human rights violations resulting from the exploitation of low income and poor women, along with the absence of truly informed consent, is growing among advocates and many fear that the situation resembles trafficking in organs such as kidneys. These procedures frequently involve the administration of synthetic hormones injected to produce abnormal numbers of eggs. As a result, when a pregnancy is successfully produced, it often consists of multiple embryos. The surrogate is then subjected to much higher levels of risk than a normal single pregnancy involves. Post-natal health care costs for treatment of complications are often not covered. Furthermore, the costs of health care provided to infants born with congenital problems may not be claimed by the intended parents. A typical situation is the case of the surrogate mother who was pressured to have an abortion after the fetus she was carrying failed to meet the quality specifications of those who hired

her when they were informed that the fetus had Down Syndrome.1 Surrogate transactions are often facilitated by entrepreneurs operating without supervision or monitoring of women's health, and with little apparent concern about protecting surrogates from exploitation or criminal abuse. In 2009, what is known as the "Romanian scandal" was exposed. Israeli doctors were involved in the trafficking of eggs of young poor women at SABYC clinic in Romania, some of whom were only 15 years old, with little understanding of the health risks involved. In one example, a 16year-old factory worker was left in critical condition after the procedure. The arrest of the doctors and agency operators by Romanian police revealed the ways the international reproductive industry is working as a free zone with no ethics or responsibility for respecting human rights or human dignity.2 Information on the magnitude of international trafficking in reproductive organs is scarce and partial, rendering many questions unanswered. Of particular interest is information regarding the health and social repercussions of this industry on women, and the economic gains of the various players in this field. While there is legislation of varying degrees among different countries, ranging from full prohibition of egg donation and surrogacy to weak attempts at regulating aspects of this reproductive trade, the gaps are enormous and the industry metastasizes largely without any accountability. Such laws as exist are implemented solely at the national level. The phenomenon of trafficking is not limited to countries that lack regulation.

GENEWATCH 45

Black markets are known to develop alongside the publicly authorized services, offering leniencies that give them advantages from the buyers' point of view. Within this market, many grey areas remain. For example, in Israel, young women may receive hormonal treatments to stimulate egg production legally, while the harvesting takes place illegally outside of the country. The transnational nature of reproductive trafficking means that activism at the local level to reduce it is not enough. In light of these realities, women's health advocates have begun an international initiative to address the increasing problem of reproductive exploitation and commodification. Over the past year, action has begun to draft a call for a UN declaration on human rights abuses in reproduction. Documents that should inform such a declaration include the Nuremburg Code (1947)3 on human experimentation; the World Health Organization's Draft Guiding Principles on Human Organ Transplantation (1991) and its Commentaries;4 the European Convention on Human Rights and Biomedicine (1997)5 and its Additional Protocol on Transplantation of Organs and Tissues of Human Origin (2002);6 and the Helsinki Declaration (Sixth Revision 2008) on human experimentation.7 Although these documents more specifically pertain to human experimentation and organ transplantation, in some cases even deliberately excluding reproductive tissues including ova, they can be applied to reproductive organs and tissues as in the case of the Draft Guiding Principles on Human Organ Transplantation of 1991.8 Universal legal agreements on the trafficking of ova and surrogacy should protect the basic rights and interests of women, which form part of the set of legally binding obligations on countries that have agreed to these treaties. An international regulation might offer a basis for determining when eggs are being trafficked. It could also determine what precautions every country should take within its boundaries in order to protect all women concerned.9 For example, the European Committee's 2004 resolution condemns any trade in human tissues and places crucial importance on encouraging EU members to incorporate in their laws the principal of voluntary donation (see clauses 14 (2) 12(1)). Furthermore, the resolution mentions the need for creating a monitoring mechanism on import

46 GENEWATCH

and export that will take into account both the protection of donors and the quality of organs and tissues (clause 9).10 The practices of reproductive organ, tissue and cell trafficking and trade, particularly ova sale and surrogacy, infringe upon several basic human rights under international law and are violations of international agreements on health and medical standards. Trade in reproductive surrogacy, organs and tissue must be recognized as a unique kind of human exploitation. The absence of an international stance on reproductive trade allows the free market to set the standard for using and selling human organs, including reproductive organs, cells and tissue. Medical technologies become a tool for people who, in the name of creating or saving life, are using women as objects of human organ stock. It is our belief that taking a feminist stance on this issue will be beneficial for women throughout the world. There must be an international platform for discussion. The field of reproductive technologies raises complicated issues regarding autonomy and commodification of women's bodies, the medicalization of women, trafficking, children's rights, and a plethora of other issues. Alongside these questions are another set of issues regarding the right course of action. Could international regulation protect women or simply achieve legitimization of reproductive trade? Although there is awareness of these questions, recognition of the legitimacy of the fertility-industrial complex and its practices affects women's rights and health negatively. Recognizing the problem and bringing these issues to the forefront of the international agenda is the crucial first step. The need to convene an international meeting of women's health and human rights advocates to develop a universal feminist stance on the issue of reproductive trade is urgent. The opportunities that these medical technologies provide also require that we face the question of who truly is paying the price. The obligation of each one of us is to acknowledge the irrelevance of national borders concerning this issue and to focus on the abuses occurring and to develop protective measures that will ensure the health and safety of women throughout the world. Several elements provide a framework for the creation of an international declaration on human rights abuses in human reproduction that protects the rights and

health of women and the children to whom they give birth: - The commercial use of women's reproductive capabilities both within and across national borders should be prohibited. - Surrogates and ova donors should be recognized as human participants in a complex birth-giving process, rather than as biological resources. Consequently, practices that bar human contact between surrogates, egg providers, and the children born through these processes should be strictly prohibited. - Surrogacy and egg donation should be permitted only under circumstances allowing for the viable possibility of a prolonged relationship between and/or among surrogate, gamete donor, child, and growing family. - All medical procedures must be conducted within the country of origin of the intended parent(s) by legally authorized fertility experts in licensed hospitals and/or clinics. - Recipients of fertility treatment hormones of any kind must be informed that past uses of synthetic hormones have led to significant increases in cancer rates among women to whom they were prescribed, and that the longterm medical risks of hormones currently used in fertility treatment (often unapproved for this purpose) are unknown due to a dearth of longterm studies of the effects of these drugs on recipients. The hope is that these elements will be a basis for international dialogue between women and organizations that address the increasing problem of reproductive organ trade and trafficking. We have seen the effects of these phenomena on women's lives, and we are asking the international community to take social responsibility and actively defend human rights.

Hedva Eyal, is Women & Medical Technologies Project Coordinator with Isha L'Isha (Woman to Woman) Haifa Feminist Center, Israel. Editorial assistant: Kathleen Sloan, Program Coordinator, CRG.

OCTOBER-DECEMBER 2010

FILM REVIEW

Eggsploitation Dreams and profits at the cost of young womenâ&#x20AC;&#x2122;s health BY KATHLEEN SLOAN A new term has entered the lexicon of the 21st century with the explosion of the fertility industry: eggsploitation. Jennifer Lahl, a San Francisco-based nurse, used the term as the title of her documentary on the subject. She defines â&#x20AC;&#x153;eggsploitationâ&#x20AC;? as follows: "to plunder, pillage, rob, despoil, fleece, and strip ruthlessly a young woman of her eggs, by means of fraud, coercion or deception, to be used selfishly for another's gain, with a total lack of regard for the wellbeing of the donor." Since 1978, when the first test tube baby was produced through in vitro fertilization, and just five years later when the first embryo was created outside the uterus using a donated egg, the fertility industry has mushroomed into a multibillion dollar global business. Nearly every college campus in the United States is blanketed with advertisements for egg donors from fertility clinics and brokers. A Wild West, anything goes climate prevails in the U.S. where there is virtually no regulation or oversight of this $6.5 billion annual business. Young women are lured by ads offering them up to $50,000 for their eggs; up to $100,000 for Harvard or Yale eggs. The numbers speak for themselves: in 2007, the Centers for Disease Control & Prevention reported 17,405 fertility treatment cycles. What is generally unknown is that approximately 70% of Assisted Reproductive Technology cycles fail. Despite the industry's great PR and effusive media stories of celebrity parents having babies through donated eggs and surrogates, there is an alarming absence of published, peer-reviewed medical research and data on egg extraction and the risks posed to women who serve as donors. As Drew Moffitt, MD, a fertility and reproductive endocrinologist stated in testimony before Congress, "In medicine, there tends to be a desire to publish positive findings and not publish negative findings." Who are these egg donors? Young women in their 20's, struggling to finance college and graduate school educations. As young women interviewed in the film explain, the industry uses bait-and-switch tactics whereby they are enticed by the

VOLUME 23 NUMBER 5-6

money offered and then pressured to continue with the often brutal procedures with appeals to altruism and without information provided regarding the health risks involved. The brokers and clinics exploit the patriarchal culture's psychological conditioning of females to be of service to others and employ guilt-inducing tactics to ensure their compliance. In essence, the donors are nameless, faceless women, too often used and left forgotten. Jennifer Lahl, who wrote, directed and executive produced the film, is among a growing number of advocates for women's health and rights arrayed against a massive industry of physicians and researchers who have every incentive to avoid both disclosure of health risks and protection of donors when the profits involved are so high. In addition, industry lobbyists will quickly rally to prevent regulation and oversight of this enormous cash cow. So what are the risks associated with egg extraction? The powerful drugs donors must take contain the short-term risk of ovarian hyperstimulation syndrome along with surgical, anesthetic, emotional and psychological risks. Additional risks include pulmonary infarctions, fluid imbalances, stroke, clotting, perforation of the bowel or bladder, bleeding, production of adhesions which cause future infertility, and death. Long-term risks include breast, ovarian and endometrial cancers and future infertility. Women normally ovulate one or two eggs a month but egg donors are administered self-injected synthetic hormones to produce dozens of eggs, so-called superovulation. The drug Lupron (leuprolide acetate) is frequently used to stop the donor's menstrual cycle, inducing a menopausal state, in order to be synchronized with the surrogate's so a successful pregnancy can result. Lupron, however, is not intended for fertility use and is unapproved by the U.S. Food & Drug Administration for that purpose. One donor featured in the documentary experienced a stroke after taking Lupron which paralyzed her left side and caused brain damage. Other horror stories include the death

of Jessica Wing at the age of 34 who was diagnosed with colon cancer after selling her eggs three times during her twenties. Angela had a history of migraines whose health concerns were dismissed by the fertility clinic. After consulting with a neurologist, she was told that the hormones used could trigger a seizure when combined with birth control pills and migraines. When she reported this information to the clinic, she was told that backing out was unacceptable; in Angela's words: "I was no longer in control." Cindy, a combined MD/PhD student, began hemorrhaging after surgical extraction and her blood pressure dropped to dangerous levels. An artery had been punctured by the needle and the situation was exacerbated by the hyperstimulation which weakens blood vessels. The young woman who had a stroke revealed that her General Practitioner told her mother that "The industry knew that this would happen sooner or later; they've just been rolling the dice and it fell on your daughter." As with so many corporate practices, when the profits generated far exceed the harms caused, it is considered a risk worth taking. In other words, greed combined with impassioned desires for parenthood trump public health concerns of the most vulnerable. As Suzanne Parisian, MD, former Chief Medical Officer of the FDA states in the film, without the benefit of medical research or tracking, it is simply impossible to know what all the risks are. "It's one thing to say they don't know the risks; it's another to know that nobody's going to look either and so you're (the egg donor) really alone." The situation is summed up succinctly by Jennifer Lahl: "Until action is taken to protect potential egg donors, we will continue to hear more stories about the reckless endangerment of vulnerable young women." The message of the documentary is that if you are a young woman thinking about donating your eggs, think again. Kathleen Sloan is Program Coordinator at CRG.

GENEWATCH 47

NCAA Imposes Mandatory Sickle Cell Testing

Are you a storeowner who has been burglarized? Frustrated that your alarm didn't help you nab the culprit? If old fashioned security cameras just aren't doing the trick, why not try a new system: one that sprays synthetic DNA all over the thief. In fact, this product does exist. Some stores in the Netherlands are already trying it out–with mixed results–and ADT is marketing a similar product in Australia, calling it "DNA Guardian." The mechanism sounds simple: a can is mounted over the door, and when triggered, it sprays a fine mist onto whoever passes below it. The mist, which is only visible under UV light, contains synthetic DNA with specific markers that can connect the culprit–once collared–to the scene of the crime. The product's distributors emphasize that the system's value is actually in prevention rather than capturing the thief-in fact, the system has led to zero arrests so far. The preventative value relies largely, they say, on the mystique of DNA, which causes potential crooks to take the sign on the door seriously: "You Steal, You're Marked."

As of August 1, the National Collegiate Athletic Association requires all Division I student-athletes–about 170,000 people– to be tested for sickle cell anemia. The intention is to protect athletes who carry the trait, a response to a lawsuit filed against the NCAA by the family of a 19-year-old who died after overexertion at a football practice, unaware that he had sickle cell anemia. However, mandatory testing carries significant privacy and discrimination concerns. "This could have an extraordinarily heavy impact on black athletes," says Troy Duster, professor of sociology at New York University. "You are going to be picking out these kids and saying, 'You are going to be scrutinized more closely than anyone else.' That's worrisome." The Sickle Cell Anemia Association of America and the U.S. Health and Human Services Department's Advisory Committee on Heritable Disorders in Newborns and Children are among those voicing concerns. While many athletic directors, doctors and parents support the program, R. Rodney Howell, chair of the HHS committee, is not convinced.

"If you are going to test for sickle cell trait, it should not be done in the locker room by a coach." The NCAA stands by the requirment and is considering extending the mandatory testing to Division II athletes.

Genetically Modified Mosquitoes Released Into the Wild In early November, U.K. biotech company Oxitec announced that genetically modified mosquitoes of its design had been released in the Cayman Islands-a year earlier. The mosquitoes are designed to reduce dengue fever by mating with existing populations and producing larvae that die unless exposed to the antibiotic tetracycline. Over three million mosquitoes were released in the Caymans-unbeknownst to opponents of the project. Oxitec defends the release, saying they worked with the Cayman government to carry out a risk analysis and gather local input, but say they made "no special effort either to spread the word internationally or not to." Although safety studies have not been released from the Cayman trials, new releases are planned for Malaysia and Oxitec is seeking approval from Panama, Brazil and the United States.

48 GENEWATCH

OCTOBER-DECEMBER 2010

Image: Wikimedia Commons

DNA Alarm Systems: "You Steal, You're Marked"

Is Government Getting Out of the Ethics Business? The Secretary’s Advisory Committee on Genetics, Health, and Society was disbanded - shortly after releasing a gene patent report that didn’t sit well with the biotech industry BY JEREMY GRUBER U.S. Health and Human Services Secretary Kathleen Sebelius recently disbanded the Secretary's Advisory Committee on Genetics, Health, and Society, a decision that was made by the Secretary in close concert with Dr. Francis Collins at the National Institute's of Health. SACGHS was initially created eight years ago by the Department of Health and Human Services to advise it and other federal agencies on the ethical, legal and social implications of emerging genetic technologies. A diverse body of national experts, SACGHS has played an important role in addressing these growing issues with thoughtful and well reasoned research and analysis. A statement posted on the SACGHS website subsequent to the decision to disband it declared: " As part of the renewal process for any committee established under the Federal Advisory Committee Act, the government must periodically assess the continuing need for the committee...In its nearly 10 years of operation, SACGHS has addressed all the major topics delineated in its charter." Really? According to its charter, SACGHS was charged with: - Assessing how genetic technologies are being integrated into health care and public health, - Studying the clinical, public health, ethical, economic, legal, and societal implications of genetic and genomic technologies and applications, - Identifying opportunities and gaps in research and data collection analysis efforts, - Examining the impact of current patent policy and licensing practices on access to genetic technologies, - Analyzing uses of genetic information in education, employment, insurance, and law, - Serving as a public forum for discussion of issues raised by genetic and genomic technologies. How can one argue with a straight face that such goals have been fully realized?

VOLUME 23 NUMBER 5-6

From its groundbreaking work on the Genetic Information Nondiscrimination Act to influential reports on issues ranging from genetic testing guidelines to direct-to-consumer genetic testing, it can hardly be claimed that SACGHS was irrelevant. Over the years, SACGHS had become the central forum for discussing the rapid developments in genetic policy; a forum designed to facilitate inter-agency discussions and one that was open to both the public and a diverse array of private stakeholders. So what was the real reason for disbanding SACGHS? Cost was cited as a contributing factor to the decision, though considering the fact that SACGHS was a body made up of largely uncompensated members, this hardly seems a legitimate justification. The annual budget for SACGHS was less than $200,000 according to its charter, a paltry sum in its own right; but consider, that's out of a total NIH 2010 budget of $31 billion! Some have suggested that there is more to it, that by making recommendations at odds with industry and its government supporters, the SACGHS initiated its own demise. Lately the Committee has released a couple of controversial reports, in particular a report entitled “Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests,” which found that: Trends in patent law appear to pose serious obstacles to the promise of these developments [in genetic research and clinical practice]. Patenting has moved upstream; instead of covering only commercial products, patents can now control foundational research discoveries, claiming the purified form of genes. Fragmented ownership of these patents on genes by multiple competing entities substantially threatens clinical and research use. The report was widely condemned by industry and its supporters. The Biotechnology Industry Organization President

Jim Greenwood declared at a press conference that the report would go so far as to: discourage investment in biotech innovation, hobble the transfer of federally-funded research, undermine university research programs, and harm patients who are waiting for lifesaving therapies and diagnostics yet to be developed. An industry supporter, writing in GenomeWeb, wrote “I'm not as sympathetic to SACGH's demise…because it has made decisions that could threaten clinical labs and patient care.” Perhaps it's just the natural hubris of scientists that think they know all the answers without necessarily understanding the questions. Either way, in the absence of SACGHS or something similar, there will no longer be a central and independent forum to address the ethical, legal and social issues of emerging genetic technologies. Yet the challenges posed by the rapid advances in genomic research, many as yet unidentified, will continue to present themselves. The disparate agencies left to address these issues have no clear expertise in doing so and no mechanism to discuss how these many issues interconnect and affect each other (representatives of at least 19 Federal departments or agencies were represented as non-voting members on SACGHS). The public deserves better from its government. Genetic research and technology will continue to have profound implications for public health, most entirely positive, but the eager enthusiasm toward emerging genetic technologies must be paired with an open and accessible discussion of ethical concerns. Jeremy Gruber, JD, is President and Executive Director of CRG.

GENEWATCH 49

Endnotes Kane 1. Diamond v. Diehr, 450 U. S. 175, 185 (1981). 2. The Supreme Court has stated: "Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work." Gottschalk v. Benson, 409 U.S. 63, 67 (1972). 3. 35 U.S.C. § 101. The statute authorizes the patenting of "any new and useful process, machine, manufacture, or composition of matter." Id. 4. Association for Molecular Pathology v. U.S. Patent & Trademark Office, 702 F. Supp.2d 181 (S.D.N.Y. 2010). 5. Id. at 227. 6. Id. at 232. 7. Id. at 198. 8. Eileen M. Kane, Splitting the Gene: DNA Patents and the Genetic Code, 71 TENNESSEE LAW REVIEW 707, 752 (2004). 9. Lily E. Kay, WHO WROTE THE BOOK OF LIFE?: A HISTORY OF THE GENETIC CODE (2000). 10. International Human Genome Sequencing Consortium, Finishing the Euchromatic Sequence of the Human Genome, 431 NATURE 931 (2004). 11. Kane, supra note 8, at 753. 12. Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948). 13. Kane, supra note 8, at 753. 14. Bilski v. Kappos, 130 S.Ct. 3218 (2010). The Supreme Court has now rejected the machine or transformation test as the exclusive test for patent eligibility, which was used by the judge to decide the method claims in AMP. 15. Lab. Corp. of Am. Holdings v. Metabolite Labs., Inc., 548 U.S. 124 (2006). 16. Prometheus Labs. v. Mayo Collaborative Servs., 581 F.3d 1336 (Fed. Cir. 2009), vacated and remanded, 2010 WL 2571881 (U.S. June 29, 2010). 17. Classen Immunotherapies v. Biogen IDEC, 304 Fed. Appx. 866 (Fed. Cir. 2008), vacated and remanded, WL 2571877 (U.S. June 29, 2010). Holman 1. Association for Molecular Pathology v. US Patent and Trademark Office, 702 F.Supp.2d 181 (SDNY 2010). 2. Brief of Amici Curiae Christopher M. Holman and Robert Cook-Deegan in Support of Neither Party, Association for Molecular Pathology v. US Patent and Trademark Office, United States Court of Appeals for the Federal Circuit Docket Number 2010-1406, available at https://docs.google.com/fileview?id=0B9_llJG o9WK0OWVkYjg3NjItYzRjYi00ODIyL-

50 GENEWATCH

WIyMjAtYmJkZDQxMGZmYTZi&hl=en&pl i=1 (last visited December 2, 2010). 3. Commercial Biotechnology: An International Analysis (Washington, D. C.: U.S. Congress, Office of Technology Assessment, OTA-BA218, January 1984); U.S. Congress, Office of Technology Assessment, Biotechnology in a Global Economy, OTA-BA-494 (Washington, DC: U.S. Government Printing Office, October 1991). 4. Emerging Healthcare Issues: Follow-On Biologic Drug Competition, Federal Trade Commission Report (June 2009). 5. Revised Draft Report on Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests (the SACGHS Report), available at http://oba.od.nih.gov/oba/SACGHS/SACGH S%20Patents%20Report%20Approved%202-520010.pdf (last visited December 2, 2010). 6. 35 USC 103. 7. 35 USC 112. 8. Joshua D. Sarnoff & Christopher M. Holman, “Recent Developments Affecting the Enforcement, Procurement, and Licensing of Research Tool Patents,” 23 Berkeley Tech. L.J. 1299 (2008). Noonan 1. Walsh et al., 2003, "Science and the Law: Working Through the Patent Problem," Science 299: 1020). 2. Straus, 2002, Genetic Inventions, Intellectual Property Rights and Licensing Practices). 3. Nicol et al., 2003, Patents and Medical Biotechnology: An Empirical Analysis of Issues Facing the Australian Industry, Centre for Law & Genetics, Occasional Paper 6. 4. Nagaoka, 2006, "An Empirical Analysis of Patenting and Licensing Practice of Research Tools from Three Perspectives," presented in OECD Conference in Research Use of Patented Inventions, Madrid). 5. Shapiro, 2001, "Navigating the Patent Thicket: Cross Licenses, Patent Pools, and Standard Setting," In: Innovation Policy and the Economy 1: 119-50. 6. Heller & Eisenberg, 1998, "Can Patents Deter Innovation? The Anticommons in Biomedical Research," Science 280: 698-701. Greenfield 1. Yochai Benkler, Free as the Air to Common Use: First Amendment constraints on Enclosure of the Public Domain, 74 N. Y. U L. Rev. 354 (1999); Yochai Benkler, "Constitutional Bounds of Database Protection: The Role of Judicial Review in the Creation and Definition of Private Right in Information," 15 Berkeley Tech. L. J. 535 (2000)' Yochai Benkler, "Siren Songs and Amish Children: Autonomy, Infor-

mation and the Law," 76 N. Y. U. L. Rev. 23 (22001) 2. U.S. Const. Art. I, §8, cl.8 3. 35 U. S. C. 4.. John Thomas, SYMPOSIUM 2002: THE FUTURE OF PATENT LAW: LIBERTY AND PROPERTY IN THE PATENT LAW, 39 Hous. L. Rev. 569 at 570 5. Eugene Thacker, The Global Genome: Biotechnology, Politics and Culture (2005) at 20; Dan Burk, “The Problem of Process in Biotechnology,” 43 Hous. L. Rev. 561, 582-587 (2006). 6. See. e.g., Dorothy Nelkin & M. Susan Lindee, The DNA Mystique: The Gene as a Cultural Icon 1-18 (1995) 7. Jonathan Kahn, "What's the Use? Law and Authroity in Patenting Human Genetic Material" 14 Stan. L & Pol'y Rev. 417 at 417-418 Beeson 1. Hamilton, J. 2000. What are the costs? Stanford Magazine. http://www.stanfordalumni.org/news/magazine/2000/novdec/articles/eggdonor.html 2. Schneider, Jennifer. 2008. Fatal colon cancer in a young egg donor: A physician mother's call for follow-up and research on the longterm risks of ovarian stimulation. Fertility and Sterility, 90:2016. 3. ECASRM (Ethics Committee of the American Society for Reproductive Medicine). 2007. Financial Compensation of oocyte donors. Fertility and Sterility. Vo. 88,No. 2, August. pp. 305-309.(quote on p. 6). 4. Andrews, L. 2000. The Clone Age: Adventures in the New World of Reproductive Technology. New York:Henry Hold and Co. p. 35. ; Corea, G. 1988. The Mother Machine: Reproductive Technologies from Artificial Insemination to Artivicial Wombs. London: The Women's Press, p.318. 5. Guidice L., Santa E. and R. Pool (Eds.) 2007. Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research: Workshop Report. Institute of Medicine and National Research Council of National Academies. Washington, DC: National Academies Press. Pp. 10-11. 6. Guidice L. p. 19 7. Guidice, p. 20 8. Guidice, p. 20. 9. Guidice, p. 18. 10. Kramer, W., J. Schneider, and N. Schultz. 2009. "US oocyte donors: retrospective study of medical and psychosocial issues." Human Reproduction. September. 11. Guidice, p. 26. 12. Guidice, p. 13. 13. Brinton, L. 2007. Long-term effects of ovulation-stimulating drugs on cancer risk.

OCTOBER-DECEMBER 2010

Reproductive BioMedicine Online. Vol. 15. No.1, pp. 38-44. 14. Brinton, p. 15. Cody, P. 2008. DES Voices: From Anger to Action. Columbus Ohio: DES Action. P. 17 16. National Institutes of Health. http://www.nhlbi.nih.gov/whi/whi_faq.htm 17. National Cancer institute. 2007. http://www.cancer.gov/newscenter/pressreleases/2007/breastincidencedrop 18. Calderon-Margalit, R. et al. 2008. "Cancer Risk After Exposure to Treatments for Ovulation Induction." American Journal of Epidemiology, (Advance Access published November 26, 2008). 19. Demirol A, Suleyman G, and Gurgan T. 2007. Aphasia: an early uncommon complication of ovarian stimulation without ovarian hyptestimulation syndrome. Reproductive Biomedicine Online. January. 20. Coli, S, et al. "Myocardial infarction complicating the initial phase of an ovarian stimulation protocol." International Journal of Cardiology, Vol. 115, Issue 1, Jan. 31, 2007. 21. Edwards, R.G. 2007. "Are minimal stimulation IVF and IVM set to replace routine IVF? Reproductive Biomedicine Online. Vol. 14, No. 2., Pp. 267-270. 22. Dennis, C. 2006. Cloning: Mining the secrets of the egg. Nature. Vol.439, 9. February. Pp. 652-655. 23. Norsigian J. 2002. Emerging Biotechnologies: Cloning. Testimony to Senate Health, Education, Labor and Pensions Committee. March 5. http://www.ourbodiesourselves.org/book/co mpanion.asp?id=25&compID=67&page=9 24. Son, Bonghee. 2006. "The Hwang Woo-suk case and the significance of a damage claim for victims of egg extraction." Paper presented at the International Forum Envisioning the Human Rights of Women in the Age of Biotechnology and Science. Seoul, Korea.

25. Memorandum of Points and Authorities in Support of Petition for Writ of Mandate and Alternative Writ of Mandate/Order to Show Cause. 2004 (Undated, no case number) Paul Berg, PhD; Robert Klein; and Larry Goldstein, Petitioners vs. Kelvin Shelly, Secretary of State of California, Respondent, Geoff Brandt, State Printer; Bill Lockyer. Attorney General of California ; Tom McClintock; H. Rex Green John M. W. Moorlach; Judy Norsigian; Francine Coeytaux; Tina Stevens; Does I through X, inclusive, Real Parties In Interest. Also see: Paul Berg, Ph.D; Robert N. Klein; and Larry Goldstein, Petitioners v. Kevin Shelly, Secretary of State of California, Respondent, Case No. 04CS01015, Superior Court of the State of California, "Declaration of Dr. Stuart A. Newman, PhD., in Opposition to Petition for Writ of Mandate and Alternative Writ of Mandate/Order to show Cause," August 4, 2004, p. 2. 26. National Academies of Science. Final Report of the National Academies' Human Embryonic Stem Cell Advisory Committee and 2010 Amendments To the National Academies' Guidelines for Human Embryonic Stem Cell Research. Section 3.4b. http://www.nap.edu/openbook.php?record_i d=12923&page=27#p2001b5399970027001 27. Personal communication. December 1, 2010. 28. Dolgin, E. CIRM to Pay for eggs?http://humanebiotech.com/cirmwantseg gs.html 29. http://californiastemcellreport.blogspot.com/ 2010/06/stem-cell-agency-bars-publicfrom.html 30. CIRM-MRC Human Somatic Cell Nuclear Transfer Workshop Report , June 13-14, 2010. www.cirm.ca.gov/files/PDFs/.../Human_SCN T_Workshop_Report.pdf 31. California Department of Public Health

Human Stem Cell Research Advisory Committee Meeting. November 30, 2010. Eyal 1. Guichon, J. "Don't let market forces govern human procreation," BioNews, 22.November 2010. 2. Scott Carrny, Red Market Blog," International Baby Market" http://redmarkets.com/2010/08/international-baby-maker.html 3. The Nuremberg Code (1947) In: Mitscherlich A, Mielke F. Doctors of infamy: the story of the Nazi medical crimes. New York: Schuman, 1949: xxiii-xxv. 4. The World Health Organization (WHO) is an organ of the United Nations and is the leading authority on health within the United Nations system 5. http://conventions.coe.int/Treaty/Commun/QueVoulezVous.asp?NT=164&CL=EN G 6. http://conventions.coe.int/Treaty/Commun/QueVoulezVous.asp?NT=186&CL=EN G 7. The Helsinki Declaration was developed by the World Medical Association. It is not a binding legal instrument, but its principles were drawn from worldwide regional and national legislation. 8. Such is the case in the Draft Guiding Principles on Human Organ Transplantation of 1991 9. Ingrid Schneider, (2007) 10. DIRECTIVE 2004/23/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004

VOLUME 23 NUMBER 5-6

GENEWATCH 51

COUNCIL FOR RESPONSIBLE GENETICS 5 Upland Road, Suite 3 Cambridge, MA 02140

GENEWATCH IS FREE ON THE WEB - BUT YOU CAN STILL SUBCRIBE TO RECEIVE PRINT ISSUES. ANNUAL PRINT SUBSCRIPTION RATES INDIVIDUAL: $35 LIBRARY: $70 CORPORATION: $100

NON - PROFIT: $50 (PROOF OF NON-PROFIT STATUS MAY BE REQUIRED)

All figures in US dollars. Future issues of GeneWatch will be exclusively electronic and free at www.councilforresponsiblegenetics.org. If you wish to obtain a special print copy of a single issue, please send a request to the address below or call 617.868.0870. PAYMENT INFORMATION

Please send a subscription request with your full name, address and email address, along with a check or credit card (MasterCard or Visa) information, to: Council for Responsible Genetics 5 Upland Road, Suite 3 Cambridge, MA 02140 Orders are also accepted by phone (617.868.0870) or online (www.councilforresponsiblegenetics.org). Additional donations are welcome. Thank you! IMPORTANT TAX INFORMATION: THE FAIR MARKET VALUE OF A ONEYEAR SUBSCRIPTION TO GENEWATCH IS

$35.00

Support from people like you makes CRG’s work possible. Much of our income comes from individuals. Your support helps keep our programs free of the restrictions that come with funding from pharmaceutical and health care companies or government sources. We are the watchdogs for accurate and unbiased information about biotechnology, even when the truth doesn’t suit current political or commercial agendas. And we depend on you to be able to do what we do. There are many ways you can help CRG. You can become a donor: an annual gift in quarterly installments of $25, $50 or $100 gives us a wonderful and predictable support with a minimal shock to your budget. You may also be able to designate CRG through your workplace giving program, including the Combined Federal Campaign. Many companies will actually match or even doublematch your donation. Check with your employer about its matching gift program. You might also consider making an investment in a future where biotechnology is properly used by remembering CRG in your will with a bequest or charitable trust gift. To learn more about helping CRG, please call us at 617.868.0870. You may also write the Council for Responsible Genetics at 5 Upland Road, Suite 3, Cambridge MA 02140, or visit www.councilforresponsiblegenetics.org.