WAKE FOREST

INTELLECTUAL PROPERTY LAW JOURNAL

VOLUME 9 NUMBER 3

SYMPOSIUM 2009

REGENERATIVE MEDICINE : AN INTRODUCTION Dr. Anthony Atala, M.D. 209

ETHICAL ISSUES IN Nancy M. P. King 215 Christine N. Coughling Mark Furth

PATENT LAW AND REGENERATIVE MEDICINE : A CONSIDERATION OF THE CURRENT LAW AND PUBLIC POLICY CONCERNS REGARDING UPSTREAM PATENTS Vincent J. Filliben III 239

WAKE FOREST INTELLECTUAL PROPERTY LAW JOURNAL

VOLUME 9 2008 - 2009 NUMBER 3

REGENERATIVE MEDICINE : AN INTRODUCTION

Dr. Anthony Atala, M.D. *

The idea of improving human life through engineering re- placement organs is not new. Aviator Charles Lindburgh experimented with the concept in the 1920s in an effort to help his ailing sister-in-law. Today, the need is even greater. Every ninety minutes, a patient dies while on the waiting list for . 1 Since older organs are more prone to failure, the problem will only increase as modern medicine extends the human lifespan. The ultimate goal of the field of regenerative medicine is to solve the critical shortage of donor organs and tissues available for transplantation. Scientists in this field use the principles of cell trans- plantation, materials science, and biomedical engineering to develop biological substitutes that can restore and maintain the normal function of damaged or lost tissues and organs. As its name implies, this science takes advantages of the body's natural healing powers. The first attempt at engineering tissue involved the use of cells for skin coverage in 1981. 2 There were few advances over the next decade because of a host of challenges, including the difficulty of get- ting cells to multiply outside the body. Once that obstacle was over- come, there have been multiple advances in the field and, today, scien- tists around the world are working to apply the technology to help pa- tients. Regenerative medicine is not a single technology or technique.

* Anthony Atala, M.D., is the W.H. Boyce Professor and Director of the Wake Forest Institute for Regenerative Medicine, and Chair of the Department of Urology at the School of Medicine. Dr. Atala is a surgeon in the area of pediatric urology and a researcher in the area of regenerative medicine and . 1 Salley Satel, Op-Ed., Death’s Waiting List , N.Y. TIMES , May 15, 2006, at A21. 2 David A. Diamond & Anthony A. Caldamone, Endoscopic Correction of Vesicoureteral Reflux in Children Using Autologous Chondrocytes: Preliminary Results , 162 J. UROLOGY 1185, 1185 (1999). 210 WAKE FOREST INTELL . PROP . L.J. Vol.9

For example, it can involve injecting functional cells into a damaged area of tissue to stimulate regeneration,3 such as injecting muscle cells to treat urinary incontinence. 4 Or, natural or synthetic scaffolds can be used to provide a three-dimensional space for cells to form into new tissues with appropriate structure and function. 5 Some scaffolds are designed by nature. For example, a pig's heart valve that has been processed to remove all cells, leaving the support structure intact, can potentially serve as a scaffold for a patient's own cells -- creating a re- placement valve that is a perfect match. Other scaffolds are made from "scratch" in the lab using materials such as collagen, the protein found in connective tissue. One example of how scaffolds are used in tissue engineering is the implantation of laboratory-engineered organs 6 into humans. 7 The goal of this project was to find a better way to replace bladder tissue than the 100-year-old procedure to fashion a new bladder from the in- testine. Because the intestine is designed to excrete, using it to hold urine can result in metabolic disorders 8 as well as an increased risk of cancer. 9 The technology to engineer a bladder begins with a small biopsy from the patient's own bladder. Cells that are programmed by nature to become bladder tissue are then extracted and multiplied in the lab. The next step is to place these cells on a bladder-shaped, porous, biodegradable scaffold, where they continue to multiply. The scaffold is then implanted in the patient's body. As the tissue continues to de- velop and integrates with the body, the scaffold degrades. In essence, the body serves as an incubator and completes the process that was begun in the lab. The lessons learned through developing the bladder and other technologies are today being applied to a variety of projects. In our own laboratory, for example, scientists are working to grow more than

3 Id. at 1185. 4 Alfred E. Bent et al., Treatment of Intrinsic Sphincter Deficiency Using Autologous Ear Chondrocytes as a Bulking Agent , 20 NEUROLOGY & URODYNAMICS 157, 158 (2001). 5 Anthony Atala et al., A Novel Inert Collagen Matrix for Hypospadias Repair , 162 J. UROLOGY 1148, 1148 (1999); see also Abdel W. El-Kassaby et al., Urethral Stricture Repair with an Off-the-Shelf Collagen Matrix , 169 J. UROLOGY 170, 170 (2003). 6 Frank Oberpenning et al., De novo Reconstitution of a Functional Mammalian Urinary Bladder by Tissue Engineering , 17 NATURE BIOTECHNOLOGY 149, 149 (1999). 7 Anthony Atala et al., Tissue-engineered Autologous Bladders for Patients Needing Cystoplasty , 367 LANCET 1241, 1242 (2006). 8 Martin Kaefer et al., Continent Urinary Diversion: The Children's Hospital Experience , 157 J. UROLOGY 1394, 1395, 1396 (1997). 9 Trevor M. Soergel et al., Transitional Cell Carcinoma of the Bladder Following Augmentation Cystoplasty for the Neuropathic Bladder , 172 J. UROLOGY 1649, 1649 (2004). 2009 REGENERATIVE MEDICINE 211

twenty tissues and organs, including the heart, lungs, blood vessels, heart valves and pancreas. Tissues are at different stages of devel- opment, with some already being used clinically, a few in preclinical trials, and some in the discovery stage. Recent advances in the field of regenerative medicine include an international team's success implanting a section of engineered trachea, created with stem cells from the patient's bone marrow, in a woman with tuberculosis. 10 This advance is exciting because it illustrates the potential for using stem cells in tissue engineering and of using donor tissue as scaffolds. In this case, the trachea scaffold was made by re- moving cells from a section of trachea from a deceased donor. Of course, as with any new technology, we must be cautious. This has been applied to only one patient and the follow up period was relatively short. Just last month, Canadian scientists reported success growing new blood vessels in laboratory animals. 11 To generate the tissue, the scientists injected a collagen-based material that attracts new cells. This injectable material is essentially a "smart scaffold" in that it at- tracts particular cells in the blood that can form the lining of blood vessel walls. Once the cells are there, the material helps keep them alive and prompts them to become blood vessels. All of these examples point out the vital role that cells play in regenerative medicine. It is ideal to use a patient's own cells because the resulting organ/tissue is a perfect match and patients don't need powerful anti-rejection medications. For patients with extensive end-stage organ failure, however, a tissue biopsy may not yield enough normal cells for expansion and transplantation. Additionally, for or- gans such as the heart and pancreas, scientists have not yet learned how to expand these cells outside the body. In these situations, stem cells are envisioned as being an alternative source of cells. True stem cells exhibit two remarkable properties: the ability to self-renew and the ability to differentiate into many specialized cell types. 12 According to the Centers for Disease Control ("CDC"), an estimated three thousand Americans die every day of diseases that could have been treated with stem-cell-derived tissues. 13

10 Toshihiko Sato & Tatsuo Nakamura, Tissue-engineered Airway Replacement , 372 LANCET 2003, 2003 (2008). 11 Erik J. Suuronen et al., An Acellular Matrix-bound Ligand Enhances the Mobilization, Recruitment and Therapeutic Effects of Circulating Progenitor Cells in a Hindlimb Ischemia Model , 23 FASEB J. 1447, 1454 (2009). 12 Ali H. Brivanlou et al., Setting Standards for Human Embryonic Stem Cells , 300 SCIENCE 913, 913 (2003). 13 Robert P. Lanza et. al., Letters, The Ethical Reasons for Research , 292 SCIENCE 1299, 1299 (2001), Robert P. Lanza, et al., Generation of Histocompatible Tissues Using Nuclear Transplantation , 20 NATURE BIOTECHNOLOGY 689, 689

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Stem cells can be derived from discarded human embryos (human embryonic stem cells) and from adult sources (bone marrow, fat, skin). In addition, a new type of stem cell has been identified in placenta and amniotic fluid that is believed to represent a develop- mental stage between embryonic and adult stem cells. 14 These amnion cells are distinct from human embryonic stem cells, but resemble them in two important ways. They can be easily expanded in the laboratory and can be induced to differentiate into multiple specialized cell types. However, unlike embryonic stem cells, the amnion cells do not form tumors when they are transplanted. Also, since they are easily obtained from afterbirth, they are non-controversial. In addition to providing scientists a ready source of stem cells for research, a national bank of amnion cells -- with approximately 100,000 specimens -- could theoretically provide up to ninety-nine percent of the population with a perfect genetic match for transplanta- tion. As science moves forward, the cells can potentially be used to engineer tissues or organs specifically for each patient Beyond the options discussed above, there are yet other ways to obtain stem cells. In fact, science has advanced to the point that the debate over whether it is appropriate to use embryonic cells has become almost obsolete. For example, a recent, exciting advance is the suc- cessful transformation of adult cells into stem cells through a type of genetic "reprogramming." 15 This technique, which causes a normal cell to become de-specialized and revert back to being a stem cell, does not involve the use of embryos. Stem cells generated by reprogram- ming would be genetically identical to the original cell and would not be rejected. It has recently been shown that reprogramming of human cells is possible. 16 Although this is an exciting phenomenon, we have limited understanding of the mechanism. Another source of stem cells is therapeutic cloning, which is also called nuclear transplantation and nuclear transfer. Most scien-

(2002). 14 Paolo De Coppi et al., Isolation of Amniotic Stem Cell Lines With Potential for Therapy , 25 NATURE BIOTECHNOLOGY 100, 100 (2007); Paolo De Coppi, et al., Amniotic Fluid and Bone Marrow Derived Mesenchymal Stem Cells can be Converted to Smooth Muscle Cells in the Cryo-Injured Rat Bladder and Prevent Compensatory Hypertrophy of Surviving Smooth Muscle Cells , 177 J. UROLOGY 369, 374 (2007). 15 See Kazutoshi Takahashi & Shinya Yamanaka, Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 126 CELL 663, 663 (2006); Marius Wernig et al., In Vitro Reprogramming of Fibroblasts into a Pluripotent ES-cell-like State , 448 NATURE 318, 318 (2007); Kazutoshi Takahashi et al., Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 131 CELL 861, 861 (2007); Junying Yu et al., Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 318 SCIENCE 1917, 1917 (2007). 16 Wernig et al., supra note 15, at 318. 2009 REGENERATIVE MEDICINE 213

tists agree that the cloning of individuals -- known as reproductive cloning -- is off-limits. The goal of therapeutic cloning, on the other hand, is not to create a new individual, but to create a line of stem cells that can be used in therapy. The process involves the introduction of a nucleus from a donor cell into an egg cell with the nucleus removed. The egg is prompted to divide, generating an early-stage embryo with a genetic makeup identical to that of the donor. 17 These early stage embryos are used to produce lines whose genetic material is identical to that of its source. These cells have the potential to become almost any type of cell in the adult body, and thus would be useful in tissue and organ replacement applications. 18 While promising, nuclear transfer technology has cer- tain limitations that require further improvements before it can be widely applied. Currently, for example, the efficiency of the overall cloning process is low. The variety of stem cell types and sources illustrates an impor- tant point about the future of regenerative medicine. Just as it is likely that all types of stem cells will play a role in regenerative medicine, it is likely that no one regenerative medicine technology is going to be best for all patients. One day, there may be a boutique of technologies that physicians and scientists can select from based on a patient's needs. For example, it is difficult to predict which form of regenerative medi- cine will eventually be used to help patients with damaged heart mus- cle. Will it be best to inject stem cells that will find their way to the damaged tissue? Or will we create patches of tissue in the lab that can be used to mend a poorly functioning organ? As we are pursuing so- lutions for patients, we should keep in mind that in many cases, we will not need an entire new organ to dramatically improve the patient's life. Our interest should not be specifically to build a human heart, or any organ for that matter, but to make patients better -- no matter what strategy is used. As the field moves forward and advances happen more rapidly, one of our biggest challenges will be to strike a balance between getting therapies to patients quickly, while at the same time ensuring that these new treatments are safe. There is nothing worse for a physician than to have a patient who is out of options. On the other hand, our profes- sional oath obligates us to "do no harm." This is a delicate balance, and the future of the field depends on us getting it right. In our striving to help patients, we must never compromise safety and risk tainting our field and the promise it holds.

17 Lanza et al., supra note 13 at 689. 18 Konrad Hochedlinger & Rudolf Jaenisch, Nuclear Transplantation, Embryonic Stem Cells and the Potential for Cell Therapy , 349 NEW ENG . J. MED . 275, 275 (2003).

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WAKE FOREST INTELLECTUAL PROPERTY LAW JOURNAL

VOLUME 9 2008 - 2009 NUMBER 3

ETHICAL ISSUES IN REGENERATIVE MEDICINE

Nancy M. P. King ♣ Christine N. Coughlin ♦ Mark Furth ⊗

INTRODUCTION

“Regenerative medicine” is an enormous category, encompassing more than a field of medicine and medical research. 1 The name “regenerative medicine” describes a set of innovative approaches to the treatment of illness, injury, and disability, focusing on the growth, replacement, and repair of cells, organs, and tissues specific to the health needs of particular individuals. 2 The extraordinary breadth of application of this approach is clear from an enumeration of just a few of the areas of regenerative medicine research: stem cells, including not only pluripotent embryonic stem cells, but also pluripotent stem cells produced by genetic reprogramming, and multipotent stem cells from fetal, perinatal,

♣ Nancy M. P. King, J.D., Department of Social Sciences and Health Policy and Translational Science Institute, Wake Forest University School of Medicine, Co- Director, Wake Forest University Center for Bioethics, Health, and Society, Wake Forest University, and Wake Forest Institute for Regenerative Medicine. ♦ Christine Nero Coughlin, J.D., Professor of Legal Practice, Wake Forest University School of Law, Translational Science Institute, Wake Forest University School of Medicine. ⊗ Mark E. Furth, Ph.D., Wake Forest Institute for Regenerative Medicine. 1 See ANTHONY ATALA ET AL ., PRINCIPLES OF REGENERATIVE MEDICINE 2 (Academic Press 2008); COMMITTEE ON THE BIOLOGICAL AND BIOMEDICAL APPLICATION OF STEM CELL RESEARCH , STEM CELLS AND THE FUTURE OF REGENERATIVE MEDICINE (National Academy Press 2002). 2 ATALA ET AL ., supra note 1, at 28. The term “regenerative medicine” was introduced by Dr. William Haseltine. See William A. Haseltine, Regenerative Medicine , BROOKINGS REV ., Winter 2003, at 38, available at http://www.brookings.edu/articles/2003/winter_healthcare_haseltine.aspx. 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 216

pediatric, and adult tissues; 3 techniques for stimulating endogenous cell growth and repair, which can be applied, for example, to the kidney, 4 the pancreas in the case of diabetes, 5 or digits and limbs in the case of trauma; 6 and the growth of replacement tissues and organs, from blood vessel 7 to bladder 8 to heart. 9 This enormous diversity of applications, all currently in various stages of research and development, arises from a profoundly effective multidisciplinary and interdisciplinary research orientation, which incorporates genetics, informatics, and basic research into the structure, mechanics, development of different tissues, and creative production techniques, as well as a range of other technologies that can scarcely be imagined by nonscientists. 10

3 See Paolo De Coppi et al. , Isolation of Amniotic Stem Cell Lines with Potential for Therapy , 25 NATURE BIOTECHNOLOGY 100 (2007); Akiva J. Marcus & Dale Woodbury, Fetal Stem Cells from Extra-Embryonic Tissues: Do Not Discard , 12 J. CELLULAR & MOLECULAR MED . 730 (2008); Sharon C. Presnell et al., Stem Cells in Adult Tissues , 13 SEMINARS CELL & DEVELOPMENTAL BIOLOGY 369 (2002); James A. Thomson et al., Embryonic Stem Cell Lines Derived from Human Blastocysts , 282 SCIENCE 1145 (1998); A. Vats et al., Stem Cells , 366 LANCET 592 (2005); Shinya Yamanaka, Pluripotency and Nuclear Reprogramming , 363 PHIL . TRANSACTIONS ROYAL SOC ’Y B 2079 (2008); Junying Yu et al., Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 318 SCIENCE 1917 (2007). 4 See Bendetta Bussolati et al., Contribution of Stem Cells to Kidney Repair , 28 AM. J. NEPHROLOGY 813 (2008); Laura Perin et al., Stem Cell and Regenerative Science Applications in the Development of Bioengineering of Renal Tissue , 63 PEDIATRIC RES . 467 (2008). 5 See L. Baeyens & L. Bouwens, Can β-Cells Be Derived from Exocrine Pancreas? , 10 DIABETES , OBESITY & METABOLISM (S PECIAL ISSUE) 170 (2008); Qiao Zhou et al., In Vivo Reprogramming of Adult Pancreatic Exocrine Cells to β-Cells , 455 NATURE 627 (2008); Gordon C. Weir, Can We Make Surrogate β-Cells Better Than the Original ?, 15 SEMINARS CELL & DEVELOPMENTAL BIOLOGY 347 (2004). 6 See Ken Muneoka et al., Regrowing Human Limbs , SCI . AM., Apr. 2008, at 57; Hitoshi Yokoyama, Initiation of Limb Regeneration: The Critical Steps for Regenerative Capacity , DEV . GROWTH DIFFERENTIATION , Jan. 2008, at 13. 7 See Laurence Bordenave et al., Developments Towards Tissue-Engineered, Small- Diameter Arterial Substitutes , 5 EXPERT REV . MED . DEVICES 337 (2008). 8 See Anthony Atala et al., Tissue-Engineered Autologous Bladders for Patients Needing Cystoplasty , 367 LANCET 1241 (2006). 9 See Shinako Masuda et al., Cell Sheet Engineering for Heart Tissue Repair , 60 ADVANCED DRUG DELIVERY REV . 277 (2008); Harold C. Ott et al., Perfusion- Decellularized Matrix: Using Nature's Platform to Engineer a Bioartificial Heart , 14 NATURE MED . 213 (2008); Vincent F.M. Segers & Richard T. Lee, Stem-cell Therapy for Cardiac Disease , 451 NATURE 937 (2008). 10 See Paul Kemp, History of Regenerative Medicine: Looking Backwards To Move Forwards , 1 REGENERATIVE MED . 653 (2006). See generally ATALA ET AL ., supra note 1. Kemp’s historical perspective is particularly helpful for consideration of the financial, social, and policy contexts in which regenerative medicine is developing. See discussion infra at Section III.A. 217 WAKE FOREST INTELL . PROP . L.J. Vol.9

Fundamentally, however, all of regenerative medicine, in its great complexity, springs from the search for understanding the basic mechanisms of generation—that is, the growth and development of living organisms. In this respect, it is the next step in a long scientific journey toward the efficient restoration of health and wholeness that comes from true knowledge. That noble goal notwithstanding, regenerative medicine’s many applications, areas, and branches together constitute a very early step along the road to fundamental understanding. Like other novel biotechnologies, regenerative medicine raises a number of interesting research ethics issues. These issues are not new. Instead, as is common in scientific advancement, familiar and longstanding questions, never perfectly or finally addressed, appear in fresh contexts and renew old debates, causing us to reexamine the productive tensions that necessarily arise in research involving human subjects. Thus, just as regenerative medicine’s many scientific components all connect to basic knowledge of human growth and development, the many ethical issues it raises similarly connect to the basic building blocks of bioethics and human relationships in medicine and research. 11 This article examines some of the novel technologies within regenerative medicine, focusing on: (1) human embryonic and pluripotent stem cell research; and (2) cell, tissue, and organ regeneration research. The range of ethical issues raised by each of these novel technologies is examined in turn, including: some of the most familiar arguments about human embryonic stem cell research; safety concerns raised by induced pluripotent stem cell research; the ethics of research design; issues to consider the first time an intervention is tested in human subjects; and informed consent and the therapeutic misconception. Finally, the article further considers whether regenerative medicine’s innovative technologies may further blur whatever distinction is thought to exist between medical treatment and enhancement, possibly creating more ethical issues to address in the long term. This article concludes by advising scholars and policymakers in bioethics to take the opportunity offered by

11 See, e.g., RUTH R. FADEN & TOM L. BEAUCHAMP WITH NANCY M. P. KING , A HISTORY AND THEORY OF INFORMED CONSENT (Oxford Univ. Press 1986); Steven Joffe & Franklin G. Miller, Bench to Bedside: Mapping the Moral Terrain of Clinical Research , HASTINGS CENTER. REP ., Mar.-Apr. 2008, at 30; Ezekiel J. Emanuel et al., What Makes Clinical Research Ethical? , 283 JAMA 2701 (2000); NAT ’L COMM ’N FOR THE PROT . OF HUMAN SUBJECTS OF BIOMEDICAL AND BEHAVIORAL RESEARCH , THE BELMONT REPORT : ETHICAL PRINCIPLES AND GUIDELINES FOR THE PROTECTION OF HUMAN SUBJECTS OF RESEARCH (1979), http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm. 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 218

regenerative medicine to reconsider these and other long-standing issues, and to move forward research ethics and policy by examining the issues anew through the lens of this groundbreaking medical science.

I. HUMAN EMBRYONIC AND PLURIPOTENT STEM CELL RESEARCH

A. HUMAN EMBRYONIC STEM CELLS

One question about the ethics of regenerative medicine has preoccupied most of the public debate for many years: whether the moral status of the embryo and fetus makes use of human embryonic stem (hES) cells ethically problematic. 12 Embryonic stem cells are highly versatile, able to give rise to all types of cells and to be “immortalized,” or perpetually propagated in a cell line. 13 Their versatility makes them valuable for research and treatment. However, they also have the intrinsic property of forming teratoma tumors. 14 Their source makes them controversial. Deeply felt differences of opinion about the moral status of the human embryo have raised questions about the sources of embryonic stem cell lines, leading to both ethical and public policy debate. 15 When embryos must be destroyed in order to create new cell lines, moral and religious concerns are raised. 16 Recently, questions have also arisen about the adequacy of consent for research with the embryos used to create approved cell lines. 17 Disagreement is long standing about the moral appropriateness of creating new cell lines, for example from “leftover” embryos created in vitro and donated for

12 See generally CYNTHIA B. COHEN , RENEWING THE STUFF OF LIFE : STEM CELLS , ETHICS , AND PUBLIC POLICY (Oxford Univ. Press 2007); COMM . ON GUIDELINES FOR HUMAN EMBRYONIC STEM CELL RESEARCH , GUIDELINES FOR HUMAN EMBRYONIC STEM CELL RESEARCH 34 (National Academy of Sciences 2005). 13 Junying Yu & James A. Thomson, Embryonic Stem Cells , as reprinted in NAT ’L INSTS . OF HEALTH , REGENERATIVE MEDICINE 2006, at 1, http://stemcells.nih.gov/ staticresources/info/scireport/PDFs/Regenerative_Medicine_2006.pdf. 14 Davor Solter, From Teratocarcinomas to Embryonic Stem Cells and Beyond: A History of Embryonic Stem Cell Research , 7 NATURE REVIEWS GENETICS 319, 319- 320 (2006). 15 See COHEN , supra note 12; Russell Korobkin, Stem Cell Research and the Cloning Wars , 18 STAN . L. & POL ’Y REV . 161, 171 (2007); John A. Robertson, Ethics and Policy in Embryonic Stem Cell Research , 9 KENNEDY INST . ETHICS J. 109 (1999). 16 See COHEN , supra note 12. 17 See Robert Streiffer, Informed Consent and Federal Funding for Stem Cell Research , 40(3) HASTINGS CENTER . REP ., May-June 2008, at 40. 219 WAKE FOREST INTELL . PROP . L.J. Vol.9

research purposes, 18 or from stored embryos that have been determined to be “dead.”19 Recent evidence that hES cell lines can be created from single embryonic cells (blastomeres) without compromising the viability of the donor embryos has not ended the controversy. 20 Similarly important and pervasive discussions concern the ethical implications of somatic cell nuclear transfer, or “research cloning,” in which the nucleus of a somatic cell replaces the nucleus of an oocyte in order to create a stem cell line that is a match for the individual from whom the somatic cell was taken. 21 This type of research requires large numbers of oocytes, giving rise to concerns about consent and payment in the procurement of human oocytes, 22 in addition to qualms about the use of a technology that is largely identical to what would be used for reproductive cloning. 23 The proposal to use non-human oocytes as hosts for the cloning of human cell nuclei potentially would resolve the procurement concerns, but raises other questions of feasibility and the ethics of creating novel chimaeras. 24 Two important considerations are likely to influence public discourse about the ethical implications of hES cell research. First, the

18 Annie D. Lyerly & Ruth R. Faden , Embryonic Stem Cells: Willingness to Donate Frozen Embryos for Stem Cell Research , 316 SCIENCE , July 2007, at 46. 19 See Xin Zhang et al., Derivation of Human Embryonic Stem Cells from Developing and Arrested Embryos , 24 STEM CELLS 2669, 2669 (2006); Donald W. Landry & Howard A. Zucker, Embryonic Death and the Creation of Human Embryonic Stem Cells , 114 J. CLINICAL INVESTIGATION 1184, 1184 (2004). 20 See Young Chung et al., Human Embryonic Stem Cell Lines Generated Without Embryo Destruction , 2 CELL STEM CELL 113 (2008). 21 See generally ATALA ET AL ., supra note 1; COHEN , supra note 12; DJ Procop, Embryonic Stem Cells versus Adult Stem Cells: Some Seemingly Simple Questions , in ESSENTIALS OF STEM CELL BIOLOGY , xxii (Robert Lanza et al. eds., 2006); Alexander Meissner and Rudolf Jaenisch, Generation of Nuclear Transfer-Derived Pluripotent ES Cells from Cloned Cdx2-Deficient Blastocysts , 439 NATURE 212 (2006); PRESIDENT ’S COUNCIL ON BIOETHICS , MONITORING STEM CELL RESEARCH 111-12 (2004), http://www.bioethics.gov/reports/stemcell/pcbe_final_version_ monitoring_stem_cell_research.pdf. 22 See David Magnus & Mildred K. Cho, Issues in Oocyte Donation for Stem Cell Research , 308 SCIENCE 1747, 1747-48 (2005). But see John A. Robertson, Technology and Motherhood: Legal and Ethical Issues in Human Egg Donation , 39 CASE W. RES . L. REV . 1, 31 (1989); Josephine Johnston, Paying Egg Donors: Exploring the Arguments , 36(1) HASTINGS CENTER REP ., Jan.-Feb. 2006, at 28, 30; Debora Spar, The Egg Trade: Making Sense of the Market for Human Oocytes , 356 NEW ENG . J. MED . 1289 (2007); David B. Resnik, Regulating the Market for Human Eggs , 15 BIOETHICS 1, 5-9 (2001). 23 See COHEN , supra note 12. 24 See Stephen Minger, Interspecies SCNT-Derived Human Embryos—a New Way Forward for Regenerative Medicine , 2 REGENERATIVE MED . 103 (2007). 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 220

debate has changed now that presidential policy regarding federal funding of this research has been liberalized. 25 Second, the moral and religious debate is not unique to hES cell research, although it has remained largely focused there. Many of the same issues arise in the extensive assisted reproduction industry, which is largely unregulated in the United States. 26 These issues include the implantation and “selective reduction” 27 of multiple embryos and the permanent storage or destruction of unused but potentially viable embryos. 28 Recent media furor over the birth of octuplets through assisted reproduction has revived interest in these ethical issues, and perhaps also in regulation. 29

B. INDUCED PLURIPOTENT STEM CELLS

The newest and perhaps most interesting development in pluripotent stem cell research is the creation of induced pluripotent stem (iPS) cells–that is, the use of various means of stimulating a somatic cell to “de-differentiate,” or evolve backward to a pluripotent stem cell. 30 Pluripotent stem cells are capable of giving rise to all adult cell types. A key consideration is the risk of harm that could result from the process of generating iPS cells. To stimulate de- differentiation, generally referred to as “reprogramming,” current methods of iPS cell creation require the introduction of genetic material into the cell. This is often achieved by using viral vectors, as in gene transfer research, and thus introduces comparable risks,

25 Exec. Order No. 13,505, 74 Fed. Reg. 10,667 (Mar. 11, 2009); Nat’l Insts. of Health, Guidelines on Human Stem Cell Research, 74 Fed. Reg. 32,170 (July 7, 2009), available at http://stemcells.nih.gov/policy/2009guidelines.htm. 26 See generally Am. Soc’y for Reproductive Med., Ethical Considerations of Assisted Reproductive Technologies: ASRM Ethics Committee Reports and Statements, http://www.asrm.org/Media/Ethics/ethicsmain.html (last visited Jan. 20, 2010); Am. Soc’y for Reproductive Med., Practice Committee Reports: Guidelines, Statements, and Opinions of the American Society for Reproductive Medicine Practice Committee, http://www.asrm.org/Media/Practice/practice.html (last visited Jan. 20, 2010). 27 See Liza Mundy, Too Much to Carry? , WASH . POST MAG ., May 20, 2007, at W14. 28 See Lyerly & Faden, supra note 18. 29 See , e.g. , Stephanie Saul, Birth of Octuplets Puts Focus on Fertility Clinics , N.Y. TIMES , Feb 12, 2009, at A1. 30 See, e.g., Keisuke Okita et al., Generation of Germline-Competent Induced Pluripotent Stem Cells , 448 NATURE 313 (2007); Marius Wernig et al., In Vitro Reprogramming of Fibroblasts into a Pluripotent ES-Cell-Like State, 448 NATURE 318 (2007); Chad A. Cowan et al., Nuclear Reprogramming of Somatic Cells After Fusion with Human Embryonic Cells , 309 SCIENCE 1369 (2005); see also Amy Zarzeczny et al., iPS Cells: Mapping the Policy Issues , 139 CELL 1032 (2009). 221 WAKE FOREST INTELL . PROP . L.J. Vol.9

including the possibility of insertional mutagenesis. 31 Uses of non- viral vectors and non-genetic means of reprogramming cells to a pluripotent state are in development in many laboratories. 32 Once this problem is solved, the intrinsic propensity of iPS cells, like ES cells, to form teratoma tumors may still present a potential risk for therapeutic applications. 33 Induced pluripotent stem cell research appears extremely promising, both for the study of genetic and other diseases and ultimately for the development of genuinely personalized therapies. 34 Nonetheless, many uncertainties accompany this exciting research; its safety, effectiveness and cost are yet to be determined, and much is still unknown. Thus, it is clearly desirable to continue pursuing the identification and development of multiple sources of human pluripotent stem cells. The availability of iPS cell technology, the collection of potentially pluripotent stem cells from biological waste materials, and other technologies for the identification and production of usable stem cells and cell lines are not alternatives; instead they are complementary. 35

C. BIOBANKING

One technology used widely in medicine and research is the collection and storage of biological materials. When biological

31 Insertional mutagenesis is the stimulation of potentially deleterious genetic mutations when new genetic material is introduced. It is most likely to be a problem when viral vectors are used to insert new genes, and has long been of concern in gene transfer research. See Salima Hacein-Bey-Abina et al., A Serious Adverse Event After Successful Gene Therapy for X-Linked Severe Combined Immunodeficiency , 348 NEW ENG . J. MED . 255, 255 (2003). 32 See, e.g. , Wenlin Li et al., Generation of Rat and Human Induced Pluripotent Stem Cells by Combining Genetic Reprogramming and Chemical Inhibitors , 4 CELL STEM CELL 16 (2009); Rudolf Jaenisch & Richard Young, Stem Cells, the Molecular Circuitry of Pluripotency and Nuclear Reprogramming, 132 CELL 567 (2008); Keisuke Okita et al., Generation of Mouse-Induced Pluripotent Stem Cells Without Viral Vectors , 322 SCIENCE 949 (2008); Takashi Tada, Genetic Modification-Free Reprogramming to Induced Pluripotent Cells: Fantasy or Reality? , 3 CELL STEM CELL 121 (2008). 33 The Food and Drug Administration has clearly indicated that extensive testing of hES cell and iPS cell products will be required, especially with respect to tumorigenicity, before human testing may begin. This safety testing reportedly could take years. See infra notes 51 and 55. 34 See, e.g. , Asa Abeliovich & Claudia A. Doege, Reprogramming Therapeutics: iPS Cell Prospects for Neurodegenerative Disease , 61 NEURON 337 (2009). 35 See generally COHEN , supra note 12; Mahendra Rao & Maureen L. Condic, Alternative Sources of Pluripotent Stem Cells: Scientific Solutions to an Ethical Dilemma , 17 STEM CELLS & DEV . 1 (2008); PRESIDENT ’S COUNCIL , supra note 21, at 111-12. 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 222

materials are stored in order to be made available to share for treatment or research, this is usually called biobanking. Blood banking is the best-known example in which the cells have a limited shelf-life. However, biobanking technology often makes it possible to store usable biospecimens for many years, generally in ultra-low temperature freezers, and even to generate long-lived cell lines so that they can serve indefinitely as a renewable resource. Regenerative medicine has come to depend on the ability to bank cells for use in so-called “cell therapy” research and treatment. Private umbilical cord blood banking services were developed in the 1980s as an expensive and exclusive option marketed to families concerned about possible future health needs. 36 Public umbilical cord stem cell banking followed, beginning in the 1990s.37 The rationale for this public banking is to provide a resource for transplantation of blood-forming hematopoietic stem cells to virtually any United States citizen. The use of cord blood stem cells represents an alternative to bone marrow transplantation for many patients. 38 However, technologies have not been developed to date for the expansion of the relatively limited number of blood-forming stem cells present in umbilical cord blood, nor for their differentiation into other types of cells. More recently, broadly multipotent stem cells capable of extensive expansion in laboratory culture have been isolated from what are often considered biological waste products: most notably amniotic fluid and placental chorionic villi, 39 as well as the stromal tissue of umbilical cord. 40 These new findings have heightened interest in large-scale national stem cell banking beyond the existing collection of cord blood. 41 Ideally, large-scale banking efforts could

36 Joanne Kurtzberg et al., Untying the Gordian Knot: Policies, Practices, and Ethical Issues Related to Banking of Umbilical Cord Blood, 115 J. CLINICAL INVESTIGATION 2592, 2592 (2005). 37 Id.; s ee also Stem Cell Therapeutic and Research Act of 2005, Pub. L. No. 109- 129, 2520 HR 2005 (codified 42 U.S.C. § 274) (providing substantial support for public cord blood banking. The target is to have enough banked umbilical cord blood units to provide good matching for virtually any US citizen.). 38 Bertram Lubin & William Shearer, Cord Blood Banking for Potential Future Transplantation , 119 PEDIATRICS 165, 165 (2007). 39 M. Minhaj Siddiqui & Anthony Atala, Amniotic Fluid-Derived Pluripotential Cells, in 2 HANDBOOK OF STEM CELLS 175 (R. Lanza et al., eds., Elesevier Academic Press 2004); De Coppi et al., supra note 3, at 104; Ming-Song Tsai et al., Clonal Amniotic-Fluid Derived Stem Cells Express Characteristics of Both Mesenchymal and Neural Stem Cells , 74 BIOLOGY REPRODUCTION 545, 550 (2006). 40 Alp Can & Sercin Karahuseyinoglu, Concise Review: Human Umbilical Cord Stroma with Regard to the Source of Fetus-Derived Stem Cells , 25 STEM CELLS 2886, 2886 (2007). 41 Senators Burr and Coleman introduced the Amniotic Fluid and Placental Stem Cell Banking Act on March 22, 2007. See Amniotic Fluid and Placental Stem Cell 223 WAKE FOREST INTELL . PROP . L.J. Vol.9

store enough different lines of broadly multipotent and pluripotent stem cells that might be used in many different regenerative medicine applications to provide good matches for nearly the entire population of the United States. 42 Systems for the collection, storage, and use of stem cells of different types are, however, still in the early stages, both technologically and from a policy standpoint, and a number of scientific, practical, and ethical issues are raised by this effort. These issues include ensuring the broad availability of matches for those in need, determining access for research as well as for therapeutic uses, refining consent forms, information, and procedures, and developing robust systems for confidentially labeling biospecimens and linking them to the information needed for research and treatment. 43 These practical, ethical and policy questions must be thoroughly and continually addressed before the promise of biobanking, in particular banking of stem cells, can be fully realized.

II. CELL, TISSUE, AND ORGAN REGENERATION RESEARCH

The ethical issues arising from the design and conduct of research into cell, tissue, and organ regeneration are distinctive and interesting, though not novel. Most of these issues are common to all early-phase research in novel biotechnologies—for example, gene transfer research, often misleadingly called “gene therapy.” 44

Banking Act, S. 957, 110th Cong. (2003). Reps. Lipinski, McIntyre, Shuler, Ellsworth, Melancon, and Donnelly introduced the National Amniotic and Placental Stem Cell Bank Act on April 17, 2007. See National Amniotic and Placental Stem Cell Bank Act, H.R. 1892, 110th Cong. (2007). 42 Ruth R. Faden et al., Public Stem Cell Banks: Considerations of Justice in Stem Cell Research and Therapy , 33(6) HASTINGS CENTER REP ., Nov.-Dec. 2003, at 13. 43 Id.; see also Jeremy Sugarman et al., Ethical Issues in Umbilical Cord Blood Banking , 278 JAMA 938, 938 (1997). Many of these issues are currently being addressed in umbilical cord blood banking. Future extensions to multipotent stem cells, such as those in amniotic fluid, may be easier in some respects—for instance, the cells can be perpetuated and thus will not be used up when samples are taken to treat an individual patient, or for a particular research use. Other issues may be more difficult to translate. For example, the processing cost for amniotic fluid stem cells is likely to be greater than for umbilical cord blood. In addition, since amniotic fluid stem cells are expected to have a broader range of (still unproven in the clinic) potential uses, their use may necessitate broader consent forms. 44 See Larry R. Churchill et al., Genetic Research as Therapy: Implications of “Gene Therapy” for Informed Consent , 26 J.L. MED . & ETHICS 38 (1998); Nancy M. P. King, Rewriting the “Points to Consider”: The Ethical Impact of Guidance Document Language, 10 HUMAN GENE THERAPY 133 (1999); Nancy M. P. King, Defining and Describing Benefit Appropriately in Clinical Trials , 28 J.L. MED . & ETHICS 332 (2000) [hereinafter King 2000]. 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 224

Although some of the research into the regeneration of cells, tissues, and organs uses hES cells and iPS cells or cells from fetal tissues, most current regenerative medicine research uses less controversial types of stem cells derived from a variety of adult and perinatal cell sources. These different types of stem cells are variously named and categorized, according to where they are found and the stage of development when they are derived. The range of stem cell types within this large group may be best described as creating a continuum of potentiality, from “adult” stem cells, able to give rise only to the cells of the tissue from which they are derived, to adult and perinatal stem cells believed to be more versatile—perhaps able to give rise to specialized cells corresponding to organs and tissues different from that of their source. 45 “Cell therapies” used in research and treatment employ stem cells of all types. Examples of cell therapy include: widespread use of transplants in cancer treatment, 46 research addressing autoimmune diseases, 47 and increasing tolerance for solid organ transplantation; injection of stem cells into the brains of patient-subjects with nervous system disorders like Parkinson’s disease, 48 or into patient-subjects with diabetes, in an effort to stimulate the growth of healthy cells that can replace those damaged by disease. 49 Another promising type of cell therapy research seeks ways to stimulate self-repair of damaged cells, or to turn one type of cell into a needed cell type, through injection of chemical or gene transfer agents directly into target organs and tissues. 50

45 ATALA ET AL ., supra note 1, at 347 (determined stem cells are found in small quantities in adult organs and tissues). Some stem cells have also been called “multipotent.” Scientific debate about the potentiality of stem cells and their categorization is ongoing. 46 Edward A. Copelan, Hematopoietic Stem-Cell Transplantation , 354 NEW ENG . J. MED . 1813, 1813 (2006). 47 Richard K. Burt et al., Clinical Applications of Blood-Derived and Marrow- Derived Stem Cells for Nonmalignant Diseases , 299 JAMA 925, 927 (2008). 48 Ole Isacson & Jeffrey H. Kordower, Future of Cell and Gene Therapies for Parkinson’s Disease , 64 ANNALS NEUROLOGY (SUPPLEMENT ) S122, S122 (2008); see also Ninette Amariglio et al., Donor-Derived Brain Tumor Following Transplantation in an Ataxia Telangiectasia Patient , 6(2) PL OS MED . 221, 222 (2009) (apparently demonstrating that tumorigenicity is a risk not limited to hES and iPS cells). 49 Mark E. Furth & Anthony Atala, Stem Cell Sources to Treat Diabetes , 106 J. CELLULAR BIOCHEMISTRY 507, 507 (2009). 50 Promising research is underway testing the ability of such injections to restart insulin production in non-functioning pancreatic islet cells, and perhaps even to turn (“reprogram”) non-insulin-producing cells in the pancreas into the insulin-producing cell type. See generally Zhou et al., supra note 5, at 627. 225 WAKE FOREST INTELL . PROP . L.J. Vol.9

In late January 2009, the Food & Drug Administration approved the first clinical trial of an hES cell-based experimental intervention for spinal cord injury. 51 This phase I study is a good example of how regenerative medicine research raises ethical questions common to all early-phase research. The industry- sponsored study plans to enroll eight to ten subjects with recent, severe spinal cord injuries. 52 The goal of the study, like that of phase I research generally, is only to determine safety. 53 Like many other phase I studies, however, it must enroll not healthy volunteers (as is usual in pharmaceutical research) but instead patients with the condition of interest (as is usual in cancer research, gene transfer, and numerous other areas). Thus, potential subjects, investigators, regulators, reporters, investors, and the general public may all have heightened and perhaps unrealistic expectations of potential benefit for the subjects, derived from the hope that this promising research could ultimately become an effective treatment. This “therapeutic misconception” 54 might be compounded by the enrollment of subjects who are patients with new, severe injuries–presumably chosen in order to provide the best data on the intervention’s potential for efficacy– rather than patients with less severe and less recent injuries, who have

51 See Karen Kaplan, Stem Cell Therapy To Be Tested on Spinal Cord Injuries , L.A. TIMES , Jan. 24, 2009, available at http://www.latimes.com/news/printedition/front/ la-sci-stemcells24-2009jan24,0,5005078.story; Andrew Pollack, Milestone in Research in Stem Cells , N.Y. TIMES , Jan. 23, 2009, at B1; Press Release, Geron Receives FDA Clearance to Begin World’s First Human Clinical Trial of Embryonic Stem Cell-Based Therapy (Jan 23, 2009), available at http://geron.com/media/ pressview.aspx?id=1148 (providing information about the study and its sponsor, Geron Corporation). 52 See sources cited supra note 51. 53 See 20 CFR 312.21(a) (2010). 54 Paul S. Appelbaum et al., The Therapeutic Misconception: Informed Consent in Psychiatric Research , 5 INT ’L J.L. & PSYCHIATRY 319 (1982); see also Rebecca Dresser, The Ubiquity and Utility of the Therapeutic Misconception . 19 SOC . PHIL . & POL ’Y 271 (2002); Gail E. Henderson et al., Clinical Trials and Medical Care: Defining the Therapeutic Misconception , 4 PLOS MED . 1735 (2007); Gail E. Henderson et al., Therapeutic Misconception in Early Phase Gene Transfer Trials , 62 SOC . SCI . & MED . 239 (2006); King 2000, supra note 44, at 332; Nancy M. P. King et al., Consent Forms and the Therapeutic Misconception: The Example of Gene Transfer Research , 27(1) IRB: ETHICS & HUMAN RES ., Jan.-Feb. 2005, at 1 [hereinafter King 2005]; Sam Horng & Christine Grady, Misunderstanding in Clinical Research: Distinguishing Therapeutic Misconception, Therapeutic Misestimation, & Therapeutic Optimism , 25(1) IRB: ETHICS & HUMAN RES ., Jan.- Feb. 2003, at 11 (2003); see generally George J. Annas, Questing for Grails: Duplicity, Betrayal and Self-Deception in Postmodern Medical Research , 12 J. CONTEMP . HEALTH L. & POL ’Y 297 (1996); Matthew Miller, Phase I Cancer Trials: A Collusion of Misunderstanding , 30(4) HASTINGS CENTER REP ., July-Aug. 2000, at 34. 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 226

lived with their disability longer and would also have more time to decide about research participation. Finally, use of an agent that has shown only moderate success in research with animals has provoked another question frequently asked about first-in-human studies: Is this really ready for prime time? 55 Organ and tissue regeneration is an even more precise and complex process than cell therapy research. It requires collaborative, deliberate, and extensive pre-clinical knowledge-building research. The prototypical example is the regeneration of hollow organs, such as human bladders, which Dr. Atala has pioneered. 56 The exogenous building of hollow organs, including blood vessels, bladders, and uteruses, requires technological sophistication and pragmatic understanding of human development and function. The regeneration of solid organs adds many further complexities, including vascularization, tissue oxygenation prior to vascular regrowth, pre- implantation development, and a host of other complex considerations. 57 Limb regeneration is yet another distinctive area of research, as yet in the early stages of understanding of the triggers for, and controls on, development and differentiation of complex structures. 58

55 See Nancy M. P. King & Odile Cohen-Haguenauer, En Route to Ethical Recommendations for Gene Transfer , 16 MOLECULAR THERAPY 432 (2008). Determining when to move into human trials, or “from the bench to the bedside,” is now often referred to as a “translational” research issue. General consideration of the quantity and quality of preclinical evidence underpins the readiness question. For any proposed clinical research involving the study of ES cell-derived products as a potential therapy, a specific concern arises: that residual undifferentiated ES cells are likely to cause teratoma tumors. The general view is that these would be “benign”–but it is still a significant safety concern. Geron has been required to complete extensive testing to provide data indicating that potentially tumorigenic cells have been eliminated from the specialized oligodendrocytes (derived from hES cells) in this cell product. Indeed, in August 2009, the trial was placed on “clinical hold” by the FDA, pending completion of a confirmatory preclinical study in an animal model of cervical injury, owing to a higher than expected incidence of cyst development at the site of the cervical spinal lesion in animals receiving the ES cell- derived product. See hESC-Derived Oligodendrocytes–GRNOPC1 , Geron, http://www.geron.com/products/productinformation/spinalcordinjury.aspx (last visited Apr. 13, 2010). Patient-subjects are likely to need immune suppressive drugs to avoid rejection of non-HLA-matched ES cells, and little is known about their possible effects on tumor growth, making the risk of tumorigenesis in such research particularly concerning. 56 Atala et al., supra note 8, at 1241. For the media’s take on the research, see Stephanie Smith, Doctors Grow Organs From Patient’s Own Cells , CNN, Apr. 5, 2006, http://www.cnn.com/2006/HEALTH/conditions/04/03/engineered.organs/index.html. 57 See Mark E. Furth & Anthony Atala, Producing Organs in the Laboratory , 9 CURRENT UROLOGY REPS . 433 (2008). 58 See Muneoka et al., supra note 6; Yokoyama, supra note 6. 227 WAKE FOREST INTELL . PROP . L.J. Vol.9

The ethical issues raised by regenerative medicine research in these areas are intriguing. As in the phase I spinal cord injury study described earlier, long-standing research ethics questions are brought into sharp focus in the context of this new technology. These issues, some of which could appear to be of heightened significance in this context, include the following: design and ethics in early-phase research; subject selection, informed consent, and the therapeutic misconception; and the distinction between treatment and enhancement.

A. ETHICAL ISSUES IN RESEARCH DESIGN

One recurring ethical concern about any novel technology is captured by the question “Is the practice morally acceptable under the circumstances?” The answer, of course, depends on what count as the relevant circumstances. One of them is always cost. Asking about resource allocation and regenerative medicine research requires us to consider this cutting-edge research in its social context, alongside other health needs and priorities, such as local and global health disparities. 59 The perennial question, of course, is: Who should determine funding priorities, and on what basis? What is arguably new—or at least highlighted—in regenerative medicine is that these priorities are being determined not only by federal funders, but also by investors with private capital, and by intellectual property considerations. 60 Most of these considerations, however, are addressed explicitly by others in this symposium. A notable aspect of regenerative medicine, which relates to questions about cost and resource allocation, is its recognition of the need to standardize and streamline production. This production perspective is an important step in lowering costs and increasing access to new technologies, but it could also have interesting ethical implications. Because the regeneration of cells, organs, and tissues is specific to the health needs of particular individuals, the trajectory of regenerative medicine research could be characterized as moving from the individual in early phase studies outward to progressively larger groups in later research phases, through the testing of increasingly

59 See, e.g. , Alex John London & Jonathan Kimmelman, Justice in Translation: From Bench to Bedside in the Developing World , 372 LANCET 82 (2008); Heather L. Greenwood et al., Regenerative Medicine and the Developing World , 3 PL OS MED . 1496 (2006); Faden et al., supra note 42. 60 See Faden et al., supra note 42; Greenwood et al., supra note 59; London & Kimmelman, supra note 59; see also Kemp, supra note 10; David B. Resnik, The Commercialization of Human Stem Cells: Ethical and Policy Issues , 10 HEALTH CARE ANALYSIS 127 (2002). 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 228

standardizable production methods. The move from individually tailored research toward standardization is arguably a distinctive trajectory, scientifically and ethically distinguishable both from traditional drug development 61 and from so-called “personalized medicine.” 62 In conventional clinical research, as typified by drug development, the number of subjects typically increases from one trial phase to the next. At the same time, however, the risks of harm and potential for benefit also become better characterized, and ideally, risks of harm decrease and evidence of potential efficacy increases as the research progresses from early to later study phases. 63 In contrast, in the new category of “personalized medicine,” the research trajectory moves from the large-scale development of genetic screening and testing to the application of test results to tailor interventions precisely for each individual.64 In order to make organ and tissue regeneration feasible and affordable outside the research context, regenerative medicine research seeks to move from individually tailored interventions toward the development of production methods that can reduce the investment of time, labor, and cost. This “reverse trajectory” is necessary and admirable if regenerative medicine is to become meaningfully available to those who need it. Attention to this goal distinguishes regenerative medicine from new technologies like gene transfer, where standardization, the development of platform technologies, and attempts at large-scale, cost-reducing production are in their infancy. 65 This emphasis on standardization and development of large-scale production, however, raises the atypical possibility that the risks of harm for individual subjects could increase over the research trajectory, and the potential for efficacy could decrease. 66 Thus, the

61 Nat’l Library of Med., U.S. Dep’t of Health & Human Servs., FAQ: ClinicalTrials.gov – Clinical Trial Phases (Apr. 18, 2008), http://www.nlm.nih.gov/ services/ctphases.html.; see also OFFICE OF BIOTECHNOLOGY ACTIVITIES , NAT ’L INSTS. OF HEALTH , NIH GUIDANCE ON INFORMED CONSENT FOR GENE TRANSFER RESEARCH (2003), http://oba.od.nih.gov/oba/rac/ic/pdfs/temp_pdf.pdf. 62 See , e.g. , Allen Buchanan et al., Pharmacogenetics: Ethical and Policy Options, 12 KENNEDY INST . ETHICS J. 1 (2002); Thomas J. Hudson, Personalized Medicine: A Transformative Approach Is Needed , 180 CAN . MED . ASS ’N J. 911 (2009); Jesse J. Swen et al., Translating Pharmacogenomics: Challenges on the Road to the Clinic , 4 PL OS MED . 1317 (2007); David J. Triggle, Drug Discovery and Delivery in the 21st Century , 16 MED . PRINCIPLES & PRAC . 1 (2007). 63 See Nat’l Library of Med., supra note 61. 64 See sources cited supra note 62. 65 See King & Cohen-Haguenauer, supra note 55. 66 The principal advantage of “personalized” tissue and organ regeneration is avoidance of immune rejection. Use of the patient’s own cells is likely to be more labor-intensive and costly than if organs could be produced “off the shelf” with 229 WAKE FOREST INTELL . PROP . L.J. Vol.9

design, ethics, and policy questions that arise throughout this research trajectory include questions about how best to balance cost and access, safety and scale in the development of production processes. Because regenerative medicine research is such a vivid exemplar of early-phase clinical research, it also raises important, under-addressed questions of design, ethics, and policy relating to first-time-in-human trials with small numbers of subjects drawn from patients with limited treatment options. Such trials pose difficult questions for reasons of subject vulnerability, 67 the difficulty of providing information when there is considerable uncertainty, 68 and the potential divergence of subjects’ desire for clinical benefit from the scientific goals of early-phase research. 69 There has been insufficient scholarly attention to the problems of early-phase research with patient-subjects, but interest in addressing these challenges is increasing, especially as novel technologies like regenerative medicine suggest or even require new study designs and translational pathways. 70

standardized donor cells. For many patients the cells needed to “personalize” the intervention may not be obtainable by biopsy. This could be due to a variety of reasons: disease condition may eliminate them or make them difficult to obtain safely (e.g., in a cancer patient, they might be contaminated by tumor cells; in a diabetes patient, the pancreatic insulin-producing cells have been destroyed already by an autoimmune mechanism; for elderly patients the cells may not grow well, as compared to younger patients). The great appeal of iPS cell technology in this context is that it, in principle, offers a way to make any cell type with the patient’s own genetic constitution. Unfortunately, the cost associated with making an iPS cell line for every patient, then validating its safety (especially with regard to teratoma formation) and efficacy could well be prohibitive. Intermediate solutions like partial matching of cell types and limited use of immunosuppressive drugs would fit the model of the “reverse trajectory.” (The more complete solution would be a technological breakthrough in the induction of selective immune protection/tolerance for transplanted engineered tissues/organs). 67 See , e.g. , Carol Levine et al ., The Limitations of “Vulnerability” as a Protection for Human Research Participants , 4(3) AM. J. BIOETHICS 44 (2004); see also Rebecca Dresser, First-in-Human Trial Participants: Not a Vulnerable Population, But Vulnerable Nonetheless , 37 J.L. MED . & ETHICS 38 (2009). 68 See Jerry A. MENIKOFF WITH EDWARD P. RICHARDS , WHAT THE DOCTOR DIDN ’T SAY : THE HIDDEN TRUTH ABOUT MEDICAL RESEARCH (2006); see also King 2005, supra note 54. 69 See sources cited supra note 54; see also Kevin P. Weinfurt et al., Expectation of Benefit in Early Phase Clinical Trials: Implications for Assessing the Adequacy of Informed Consent , 28 MED . DECISION MAKING 575 (2008). 70 See BARUCH BRODY , THE ETHICS OF BIOMEDICAL RESEARCH : AN INTERNATIONAL PERSPECTIVE (Oxford U. Press 1998); King & Cohen-Haguenauer, supra note 55. 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 230

B. THE FIRST SUBJECTS

Regenerative medicine research, at least as practiced at Wake Forest Institute of Regenerative Medicine, has distinguished itself by the care and caution with which decisions have been made about when to begin human studies. Safety is paramount in first-in-human trials. Yet, when the first human subjects are patients with the disease or condition of interest, as is necessarily the case in regenerative medicine research, it is especially challenging to protect subjects from harm if the intervention is both uncertain and potentially irrevocable. This combination is by no means unique to regenerative medicine research, or even to research at all. Many medical treatment decisions similarly involve standard treatments of uncertain efficacy and high risk that require irrevocable decisions. 71 Certainly, however, the issues raised by these extremely difficult decisions arise even more starkly in the regenerative medicine research context, where what is uncertain and unknown may be more apparent than in standard treatment. Patient-subjects, whether seriously injured, terminally ill, moderately disabled, or chronically impaired, must weigh the likelihood that an experimental or standard intervention may be inefficacious or harmful, and compare experimental and standard apples and oranges, on a regular basis. 72 Organ regeneration research resembles surgical research, in that it often must necessarily offer a prospect of direct benefit to patient-subjects in order to be justifiable. 73 Surgery’s clinical research tradition is relatively weak, since surgical innovation has historically

71 The ongoing course of decision-making about treatment for advanced or difficult- to-treat cancers is one familiar example; similarly, decision-making about surgical repair and rehabilitation in traumatic injury is another. See, e.g., A DEATH RETOLD : JESICA SANTILLAN , THE BUNGLED TRANSPLANT , AND THE PARADOXES OF MEDICAL CITIZENSHIP (Keith Wailoo, Julie Livingston, & Peter Guarnaccia eds., 2006). Media sensations like face transplantation and the artificial heart are by no means the only examples. Most organ transplantation falls into this category of difficult decisions. 72 In oncology, it is common to present patients with a range of choices, including both standard treatment and enrollment in research protocols, at a meeting called an “options interview.” See generally Elisa J. Gordon & Christopher K. Daugherty, ‘Hitting You Over the Head’: Oncologists’ Disclosure of Prognosis to Advanced Cancer Patients , 17 BIOETHICS 142 (2003). 73 This is why research protocols that include sham surgery arms have been so controversial. See, e.g., Sam Horng & Franklin G. Miller, Ethical Framework for the Use of Sham Procedures in Clinical Trials , 31 CRITICAL CARE MED . S126 (2003); see also Larry R. Churchill et al ., Assessing Benefits in Clinical Research: Why Diversity in Benefit Assessment Can Be Risky , IRB: ETHICS & HUMAN RES ., May-June 2003, at 1 (2003) (on the perceived need to offer direct benefit to research subjects in early phase trials). 231 WAKE FOREST INTELL . PROP . L.J. Vol.9

not been viewed as research. 74 This perspective is changing, however, 75 in part because of regenerative medicine research. The goals of first-in-humans research in regenerative medicine are both to minimize risks of harm and to maximize potential efficacy. 76 In regenerative medicine research, therefore, it will be difficult to maintain the distinction between research and treatment, and to reduce the likelihood that either subjects or investigators fall prey to the therapeutic misconception. 77 The urgency of research progress may pose risks of conflict of interest in at least two ways: research may move forward too quickly when (1) research sponsors have financial stakes in the success of the field, 78 and (2) when investigators are true believers in what is yet unproven. 79 Finally, when catastrophic illness or injury defines the subject population, as in the spinal cord study, narrow temporal decision making windows may adversely affect understanding and consent. This has been an issue in emergency research, 80 and might also be the case for limb regeneration research focusing on civilian and military combat injuries. 81

74 See generally Nancy M. P. King, The Line Between Clinical Innovation and Human Experimentation , 32 SETON HALL L. REV . 573 (2002). 75 See id. 76 The potential efficacy in early studies will nonetheless remain limited and uncertain. See generally Jonathan Kimmelman, The Therapeutic Misconception at 25: Treatment, Research, and Confusion , HASTINGS CENTER REP ., Nov.-Dec. 2007,at 36; Mildred K. Cho & David Magnus, Therapeutic Misconception and Stem Cell Research, NATURE REPORTS STEM CELLS , Sept. 27, 2007, available at http://www.nature.com/stemcells/2007/0709/070927/full/stemcells.2007.88.html. 77 See generally Cho & Magnus, supra note 76; Ricki Lewis, Stem Cells and Genetic Testing: The Gap Between Science and Society Widens, 8(4) AM. J. BIOETHICS , Apr. 2008, at 1; see also sources cited supra note 54. 78 See, e.g., Robin Fretwell Wilson, Estate of Gelsinger v. Trustees of University of Pennsylvania : Money, Prestige, and Conflicts of Interest in Human Subjects Research, in HEALTH LAW AND BIOETHICS : CASES IN CONTEXT 229 (2009). 79 See, e.g., Gail E. Henderson et al., Uncertain Benefit: Investigators’ Views and Communications in Early Phase Gene Transfer Trials , 10 M OLECULAR THERAPY 225 (2004); Miller, supra note 54; Annas, supra note 54. 80 See CTR . FOR DRUG EVALUATION & RES ., FOOD & DRUG ADMIN ., GUIDANCE FOR INSTITUTIONAL REVIEW BOARDS , CLINICAL INVESTIGATORS , AND SPONSORS : EXCEPTION FROM INFORMED CONSENT REQUIREMENTS FOR EMERGENCY RESEARCH (2006), http://www.fda.gov/RegulatoryInformation/Guidances/ucm127635.htm.; see also Ken Kipnis, Nancy M.P. King & Robert M. Nelson, Trials and Errors: Barriers to Oversight of Emergency Research , 28(2) IRB: E THICS & H UMAN RES ., Mar.-Apr. 2006, at 16 (highlighting the controversial nature of the exception). 81 Press Release. U.S. Dept. of Defense, New Armed Forces Institute for Regenerative Medicine to Lead Way in Caring for Wounded (Apr. 17, 2008), available at http://www.defenselink.mil/releases/release.aspx?releaseid=11842. 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 232

C. INFORMED CONSENT

Familiar questions of information and consent in early-phase research arise in regenerative medicine research as well. They include, as already mentioned, the challenges of discussing uncertainty, especially when potential subjects believe they have no other viable choices. For organ and tissue regeneration research, discussion of available alternatives, the irrevocability of some decisions, and adverse consequences may be especially difficult, especially when the science appears exciting and full of promise to investigators and potential subjects alike. This is a well-recognized problem in other early-phase research, including oncology research, gene transfer, and even face transplantation. 82 Notably, the caution and care with which organ and tissue regeneration research has been conducted to date has shown that the therapeutic misconception is not inevitable. Decision-making about research participation, however, is difficult nonetheless. Limb regeneration research is a novel instance of the decision-making challenges that arise routinely in trauma care. Trauma patients often face difficult and irrevocable choices: between amputation and attempting limb preservation, between different approaches to amputation that match with differences in the number and type of reconstructive surgeries needed, different limb prostheses with different mechanisms and functional capacities, different rehabilitation regimens with different potential, and so forth. The consequences of initial decisions are often unpredictable, unforeseeable, and unchangeable. The addition of novel and uncertain treatment options complicates decision-making and consent even further, especially when innovation and improvisation rapidly change the context of every choice. Including limb regeneration research compounds the difficulties of this dynamic decision matrix, especially if early and rapid decision-making about research participation is necessary. Choosing between enrollment in an experimental limb regeneration protocol and embarking on a more established, but constantly changing, course of attempted limb preservation and repair, or amputation and prosthetics, is not easy. Careful consideration of

82 See W. Y. Cheung et al., The Quality of Informed Consent Forms for Oncology Clinical Trials , 26 J. CLINICAL ONCOLOGY (S UPPLEMENT ) 6544 (2008); J. Kimmelman & N. Palmour, Therapeutic Optimism in Consent Forms for Phase I Gene Transfer Trials: An Empirical Analysis , 31 J. MED . ETHICS 209 (2005); Osborne P. Wiggins et al., On the Ethics of Facial Transplant Research, 4 AM. J. BIOETHICS 1 (2004); Laurie Barclay, First Face Transplant Raises Ethical Issues , Medscape Med. News, Dec. 16, 2005, ttp://www.medscape.com/viewarticle/520031; see also sources cited supra note 54. 233 WAKE FOREST INTELL . PROP . L.J. Vol.9

informed decision-making as an ongoing collaborative process, based in an ethically robust researcher-subject relationship, is essential. 83 This leads to a final point about informed consent in research: the often-neglected discussion of what it really means to be a subject, especially in early-phase research involving novel biotechnologies. Many research subjects who are also patients are allowed or even encouraged to see themselves as patients only–that is, to focus only on the potential for direct benefit from research participation. As a result, the requirements and burdens of long-term follow-up may not be emphasized or even discussed in the consent process. 84 Some study teams assume that this focus is necessary to ensure adequate enrollment. 85 Many novel biotechnological interventions, however, must be followed for the life of the patient-subject in order to gather much-needed information about their real benefits and harms over time. Life-long follow-up may be especially necessary for regenerative medicine interventions, which are intended, like many gene transfer interventions, to persist in the body over the long term. If the patient-subject’s role as subject is not described in detail—and not supported by the investigative team—then many subjects will be lost to follow-up, having viewed themselves as receiving treatment that is now completed. The development of a genuine investigator- subject partnership, in which the patient-subject’s contribution to knowledge is ongoing, is essential not only to the subject’s informed participation but also to successful research. While every research subject remains free to leave the research at any time, consistent with safety concerns, 86 such partnerships make it possible for subjects to make knowledgeable choices about leaving or staying.

83 See Nancy M. P. King et al., Introduction: Relationships in Research: A New Paradigm in BEYOND REGULATIONS : ETHICS IN HUMAN SUBJECTS RESEARCH 8 (Nancy M. P. King, Gail E. Henderson & Jane Stein eds., 1999) (“Respect for persons . . . includes both respect for the choices of autonomous persons and protection of the rights, needs, and interests of persons who lack the capacity to decide for themselves or have constraints upon their freedom of choice. This principle requires that the autonomy of subjects and potential subjects be supported in the informed consent process . . .”); Faden et al., supra note 11. 84 See OFFICE OF BIOTECHNOLOGY ACTIVITIES , supra note 61, at 6. 85 Variations on the statement “If we tell the truth, they won’t enroll!” are commonly heard in discussion sessions after bioethics scholars give informed consent talks to clinical researchers and study staff members. 86 General requirements for informed consent include: “A statement that participation is voluntary . . . and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.” 45 C.F.R. § 46.116(a)(8) (2008); see also OFFICE OF BIOTECHNOLOGY ACTIVITIES , supra note 61, at 16. 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 234

III. TREATMENT VERSUS ENHANCEMENT?

The last area for discussion is perhaps the most distinctive for regenerative medicine research: how regenerative medicine could change our understanding of the difference between treatment and enhancement. “Treatment” in medicine is generally understood as a restoration to the norm. 87 “Enhancement” is generally understood as deliberately intervening to exceed individual or population norms. 88 Enhancement has been widely discussed in contexts like lifespan extension and the alteration of individual characteristics like height, strength and endurance, or even behavior. 89 Of course, what is considered normal changes continually over time, making the distinction an inherently moving target. Some areas of research have uncovered a different but equally inevitable blurring of the distinction; for example, we seek to prevent, and even treat, disease by strengthening the immune system beyond that which is considered normal–that is, by means of enhancement. 90 The ideal of regenerative medicine, with its prospects for regeneration of perfectly tissue-matched organs, is in one respect a reflection of changing treatment norms—simply the next step in progress, for example, from dialysis to kidney transplantation to kidney regeneration. Yet the blurring of treatment and enhancement, while inevitable and in some respects uncontroversial, poses ethical challenges. 91 For instance, although success in regeneration of “matching” body parts can readily be assessed by comparison with the normal functioning of an original, it may be harder to assess or predict partial functioning in terms of efficacy in an imperfectly or

87 See Norman Daniels, Normal Functioning and the Treatment-Enhancement Distinction , 9 CAMBRIDGE Q. HEALTHCARE ETHICS 309 (2000). 88 Id. 89 See , e.g. , Eric T. Juengst et al., Biogerontology , “ Anti-Aging Medicine, ” and the Challenges of Human Enhancement , 33(4) HASTINGS CENTER REP ., July-Aug. 2003, at 21; Peter J. Whitehouse et al ., Enhancing Cognition in the Intellectually Intact , 27(3) HASTINGS CENTER REP ., May-June 1997, at 14; see also Nancy M.P. King & Richard Robeson, Athlete or Guinea Pig? Sports and Enhancement Research , 1 STUD. ETHICS L. & TECH . 1 (2007) , available at http://www.bepress.com/selt/vol1/iss1/art1/ (the inaugural issue of this journal is dedicated exclusively to human enhancement through genetic engineering and features articles from a range of viewpoints). 90 Eric T. Juengst, Can Enhancement Be Distinguished from Prevention in Genetic Medicine? , 22 J. MED . PHIL . 125 (1997). 91 See , e.g., Maxwell J. Mehlman & Jessica W. Berg, Human Subjects Protections in Biomedical Enhancement Research: Assessing Risk and Benefit and Obtaining Informed Consent , 36 J. L. MED . ETHICS 546 (2008); Sarah Chan & John Harris, Cognitive Regeneration or Enhancement: The Ethical Issues , 1 REGENERATIVE MED . 361 (2006). 235 WAKE FOREST INTELL . PROP . L.J. Vol.9

incompletely regenerated organ or limb than in conventional replacement or repair. 92 Thus, at least in early-phase research, it may be hard to provide information for potential subjects that can help them to compare partial success in research and in conventional treatment. An exogenously grown kidney can perhaps be tested, to a limited extent, before implantation. Will incomplete endogenous stimulation of healthy cell growth result in partial kidney function? An attempted surgical repair of an injured hand may gain the patient sufficient partial function, or require later amputation. Will a partially successful regeneration be functional at all? 93 Once again, questions like these are common to novel technologies in their early stages. For example, every phase I dose escalation study involving a biologic agent must confront profound uncertainties about the dose-response relationship. The dose-response curve is fairly well understood for many pharmacologic agents, where higher doses are more likely to do both good and harm. 94 However, cancer chemotherapy research has shown us that more toxicity is not always paired with greater efficacy. 95 Potential harms and benefits at different doses are even more different for biologics, where there may be no expectation that higher doses will be more effective, or lower doses safer. Every new agent may have a new dose-response curve, such as the “elbows” or “thresholds” seen in some gene transfer research, whereby all doses are equally without effect below a certain level, and toxicities move from minimal to profound with small

92 In regenerative medicine, there is the unusual expectation that maximum benefit may not be derived for months to years after a procedure is done. 93 Id. Given the expectation that there will be considerable ongoing maturation of the implanted organ, getting good predictors of outcome will be a slow process. Thus, the pace of rehabilitation hoped for by patient-subjects, and the time points at which success will be measured by investigators, may not coincide. 94 See, e.g. , Edward V. Flynn, Pharmacodynamic and Pharmacokinetic Principles of Pharmacology and Gene Therapy , 27 J. NEUROLOGIC PHYSICAL THERAPY 93, 94-95 (2003); King & Cohen-Haguenauer, supra note 55, at 436. 95 To cite one well-known example, despite a media furor and much litigation against health insurance companies for denying coverage for this experimental procedure, high-dose chemotherapy combined with autologous stem cell transplant has not been shown to be more beneficial for treatment of high risk breast cancer patients than standard chemotherapy regimens, though the former is far more toxic. See Cynthia M. Farquhar et al., High Dose Chemotherapy for Poor Prognosis Breast Cancer: Systematic Review & Meta-Analysis , 33 CANCER TREATMENT REVIEWS 325, 325-326, 335-36 (2007); DT Vogl & EA Stadtmauer, High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation for Metastatic Breast Cancer: A Therapy Whose Time Has Passed , 37 BONE MARROW TRANSPLANTATION 985, 985-87 (2006); see also Nancy M.P. King & Gail W. Henderson, Treatments of Last Resort: Informed Consent and the Diffusion of New Technology , 42 MERCER L. REV . 1007, 1014 n. 39; 1021 n. 77 (1991). 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 236

changes in dosage. 96 Nonetheless, the way this issue arises in regenerative medicine research is somewhat distinctive, again highlighting a familiar issue in a novel way. Finally, a more speculative but still significant ethical issue arises from considering not only individual research subjects but also the future of regenerative medicine technologies themselves. Returning to the larger ethical issues raised when new biotechnologies are introduced, we would do well to consider now some of the longer- term implications of success in regenerative medicine. As this area of research moves forward, it will inevitably create shifts in human norms, again and again. If cells, organs, and tissues become easier to replace, then humans may begin to take on the character of George Washington’s hatchet: 97 all new parts many times over. The relationship between treatment of disease, injury, and disability and enhancement in the form of life extension is thus raised by the “piecemeal” application of regenerative medicine. But the same relationship is also implicated by the obvious next step: from George Washington’s hatchet to the human salamander. 98 Mastery of the mechanisms of regeneration at the level not of the organ but of the organism presents the same questions about life extension and the alteration of human norms. 99 When medical science can readily

96 After the death of Jesse Gelsinger, the investigator, James Wilson, told the Recombinant DNA Advisory Committee that he had not anticipated the shape of the dose-response curve that appeared in the study, which he described as an “elbow.” “Asked what he would have done differently, Wilson replied, ‘Including not having done this at all, the trial could have been designed differently [with respect to] the half-log increments. The increments should be smaller.’ He noted that the dose- toxicity relationship appeared to be ‘elbow shaped’ and that at the half-log increment the difference in dosage between the later cohorts is significantly greater than that between the earlier ones and ‘may be breaching that elbow.’ A RAC member agreed that there appeared to be a narrow window between early and severe toxicity, requiring meticulous measures.’” Fran Pollner, Gene Therapy Trial and Errors Raise Scientific, Ethical, and Oversight Questions , NIH CATALYST , Jan-Feb 2000, at 7, available at http://www.nih.gov/catalyst/2000/00.01.01/page1.html. See also Wilson, supra note 78. 97 See James Baldwin, George Washington and His Hatchet, in FIFTY FAMOUS STORIES RETOLD (2005) (summarizing the story on which the analogy is based). 98 See , e.g. , Wyatt Andrews, Medicine’s Cutting Edge: Re-Growing Organs , CBSNews.com, Mar. 23, 2008, http://www.cbsnews.com/stories/2008/03/22/sunday/main3960219.shtml#; Salamanders Regrow Lost Limbs, Could Human Medicine Benefit from Understanding Regeneration , SCIENCE DAILY , Apr. 1, 2007, http://www.sciencedaily.com/releases/2007/03/070330111307.htm; Larry Shaughnessy, Salamander Therapy May Aid Injured Vets , CNN.com, May 27, 2008, http://www.cnn.com/2008/HEALTH/05/26/regrowing.body.parts/index.html. 99 See H. TRISTRAM ENGELHARDT , REGENERATIVE MEDICINE AFTER HUMANISM : PUZZLES REGARDING THE USE OF EMBRYONIC STEM CELLS , GERM -LINE GENETIC 237 WAKE FOREST INTELL . PROP . L.J. Vol.9

stimulate regrowth of cells, tissues, and organs in humans, then we may have permanently altered not just human norms but humanity itself. In this respect, regenerative medicine research is one of the premier components of so-called “anti-aging medicine” 100 –a topic of considerable interest, profound controversy, and lively debate, now and for a long time to come.

IV. CONCLUSION

Regenerative medicine is a broad, complex, nuanced, and potentially groundbreaking area of research. It is not necessary, or necessarily helpful, to invent novel ethical issues or to exaggerate the novelty of ethical issues as applied to the new biotechnologies that regenerative medicine investigates. It is instead essential to acknowledge the persistence of fundamental issues of long standing: the nature of the medical research enterprise, the relationships between researchers and patients who are research subjects, and how medical research and medical practice complement and reshape each other in contemporary society. It is also worth noting that new technologies and new research designs are often presented as obviating some of these persistent ethical issues, but generally fail to achieve that goal. An ethics and policy framework for further consideration of ethical issues in regenerative medicine research should include the following “points to consider:” • Regenerative medicine research raises ethical issues in common with other first-in-human studies. • Regenerative medicine research raises ethical issues in common with other clinical trials enrolling patients as research subjects. • Regenerative medicine research raises ethical issues related to trial design, which should be considered as important as the ethical issues related to protecting the rights and welfare of human subjects. • Regenerative medicine research raises ethical issues related to financial and nonfinancial conflicts of interest. • Regenerative medicine research, like other new and costly medical technologies, raises ethical issues related to cost and access, including the role of public-private partnerships, venture capital, and intellectual property considerations.

ENGINEERING , AND THE IMMANENT PURSUIT OF HUMAN FLOURISHING , THE BIOETHICS OF REGENERATIVE MEDICINE (Springer Netherlands 2008). 100 Nicholas Wade, The Stem Cell Debate: Apostle of Regenerative Medicine Foresees Longer Health and Life , N.Y. TIMES , Dec. 18, 2001, at F5 (interview with William Haseltine); see also Juengst et al., supra note 89. 2009 ETHICAL ISSUES IN REGENERATIVE MEDICINE 238

Regenerative medicine research thus provides scholars and policymakers in bioethics and law with a fresh opportunity to consider, discuss, and move forward on all these issues by examining them through the lens of this groundbreaking medical science.

WAKE FOREST INTELLECTUAL PROPERTY LAW JOURNAL

VOLUME 9 2008 - 2009 NUMBER 3

PATENT LAW AND REGENERATIVE MEDICINE : A CONSIDERATION OF THE CURRENT LAW AND PUBLIC POLICY CONCERNS REGARDING UPSTREAM PATENTS

⊗ Vincent J. Filliben III

INTRODUCTION

This article focuses on patentability issues concerning biotechnology, with specific emphasis on the status of patent law as it applies to regenerative medicine. The purpose of the article is to consider whether the United States’ protection of patents covering gene sequences and human embryonic stem cells is consistent with traditional patentability standards of patent law. In addition, the article provides an analysis of the impact and potential consequences of providing broad patent protection over what are, essentially, the building blocks of human life and essential keys to the progress of biotechnology. Part I provides a brief overview of biotechnology in general. This section notes the impressive advances that are currently developing and the exciting opportunities and growth the field of biotechnology promises. Furthermore, Part I introduces the somewhat controversial and recently upheld Wisconsin Alumni Research Foundation (“WARF”) patents which broadly cover the creation and use of embryonic stem cells. 1 This section briefly reflects on the

⊗ At the time of this Symposium, Vincent J. Filliben III served as Executive Articles Editor of the Wake Forest Intellectual Property Law Journal. He is now a practicing attorney in Winston-Salem, at The Law Offices of J. Darren Byers, P.A. 1 These controversial patents which have been embroiled in controversy for over two years include Patent 6,200,806, widely known as the “stem cell patent,” which claims a method of “isolating a . . . human embryonic stem cell line,” as well as the “purified preparation of . . . human embryonic stem cells.” Amy Rachel Davis, Patented Embryonic Stem Cells: The Quintessential “Essential Facility”? , 94 GEO . L.J. 205, 207 (2005). 240 WAKE FOREST INTELL . PROP . L.J. Vol.9

potentially adverse goals of the biotechnology industry: the societal goal of providing optimal and holistic healthcare and open sharing of knowledge versus the fiscal goal of investing in important research for commercial gain and protecting that commercial interest. Simply put, patents ensure that the inventor is granted a limited monopoly. After the monopoly period runs, other players in the market will be able to enter and utilize the technology to benefit society; patent owners can also recoup their investments in technology through licensing their patented inventions and processes to others in the field. However, the broad granting of upstream patents can result in prohibitive costs and prevent small biotechnology companies from entering the field, thereby potentially hindering the advance and availability of important inventions benefiting society. Part II analyzes the law regarding patents granted for living organisms and their building blocks like genes and stem cells. The analysis begins with an explanation of Diamond v. Chakrabarty , the first case to recognize that under 35 U.S.C. § 101 2 living organisms are indeed patentable. 3 Part II continues with a synopsis of the history of patent law regarding controversial gene patents—patents that seek to protect human DNA sequences responsible for forming proteins and other necessary building blocks of human life. Finally, Part II applies the United States Patent and Trademark Office’s treatment of gene patents to the future of patents like those held by WARF regarding human stem cells, the very tools regenerative medicine currently utilizes to attempt relative medical miracles. Part III considers the policy arguments against the issuance of broad patent protection with regard to genes and regenerative medicine. Additionally, this section outlines legislative attempts to regulate the issuance of upstream patents for inventions that are inherently part of human life, as well as several recommended approaches set forth by scholars to address biotechnology patents. Furthermore, Part III discusses the benefits and shortcomings of the advocated reforms and looks to the future of patent law as it affects the progress of the science of biotechnology and its potential benefits for society.

2 “Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement therefor, may obtain a patent therefore, subject to the conditions and requirements of this title.” 35 U.S.C. § 101 (2000). 3 Diamond v. Chakrabarty, 447 U.S. 303, 309 (1980). 2009 PATENT LAW AND REGENERATIVE MEDICINE 241

I. THE PROGRESS, PROMISE, AND POTENTIAL PITFALLS OF BIOTECHNOLOGY

Advances in the field of biotechnology seek to revolutionize humans’ ability to treat diseases and conditions in ways that years ago would have seemed impossible fantasies of science fiction. Today biotechnology is a multi-billion-dollar industry that has the potential to improve human life in significant ways. 4 From regenerating human tissue like fingers, or muscle tissue, to cultivating entire organs to be transplanted into humans, regenerative medicine promises just a few of the exciting developments in the field of biotechnology that await society. 5 Dr. Steven Badylak of the University of Pittsburgh’s McGowan Institute of Regenerative Medicine has reported using a powder made from pig bladders to “tell” the body to start the process of tissue re-growth of a human finger. 6 Perhaps even more impressive, Dr. Atala who is the head of the Wake Forest Institute of Regenerative Medicine has successfully grown tissues and organs, including human bladders cultivated in a lab from patients’ own cells, which were then successfully transplanted into those patients. 7 Other efforts in the regenerative medicine field include clinical trials that attempt to grow new arteries to supply the heart with blood by injecting a patient’s stem cells into her heart, an experiment that, if successful, would substantially limit the need for actual open-heart surgery. 8 In addition, advances in gene therapy and the mapping of the human genome have led to a multitude of medical and technological

4 See , e.g. , Press Release, Wake Forest University Baptist Medical Center , Wake Forest Baptist’s Selection to Co-Lead Regenerative Medicine Project Will Increase Activity at Piedmont Triad Research Park , (Apr. 17, 2008), http://www.wfubmc.edu/news/newsprintfriendly.htm?ArticleID=2349. Tens of millions of dollars have been invested in research projects like Wake Forest University Baptist Medical Center’s project for regenerative medicine. Id. Eighty- five million dollars in federal funds has been provided by the Armed Forces Institute for Regenerative Medicine (“AFIRM”). Id. These funds will supplement close to the two hundred million dollars raised by Wake Forest’s consortium of partners who have pledged funds for regenerative medicine projects in the region. Id. 5 Wyatt Andrews, Medicine’s Cutting Edge: Re-Growing Organs , Mar. 23, 2008, CBS News, http://www.cbsnews.com/stories/2008/03/22/sunday/ printable3960219.shtml. 6 Id. The McGowan Institute has also recently patented technology for providing a platform for bone and tooth engineering and repair applications and in gene delivery. U.S. Patent No. 7,247,288 (filed Jul. 24, 2007). 7 Press Release, Wake Forest University Baptist Medical Center, Wake Forest Physician Reports First Human Recipients of Laboratory-Grown Organs , (Apr. 3, 2006), http://www1.wfubmc.edu/News/NewsARticle.htm?ArticleID=1821. 8 See Andrews, supra note 5. 242 WAKE FOREST INTELL . PROP . L.J. Vol.9

advances that have significantly benefited society. Through the successful efforts of the Human Genome Project to identify the sequence of the human genome, scientists are now capable of identifying all human genes by their DNA sequence. 9 This capability creates a number of “opportunities for genetic intervention that include medical therapy (gene therapy), diagnostic screening for diseases (genetic testing), and large-scale production of medically-relevant purified proteins.” 10 In order to facilitate and stimulate research and development in the field of biotechnology, the U.S. Patent and Trademark Office has been quite liberal in its consideration of broad patents in the field of biotechnology. Faced with the pressure of attracting biotechnology investment to advance the domestic biotechnology industry, patent protection has increased, arguably at the expense of moral and ethical considerations and possibly to the disadvantage of progress in the field. 11 Patents have been awarded to protect necessary tools for the development and progress of biotechnology like gene sequences and human embryonic stem cells. As a result, downstream technologies may be prohibited from entering the market due to upstream patent holders setting up ‘tollbooths’ of high bargaining costs and licensing fees which arguably slow the pace of innovation. 12

9 Laurie L. Hill, The Race to Patent the Genome: Free Riders, Hold Ups, and the Future of Medical Breakthroughs , 11 TEX . INTELL . PROP . L.J. 221, 226 (2003). 10 Id. Gene therapy consists of replacing a malfunctioning gene with a functional gene. Id. This process enables scientists and researchers to explore new avenues for treating diseases that were once thought to be untreatable or intractable. Id. Genetic testing enables screening of individuals for genetic predispositions to specific diseases. Id. at 228. This field helps predict future risks, permit early intervention, and design patient-specific therapies. Id. Finally, purified protein production creates a stockpile of biologically functional proteins that can be used to treat disease and other disorders. Id. 11 See, e.g. , Michael A. Heller & Rebecca S. Eisenberg, Can Patents Deter Innovation? The Anticommons in Biomedical Research , 280 SCI . 698, 698 (1998) (warning of “the tragedy of the anticommons” where “a proliferation of intellectual property rights upstream may be stifling life-saving innovations further downstream in the course of research and product development”). A counterpoint to this argument is the reality that encouraging patent filing ensures the full disclosure that is required for patentability. Without patents in this field, those who would have only held a limited monopoly through a patent for a set period of time might keep their discovery undisclosed through the use of trade secret protection. This could potentially have a devastating effect on the free dissemination of research and discovery in the field of biotechnology; one that would rival the tragedy of the anticommons that Professors Heller and Eisenberg describe. 12 Gregory C. Ellis, Emerging Biotechnologies Demand Defeat of Proposed Legislation That Attempts to Ban Gene Patents , 15 RICH . J.L. & TECH . 1, 18 (2008) (citing Linda J. Demaine & Aaron Xavier Fellmeth, Reinventing the Double Helix: A 2009 PATENT LAW AND REGENERATIVE MEDICINE 243

The recent decision to uphold the WARF patents, covering three broad patents relating to embryonic stem cell research, potentially creates one such tollbooth. 13 These patents “broadly cover the preparation of embryonic stem cells, which are the basic material from which virtually all organs, cells and other body tissues are formed.” 14 According to Tom Still, president of the Wisconsin Technology Council, the Patent Office’s decision “secures the WARF intellectual property and secures WARF’s place as a must-visit stop for people interested in stem cell technology.” 15 Adding to the controversy of these patents, Geron Corporation, a leader in the development of human embryonic stem cell-based therapeutics, holds an exclusive licensing agreement under these patents “to develop and commercialize therapies based on the three types of cells derived from human embryonic stem cells: neural cells, cardiomyocytes and pancreatic islet cells.” 16 Though WARF has “adopted a policy of making [embryonic stem cells] widely available to non-profit researchers and granting non-exclusive licenses to firms pursuing commercial development of [embryonic stem cells],” Geron’s exclusive contract to the three types of stem cells mentioned creates a potential dilemma for the advance of research requiring embryonic stem cells. 17 Geron has merely indicated that it will entertain licensing offers from commercial researchers, and its position as a large corporate entity might afford it the opportunity to refrain from licensing its cells, “forfeiting millions of dollars in royalties . . . [but] holding out for billions of dollars in profits . . . [once the company] finds its first groundbreaking cure.” 18 The implications of granting patents over such critical research tools are a major concern and the resulting public policy considerations are further developed in Part III. First, Part II will explore the statutory hurdles found in 35 U.S.C. §§ 101, 102, and 103,

Novel and Nonobvious Reconceptualization of the Biotechnology Patent , 55 STAN . L. REV . 303, 418 (2002)). 13 These include U.S. Patent No. 5,843,780 (filed Jan. 18, 1996), U.S. Patent No. 6,200,806 (filed Jun.26, 1998), and U.S. Patent No. 7,029,913 (filed Oct. 18, 2001). 14 Kathleen Gallagher, U.S. Office Upholds Embryonic Stem Cell Patents , MILWAUKEE JOURNAL SENTINEL , June 27 2008, at D1, available at http://www.jsonline.com/business/29551579.html. 15 Id. 16 Press Release, U.S. Patent Office Upholds Key Human Embryonic Stem Cell Patent , Feb. 28, 2008, REUTERS , http://www.reuters.com/article/pressRelease/ idUS144413+28-Feb-2008+BW20080228 (last visited Dec. 17, 2008). 17 Davis, supra note 1, at 210 n.21. 18 Id. at 210. Admittedly, this would amount to a significant gamble on the part of Geron; however, the possibility remains that a company could at least theoretically use their patent in such a way. 244 WAKE FOREST INTELL . PROP . L.J. Vol.9

and their application with regard to gene patents, embryonic stem cells and the future of biotechnology and regenerative medicine.

II. THE PATENTABILITY, UTILITY, AND NON- OBVIOUSNESS OF REGENERATIVE MEDICINE THROUGH THE LENS OF GENE PATENTS

The United States Constitution grants Congress the power “[t]o promote the Progress of Science and useful Arts, by securing for limited Times to Authors and Inventors the exclusive Right to their respective Writings and Discoveries.” 19 The underlying purpose of the Patent Clause is to promote a balance between encouraging innovation and avoiding stifling competition by awarding monopolies. In achieving this end, the current federal law permits patents to provide for monopolies for a limited time of about twenty-years. In return, a patentee is required to specifically describe the invention, and the manner and process for making and using the invention “in such full, clear, concise, and exact terms as to enable any person skilled in the art” to make and use the claimed invention. 20

A. 35 U.S. § 101—“P ATENTABLE SUBJECT MATTER ” AND “U SEFULNESS ” STANDARDS AS APPLIED TO GENE PATENTS AND REGENERATIVE MEDICINE

Once a claimed patent fulfills the requirements of specificity and exactness required by 35 U.S.C. § 112, it must overcome the hurdles of §§ 101, 102, and 103. The first hurdle, 35 U.S.C. § 101, describes what qualifies as patentable statutory subject matter under the statute. The statute states that: “[w]hoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefore, subject to the conditions and requirements of this title.” 21 Generally, three areas do not qualify as patentable: (1) natural laws, (2) phenomena of nature, and (3) abstract principles (i.e., algorithms). 22 Thus, the question regarding the patentability of

19 U.S. CONST . art. I, § 8, cl. 8. 20 35 U.S.C. § 112 (2006). It should be noted that in addition to meeting the statutory hurdles of §§ 101, 102 and 103, those seeking a patent must also satisfy the requirements of the “enablement doctrine” codified in § 112. It is this principle of patent law that provides for the full disclosure that is the consideration for granting a limited monopoly in the first place. 21 35 U.S.C. § 101 (2006). 22 See Parker v. Flook, 437 U.S. 584 (1977); Gottschalk v. Benson, 409 U.S. 63 (1972). 2009 PATENT LAW AND REGENERATIVE MEDICINE 245

regenerative medicine is dependent upon whether patenting something like stem cells or genes, which occur in nature, are un-patentable phenomena of nature. In a landmark case, Diamond v. Chakrabarty , the Supreme Court considered whether a human-made, genetically-engineered bacterium capable of breaking down crude oil, a property which is not possessed by any naturally-occurring bacteria, is patentable under § 101. 23 Originally, the patent examiner’s rejection of the patent applicant’s claims was affirmed by the Patent Office Board of Appeals on the ground that living things are not patentable subject matter under § 101. 24 The Court of Customs and Patent Appeals reversed, concluding that the fact that microorganisms are alive lacks legal significance. 25 The Supreme Court affirmed, holding that a live, human-made microorganism is patentable and that it constitutes a “manufacture” or “composition of matter” under the statute. 26 In reaching its decision, the Court took note of the legislative history regarding the 1930 Plant Patent Act. 27 The Court noted that Congress “recognized that the relevant distinction was not between living and inanimate things, but between products of nature, whether living or not, and human-made inventions.” Thus, the Court found that respondent’s microorganism, though living, was the result of human ingenuity and research. 28 Furthermore, the Court rejected The Commissioner of Patents’ argument that microorganisms could not qualify as patentable subject matter until Congress expressly authorized such protection. 29 The Commissioner warned that the legislative process was best equipped

23 See Diamond v. Chakrabarty, 447 U.S. 303, 305 (1980). 24 Id. at 306. The patent examiner rejected the claims for bacteria, stating (1) that microorganisms are “products of nature,” and (2) that as living things they are not patentable subject matter under 35 U.S.C. § 101. Id. The Patent Office Board of Appeals relied on the legislative history of the 1930 Plant Act in affirming the rejection of the patent examiner. Id. The Board concluded that the bacteria were not “products of nature” because they were not naturally occurring, but nonetheless concluded that § 101 was not intended to cover living things. Id. at n.3. 25 Id. 26 Id. at 309-10 (stating that “[r]espondent’s micro-organism plainly qualifies as patentable subject matter. His claim is not to a hitherto unknown natural phenomenon, but to a nonnaturally occurring manufacture or composition of matter—a product of human ingenuity ‘having a distinctive name, character [and] use.’”) (citation omitted). 27 Id. at 311. The Court explained that, prior to 1930, two factors were relevant in excluding plants from patent protection: (1) the belief that plants were products of nature and (2) that plants were thought not amenable to written description. Id. at 311-12. 28 Id . at 313. 29 Id. at 314. 246 WAKE FOREST INTELL . PROP . L.J. Vol.9

to weigh the competing economic, social and scientific considerations regarding “whether living organisms produced by genetic engineering should receive patent protection.” 30 However, the Court rejected these arguments and the foreboding warnings of the implications of granting patent protection to such genetic research, finding it was the legislature’s job to consider the policy, while the Court’s job is the narrow task of determining what Congress meant by the words Congress used in the statute. 31 Thus, the Court interpreted the statutory language to protect respondent’s invention and advised that Congress was free to amend § 101 to exclude from patent protection organisms produced by genetic engineering as it saw fit. 32 Congress did no such thing and because of the judicial acceptance, demonstrated by the Chakrabarty case, a number of patents relating to biotechnology, including gene patents, and most recently, patents for developing human embryonic stem cells, have been found to be valid. Critics of gene patents have asserted that genes are “products of nature” and, therefore, are not patentable, echoing the original criticisms against the patent issued in Chakrabarty .33 Today, despite these criticisms, the relaxed standard of Chakrabarty has extended from genetically modified microorganisms to the U.S. Patent and Trademark Office’s (“USTPO”) recognition of purified DNA sequences as patentable subject matter. 34 In 2001, the USTPO published a revised version of guidelines for office personnel in their review of patent applications for compliance with the “utility” requirements of 35 U.S.C. § 101. 35 This revision was published in response to numerous comments urging that genes are discoveries rather than inventions, thereby suggesting that patents should not be issued for genes. 36 The USTPO looked to the Patent Clause and the relevant statute in determining that “an inventor’s discovery of a gene can be the basis for a patent on the genetic composition isolated from its natural state and processed through purifying steps that separate the gene from other molecules naturally associated with it.” 37 In response to concerns that genes are not a new composition of matter because they exist in nature, the

30 Id at 314 . The Petitioner further points to the grave risks that may be generated by research endeavors such as respondent’s. Id. at 316. 31 Id . at 318. 32 Id. According to the Court’s interpretation of the statutory language, “Congress intended statutory subject matter to include anything under the sun that is made by man.” Id. at 309 (citation omitted). 33 Ellis, supra , note 12, at 12. 34 See Utility Examination Guidelines, 66 Fed. Reg. 1092, 1095 (Jan. 5, 2001). 35 Id. at 1092. 36 Id. at 1093. 37 Id. 2009 PATENT LAW AND REGENERATIVE MEDICINE 247

USPTO observed that “synthetic DNA preparations are eligible for patents because their purified state is different from the naturally occurring compound.” 38 This reaffirmed principles set out in legislative history and judicial precedent, upholding the granting of patents to chemical compounds, hormones, and other naturally occurring phenomena that did not occur in an isolated form in nature. 39 This principle can be applied to the WARF patents for embryonic stem cells since the patents cover all purified preparations of isolated stem cells matching the patents’ descriptions, making these inventions patentable statutory subject matter under § 101. 40 Despite being found to be patentable under § 101, the claimed invention must also satisfy the “utility” requirement of the statute. Prior to the issuance of the revised Guidelines it was relatively unclear what degree of disclosure was necessary to satisfy the utility requirement, and further, how broad disclosure affected previously unconsidered applications. 41 For example, in 1992, Dr. Craig Ventner applied for gene patents covering expressed sequence tags, short segments of DNA that represent portions of expressed genes that could be useful in mapping which DNA sequences are protein-coding genes. 42 Though Ventner eventually applied for patents for these sequences citing their utility to diagnose genetic disorders, the USPTO denied his applications, implying that “simply finding a gene sequence without an established utility does not merit patent protection.” 43 The issue of undiscovered uses for genes not disclosed in gene patents raises an even larger and more complex issue. 44 In 1995, the Human Genome Sciences (“HGS”) filed an application for a gene known as HDGNR10, citing generic claims that the gene was useful

38 Id. 39 See , e.g. , Parke-Davis & Co. v. H.K. Mulford Co., 189 F. 95, 103 (S.D.N.Y. 1911) (holding that adrenaline removed from the gland in which it was found was patentable where it became a new thing commercially and therapeutically); In re Bergstrom, 427 F.2d 1394, 1397 (CCPA 1970) (holding purified compounds that do not exist in nature in pure form are patentable). See also Amgen, Inc. v. Chugai Pharm. Co., Ltd., 927 F.2d 1200, 1206 (1991). Amgen established the “human intervention” standard that the U.S. Court of Appeals observes in upholding the patentability of human DNA sequences in their purified and isolated form. Donna M. Gitter, International Conflicts Over Patenting Human DNA Sequences In the United States and the European Union: An Argument For Compulsory Licensing and a Fair-Use Exemption , 76 N.Y.U. L. REV . 1623, 1642 (2001) (citing Amgen , 927 F.2d 1200 (1991)). 40 Davis, supra note 1, at 219. 41 Ellis, supra note 12, at 16-22. 42 Id. at 17 (citation omitted). 43 Id. (citation omitted). 44 Id. at 18. 248 WAKE FOREST INTELL . PROP . L.J. Vol.9

for “‘identifying [receptor] antagonists and agonists.’”45 Unbeknownst to HGS and discovered just a year later by the National Institutes of Health (“NIH”) was the fact “that the protein encoded by the gene, named CCR5 by the NIH scientists, was . . . a receptor essential for HIV infection.” 46 Thus, despite being unaware of the true utility of its patent, HGS ultimately enjoys the exclusive right to license and patent the CCR5 protein to companies attempting to develop an HIV vaccine, based merely on its generic and broadly stated patent. 47 In addressing these issues, the USPTO added in its revisions regarding gene patents that “[when] the inventor also discloses how to use the purified gene isolated from its natural state, the application satisfies the ‘utility’ requirement.” 48 In disclosing “how to use” the claimed gene sequence, the patentee must meet three utility criteria: the utility must be specific, substantial and credible. 49 While the USTPO guidelines are not law, In re Fisher , a 2005 Federal Circuit decision, affirms the heightened utility guidelines. 50 In re Fisher concerned a claimed invention relating to five purified nucleic acid sequences and protein fragments in maize plants. 51 Like Ventner’s failed patent claim discussed above, Fisher’s claimed sequences were also expressed sequence tags or “ESTs.” 52 The patent examiner rejected claim one for lack of utility under § 101, finding that the disclosed uses were “not supported by a specific and substantial utility.” In reviewing the examiner’s decision, the Board focused on two claimed utilities: “(1) use for identification of polymorphisms; and (2) use as probes or as a source for primers.” 53 The Board concluded that the use of ESTs to isolate nucleic acid molecules of other plants and organisms which had no known utility is not a substantial utility. 54 The Board also held that the claimed sequence must provide some sort of teaching regarding how to use the data relating to gene expression observed using the ESTs.55

45 Id. at 18. See also U.S. Patent No. 6,025,154 (filed June 6, 1995). 46 Ellis, supra note 12, at 18. 47 Id. 48 Utility Examination Guidelines, 66 Fed. Reg. 1092, 1093 (Jan. 5, 2001). 49 Id. at 1092. 50 Ellis, supra note 12, at 22. 51 In re Fisher, 421 F.3d 1365, 1367 (2005). 52 Id. 53 Id. at 1368. 54 Id. at 1369. 55 Id. 2009 PATENT LAW AND REGENERATIVE MEDICINE 249

In explaining its reasoning, the Board relied on the Supreme Court’s decision in Brenner v. Manson in which the Court rejected a process for making a compound with no known use. 56 The Court of Customs and Patent Appeals, in considering the Board’s rejection of the patent, held that a patent application must contain disclosure which establishes a specific and substantial utility for the claimed invention. 57 Recognizing that the Supreme Court has not defined what the terms “specific” and “substantial” mean per se, the court explained that “substantial utility” has been used by the courts interchangeably with the labels “practical utility” and “real world” utility. 58 The court observed that these terms mean that one skilled in the art can use the claimed discovery in a manner that provides some “‘ immediate benefit to the public .’” 59 The court reasoned that this means that “an application must show that an invention is useful to the public as disclosed in its current form, not that it may prove useful at some future date after further research.” 60 In considering the WARF Patent No. 6,200,806, covering primate embryonic stem cells, the utility function is clearly and concisely stated and, as stated, provides immediate benefits to society. 61 Specifically, the patent covering these human embryonic stem cells cites uses, such as “generating transgenic non-human primates for models of specific human genetic diseases,” as well as usage in “[t]issue transplantation.” 62 Thus, because the isolated and purified human stem cell does not occur naturally in its isolated form, and because the stated uses in the patent are specific and provide immediate benefit to the public, the WARF stem cell patent adequately satisfies the first prong of the three-hurdle analysis.

B. 35 U.S.C. §§ 102 AND 103—“N OVELTY ” AND “N ON -OBVIOUSNESS ” STANDARDS AS APPLIED TO GENE PATENTS AND REGENERATIVE MEDICINE

56 Id. (“Just as the process in Brenner lacked utility because the specification did not disclose how to use the end-product, the products claimed here lack utility, because even if used in gene expression assays, the specification does not disclose how to use SEQ ID NO: 1-5 specific gene expression data.” (citing Brenner v. Manson, No. 58, slip op. at 22 (U.S. March 21, 1966))). 57 In re Fisher, 421 F.3d 1365, 1371 (2005). 58 Id. 59 Id. (citing Nelson v. Bowler, 626 F.2d 853, 856 (C.C.P.A. 1980)). 60 Id. 61 U.S. Patent No. 6,200,806 (filed June 26, 1998) (issued Mar. 13, 2001). 62 Id. at col. 6 ll. 4-5, 14. 250 WAKE FOREST INTELL . PROP . L.J. Vol.9

After establishing under Title 35 of the United States Code (i.e. the Patent Act) that an invention is indeed patentable, statutory subject matter and that the invention has substantial utility in that it has immediate public benefit, one seeking a patent must next overcome the statutory hurdles set forth in 35 U.S.C. §§ 102 and 103. These provisions consider whether an invention seeking patent protection is “novel” and “non-obvious” respectively. 63 The Federal Circuit Court of Appeals considered these requirements in detail in the gene patent discussion set forth in Amgen, Inc. v. Chugai Pharmaceutical, Co., in 2001. 64 Amgen involved Erythropoietin (EPO), 65 a protein that stimulates the production of red blood cells. 66 EPO is commonly used as a therapeutic agent in the treatment of anemias or blood disorders stemming from low or defective bone marrow production of red blood cells. 67 Prior to the inventions claimed in this case, EPO was appropriated through the purification of urine from individuals exhibiting high EPO levels. 68 The new technology claimed in Amgen was a technique for producing EPO using “recombinant DNA technology in which EPO is produced from cell cultures into which genetically-engineered vectors containing the EPO gene have been introduced.” 69 The litigation in Amgen centered on two patents granted by the United States Patent and Trademark Office, U.S. Patent 4,677,195 entitled “Method for Purification of Erythropoietin and Erythropoietin Compositions,” issued June 30, 1987, and U.S. Patent 4,703,008 entitled “DNA Sequences Encoding Erythropoietin,” issued October 27, 1987. 70 Chugai claimed that their Dr. Fritsch “was first to conceive a probing strategy of using two sets of fully-degenerate cDNA probes of two different regions of the EPO gene to screen a g[enomic] DNA library, which was the strategy which the district court found eventually resulted in the successful identification and isolation of the EPO gene.” 71 Chugai further alleged that because Frisch conceived of the strategy in 1981 and “was diligent until he reduced the invention in May of 1984,” he should be considered a § 102(g) prior inventor over

63 35 U.S.C. §§ 102-03 (2008). 64 Amgen, Inc. v. Chugai Pharm., Co.,927 F.2d 1200, 1205-09 (Fed. Cir. 1991). 65 EPO is the performance enhancer American cyclist Lance Armstrong was accused of using in the Tour de France. 66 Amgen , 927 F.2d at 1203. 67 Id. 68 Id. 69 Id. 70 Id. 71 Id. at 1205. 2009 PATENT LAW AND REGENERATIVE MEDICINE 251

Amgen’s Dr. Lin “who reduced the invention to practice in September of 1983.” 72 To satisfy the “novelty” standard for obtaining a patent, the patentee must establish that the invention is in fact new and not “prior art.” Section 102(g)(2) of Title 35 provides in part that: A person is entitled to a patent unless— (g)(2) before such person’s invention thereof, the invention was made . . . by another who had not abandoned, suppressed, or concealed it. In determining priority of invention under this subsection, there shall be considered not only the respective dates of conception and reduction to practice of the invention, but also the reasonable diligence of one who was first to conceive and last to reduce to practice, from a time prior to conception by the other. 73 In Amgen , the court found that the pertinent subject matter was “the novel purified and isolated sequence which codes for EPO, and neither Fritsch nor Lin knew the structure or physical characteristics of it and had a viable method of obtaining that subject matter until it was actually obtained and characterized.”74 For Fritsch’s work to be considered prior art, his conception had to be “sufficiently specific that one skilled in the relevant art would succeed in cloning the EPO gene.” 75 In determining that Fritsch’s conception did not constitute prior art, the court reasoned that “conception of a generalized approach for screening a DNA library that might be used to identify and clone the EPO of then unknown constitution is not conception of a ‘purified and isolated DNA sequence’ encoding human EPO.” 76 According to the Amgen court’s reading of § 102, in order to claim that a purified and isolated gene, human embryonic stem cell, or protein is indeed novel and not precluded from patent protection under prior art, the conception must not have been reduced to an isolated, purified and useable form through human intervention. Thus, despite the fact that several institutions and companies may have conceived of a strategy for isolating embryonic stem cells, WARF’s actual success in reducing that conception to a tangible form makes it novel under § 102.

72 Id. at 1205-06. 73 35 U.S.C. § 102(g)(2) (2006). 74 Amgen , 927 F.2d at 1206 (emphasis added). 75 Id. at 1207. 76 Id . at 1209. 252 WAKE FOREST INTELL . PROP . L.J. Vol.9

In addition, the court in Amgen considered the alleged obviousness of the inventions claimed by Amgen. 77 The test for obviousness under 35 U.S.C. § 103 is “whether the prior art would have suggested to [a person] of ordinary skill in the art” that a particular method “should be carried out and would have a reasonable expectation of success, viewed in light of the prior art.”78 The district court found that as of 1983, no prior art references suggested the probing strategy employed by Chugai and Amgen would be likely to succeed in isolating the human EPO gene. 79 The court found that the procedures were “obvious to try,” but lacked any reasonable expectation of success. 80 The Court of Appeals found that the district court applied the proper analysis in determining that the claims asserted by Amgen were not invalid due to obviousness under § 103. 81 Some critics in the public and non-profit sectors contend that “with the advent of automated sequencing machines, ‘virtually any monkey’ can generate numerous unidentified gene sequences,” and call for heightened standards in the USTPO’s granting of gene patents. 82 These criticisms are seemingly dismissed by the court’s holding that while procedures may be “obvious to try,” they must in addition have a “reasonable expectation of success.” Therefore, as long as a sought gene has not been identified, reduced and purified, it seems that the first claimed process to successfully extract that particular gene will qualify for patent protection in the future, despite the use of methods that are arguably obvious to try. Thus, the WARF patents protecting the isolation and purification of human embryonic stem cells, viewed according to the courts’ treatment of other biotechnology patents such as gene patents, would likely be found to be valid under the statutory analysis of 35

77 Id. at 1207. 78 Id. 79 Id. 80 Id at 1208 . (citing In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988). The court in O’Farrel held that: Obviousness does not require absolute predictability of success. Indeed, for many inventions that seem quite obvious, there is no absolute predictability of success until the invention is reduced to practice. There is always at least a possibility of unexpected results, that would then provide an objective basis for showing that the invention, although apparently obvious, was in law nonobvious. For obviousness under § 103, all that is required is a reasonable expectation of success. O’Farrel 853 F.2d at 903-04 (citations omitted). 81 Amgen , 927 F.2d at 1209. 82 Gitter, supra note 39 at 1673. 2009 PATENT LAW AND REGENERATIVE MEDICINE 253

U.S.C. §§ 101, 102, 103 and 112. Close to one-hundred years of legislative history and judicial precedent has established that patents will be issued for novel and non-obvious creations that are the product of human ingenuity. Indeed, the Supreme Court observed in Chakrabarty that Congress intended that “anything under the sun made by man” would constitute patentable, statutory subject matter. 83 Thus, where something occurs in nature, but does not exist in a purified and isolated state, the human intervention of extracting and reducing that product to a useable form is a discovery worthy of patent protection.

III. CRITICISMS, PUBLIC POLICY AND LEGAL SOLUTIONS REGARDING THE ISSUANCE OF UPSTREAM BIOTECHNOLOGY PATENTS

Perhaps the most poignant policy consideration against the issuance of broad biotechnology patents is the notion of the “tragedy of the anticommons” as articulated by Professors Michael A. Heller and Rebecca S. Eisenberg. 84 Under this theory, “[e]ach upstream patent allows its owner to set up a tollbooth on the road to product development, adding to the cost and slowing the pace of downstream biomedical innovation.” 85 In biotechnology, scenarios can exist where, for example, drug developers are required to pay several separate entities and arrange licensing agreements of many interrelated genes in order to produce just one drug or treatment. 86 The danger inherent in this scenario is compounded by other concerns such as foreseeability, as discussed above, with regard to the HGS patent issued for the receptor gene that was later found to be an entry point in humans for the HIV infection. 87 When patents are broadly granted for essential tools of discovery and progress in the field of biotechnology, the danger for stifling innovation and progress due to high bargaining costs, exclusive licensing agreements, and licensing fees is very real. As a proliferation of patents has been broadly and liberally issued in the field of biotechnology concerning many of these basic tools, and the warned against “tollbooths” have emerged, critics and scholars alike have grappled with how to deal with biotechnology

83 Chakrabarty , 447 U.S. at 309 (citing S. Rep. No. 1979, 82d Cong., 2d Sess., 5 (1952); H.R. Rep. No. 1923, 82d Cong., 2d Sess., 6 (1952)). 84 Gitter, supra note 39 at 1669 (citing Heller, supra note 11 at 698). 85 Id. 86 Id. (citation omitted). 87 Id. ; s ee supra note 45. 254 WAKE FOREST INTELL . PROP . L.J. Vol.9

patents. 88 One approach to solving the problems surrounding broad biotechnology is through legislative action limiting the protection available for such patents. Indeed, the Supreme Court in Chakrabarty took notice of the fact that public policy considerations regarding the implications of granting biotechnology patents were not the domain of the courts, but were the responsibility of the legislature. 89 One such attempt by the legislature to curb the patent protection afforded to biotechnology tools like gene patents has been introduced by Congressmen Xavier Becerra and Dave Weldon, known as the Genomic Research Accessibility Act (“GRAA”). 90 The GRAA calls broadly for the banning of patent eligibility for all nucleotide sequences as well as their functions and occurrences. 91 At least one scholar warns that this bill is “unnecessary and would have ruinous effects on health care . . .” and recommends that a bill similar to the Genomic Research and Diagnostic Accessibility Act of 2002 (“GRDAA”), which allows for infringement exemptions for noncommercial research and diagnostic testing, would be more appropriate. 92 In his article explaining the likely detrimental effects of the GRAA, Gregory C. Ellis asserts that gene patents do not restrain basic or biomedical research. 93 In support of his thesis, Ellis cites studies that found that although access to research materials may be restricted at times “the patent status of the requested material had no significant effect” on why those materials were restricted. 94 Ellis goes on to note that only one percent of researchers questioned in the study “stated that their research was delayed as a result of another party’s patent.” 95 Ellis also points out the legitimate concern that legislation banning such patents could have the effect of preventing recent advances in biotechnology from ever materializing. 96 Without patents,

88 See , e.g. , Ellis, supra note 12; Gitter, supra note 39. See also Michael John Gulliford, Much Ado About Gene Patents: The Role of Foreseeability , 34 SETON HALL L. REV . 711 (2004); Lori B. Andrews & Jordan Paradise, Gene Patents: The Need for Bioethics Scrutiny and Legal Change , 5 YALE J. HEALTH POL ’Y, L. & ETHICS 403 (2005). 89 See Chakrabarty, 447 U.S. at 305 (1980). 90 Ellis, supra note 12, at 4. 91 Id. (citing Genomic Research Accessibility Act, H.R. 977, 110 th Cong. § 2(a) (1 st Sess. 2007) (“Notwithstanding any other provision of law, no patent may be obtained for a nucleotide sequence, or its functions or correlations, or the naturally occurring products it specifies.”)). 92 Ellis, supra note 12, at 62, 63. 93 Id. at 26. 94 Id. at 14 (quoting John P. Walsh et al., View from the Bench: Patents and Material Transfers , 309 SCI . 2002, 2002 (2005). 95 Id. 96 Id. at 31. 2009 PATENT LAW AND REGENERATIVE MEDICINE 255

biotechnology companies might choose to rely on trade secrets. 97 In the event robust patent protection is not afforded to biomedical companies, the use of trade secrets could greatly reduce the “instances of innovative advancement for all biotechnologies requiring substantial investment costs.” 98 Indeed, “[b]iotechnology industrialists strenuously defend the patentability of genes and resist industry- specific intervention by Congress.” 99 Proponents of biotechnology patent protection assert its limited duration is important for the dissemination of genomic research. 100 Without protection, research might remain undisclosed under the protection of trade secrets, never to be shared and disseminated for the public benefit. While it seems an outright legislative ban on issuing biotechnology patents is largely unnecessary and possibly unwise, scholars have suggested a number of other legal alternatives for addressing issues inherent in biotechnology patents and achieving the balance sought by the Patent Clause, such as a shorter patent term. 101 This would accelerate the time when genes or other valuable research tools are dedicated to the public domain. 102 In addition, this would reduce the duration of royalty payments and licensing negotiations, 103 which would have the effect of reducing the “tragedy of the anticommons” discussed above. Critics of this view argue that shortening the patent term available for biotechnology would act as a disincentive for invention and innovation. 104 Another approach would be for Congress to enact a compulsory licensing scheme that would “ensure that, in return for a fair sum, researchers would have access to the DNA sequence data [or other essential research tools] they require for further experimentation.” 105 This might lead to companies maintaining less bargaining power over particular licensing agreements and enable smaller biotechnology firms to enter the market and seek to find new and useful inventions based on the research tools which, under today’s scheme, might be prohibitively expensive. One final unique approach considers the WARF stem cell patents specifically and cleverly suggests that the essential facilities doctrine might be a way to ensure the availability of necessary tools in

97 Id. 98 Id. 99 Hill, supra note 9 at 240. 100 Id. at 239-40. 101 Id. at 251. 102 Id. 103 Id. 104 Id. 105 Gitter, supra note 39 at 1679. 256 WAKE FOREST INTELL . PROP . L.J. Vol.9

biotechnology while retaining the continued patent protection afforded to such inventions. 106 In an article written by Amy Rachel Davis for the Georgetown Law Journal, Davis articulates the dilemma presented by a patent granted for stem cells that holds true for gene patents as well: “Unlike a patent claiming a particular reclining chair or a specific formula of cough medicine (either of which could be ‘invented around’ by a company able to devise a different reclining mechanism or an alternate cough elixir), embryonic stem cells are unique combinations of matter with no possible substitutes.” 107 Davis also points out stem cells’ status as a necessary input for downstream products rather than a marketable product. 108 In describing her solution to the issues presented by broad biotechnology patents being granted for such essential inputs for downstream products such as embryonic stem cells, Davis explains the essential facilities doctrine, a doctrine rooted in the Supreme Court’s antitrust jurisprudence. 109 The essential facilities doctrine is traced by most scholars to the Supreme Court decision in United States v. Terminal Railroad Association .110 In that case, the Court held that it was a violation of antitrust law to “create a corporation consisting of every terminal company with rights to the only existing railroad bridge into or out of St. Louis.” 111 The Court reasoned that holding otherwise would prevent any other company from entering the city without using the facilities entirely owned by the terminal company. 112 In analogizing the embryonic stem cell patents with the antitrust violation present in Terminal Railroad , Davis points to five reasons embryonic stem cells should be considered an essential facility: (1) embryonic stem cells are an essential input that is controlled by a monopolist, namely WARF; (2) the input cannot be duplicated, which is a “literal inability” with regard to the WARF stem cells whose patent covers all such cells, no matter what method is used to derive them; (3) access to the input could be denied, which could be realized if Geron were to act on its exclusive license and decide not to license the stem cells to other researchers and competing companies;

106 Davis, supra note 1, at 209. 107 Id. at 211. 108 Id. Scientists anticipate that such downstream products could include the use of stem cells as “‘universal donor cells’ that could serve as ‘the raw material for new liver cells . . . or new spinal cord cells’ . . . .” Id. at 212. 109 Id. at 222. Though never expressly embraced by the Supreme Court, this doctrine is traced back to 1912 when the Supreme Court decided United States v. Terminal Railroad Association , 224 U.S. 383, 397 (1912). 110 Id. 111 Id. 112 Id. at 223 (citing United States v. Terminal R.R. Ass’n ., 224 U.S. 383, 397 (1912)). 2009 PATENT LAW AND REGENERATIVE MEDICINE 257

(4) providing access to the input would be economically feasible for the entity controlling it, satisfied by the fact that licensing the stem cells for others to use would in no way impede WARF or Geron’s use of the cells in their own research; and (5) a distinct downstream market exists. 113 Under this analysis, it seems that the essential facilities doctrine could protect future medical research from one company attempting to assert a monopoly over essential biomedical tools such as embryonic stem cells or particular genes.

CONCLUSION

In conclusion, the United States Patent and Trademark Office’s treatment of biotechnology patents and its liberal issuance of broad patents over essential upstream research tools such as gene patents and human embryonic stem cells raises serious questions about the patentability, utility, novelty, and non-obviousness requirements of 35 U.S.C §§ 101, 102 and 103, as well as important public policy concerns. The purpose of the Patent Clause of the United States Constitution is to promote the progress of the Arts and Sciences by granting patents for a limited time to inventors. This clause demonstrates a delicate balance between the encouraging innovation for the public benefit and stifling competition by awarding limited monopolies to compensate the inventors. The recent debate over whether gene patents or patents claiming a process for isolating human embryonic stem cells are indeed patentable has been viewed in favor of promoting industry and encouraging innovation through the issuance of robust and broad patent protection. Though these tools occur in nature, they do not occur naturally in their purified and isolated forms without human intervention. Where the claims specifically state the function of the invention seeking patent protection, the patent will likely be found to be patentable under § 101. In addition, while methods exist for isolating DNA sequences, cells and proteins, these methods do not necessarily lead to a reasonable expectation of success in deriving a particular gene, protein or cell type. Furthermore, until that particular product is isolated and the concept of isolating the gene is reduced to a marketable form for the public benefit, a process for reducing the concept to a marketable form will be found to be novel under § 102. Despite the fact that a process for deriving an isolated and purified form of a product may be obvious to try, there must also be a reasonable expectation of success in order to be prevented under § 103 scrutiny.

113 Id. at 232-39. 258 WAKE FOREST INTELL . PROP . L.J. Vol.9

The tragedy of the anticommons presents a challenge that suggests that awarding too many rights to exclude others might lead to a reduction in progress and innovation. Under this theory, broad upstream patents establish tollbooths that slow progress and innovation by increasing costs, thereby limiting downstream product development. Despite efforts, the legislature has been unable to effectively address the problems inherent in the issuance of broad biotechnology patents. However, a number of alternative solutions, including a shortened patent period, compulsory licensing, and application of the essential facilities doctrine, might have the potential to successfully and appropriately balance public policy with commercial interests. For now, upstream biotechnology patents will continue to be awarded in order to encourage investment and progress in the field. It is hoped that these broad patent rights will not be abused and act as a deterrent for future innovation, but rather will be exploited fairly, in a way that benefits society and rewards innovators for their investment.