CASRIP Newsletter - Autumn 2007, Volume 14, Issue 4
Patenting Human Embryonic Stem Cells in the United States: The Legal and Ethical Debate
By Janice M. Mueller
I. Significance and Potential of Stem Cell Technology
What’s so special about the unspecialized, primitive, and immature cells known as stem cells? Not only do stem cells divide and renew themselves for long periods of time, but more importantly, they are capable of morphing into many specialized types of cells such as heart muscle cells, brain cells, or pancreatic cells that make insulin. Their potential use in cell-based therapies is tremendously exciting. Imagine the ability to treat a patient’s advanced heart disease by transfusing newly-generated healthy heart cells grown from stem cells, rather than subjecting the patient to heart transplant surgery. “Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases” such as Parkinson’s, Alzheimer’s, heart disease, diabetes, spinal cord injuries, and many more illnesses.
This article explores the legal and moral implications surrounding one particular kind of stem cell--human embryonic stem cells (HESCs). HESCs are derived from human embryos that have been artificially fertilized but not yet implanted in a woman’s uterus. Stem cells can also be derived from fetal, neo-natal, and adult tissue. Each of these other types of stem cells has its own advantages and drawbacks. For example, most adult stem cells are much more limited than HESCs in the number of different types of cells into which they can develop. In contrast, HESCs are considered “pluripotent,” i.e., able to give rise to cells found in all tissues of the body.
Public awareness of stem cell technology’s enormous potential ignited in November 1998, when University of Wisconsin biologist Dr. James Thomson and his team announced that they had successfully isolated and cultured HESCs. Although other scientists isolated stem cells from embryos of mice in the 1980s, it was Thomson and his colleagues who ultimately succeeded in isolating and culturing embryonic stem cells from monkeys in 1995 and from humans in 1998. Medical researchers around the globe hailed Thomson’s achievement as one of the leading scientific breakthroughs in recent history.
The Wisconsin Alumni Research Foundation (WARF), the licensing arm of Dr. Thomson’s employer, the University of Wisconsin, owns a broad portfolio of U.S. patents directed to the fruits of Thomson’s work in primate/human embryonic stem cells. WARF contends that its patents “apply to all human embryonic stem cells in the United States.” Despite WARF’s policy of granting free licenses for academic research use of the patented cells, the patents’ existence and their licensing and commercialization have proved controversial. As detailed below, the United States Patent and Trademark Office (USPTO) is currently reexamining three of WARF’s fundamental patents on HESCs, indicating that substantial new questions exist concerning the patents’ validity.
II. Ethical and Moral Issues
While sparking a debate about intellectual property ownership in HESCs and medical researchers’ access to them, Thomson’s success at isolating the cells from human embryos also triggered difficult ethical and moral issues. HESC research is controversial because it involves the destruction of fertilized human embryos. Some individuals believe that life begins when a human embryo is fertilized, even though it is in a test tube and not implanted in the human body.
In practice, HESCs usually are derived from the excess embryos generated by in vitro fertilization (IVF) clinics; these spares would otherwise be discarded. The journal Science in July 2007 reported that about half of patients with embryos left over from fertility treatments would rather donate those embryos to research than have them discarded or even donated to other infertile couples. Proponents and opponents of HESC research nevertheless sharply diverge on the morality and ethics of using these spare embryos, even with the informed consent of the embryo donor.
Rapid technological advances continue to re-frame the ethical issues raised by HESCs. In early June 2007, scientists at Kyoto University announced that they had successfully reprogrammed the skin cells of mice back to an embryonic state, such that the mice cells were indistinguishable from embryonic stem cells. Two other teams have verified the Japanese method (in mice). If the reprogramming technique can be made to work in humans, it could avoid the moral dilemmas associated with destroying fertilized embryos.
III. Funding for Stem Cell Research in the United States: The Shift to the States
In August 2001, President George W. Bush announced that federal funding for HESC research would be limited to the use of cell lines already in existence at that time; no new stem cell lines could henceforth be created with federal funds. President Bush’s June 20, 2007 veto of the Stem Cell Research Enhancement Act reaffirmed the federal funding restrictions.
Once federal funds for generating new HESCs were cut off, a great deal of funding activity shifted to state governments. For example, California voters in 2004 approved Proposition 71, which created the California Institute of Regenerative Medicine (CIRM), the California state agency that provides grant money for stem cell and related scientific and medical research. Through CIRM, three billion dollars in grant money has been allocated over a ten-year period for stem cell research. Other states with significant funding initiatives for stem cell research include Connecticut, Illinois, Maryland, Massachusetts, and New Jersey.
In January 2007, WARF announced changes intended to ease licensing restrictions on academic and non-profit institutions using WARF-patented stem cells. Under the new policy, WARF does not require that such institutions pay it licensing fees when they conduct corporate-sponsored research (although fees would be imposed when and if the research results were brought to market). WARF also clarified that CIRM, the California funding agency, would not have to pay WARF any portion of funds received from CIRM’s grantees. While reacting favorably to WARF’s easing of licensing restrictions, public interest groups nevertheless cited the changes as proof that WARF’s prior licensing policies had posed “a substantial impediment to stem cell research.”
IV. Reexamination of the Wisconsin Alumni Research Foundation’s Stem Cell Patents
Several months before WARF modified its licensing policies, the Foundation for Taxpayer and Consumer Rights and the Public Patent Foundation filed requests for reexamination of three key WARF/Thomson patents. The requesters challenged the validity of the patents and charged that they were draining U.S. scientific talent and funding to offshore locales where stem cell patents have not been granted.
The USPTO granted the requests for reexamination in September 2006. Figure 1 below depicts the genealogical and funding history of the WARF/Thomson patents under reexamination:
The claims of the WARF/Thomson patents as issued are functionally defined and seemingly quite broad in scope. Figure 2 below sets forth the text of claim 1 in each of the patents:
Issued Dec. 1, 1998
Issued Mar. 13, 2001
Issued Apr. 18, 2006
1. A purified preparation of primate embryonic stem cells which
(i) is capable of proliferation in an in vitro culture for over one year,
(ii) maintains a karyotype in which all the chromosomes characteristic of the primate species are present and not noticeably altered through prolonged culture,
(iii) maintains the potential to differentiate into derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, and
(iv) will not differentiate when cultured on a fibroblast feeder layer.
1. A purified preparation of pluripotent human embryonic stem cells which
(i) will proliferate in an in vitro culture for over one year,
(ii) maintains a karyotype in which the chromosomes are euploid and not altered through prolonged culture,
(iii) maintains the potential to differentiate to derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, and
(iv) is inhibited from differentiation when cultured on a fibroblast feeder layer.
1. A replicating in vitro cell culture of human embryonic stem cells comprising cells which
(i) are capable of proliferation in in vitro culture for over one year without the application of exogenous leukemia inhibitory factor,
(ii) maintain a karyotype in which the chromosomes are euploid through prolonged culture,
(iii) maintain the potential to differentiate to derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, and
(iv) are inhibited from differentiation when cultured on a fibroblast feeder layer.
The USPTO issued first Office Actions in each of the reexamination proceedings on March 30, 2007, rejecting all claims of the ‘780, ‘806, and ‘913 patents as anticipated and/or obvious in view of prior art. The USPTO relied primarily on the teachings of two prior art patents, neither of which had been cited in the original prosecutions:
U.S. Patent No. 5,166,065, issued in 1992 to Williams et al., cited in the reexaminations as a 35 U.S.C. § 102(b)/103 reference. Williams discloses isolation of mouse embryonic stem cells, and states that his method could be used to isolate HESCs. The third-party reexamination requesters brought the Williams patent to the USPTO’s attention.
U.S. Patent No. 5,690,926, issued to Hogan, cited in the reexaminations as a 35 U.S.C. § 102(e)/103 reference. Hogan discloses “embryonic stem cells . . . derived from primordial germ cells dissected from post-implantation [human] embryos” (emphases added). The USPTO cited the Hogan patent for the first time in the reexamination proceedings.
WARF published its May 30, 2007 Responses to the USPTO’s first Office Actions in the reexamination proceedings. Each Response emphasized the numerous accolades received for Dr. Thomson’s work, including the American Association for the Advancement of Science’s 2005 identification of his embryonic stem cell research as “one of the most significant ‘Milestones of Science’” and a 2001 profile in TIME magazine identifying Dr. Thomson as “[t]he man who brought you stem cells.”
Responding to the merits of the USPTO’s rejections, WARF contended that the Williams reference was non-enabling for anything other than mouse embryonic stem cells, and that the Hogan reference’s cells were not embryonic stem cells but rather embryonic germ cells. To further distinguish Hogan, WARF amended the product claims in all three of its patents to recite that the claimed cells are derived from pre-implantation embryos. For example, claim 1 of the ‘780 patent as amended on May 30, 2007 read:
A purified preparation of primate embryonic stem cells derived from a pre-implantation embryo which [possesses functional characteristics (i)-(iv) as enumerated in Figure 2 above].
WARF also added new method claims to the ‘780 and ‘806 patents.
WARF’s May 30, 2007 Responses included a declaration by Dr. Colin Stewart of the Institute of Medical Biology in Singapore. According to WARF, Dr. Stewart’s declaration “emphasized the differences between mouse stem cells, which were prominent in the PTO's rejections, and the human embryonic stem cells that were isolated and characterized by Thomson.”
WARF again amended the claims of its three patents in reexamination on October 2, 2007, following in-person and telephonic interviews by WARF’s outside patent prosecution counsel with the examiners assigned to the ‘780 patent and ‘806 patent ex parte reexaminations. These second-round amendments addressed issues including the pluripotency of the claimed stem cells and language inconsistencies between the three patents in reexamination. For example, claim 1 of the ‘780 patent as amended on October 2, 2007 now reads:
A purified preparation of pluripotent primate embryonic stem cells derived from a pre-implantation embryo wherein the stem cells [which] (i) [is capable of proliferation] will proliferate in an in vitro culture for over one year in an undifferentiated state, (ii) [maintains] maintain a karyotype in which all the chromosomes characteristic of the primate species are present and not noticeably altered through prolonged culture, (iii) [maintains] maintain the potential to differentiate into derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, and (iv) will not differentiate when cultured on a fibroblast feeder layer.
Based on the publicly available documents, it appears that at least the ex parte reexaminations of the ’708 and ‘806 patents will soon conclude with the USPTO issuing certificates confirming the patentability of the claims as narrowed by the amendments described above. If the USPTO maintains any of the reexamination rejections, however, WARF will likely appeal to the Board of Patent Appeals and thereafter (if necessary) to the courts. Thus any decision may not be final for several years. Meanwhile, the WARF/Thomson patents in their original, broader form remain in force. If not invalidated, the patents will not expire until 2015 (because all three claim priority back to the WARF/Thomson parent ‘327 application, filed January 20, 1995).
Assuming that the WARF/Thomson patents emerge from reexamination and remain in force for seven to eight more years, it is worth considering whether the patents will become less relevant as time passes and hence of diminished concern to researchers and health care advocates. Stem cell research advances quite rapidly, as evidenced by the June 2007 announcement that Japanese scientists successfully reprogrammed the skin cells of mice back to an embryonic state. If these new reprogramming techniques can be adapted to work in human cells (admittedly a non-trivial assumption), the resulting therapeutic products or diagnostics most likely would not literally infringe any WARF/Thomson patent claims that emerge from reexamination. WARF has narrowed its claims in reexamination to require that the claimed primate/human stem cells be “derived from a pre-implantation embryo.” Absent an exceedingly broad interpretation of the phrase “derived from,” this new claim limitation would not seem to read on stem cells obtained by the Japanese method of reprogramming mature cells back to an embryonic state.
WARF’s reexamination amendments do not entirely dispose of the above infringement hypothetical, however. Even absent a basis for asserting literal infringement, WARF might still assert the doctrine of equivalents. Given that the Japanese announcement came about a week after WARF’s May 30, 2007 narrowing amendment in the reexamination, WARF could assert that it is not barred by prosecution history estoppel from asserting equivalency. More specifically, WARF might argue that it satisfies the “unforeseeability” rebuttal criteria of Festo Corp. v. Shoketsu Ltd. if it amended its claims without knowledge of the Japanese reprogramming method.
V. Recent Federal Circuit Invalidation of Other Stem Cell Patents
The United States Court of Appeals for the Federal Circuit has not yet confronted the WARF/Thomson patents on HESCs, but it has already encountered--and invalidated--other stem cell patents. In July 2007 the court struck down as obvious two patents on a different type of stem cell technology, relying in part on the Supreme Court’s recent, expansive pronouncements about the nonobviousness requirement in KSR Int’l Co. v. Teleflex Int’l. In PharmaStem Therapeutics Inc. v. ViaCell, Inc., a divided panel of the Federal Circuit reversed the District of Delaware’s judgment, entered on jury verdicts, which had sustained the validity of PharmaStem’s previously-reexamined composition and method claims directed to use of stem cells from infant umbilical cord blood. Although the stem cells involved in PharmaStem are not the HESCs of the WARF/Thomson patents, the result in PharmStem suggests that the Federal Circuit will scrutinize with equivalent rigor any other stem cell patents that may reach its review.
PharmaStem’s predecessor, Biocyte, Inc., applied for a U.S. patent in 1987 based on its inventors’ discovery that the umbilical cord blood of newborn infants is rich in hematopoietic stem cells, a particular type of stem cell useful for rebuilding the blood and immune system of immuno-compromised adults. The inventors were the first to successfully transplant hematopoietic stem cells for reconstitution of the human hematopoietic system. Biocyte’s work spawned an industry of cryo-preserving cord blood stem cells for later use in blood transplant surgeries, with significant advantages over conventional bone marrow transplants.
The PharmaStem majority (in an opinion authored by Circuit Judge Byrson, joined by Circuit Judge Prost) concluded that the prior art, as described in the patentee’s specification and considered in previous USPTO reexaminations, not only would have motivated a person of ordinary skill in the art to make the claimed inventions, but also would have provided a reasonable expectation of success in so doing:
While the inventors may have proved conclusively what was strongly suspected before--that umbilical cord blood is capable of hematopoietic reconstitution--and while their work may have significantly advanced the state of the science of hematopoietic transplantations by eliminating any doubt as to the presence of stem cells in cord blood, the mouse experiments and the conclusions drawn from them were not inventive in nature. Instead, the inventors merely used routine research methods to prove what was already believed to be the case. Scientific confirmation of what was already believed to be true may be a valuable contribution, but it does not give rise to a patentable invention. See KSR, 127 S. Ct. at 1732 (“Granting patent protection to advances that would occur in the ordinary course without real innovation retards progress . . . .”) . . . . Good science and useful contributions do not necessarily result in patentability.
Circuit Judge Newman’s extensive dissent criticized the PharmaStem majority for its “perfect hindsight” and “rearrang[ing] the past.” Substantial evidence supported the jury’s verdict upholding validity of PharmaStem’s patents following a three-week trial. According to Judge Newman, the majority failed to appreciate the commercial success of PharmaStem’s inventions in the face of “extreme skepticism” regarding the use of cord blood as transplant tissue; the inventors’ achievement drew universal acclaim and catalyzed a new industry of cryo-preserving cord blood. The majority also ignored the Supreme Court’s guidance in Dickinson v. Zurko by failing to give sufficient deference to the USPTO’s fact findings concerning the teachings of the prior art references, which the agency had previously considered in its initial examinations and subsequent reexaminations of the PharmaStem patents.
the USPTO’s reexaminations of the WARF/Thomson HESC patents remain pending as of mid-October 2007. The WARF/Thomson stem cells are quite different from those claimed in the patents invalidated in PharmaStem. Nevertheless, the Federal Circuit majority’s characterization of PharmaStem’s industry-launching technology as “good science” but “not inventive,” coupled with the court’s KSR-enhanced scrutiny of obviousness, suggest that the patentability of stem cell technology in the United States is no longer guaranteed. As these complex issues plod inexorably through the U.S. administrative and court systems, rapid scientific breakthroughs in stem cell technology promise to lessen the exclusionary power of existing stem cell patents and may defuse the difficult ethical and moral issues they raise.
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