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2013-1377 IN THE

UNITED STATES COURT OF APPEALS

FOR THE FEDERAL CIRCUIT
CONSUMER WATCHDOG (formerly known as The Foundation for Taxpayer and Consumer Rights), Appellant, v. WISCONSIN ALUMNI RESEARCH FOUNDATION, Appellee.

Appeal from the United States Patent and Trademark Office, Patent Trial and Appeal Board in Reexamination No. 95/000,154.

BRIEF FOR APPELLEE WISCONSIN ALUMNI RESEARCH FOUNDATION

August 14, 2013

Kara F. Stoll William B. Raich Sarah E. Craven FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP 901 New York Avenue, NW Washington, DC 20001-4413 (202) 408-4000 Counsel for Appellee Wisconsin Alumni Research Foundation

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CERTIFICATE OF INTEREST Counsel for Appellee, Wisconsin Alumni Research Foundation, certify the following: 1. The full name of every party or amicus represented by me is: Wisconsin Alumni Research Foundation 2. The name of the real party in interest represented by me is: Wisconsin Alumni Research Foundation 3. All parent corporations and any publicly held companies that own 10 percent or more of the stock of the party represented by me are: There are no such corporations 4. The names of all law firms and the partners or associates that appeared for the party or amicus now represented by me in the trial court or agency or are expected to appear in this Court are: FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP Kara F. Stoll, William B. Raich, Sarah E. Craven 901 New York Avenue, NW Washington, DC 20001-4413 RIVERSIDE LAW LLP Kathryn R. Doyle 300 Four Falls Corporate Center, Suite 710 300 Conshohocken State Road West Conshohocken, PA 19428 DRINKER BIDDLE & REATH LLP Michael J. Remington Joseph R. DelMaster, John Marshall (both formerly of Drinker Biddle & Reath LLP) 1500 K Street, NW Washington, DC 20005

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TABLE OF CONTENTS Page TABLE OF AUTHORITIES ................................................................................... iii STATEMENT OF RELATED CASES ....................................................................vi STATEMENT OF ISSUES PRESENTED................................................................ 1 STATEMENT OF THE CASE .................................................................................. 1 STATEMENT OF FACTS ........................................................................................5 I. II. III. Embryonic Stem Cells .....................................................................................5 Robertson and Williams: Discovery of Mouse Embryonic Stem Cell Cultures ....................................................................................................6 Piedrahita and Bongso: Methods Developed for Mouse Embryonic Stem Cells Proved Unsuccessful in Deriving Embryonic Stem Cell Cultures from Other Species, Including Humans ..........................................11 Dr. James Thomsons Successful Invention of Primate and Human Embryonic Stem Cell Cultures ......................................................................13 The 913 Patent ..............................................................................................18 Inter Partes Reexamination ...........................................................................20

IV. V. VI.

SUMMARY OF THE ARGUMENT ......................................................................27 ARGUMENT ...........................................................................................................30 I. II. Standard of Review........................................................................................30 Watchdogs Newly Raised 101 Challenge Is Improper in Inter Partes Reexamination Proceedings and, in Any Event, Was Waived ...........................................................................................................31 A. B. Watchdogs 101 Challenge Is Not Properly Before This Court ....................................................................................................31 Watchdog Waived Its Newly Raised 101 Challenge .......................32

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C.

Claims to an In Vitro Cell Culture of Human Embryonic Stem Cells Recite Non-Naturally Occurring Subject Matter and Thus Are Patent Eligible Under 101 .........................................35

III.

Williams Failed to Enable an In Vitro Cell Culture of Human Embryonic Stem Cells, and Thus the Board Correctly Held that Williams Does Not Anticipate the Claims ....................................................38 A. Williams Does Not Describe Deriving Embryonic Stem Cell Cultures Using a Feeder Layer, and Thus Would Not Work to Derive Human Embryonic Stem Cell Cultures ...............................38 Williams Also Does Not Describe the Distinct Morphology of Human Embryonic Stem Cell Colonies ..........................................44

B. IV.

The Boards Holding that Prior Art Directed to Mouse Embryonic Stem Cell Cultures Would Not Have Rendered Obvious Claims to Human Embryonic Stem Cell Cultures Is Supported by Substantial Evidence.........................................................................................................48 A. The Distinct Morphology of Human Embryonic Stem Cell Colonies, the Unpredictable Nature of the Art, and the Failure of Others Provide Substantial Evidence of Nonobviousness...................................................................................48 Watchdogs Arguments Fail to Undermine the Substantial Evidence Supporting the Boards Nonobviousness Decision ............. 53 1. The Failure to Derive Rat Embryonic Stem Cell Cultures Until 2008 Shows the Unpredictability in the Art at the Time of the Invention ...............................................53 The Evidence Supports the Boards Finding that Others Who Made Human Embryonic Stem Cell Cultures Did So by Following Dr. Thomsons Work, Not the Prior Art .......................................................................57 The Acclaim for Dr. Thomsons Invention of Human Embryonic Stem Cell Cultures Is an Integral Part of the Obviousness Analysis .........................................................58

B.

2.

3.

CONCLUSION ........................................................................................................60

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TABLE OF AUTHORITIES CASES Al-Site Corp. v. VSI International, Inc., 174 F.3d 1308 (Fed. Cir. 1999) .........................................................................60 Arrhythmia Research Technology, Inc. v. Corazonix Corp., 958 F.2d 1053 (Fed. Cir. 1992) .........................................................................30 Association for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107 (2013) .......................................................................... 34, 35, 36 Baxter, International Inc., In re, 678 F.3d 1357 (Fed. Cir. 2012) .........................................................................32 Bayer Schering Pharma AG v. Barr Laboratories, Inc., 575 F.3d 1341 (Fed. Cir. 2009) ..........................................................................55 Comiskey, In re, 554 F.3d 967 (Fed. Cir. 2009) ...........................................................................33 Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, In re, 676 F.3d 1063 (Fed. Cir. 2012) ............................................................ 48, 50, 60 DBC, In re, 545 F.3d 1373 (Fed. Cir. 2008) ..........................................................................34 Diamond v. Chakrabarty, 447 U.S. 303 (1980) ............................................................................................35 Donohue, In re, 766 F.2d 531 (Fed. Cir. 1985) ..................................................................... 38, 39 Eli Lilly & Co. v. Teva Pharmaceuticals USA, Inc., 619 F.3d 1329 (Fed. Cir. 2010) .........................................................................54 Falkner v. Inglis, 448 F.3d 1357 (Fed. Cir. 2006) .................................................................. 30, 40

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Forest Laboratories, Inc. v. Ivax Pharmaceuticals, Inc., 501 F.3d 1263 (Fed. Cir. 2007) .................................................................. 30, 38 Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127 (1948) ............................................................................................35 Glatt Air Techniques, Inc., In re, 630 F.3d 1026 (Fed. Cir. 2011) .........................................................................33 Hormel v. Helvering, 312 U.S. 552 (1941) ............................................................................................34 Impax Laboratories, Inc. v. Aventis Pharmaceuticals, Inc., 545 F.3d 1312 (Fed. Cir. 2008) .................................................................. 30, 38 Kimberly-Clark Corp. v. Johnson & Johnson, 745 F.2d 1437 (Fed. Cir. 1984) ..........................................................................54 Kinetic Concepts, Inc. v. Blue Sky Medical Group, Inc., 554 F.3d 1010 (Fed. Cir. 2009) .................................................................. 48, 50 KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007) ............................................................................................55 Mintz v. Dietz & Watson, Inc., 679 F.3d 1372 (Fed. Cir. 2012) ..........................................................................50 NTP, Inc., In re, 654 F.3d 1268 (Fed. Cir. 2011) ..........................................................................31 Sage Products, Inc. v. Devon Industries, Inc., 126 F.3d 1420 (Fed. Cir. 1997) .........................................................................32 Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075 (Fed. Cir. 2008) .................................................................. 48, 52 Securities & Exchange Commission v. Chenery Corp., 318 U.S. 80 (1943) .............................................................................................33 Standard Havens Products, Inc. v. Gencor Industries, Inc., 897 F.2d 511 (Fed. Cir. 1990) ............................................................................37

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Vulcan Engineering Co. v. Fata Aluminium, Inc., 278 F.3d 1366 (Fed. Cir. 2002) .........................................................................52 WMS Gaming Inc. v. International Game Technology, 184 F.3d 1339 (Fed. Cir. 1999) .........................................................................60 STATUTES 28 U.S.C. 1295(a)(4) .............................................................................................32 35 U.S.C. 101 ................................................................................................ passim 35 U.S.C. 102 ....................................................................................................1, 22 35 U.S.C. 103 ............................................................................................. 1, 22, 59 35 U.S.C. 112 ....................................................................................... 1, 27, 31, 58 35 U.S.C. 141-144...............................................................................................32 35 U.S.C. 301 ........................................................................................................31 35 U.S.C. 311(a) ...................................................................................................31 OTHER AUTHORITIES Fed. R. Evid. 201(b)(2) ............................................................................................37 MPEP 2258 ...........................................................................................................31 MPEP 2658 ...........................................................................................................31 REGULATIONS 37 C.F.R. 1.906 .....................................................................................................31

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STATEMENT OF RELATED CASES No other appeal in or from the same proceeding was previously before this Court or any other appellate court. There are no other cases known to counsel to be pending in this Court or any other court that will directly affect or be directly affected by the Courts decision in this appeal.

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STATEMENT OF ISSUES PRESENTED Whether this Court should hear Consumer Watchdogs newly raised 101 challenge to claims reciting a non-naturally occurring in vitro cell culture of human embryonic stem cells on appeal from an inter partes reexamination proceeding, which is limited by statute and regulation to challenges based on prior art patents and printed publications and to compliance with 112 requirements for new or deleted matter. Whether substantial evidence supports the Boards decision that prior art directed to deriving mouse embryonic stem cell cultures neither anticipates under 102 nor renders obvious under 103 claims to human embryonic stem cell cultures when (1) no prior art reference disclosed methods that would have actually worked to select and derive human embryonic stem cell cultures; (2) those of ordinary skill in the art had repeatedly failed in their attempts to apply the methods developed for generating cultured mouse embryonic stem cells to other species, including rats and humans; and (3) the successful generation of human embryonic stem cell cultures garnered significant acclaim and commercial success. STATEMENT OF THE CASE This appeal arises from a Board decision in an inter partes reexamination. The Board found that the claims-at-issue, directed to human embryonic stem cell cultures, were novel and nonobvious in light of the prior art of record.

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The technology-at-issue involves cultures of embryonic stem cells (ES cells). Because of their unique ability to develop into all the different adult cell types, ES cells have enormous biomedical potential to treat damaged tissue and diseases resulting from the failure of specific cell types. See A99(col.17,ll.7-28). Harnessing these cells potential could lead to treatments for Parkinsons disease, type 1 diabetes mellitus, spinal-cord injuries, and heart disease, to name a few. See id. Thus, after scientists first succeeded in generating mouse ES cell cultures, many researchers spent years trying to apply those methods to other species, including humans, without success. Dr. James Thomson succeeded where others had failed. Working at the University of Wisconsin in the mid-1990s, Dr. Thomson was the first to generate cultures of ES cells from primates and then humans. This landmark discovery, hailed by another ES cell scientist as an astounding breakthrough, continues to earn Dr. Thomson awards to this day. Scientists first generated cultured ES cells from mice in the early 1980s. Yet, these methods repeatedly failed to translate to other species, and even to other strains of mice. By the mid-1990s, scientists could not generate ES cell cultures from certain mouse strains. For example, despite extensive efforts, researchers did not succeed in creating cultures of ES cells from the medically important nonobese diabetic (NOD) mouse strain until 2009, twenty-eight years after mouse ES

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cultures had first been obtained. Similarly, although rats are closely related to mice, deriving rat ES cell cultures remained elusive for over a quarter of a century. Only in 2008, twenty-seven years after mouse ES cells, did researchers successfully prepare rat ES cell cultures. Researchers working with higher-order animals faced the same defeats. In 1990, application of the methods developed for mice failed to produce cultures of ES cells from either pigs or sheep. Even by 1997, researchers continued to report that, despite intense efforts, ES cell cultures had still not been obtained from pigs. At least one researcher also struck out in humans, failing to generate stable cultures of human ES cells using methods that had succeeded in mice. Some researchers even turned to alternative approaches, using older embryos to derive stem cell-like cells. In the face of such failures, Dr. Thomsons success in the mid-1990s was anything but routine. He did not apply a finite number of identified and

predictable solutions to the problem of deriving ES cells from primates and humans. Rather, confronted with a multitude of options in an unpredictable field, he identified the critical steps needed to generate and culture these cells, including the discovery of the distinct morphology of primate and human ES cell colonies. No prior art reference taught these insights.

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Dr. Thomsons methods resulted in a non-naturally occurring in vitro cell culture of human ES cells. These cultured cells are distinct from cells found in the embryo, having their own unique cellular composition and properties. Furthermore, ES cell cultures, unlike cells found in the embryo, are bathed in a culture medium containing nutrients and other components necessary to sustain their existence in a plastic culture dish. Recognition for Dr. Thomsons invention was instantaneous and sustained. In 1999, a year after Dr. Thomson published his creation of human ES cell cultures, Science magazine featured his work in its Scientific Breakthrough of the Year issue. Over the years, the awards and grants accumulated. Just this year, Dr. Thomsons work on human ES cells earned him the McEwen Award for Innovation from The International Society of Stem Cell Research. Based on Dr. Thomsons work, appellee Wisconsin Alumni Research Foundation (WARF) filed the first in a series of U.S. patent applications on January 20, 1995. The patent-at-issue here, U.S. Patent No. 7,029,913 (the 913 patent), issued with three claims, all directed to a replicating in vitro cell culture of human ES cells with certain characteristics. A82-101. Just a few months after issuance of the 913 patent, Consumer Watchdog (Watchdog) filed this inter partes reexamination, challenging the issued claims. A106-07. As required by statute and regulation, Watchdog based its reexamination

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request on prior art printed publications.

At no time during the inter partes

reexamination did Watchdog assert that the claims recite nonpatentable subject matter or that the PTO should review the claims on this ground. The Examiner ultimately found the claims (which had been amended by that time) patentable (A14-33), and the Board affirmed (A1-13). decision to this Court. STATEMENT OF FACTS I. Embryonic Stem Cells During development, cells undergo a process of cellular differentiation in which unspecialized (or undifferentiated) cells give rise to more specialized cells. Underlying this process are stem cells, undifferentiated cells with the potential both to undergo unlimited self-renewal to produce new stem cells and to differentiate into other specialized cell types. A92(col.3,ll.62-67). Stem cells exist in both developing and mature animals. In the adult See A91(col.1,ll.29-30); Watchdog appealed the Boards

organism, stem cells are multipotent, meaning that they have the potential to give rise to a limited number of terminally differentiated cells. For example,

hematopoietic stem cells are the stem cells that give rise to all differentiated bloodcell types, such as red blood cells, but not to any other cell type in the body. A91(col.1,ll.30-32).

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Embryonic stem cells (ES cells), in contrast, are pluripotent. Id.(col.1,ll.3336). They can give rise to any organ or tissue type, and thus to cells from all three germ layers of the body: endoderm (e.g., intestinal cells); mesoderm (e.g., muscle cells); or ectoderm (e.g., neurons of the brain and spinal cord). Id.(col.1,ll.34-35); A92(col.3,ll.62-67). To achieve this potential, ES cells must also maintain a normal (euploid) set of chromosomes, or karyotype. Thus, true ES cells should (1) be capable of indefinite proliferation outside the body (in vitro) in an undifferentiated state (unlimited self-renewal), (2) maintain a normal karyotype through prolonged culture, and (3) maintain the potential to differentiate to derivatives of all three embryonic germ layers (remain pluripotent) even after prolonged culture. A92(col.3,ll.62-67). II. Robertson and Williams: Discovery of Mouse Embryonic Stem Cell Cultures Scientists derived the first ES cell cultures from mice in the early 1980s. See A91(col.1,ll.42-47). The ES cells originate from the inner cell mass (ICM) of an early-stage, pre-implantation embryo, or blastocyst, which has yet to implant into the wall of the uterus. A91(col.1,ll.42-44); A92(col.3,ll.50-51;col.4,ll.47-51). The blastocyst consists of both the ICM cells and an outer surrounding layer of extra-embryonic placental cells called trophoblasts (or trophoectoderm). A94(col.8,ll.53-55). See

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The derivation process results in ES cell cultures: ES cells outside a living organism and placed (or plated) in culture dishes (i.e., in vitro). Cell culture includes a culture medium, which the patent-in-suit describes as a defined salt solution supplemented with animal serum and other nutrients necessary to sustain the cultured cells. See id.(col.7,ll.57-65). The first mouse ES cell cultures also relied on fibroblast cells, which are plated as a single-cell layer on the bottom of the culture dishes (called a feeder layer) to maintain the ES cells in an undifferentiated and pluripotent state. A1553-54. Robertson 83 and Robertson 87 both describe methods for generating in vitro cell cultures of ES cells from pre-implantation mouse embryos. A990-1009; A1545-90. In the first step, mouse blastocysts are isolated and then plated on plastic culture dishes, with or without a feeder layer, and bathed in a culture medium. A1562-64. In the cell culture, the blastocysts attach to the culture dish or feeder cells by outgrowth of the trophoblast cells, which exposes the ICM cells to the culture environment. A1563. Alternatively, the isolated mouse blastocysts are subjected to immunosurgery to remove the trophoblast cells, and the ICM cells are plated in culture medium. A1562. The cultures are left undisturbed for four to six days. A1563. In the next step, the ICM-derived cells are removed from the cell culture and disaggregated into smaller cellular aggregates using the digestive enzyme trypsin.

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A1564-67. These cellular aggregates are then plated in cell culture on a feeder layer of fibroblast cells. A1567; A1570. Under these culture conditions, the ES cells divide to produce new ES cells, forming collections of cells called colonies. A1570. Four days later, ES cell colonies are selected based on their morphology. Robertson 87 states that the mouse stem cells are typically small with a large nucleus, minimal cytoplasm, and prominent nucleoli, and they form compact colonies in which individual cells are difficult to discern. Id. Once generated, ES cell cultures continue to grow and must be maintained. Routine maintenance includes culturing the cells in culture medium at high density on a feeder layer. A1580. Long-term cultures of ES cells are also referred to as ES cell lines. See id. Building on this early work, in the late 1980s, Dr. Robert Williams developed new methods for both deriving and maintaining mouse ES cell cultures from pre-implantation embryos, described in U.S. Patent No. 5,166,065 (the 065 patent). A1847-58. In these methods, mouse blastocysts and ICM cells are

isolated in culture medium containing a protein called leukemia inhibitory factor (LIF), which allows the derivation and maintenance of pluripotent ES cells in the absence of a fibroblast feeder layer. A1852(col.2,ll.10-14). In Dr. Williamss first method, isolated mouse blastocysts were plated directly onto culture dishes in LIF-containing culture medium without a feeder

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layer. A1854(col.6,ll.52-65); A1855(col.8,ll.9-15). The outgrowing ICMs were then removed from culture, dissociated in trypsin, and the resulting cells replated on culture dishes in fresh LIF-containing medium, again without a feeder layer. A1854(col.6,ll.59-63); A1855(col.8,ll.15-21). Williams also described a method in which the mouse blastocysts were subjected to immunosurgery. In this method, the isolated ICM cells were also cultured in a LIF-containing medium without a feeder layer. A1854-55(col.6,l.66col.7,l.4); A1855(col.8,ll.22-31). In addition to deriving mouse ES cell cultures, Williams also taught maintaining ES cell cultures in LIF-containing culture medium. A1854(col.5,l.35 col.6,l.49). For established ES cell lines, Williams described maintaining these lines in culture medium on a fibroblast feeder layer prior to culture in LIF. Id.(col.5,ll.26-30). Thus, in describing the growth of ES cells, Williams allowed that [t]he culture medium may or may not contain feeder cells.

A1853(col.3,ll.54-55,62-64). Williamss 065 patent provides working examples only for mouse ES cells. While the 065 patent contemplates the generation of ES cells from numerous other species, including humans (see, e.g., A1853(col.3,ll.6-8)), a later prior art publication from Dr. Williams (referred to as Cherny) acknowledged the inability to isolate ES cells from any other species using his disclosed methods (A1215-20). Specifically, the Cherny article, on which Dr. Williams is listed as an

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author, states that [t]he murine model for totipotential stem cell isolation is yet to prove applicable to domestic animals, and thus ES cells have only been successfully isolated from the mouse. 1 A1215; A1220. In fact, as it turns out, scientists could not even reliably apply known methods for obtaining mouse ES cell cultures to certain strains of mice. By the mid-1990s, success in isolating ES cell cultures from even the most permissive mouse strain, called the 129 strain, stood at or below thirty percent, and ES cell cultures had been obtained from only a few other strains. A1374. Moreover, researchers derived ES cells from some of these other mouse strains only after significant alterations to the methods, including culturing the source of ES cells away from other tissues in the mouse embryo. A1377. Even with these

alterations, those skilled in the art still failed to generate cultures of ES cells from the medically important nonobese diabetic (NOD) mouse strain. A1379-82. Not until 2009, twenty-eight years after ES cells were derived from the first mouse strain, did researchers successfully generate cultures of ES cells from NOD mice. A1803-07.

The murine model described in Cherny is the same as that described in the Williams patent. See A1757-58.

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III.

Piedrahita and Bongso: Methods Developed for Mouse Embryonic Stem Cells Proved Unsuccessful in Deriving Embryonic Stem Cell Cultures from Other Species, Including Humans The early methods for deriving mouse ES cells also proved unsuccessful

when applied to other species, including rats, pigs, sheep, and humans. The rat, a close relative of the mouse, is another rodent commonly used in biomedical research. Yet, despite their similarities, researchers could not apply the methods developed for mouse to rat. Researchers first reported the generation of rat ES cell cultures in 1994, thirteen years after mouse, in a paper indicating that the work required the establishment of complex culture media and optimal culture conditions. A1384-88. But even this first report turned out to be premature, as the purported rat ES cells turned out to be contaminating mouse ES cells. A139094. Only after another fourteen years, in 2008, a full twenty-seven years after the identification of mouse ES cells, did researchers, specifically Dr. Mia Buehr and colleagues, generate true cultures of rat ES cells. A1790-801. Researchers also failed to derive cultures of pig and sheep ES cells using the methods developed for mouse. A1416-38. Following conventional methods for deriving mouse ES cells (A1419-20), Dr. Jorge Piedrahita generated additional mouse ES cell lines, but failed to generate either sheep or pig ES cells (A1433). As Dr. Piedrahita wrote in a 1990 publication, only cell lines with epithelial-like morphology were isolated from ovine [sheep] embryos. Id. And while cells with

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an ES-like morphology were isolated from pig, these cells failed to differentiate into other cell types either in vitro or in vivo. A1416; A1426; A1431-33. Even by 1995, pig ES cell cultures remained elusive (A1440-49), with researchers reporting that, [i]n spite of intense efforts by many investigators, it has not been possible to isolate stable porcine [pig] ES cell lines using conditions optimized for the mouse (A1445-47). Finally, in 1994, another researcher, Dr. Ariff Bongso, reported that methods used to generate mouse ES cell cultures failed to produce stable human ES cell cultures capable of proliferating in culture for even two weeks. A1470-77.

Dr. Bongsos method included culturing human blastocysts for one to two days to allow the ICM cells to emerge. A1471. After a total of eight to nine days, the ICM clusters were removed from the culture and disaggregated using trypsin. Id. Then, as in Williams, the disaggregated cells were plated directly onto culture dishes in LIF-containing culture medium without a feeder layer. A1471-72. This method produced cell colonies that resembled mouse ES cell colonies: the cells displayed a typical stem-cell morphology, and they formed tightly packed (or compact) colonies in which individual cells were difficult to recognize. A1474. Yet, the cell cultures were not stable; after two passages, the cells either differentiated into fibroblasts or died. Id.

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In light of these failures, several research groups in the early to mid-1990s turned to alternative approaches for deriving pluripotent cells from domestic animals and humans. For example, as described in the Cherny article,

Dr. Williams and his research team isolated primordial germ cells (PGCs), cells that give rise to eggs or sperm, from post-implantation cow embryos as a substitute for ES cells from blastocyst embryos. A1215; A1217. Another scientist,

Dr. Brigid Hogan, likewise turned to post-implantation embryos, including postimplantation human embryos, to derive PGCs (A1507-22), concluding that [a]ttempts at isolating ES cells from other animals [than mouse] apparently have failed (A1515 (U.S. Patent No. 5,690,926, col.1,ll.60-64)). IV. Dr. James Thomsons Successful Invention of Primate and Human Embryonic Stem Cell Cultures Others persisted in their efforts to derive ES cells from pre-implantation blastocysts of non-murine species. One of these individuals, Dr. James Thomson from the University of Wisconsin, ultimately succeeded where others had failed he generated stable cultures of ES cells from human embryos. Dr. Thomson first derived ES cell cultures from two primate speciesthe common marmoset and the rhesus monkey. A93(col.6,ll.11-15); A94(col.8,ll.1144). Specifically, he established primate ES cell cultures using specific culture conditions. In the first stage, blastocysts were isolated, placental trophoectoderm cells were removed by immunosurgery, and the resulting ICM cells were plated in 13

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defined culture medium on culture dishes with a feeder layer of mouse fibroblast cells. A94(col.8,ll.11-56). After seven to twenty-one days in culture, the ICMderived cell masses were removed from culture and separated (or dissociated) into individual cells. Id.(col.8,ll.57-62). These dissociated cells were then recultured in fresh culture medium and, unlike the methods described by Williams and Bongso, on a feeder layer. Id.(col.8,ll.63-64). From this second culture, ES cell colonies were individually selected. A94-95(col.8,l.65col.9,l.6). The primate ES cell colonies Dr. Thomson selected differed

morphologically from mouse ES colonies. While both primate and mouse cell colonies are compact, primate ES cell colonies are flatter than those of mouse. A95(col.9,ll.62-63); see also A97(col.14,ll.42-43). Flat, compact colonies of ES cells were not known to exist before Dr. Thomson isolated primate ES cells. A1761. And unlike mouse ES cell colonies, individual primate ES cells within the colony are easily distinguished. A95(col.9,ll.63-64); see also A97(col.14,ll.42-43). Dr. Thomson determined that primate ES cells also differ from mouse ES cells in their required culture conditions. Namely, as described in the 913 patent, primate ES cells require a feeder layer to retain their undifferentiated state, both during derivation and maintenance. A94(col.8,ll.53-64); A96(col.12,ll.51-63).

Mouse ES cells, in contrast, retain their undifferentiated state in LIF-containing medium without a feeder layer. A96(col.12,ll.51-63).

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Primate ES cells also differ from those of mouse in their expression of certain cell-surface proteins, or markers (A95-96(col.10,l.1col.11,l.24)), and in their ability to differentiate into extra-embryonic tissue (A96-97(col.12,l.64 col.13,l.4)). Primate ES cells are negative for the SSEA-1 cell-surface marker, but positive for SSEA-3, SSEA-4, Tra-1-60, and Tra-1-81. Mouse ES cells, in

contrast, express SSEA-1, but none of the other markers. A96(col.11,ll.15-24). Primate ES cells can also, when cultured at high density, differentiate into trophoblast cells that express a protein called chorionic gonadotropin. Mouse ES cells do not. A96-97(col.12,l.64col.13,l.4; col.13,ll.64-67). Dr. Thomson then followed the same method to generate cultures of ES cells from human pre-implantation embryos, 2 something that no one else had achieved despite significant interest in the scientific and medical communities. He reported his invention of human ES cell cultures in 1998 in the prestigious magazine Science. A5079-81. After Dr. Thomsons 1998 publication, other researchers soon succeeded in deriving human ES cell cultures using Thomsons method. In early 2000,

Dr. Bongso, who had previously failed to obtain stable human ES cell cultures, now reported success. A1479-84. His research groups 2000 publication

U.S. Patent Application No. 09/106,390, Non-final Rejection 9-24-1999 (A5010-18); Affidavit 1-7-2000 (A5007-09).

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acknowledged that, [s]ince the[ir] early studies did not use embryonic feeder cell support . . . but relied instead on LIF supplementation of the culture medium, these cells eventually underwent differentiation or death. A1479. Using the feeder cell-based culture system described by Dr. Thomson (A1479; A1484), Dr. Bongsos group now selected flat colonies of cells with the morphological appearance of . . . primate ES cells (A1479). Unlike their 1994 publication, they now recognized that human ES cell colonies differ substantially from mouse ES cells in terms of morphology . . . and response to LIF. A1482. Dr. Bongsos 2000 publication cited Dr. Thomsons work deriving cultures of ES cells from rhesus monkeys, marmosets, and humans, and acknowledged that the ES cell lines his group had obtained are similar in properties to those described by Thomson and coworkers and share many features of . . . monkey ES cells. A1482; A1484. Similarly, in 2004, Dr. Melton, Dr. McMahon, Dr. Cowan, and their colleagues at Harvard University obtained an additional seventeen ES cell lines from human embryos. A1774-77. They derived these ES cell lines according to published protocols, citing Dr. Thomsons published work. A1774; A1776. They then reported that these human ES cell colonies had a compact colony structure, as reported for other embryonic stem-cell lines, again citing Thomson. A1775. Notably, as discussed below, Drs. Melton and Cowan later submitted declarations to the PTO in this reexamination on behalf of Watchdog.

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Dr. Thomsons invention of human ES cell cultures earned him significant acclaim in the scientific community, including from scientists active in the stemcell field. Interviewed by Harvard Magazine for a 2004 article on stem cells (A1779), Dr. Meltons colleague and coauthor, Dr. McMahon, opined that harvesting and maintaining a line of stem cells from any animal is not routine at all, and thus it was an astounding breakthrough when, in 1998, University of Wisconsin researcher James Thomson successfully established and sustained several human stem-cell lines in culture (A1780). Dr. Thomson also received awards and grants from numerous scientific and medical organizations for his generation of human ES cell cultures. See A207-08. For example, in 1999, Science magazine featured Dr. Thomsons work in its Scientific Breakthrough of the Year issue. 3 In 2001, Dr. Thomson was inducted into the Biotech Hall of Fame, which noted that his work on human ES cells set the stage for a revolution in medicine and science, and, in 2003, Dr. Thomsons work won him the World Technology Summit Award in Health & Medicine sponsored by the World Technology Network. A208. In 2005, the AAAS

identified Dr. Thomsons derivation of human ES cells as one of the most significant Milestones of Science. A207. More recently, in 2013, Dr.

Available at, http://www.sciencemag.org/content/286/5448/2238.summary.

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Thomsons invention earned him the McEwen Award for Innovation from The International Society of Stem Cell Research. 4 Human ES cells have also been a commercial success. As of June 2010, WARF had entered into 1,822 academic licenses (at no cost to academic researchers) and shipped 1,633 vials of human ES cells to academic institutions. A1809-10. WARF had also executed 39 commercial license agreements with 29 companies for use of human ES cell cultures covered by the 913 patent. Id. V. The 913 Patent The 913 patent discloses Dr. Thomsons invention of primate embryonic stem cell cultures. A91(col.1,ll.26-28). The 913 patent claims priority to an application filed on January 20, 1995, and issued on April 18, 2006, with three claims directed to a replicating in vitro cell culture of human ES cells with certain characteristics. Specifically, claim 1, as amended during the inter partes

reexamination and considered by the Board, recites as follows: 1. A replicating in vitro cell culture of pluripotent human embryonic stem cells derived from a pre-implantation embryo, wherein the stem cells (i) will proliferate in an in vitro culture for over one year in an undifferentiated state 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
4

Available innovation.

at

http://www.isscr.org/home/awards/mcewen-award-for-

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of endoderm, mesoderm, and ectoderm tissues throughout the culture, and (iv) are inhibited from differentiation when cultured on a fibroblast feeder layer. A1714 (emphases added). Claim 1 thus covers a cell culture of human ES cells with the properties of true ES cells: the cells will proliferate in an undifferentiated state (self-renew) for over one year, maintain a normal karyotype, and maintain pluripotency in prolonged culture. See A92(col.3,ll.62-67). The claim also covers the specific culture conditions Dr. Thomson identified as necessary to derive and maintain human ES cell cultures. Namely, the claim recites that the human ES cell cultures will proliferate in an undifferentiated state (i.e., are inhibited from differentiation) without the presence of LIF and when cultured on a fibroblast feeder layer. See A96(col.12,ll.51-63). Claims 2 and 3 recite additional characteristics of the in vitro human ES cell culture and were each amended during the reexamination to be written in independent form. Specifically, claim 2 requires that the ES cells of the cell culture will spontaneously differentiate to trophoblast and produce chorionic gonadotropin when cultured to high density. A1714. Claim 3 requires that the ES cells of the culture do or do not express certain cell markers: the stem cells are negative for the SSEA-1 marker, positive for the SSEA-4 marker, and express

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alkaline phosphatase. Id. Independent claim 4, added during reexamination, includes all the limitations of claims 1, 2, and 3. 5 A1715. VI. Inter Partes Reexamination Watchdog filed a request for inter partes reexamination of the 913 patent in 2006.6 A106-07. In its request, Watchdog asserted a substantial new question of patentability based on the printed publications of Robertson 83, Robertson 87, and Piedrahita. A109-10. The PTO granted the reexamination and subsequently rejected the claims as anticipated by or obvious over either Williams or Hogan and as obvious over combinations of Robertson 83, Robertson 87, and/or Piedrahita in view of Williams and Hogan. A179; A186-200.

Watchdog contends that claims 1-3 are the only claims before this Court (App. Br. 7 n.1), because the Boards decision in two places states that it affirm[s] the Examiner decision in the Answer dated July 30, 2009 confirming the patentability of claims 1-3 of the 913 patent. A3; A13. But, as acknowledged by the Board elsewhere in its decision, amended claims 1-4 were the actual claims before the Board. Indeed, the Board expressly stated that it reviewed and agree[d] with the Examiners determination of November 23, 2011, finding that claims 13 and new claim 4 are patentable over the cited prior art. A5. Accordingly, contrary to Watchdogs contention, claims 1-4 set forth at pages A1714-15 of the joint appendix are the claims affirmed by the Board and now before this Court on appeal. On the same day, Watchdog also filed two requests for ex parte reexamination of related U.S. Patent Nos. 5,843,780 and 6,200,806, which claim a purified preparation of primate and human ES cells, respectively. In both, reexamination certificates have issued finding patentable amended claims. Reexamination No. 90/008,139, Certificate 6-17-2008 (A5048-50); Reexamination No. 90/008,102, Certificate 6-17-2008 (A5045-47). The amendments mirror those made during this inter partes reexamination proceeding.
6

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In response, WARF filed evidence in support of patentability, including a declaration by Dr. Colin Stewart, a world-renowned expert on ES cells. A1323-31. In his declaration, Dr. Stewart described his belief in 1990 that generating primate or human ES cells would be very difficult as well as his later surprise at Dr. Thomsons success. A1324-35. Dr. Stewart also described the technical

shortcomings of the Williams patent and the numerous failures by others to derive ES cells from species other than mouse. A1325-29. WARF explained that

Williams did not enable the production of human ES cell cultures, as acknowledged by Williamss later statements in Cherny, and thus Williams could not anticipate the claims. A212-16. WARF also amended the claims. A205; A493-94. Watchdog countered with declarations from several stem-cell researchers, including Drs. Melton and Cowan, both of who opined that they had successfully isolated human ES cells in our lab by simply following the[] methods taught for deriving mouse, rat, pig and sheep ES cells and without recourse to Dr. Thomsons publications or patents. A337-42; A451-56. As noted above, however, Drs. Melton and Cowans 2004 publication reported deriving human ES cell lines according to protocols in Dr. Thomsons published work. A1776. A1774;

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Based on this evidence, the Examiner determined that the amended claims were patentable (A512-13), and Watchdog appealed to the Board. The Board reversed the Examiner and entered new grounds of rejection, including a 102(b) rejection based on Williams and four 103 rejections based on Williams, Robertson 83, Robertson 87, Piedrahita, and Hogan. A41-79. Regarding anticipation, the Board held that Williams taught and enabled a replicating cell culture of human ES cells. The Board concluded that Williams disclosed that feeder cells can be used in its methods (A53), and that WARF had not provided evidence that the Williams method [for deriving mouse ES cell cultures] would not work when applied to human embryos (A53). The Board also held that the claims would have been obvious based on the cited prior art, lumping all four obviousness rejections together. A60.

Specifically, the Board concluded that, based on the techniques taught in Williams and Robertson 87, it would have been obvious to try to apply mouse techniques to human embryos. A74-75. In so holding, the Board acknowledged the

shortcomings of ES cells derived from other mammalian species, but relied on (1) the 1994 report of success in generating rat ES cell cultures, and (2) Drs. Melton and Cowans declarations that they had successfully isolated ES cells by following the methods taught for mouse, rat, pig, and sheep. A76-77.

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WARF moved to reopen prosecution. A1713. WARF then amended claims 2 and 3but only to rewrite them in independent formand added new independent claim 4, which simply includes all the limitations of claims 1-3. A1714-15. WARF also introduced new evidence, including a second declaration by Dr. Stewart, to support its nonenablement and nonobviousness positions. A175562. Dr. Stewart explained that the methods of Williams would not work to

generate a replicating human ES cell culture because Williams cultured ICM cells directly on a culture dish in the presence of LIF but without a feeder cell layer. A1718-20; A1756. As further support, Dr. Stewart pointed to the failure of

Dr. Bongso to obtain stable human ES cell lines using the same technique. A1720; A1757. Dr. Stewart also explained that Williams refers to using a feeder layer not for isolating ES cells, but for growing the ES cells once isolated. A1721; A1756. Regarding obviousness, WARF explained that the Board misapplied the obvious-to-try obviousness standard because the solutions to deriving human ES cell cultures were neither finite nor predictable. A1729-37. In particular, WARF stated that there were a myriad of methods to try and that Dr. Thomson succeeded in part because he was the first to identify the distinct morphology of primate ES cell colonies. A1730; A1735; A1761. WARF also explained that the methods developed to generate mouse ES cells failed to yield predictable results when

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applied to other species, introducing evidence that the scientific community had failed to obtain either true rat ES cells or NOD mouse ES cells until twenty-seven and twenty-eight years, respectively, after the first creation of cultures of mouse ES cells. A1730-31; A1736; A1760. WARF also introduced new evidence discrediting Drs. Melton and Cowans declarations. Specifically, WARF submitted the 2004 publication by these very researchers, which, as discussed above, credited Dr. Thomsons 1998 Science paper as guiding their work. A1737-38; A1774-77. WARF also introduced a 2004 Harvard Magazine article in which Dr. McMahon, a member of Dr. Meltons team, stated that harvesting ES cells from any animal is not routine at all, and that Dr. Thomsons generation of human ES cells was an astounding breakthrough. A1739; A1779-80. Finally, WARF introduced evidence of secondary considerations of nonobviousness. WARF pointed to the acclaim Dr. Thomson had received for inventing cultured human ES cells. A1739-41. And WARF introduced new

evidence of commercial success, including the numerous academic and commercial licenses for human ES cells as claimed by the 913 patent. A1741-42; A1808-10. Although afforded the opportunity to, Watchdog did not reply to any of the new evidence presented by WARF. See A18-19.

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The Examiner again found pending claims 1-4 patentable. A14-18. The Examiner found that, based on Dr. Stewarts second declaration, the methods in Williams were nonenabling for human ES cell cultures. According to the

Examiner, Williams did not teach the use of a feeder layer to derive ES cells or the morphology of the colonies to select, and thus the methods described by Williams would not have worked to isolate human ES cells. A22-26. The Examiner also relied on (1) Dr. Williamss statements in Cherny acknowledging the murine models failure in other domestic animals, and (2) the prosecution history of Williamss patent, in which claims to ES cells from any animal, including human, were narrowed to mouse ES cells following an enablement rejection. A26-28. The Examiner also concluded that the unpredictability in the art demonstrated nonobviousness. A29. Relying on the decades it took researchers to identify ES cells from rats and NOD mice, and the decision by Cherny and Hogan to seek an alternative route, i.e., primordial germ cells, the Examiner concluded that, at the time of the invention, the scientific community viewed ES cell research as lacking in any substantiated evidence of any reasonable progression from the mouse model, through other rodents including rats, and on through domesticated mammals. A30-31. This, according to the Examiner, set the stage for the reaction of the scientific community in 1998 when Dr. Thomson reported the isolation of human ES cells, as seen in the accolades which Thomson

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received, especially from the American Association for the Advancement of Science (AAAS), the premiere scientific organization in this country, and Dr. McMahon, the Harvard University ES cell researcher who called Dr. Thomsons invention an astounding breakthrough. A31-32. The Board affirmed (A1-13), finding first that the Williams patent was nonenabling because (1) it did not teach the use of a feeder layer to isolate ES cells from the embryo, and (2) Dr. Bongso had reported negative results for human ES cell cultures without the use of feeder cells (A6-7). Accordingly, the Board held that Williams did not anticipate claims 1-4. A7. Turning to obviousness, the Board found that WARFs evidence that human ES cell colonies have a distinct morphology from mouse colonies established that identifying human ES cells was not routine. A9. The Board found that

Dr. Thomson, in deriving embryonic stem cells from human embryos, did more than just follow the path that had already been taken in the mouse; rather, the invention took innovation by Dr. Thomson. A10. The Board also relied on the repeated failures to derive rat ES cells using the available ES cell technology, Dr. McMahons statement that deriving ES cells from any animal is not routine at all, and the accolades Dr. Thomsons work received in the scientific community. A10-11. Finally, the Board gave less weight to Dr. Meltons declaration in light of his 2004 publication crediting Dr. Thomsons published work. A11-12. The

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Board concluded that any reason to try the prior art methods to derive human ES cell cultures was outweighed by the strong countervailing evidence of nonobviousness. A12. Watchdog appealed. SUMMARY OF THE ARGUMENT Watchdogs newly raised 101 challenge on appeal from an inter partes reexamination is not properly before this Court. The patent statute and PTO regulations limit the scope of reexamination to challenges based on prior art patents and printed publications and to compliance with 112 requirements for new or deleted matter. Since this Court has jurisdiction to review only the merits of decisions within the PTOs jurisdiction, this Court does not properly have jurisdiction to resolve this issue. Alternatively, if the Court determines that the PTO could have considered 101, Watchdog waived its patent-eligibility challenge by not raising it before the PTO. This Court need not consider 101 as an antecedent issue when it was neither briefed to nor addressed by the Board. Furthermore, Watchdog cannot rely on the Supreme Courts Myriad decision as intervening authority, not only because Watchdog was keenly aware of the case and the 101 issues it raised, but also because Myriad does not materially alter the Boards decision in this case. Regardless, Watchdogs argument fails on the merits. All the claims recite a non-naturally occurring in vitro cell culture of human ES cells. These cultured ES

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cells are distinct from cells in an embryo in their cellular composition and properties. Moreover, the claimed cells exist as a culture, which the patent-insuit explains encompasses the culture medium, nutrients, and other components that sustain these cells outside the body in a plastic culture dish. Turning to the merits of the issues decided by the Board, substantial evidence supports the Boards decision that the prior art failed either to anticipate or render obvious claims to human ES cell cultures. Williams failed to enable an in vitro cell culture of human ES cells, and thus cannot anticipate the claims. As the Board found, Williams fails to describe using a feeder layer to isolate ES cells, and thus its methods would not have worked to generate human ES cell cultures. A6-7. These findings are supported by

substantial evidence, including the second declaration of Dr. Colin Stewart and the failure of Dr. Bongso to obtain stable human ES cell cultures without using a feeder layer. Moreover, Williams does not teach the distinct morphology of

human ES cell colonies, which differs substantially from that of mouse ES cell colonies. As Dr. Stewart stated, before Dr. Thomsons work, no one knew which cell colonies to select. And only after Dr. Thomsons discovery did others, relying on his insight, succeed in deriving additional ES cell lines from human embryos. The prior art also would not have rendered obvious an in vitro cell culture of human ES cells. No prior art reference taught the morphology of primate or

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human ES cell colonies, which the Board found took innovation.

A10.

Furthermore, despite extensive work, methods developed for mouse ES cells did not provide identified, predictable solutions for deriving ES cells from other species, including humans. Following the derivation of mouse ES cells in 1981, researchers had by 1995 failed to derive ES cells from other strains of mice and from other species, including rats, sheep, pigs, and humans. In fact, as relied on by the Board, it took until 2008, twenty-seven years after first obtaining cultures of mouse ES cells, before researchers successfully derived ES cells from rats. Accordingly, the Board correctly concluded that one of ordinary skill in the art would not have reasonably expected to successfully derive human ES cells armed solely with the knowledge of ES cells gained from mouse. Evidence of secondary considerations of nonobviousness provides further support for the Boards decision. Dr. Thomson received numerous awards and grants for his invention of human ES cells, including recognition from the AAAS, The International Society of Stem Cell Research, and fellow researchers. The discovery of human ES cells has also been a commercial success, generating numerous academic and commercial licenses for the use of the 913 patent. The Boards decision upholding the patentability of amended claims 1-4 is supported by substantial evidence and should be affirmed.

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ARGUMENT I. Standard of Review Whether a claim is directed to patentable subject matter is a question of law with underlying facts. Arrhythmia Research Tech., Inc. v. Corazonix Corp.,

958 F.2d 1053, 1055-56 (Fed. Cir. 1992). Anticipation is a question of fact, Forest Labs., Inc. v. Ivax Pharms., Inc., 501 F.3d 1263, 1268 (Fed. Cir. 2007), but [w]hether a prior art reference is enabling presents a question of law based upon underlying factual findings, Impax Labs., Inc. v. Aventis Pharms., Inc., 545 F.3d 1312, 1315 (Fed. Cir. 2008). Obviousness is also a question of law based upon underlying facts. Forest Labs., 501 F.3d at 1269. In reviewing decisions of the Board, this Court reviews questions of law de novo and reviews issues of fact for substantial evidence. Falkner v. Inglis, 448 F.3d 1357, 1363 (Fed. Cir. 2006). Substantial evidence is evidence that a reasonable person might accept as adequate to support a conclusion based on an examination of the record as a whole. Id. An agency decision can be supported by substantial evidence, even where the record will support several reasonable but contradictory conclusions. Id. at 1364.

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II.

Watchdogs Newly Raised 101 Challenge Is Improper in Inter Partes Reexamination Proceedings and, in Any Event, Was Waived A. Watchdogs 101 Challenge Is Not Properly Before This Court

The patent statute restricts the scope of reexamination to certain limited grounds, including prior art challenges based on patents and printed publications, as well as 112 requirements for new or deleted matter. But 101 cannot be resolved by reexamination. 35 U.S.C. 301, 311(a); 37 C.F.R. 1.906(a)-(c); see also In re NTP, Inc., 654 F.3d 1268, 1275-76 (Fed. Cir. 2011) (stating that challenges under 101 may not be raised in reexamination proceedings). According to 37 C.F.R. 1.906(c), [i]ssues other than those indicated in paragraphs (a) [prior art patents and printed publications] and (b) [claim scope] of this section will not be resolved in an inter partes reexamination proceeding. (Emphasis added.) The Manual of Patent Examining Procedure explains that, in ex parte reexamination, [r]ejections will not be based on matters other than patents or printed publications, such as . . . 35 U.S.C. 101. MPEP 2258. This same rule applies to inter partes reexaminations. See MPEP 2658 (Inter partes reexamination does not, however, differ from ex parte reexamination as to the substance to be considered in the proceeding.). Watchdog can point to no case, Board decision, or reexamination proceedingand WARF is aware of nonewhere the PTO considered 101 in a

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reexamination. Because Watchdog could not have raised 101 during the inter partes reexamination, it should be precluded from doing so now. Indeed, WARF respectfully submits that this Court does not properly have jurisdiction to resolve this issue, because this Court has jurisdiction to review only the merits of decisions that the PTO tribunal has jurisdiction to make. 35 U.S.C. 141-144; 28 U.S.C. 1295(a)(4); see also Sage Prods., Inc. v. Devon Indus., Inc., 126 F.3d 1420, 1426 (Fed. Cir. 1997) (By and large, it is our place to review judicial decisions . . . [n]o matter how independent an appellate courts review of an issue may be, it is still no more than thata review.). Accordingly, an appeal from an inter partes

reexamination is an inappropriate forum for resolving a newly raised challenge under 101, and Watchdogs claim should be dismissed. B. Watchdog Waived Its Newly Raised 101 Challenge

Alternately, if the Court determines that 101 could have been addressed during the reexamination proceeding, Watchdog waived its 101 challenge by not raising it before the Board. Absent exceptional circumstances . . . we generally do not consider arguments that the applicant failed to present to the Board . . . . In re Baxter Intl Inc., 678 F.3d 1357, 1362 (Fed. Cir. 2012) (citations omitted). Watchdog raises several arguments in an effort to justify its failure to raise 101 before the Board, but none has merit. First, Watchdog argues that the Court should decide this case on 101 because it is an antecedent issue and purportedly

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dispositive, noting that the Court addressed 101 in Comiskey in an appeal of a PTO decision finding the claims invalid for obviousness. Appellant Brief (App. Br.) 16 (citing In re Comiskey, 554 F.3d 967, 975 (Fed. Cir. 2009)). But no case holds that the Federal Circuit must separately consider 101 when it was neither briefed to nor addressed by the Board, and a legion of Board decisions have been reviewed by this Court without separately addressing 101. See, e.g., In re Glatt Air Techniques, Inc., 630 F.3d 1026, 1027 (Fed. Cir. 2011). Moreover, in Comiskey, the Court affirmed an agency decision on alternate grounds, relying on well-established precedent that, for reasons of judicial economy, a reviewing court can affirm an agency decision on a legal ground not relied on by the agency if there is no issue of fact, policy, or agency expertise. Comiskey, 554 F.3d at 974 (citing Sec. & Exch. Commn v. Chenery Corp., 318 U.S. 80 (1943)). But Watchdog does not seek to affirm the decision of the Board confirming the patentability of the claims; rather, it seeks to reverse it. As explained in Comiskey, [t]he situation is quite different where a party seeks for the first time on appeal to raise a new ground on appeal for setting aside agency action. Id. at 975 n.6. Permitting an appellant to do so raises judicial economy concerns as well as concerns about sandbagging, where a party pursues a particular strategy before the Board and later, if the outcome is unfavorable, claims that the course it followed was reversible error. See In re DBC, 545 F.3d 1373,

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1380 (Fed. Cir. 2008) (declining to hear a challenge on appeal that was not raised before the Board). Watchdog also argues that the Supreme Courts decision in Association for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107 (2013), constitutes intervening authority that favors Federal Circuit action, because it could have materially altered the decision of the Board. See Hormel v. Helvering, 312 U.S. 552, 558-59 (1941). This argument lacks merit. As an initial matter, Myriad could not have materially altered the decision of the Board because the reexamination statute did not confer jurisdiction on the Board to resolve 101. Moreover, as Watchdog itself acknowledges, the Supreme Court in Myriad merely restated existing 101 law regarding products of nature (App. Br. 14), in a holding that was expressly limited to genes, Myriad, 133 S. Ct. at 2120. Thus, assuming for the sake of argument that 101 could have been reviewed during reexamination, Myriad would not have materially altered the analysis of claims directed to in vitro embryonic stem cell culturesan entirely different technology. Finally, it is undisputed that Watchdog was aware of Myriad and the 101 issues raised in Myriad during the reexamination proceedings before the PTO. Indeed, Watchdogs lawyers in the reexamination, the Public Patent Foundation, also litigated that case. Id. at 2110. Despite this, Watchdog never raised 101 before the PTO. It should be precluded from doing so now.

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C.

Claims to an In Vitro Cell Culture of Human Embryonic Stem Cells Recite Non-Naturally Occurring Subject Matter and Thus Are Patent Eligible Under 101

If the Court determines that it should address 101 on the merits, the claims at issue are clearly patent eligible. Section 101 of the Patent Act states that [w]hoever invents or discovers any new and useful . . . composition of matter, or any new and useful improvement thereof, may obtain a patent therefor . . . . Under cases such as Myriad, Chakrabarty, and Funk Brothers, the Supreme Court has explained that new and useful compositions of matter, as opposed to merely naturally occurring phenomena, constitute patent-eligible subject matter. Myriad, 133 S. Ct. at 2116; Diamond v. Chakrabarty, 447 U.S. 303, 308-09 (1980); Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948). All of the claims-at-issue recite a replicating in vitro cell culture of pluripotent human embryonic stem cells having certain characteristics. Importantly, and notwithstanding Watchdogs unsupported attorney argument to the contrary, embryonic stem cells in culture are distinct from cells found in the ICM of an embryo. As explained by Dr. Colin Stewart, a world-renowned expert on ES cells: The ES cells within the ICM and an established replicating culture of ES cells are distinct cell populations, each with its own unique cellular composition and properties.

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A1756, 12. In other words, replicating stem cells in culture are a unique product of human ingenuity, not nature, and have a distinctive character and use. This contrasts with the genes at issue in Myriad, which existed in nature before Myriad found them. 133 S. Ct. at 2116. Additionally, the claims on appeal recite not just cells, but an in vitro cell culture. Cells in culture are, as defined in the 913 patent, grown in a culture medium containing processed ingredients. For example, the 913 patent describes an exemplary ES medium containing 80% Dulbeccos modified Eagles medium, 20% fetal bovine serum, 0.1 mM -mercaptoethanol, and 1% nonessential amino acid stock. A94(col.7,ll.56-62). Accordingly, the subject matter of the claimed invention is not a natural phenomenon and therefore is patent eligible as a new and useful composition of matter. Consistent with this view, during the original prosecution of the 913 patent (prior to the reexamination), the PTO expressly confirmed the patent eligibility of a replicating in vitro cell culture. While the claims were initially rejected under 101 because they purportedly encompassed products of nature, the PTO found that amending the claims to recite a replicating in vitro cell culture overcame

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the basis of the rejection. 7 Thus, the PTO expressly found that the claims were directed to patent-eligible subject matter. 8 Watchdogs 101 argument relies almost exclusively on a series of unsupported allegations: that ES cells in culture are chemically identical to those in the embryo (even though Dr. Stewart declared that ES cells in culture have a unique composition and properties); that Dr. Thomson did not create or alter the properties of stem cells (even though Dr. Stewart explained that Dr. Thomsons cell cultures proliferated well past the stage where cells would normally die or differentiate); and that ES cells in culture are the same as cells inside an embryo (even though Dr. Stewart declared that ES cells in culture and those in the ICM are distinct cell populations). A1325, 11. WARF submits that, even based on the limited factual record available for review, it is evident that the claimed invention satisfies the requirements of 101 as interpreted by this Court and the Supreme Court. 9
7

Compare App. Br. 15-16 with A1756, 11-12;

U.S. Patent Application No. 09/982,637, Non-final Rejection 11-5-2003, at 3 (A5036; A5039); Final Rejection 6-25-2004 (A5027; A5029); Claims 4-8-2004 (A5023-26). Although the file wrappers of the original prosecution are not in the record, they are part of the public record, of which this Court may take judicial notice. See Fed. R. Evid. 201(b)(2); Standard Havens Prods., Inc. v. Gencor Indus., Inc., 897 F.2d 511, 514 n.3 (Fed. Cir. 1990).
8

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III.

Williams Failed to Enable an In Vitro Cell Culture of Human Embryonic Stem Cells, and Thus the Board Correctly Held that Williams Does Not Anticipate the Claims To be anticipatory, a prior art reference must enable one of ordinary skill in

the art to make the claimed invention. Impax Labs., 545 F.3d at 1314. Failures by others skilled in the art are strong evidence that the references disclosure was nonenabling. In re Donohue, 766 F.2d 531, 533 (Fed. Cir. 1985); see also Forest Labs., 501 F.3d at 1268-69. A. Williams Does Not Describe Deriving Embryonic Stem Cell Cultures Using a Feeder Layer, and Thus Would Not Work to Derive Human Embryonic Stem Cell Cultures

As the Board properly found, Williams does not disclose using a feeder layer to derive ES cells, and thus, as evidenced by Bongso, would not have worked to generate stable human ES cell cultures. A6-7. Substantial evidence, including the second declaration of Dr. Stewart, supports the Boards decision that Williams failed to enable an in vitro cell culture of human ES cells. Williams teaches two methods of deriving mouse ES cell cultures. As Dr. Stewart explained, both methods involve directly plating mouse blastocysts and ICM cells on culture dishes in a LIF-containing culture medium without a

(continued) Of course, had Watchdog raised a proper 101 challenge, WARF would have presented further evidence to establish the subject-matter eligibility of the claimed invention.
9

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feeder layer. A1756. Dr. Stewart explained that this technique will not work to generate human ES cell cultures, which, as described in the 913 patent, can be generated only by plating human ICM cells on a feeder layer of cells. A1756; A94(col.8,ll.53-64); A96(col.12,ll.51-63). The Boards decision is also supported by Dr. Bongsos failure to establish stable human ES cell cultures in 1994. See A6-7. Specifically, as explained by Dr. Stewart, Dr. Bongso used the Williams method of plating human ICM cells directly onto a culture dish with LIF but without a feeder layer. A1756-57. As Dr. Bongso later acknowledged, outside the context of any legal dispute: Since these early studies did not use embryonic feeder cell support . . . but relied instead on LIF supplementation of the culture medium, these cells eventually underwent differentiation or death. A1479. Dr. Bongsos failure to make the claimed

invention in 1994 is strong evidence that Williamss earlier disclosure was nonenabling. See Donohue, 766 F.2d at 533. The Boards decision is further supported by the PTOs earlier determination during prosecution of the Williams patent that Williams failed to enable methods of isolating ES cells from any animal other than mouse. 10 Indeed, despite

proposing that his invention extended to the generation of ES cells from other
10

U.S. Patent Application No. 07/477,960, Claims 5-31-1990 (A5051; A507477); Final Office Action 2-21-1992, at 3-5 (A5000; A5002-04); Response After Final Action 5-8-1992 (A5005-06); Certificate of Corrections (A1857-58).

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domestic animals and humans, Dr. Williams acknowledged in a 1994 prior art publication that [t]he murine model for totipotential stem cell isolation is yet to prove applicable to domestic animals, and [a]t this time ES cells have only been successfully isolated from the mouse. A1215; A1220. Watchdogs sole challenge to the Boards nonenablement decision is the Boards reliance on the declaration of Dr. Stewart. Calling the declaration

biased,11 Watchdog argues that Dr. Stewart mischaracterizes Williams by incorrectly claim[ing] that the use of feeder cells was taught by Williams in conjunction with ES cell maintenance, but not ES cell isolation. App. Br. 17-18. Not only is Watchdogs claim of bias misplaced, but its selective and unsupported reading of Williams fails to undermine the substantial evidence supporting the Boards findings. See Falkner, 448 F.3d at 1364. Dr. Stewart is an experienced ES cell scientist with no financial interest in the outcome of this reexamination. A1755. After reading the Williams patent, Dr. Stewart concluded that the patent does not teach using a feeder layer of cells to isolate ES cells. A1756, 11. While Williams states that the culture medium may or may not contain feeder cells, Dr. Stewart explained that this relates to the maintenance, or growth, of the ES cell colonies, and not the actual isolation of
11

Watchdog also criticizes the declaration as unchallenged. App. Br. 17. Watchdog, however, had but ignored the opportunity to present evidence in response to Dr. Stewarts second declaration after the reopening of prosecution.

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ES cells. Id. And that is, in fact, exactly what the Williams patent states: By culture medium is meant a suitable medium capable of supporting growth of ES cells. A1853(col.3,ll.54-55) (emphasis added). Watchdog comes to the exact opposite conclusionthat the definition of culture medium relates only to isolationthrough a misleading selection of patent excerpts. Watchdog suggests that the portion of Williams that discussed

isolation, starts at column 2, line 30 of the patent: a first aspect of the present invention relates to a method for the isolation of embryonic stem (ES) cells . . . . App. Br. 18 (citing A1852). According to Watchdog, this isolation portion of Williams continues until column 4, line 12, where the patent recites: Another aspect of the present invention contemplates a process for maintaining animal ES cells. A1853. Watchdog claims that, at this point, the patent beg[i]ns to discuss maintenance. App. Br. 19. Watchdog thus concludes that because the definition of culture medium falls between these two statements, it relates to the isolation and not the maintenance of ES cells. Id. at 18. Watchdog bolsters its argument with references to ES cell isolation (A1853,col.3,ll.35-39) and derivation (id.(col.4,ll.8-11) that also happen to fall between these two statements. App. Br. 18. But this selective reading ignores numerous references to growth and maintenance of ES cells within Watchdogs isolation portion of the specification.

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Specifically, starting at column 2, line 41, just eleven lines down from where Watchdog claims the isolation portion of Williams begins, the specification reads: A second aspect of the present invention, contemplates a process for maintaining animal embryonic stem (ES) cells. A1852 (emphasis added). Maintenance is again referred to throughout column 3, including at lines 6-7, 28-29, and 34-35. A1853. And finally, as described above, the definition of culture medium makes specific reference to the growth of ES cells. Id.(col.3,ll.54-55). Furthermore, unlike Watchdogs interpretation, Dr. Stewarts reading of Williams is supported by other sections of the patent. First, the only other

reference in Williams to a culture medium that may or may not contain feeder cells comes at the end of a paragraph directed to a process for maintaining animal ES cells. Id.(col.4,ll.12-26) (emphasis added). Second, Step 1 of Example 1, which is directed to the maintenance and growth of ES cells, describes a culture medium that includes a feeder layer of cells. Specifically, two ES cell lines, prior to culture in LIF, were maintained in a specific culture medium on a feeder layer. A1854(col.5,ll.26-29). And subsequent culture in LIF did not alter the growth of these cells. Id.(col.6,ll.33-34). In contrast, in Steps 2 and 3, directed to the derivation of ES cells, the cell culture medium never includes a feeder layer, a fact Watchdog does not dispute. A1854-55(col.6,l.59col.7,l.3; col.8,ll.9-31).

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Watchdog also asserts that it was flawed logic for the Board to cite evidence that one step of Williams process included feeder cells as proof that another step of the process did not. App. Br. 20. This is not what the Board did, however. Rather, the Board reviewed the evidence and concluded that in

instances in which feeder cells are utilized by Williams, the feeder cells were used to maintain ES cells, but not to derive them. A7. Finally, Watchdog claims that the Boards nonenablement decision contradicts statements in its earlier decision. Specifically, Watchdog points to statements by the Board that feeder cells were known in the art for deriving stem cells, and that Robertson 87 taught that feeder layers are essential for isolation of ES cell lines. App. Br. 19. First, anticipation cannot be based on a combination of references, so to the extent that Watchdog is arguing that the Board should have combined Williams with Robertson, that argument fails to address anticipation by Williams. Regardless, in its first decision, the Board did not have the additional evidence placed on the record by WARF. Presented with Dr. Stewarts testimony that Williamss method would not, in fact, have worked when applied to human embryos, the Board did not flip-flop, as Watchdog charges (id. at 2), but rather reevaluated the issue in light of the new, unrebutted evidence and properly concluded that Williams failed to enable the derivation of human ES cell cultures.

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B.

Williams Also Does Not Describe the Distinct Morphology of Human Embryonic Stem Cell Colonies

The Board also found that primate and human ES cell colonies have a distinct morphology. This finding is itself supported by substantial evidence and provides further support for the Boards decision that Williams, which undisputedly does not teach the morphology of non-murine ES cell colonies, failed to enable the isolation of human ES cell cultures. Specifically, the Board found that identifying human ES cells was not routine because human ES cell colonies have a different morphology than mouse ES cell colonies. A9-10. As the 913 patent itself explains, [t]he colonies of primate ES cells are flatter than mouse ES cell colonies and individual primate ES cells can be easily distinguished. A95(col.9,ll.62-64). According to Dr. Stewart: Flat, compact colonies of hES cells had not been described at any time before Dr. Thomsons invention. It should be remembered that at this stage in the process, the culture dish contains a heterogeneous mixture of cells and debris, a plethora of colonies, and it would not have been apparent what cells/colonies to choose for further study without the insight exhibited by Dr. Thomson. A1761, 35. Accordingly, the Board found that it would not have been known which cells to select during the stem cell derivation process, and thus deriving human ES cell cultures took more than just following the path taken in mouseit took innovation by Dr. Thomson. A9-10.

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This finding is supported by Dr. Bongsos 1994 failed attempt to derive stable human ES cell lines. Based on the knowledge in the art, Dr. Bongso selected cell colonies with a typical stem cell-like morphology reported for other species. A1474. Like mouse ES cell colonies, the colonies described in

Dr. Bongsos publication were tightly packed (or compact), but they were not described as flat like human ES cell colonies. Also, in Bongso, unlike human ES cell colonies, the individual cells were difficult to recognize. Id. And selection of these cells did not generate replicating cell cultures of human ES cells as claimed in the 913 patent. Only after Dr. Thomson determined and reported the distinct morphology of human ES cell colonies did others succeed in deriving ES cells from human blastocysts. In early 2000, Dr. Bongso and his research group reported deriving stable pluripotent human ES cell lines by using a feeder cell layer and selecting flat colonies of cells with the morphological appearance of . . . primate ES cells. A1479. Based on the teaching of Dr. Thomson, this 2000 publication recognized that human ES cells differ substantially from mouse ES cells in terms of morphology . . . . A1482. Similarly, in 2004, Drs. Melton and McMahon and colleagues generated an additional seventeen ES cell lines from human embryos. A1774-77. These researchers reported that the cultured cells displayed the same

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compact colony structure as reported for other stem-cell lines, citing Thomsons initial and Bongsos subsequent derivation of human ES cells. A1775-76. Watchdog argues that Dr. Stewarts testimony regarding the different morphology of primate and mouse ES cell colonies is inconsistent with and insufficient to overcome all the other evidence regarding colony morphology. App. Br. 21. Yet, the only evidence Watchdog recites is the similarities between the cells (high nuclear to cytoplasmic ratio and prominent nucleoli) and the similar compact colony formation described in the 913 patent. Id. at 22. Watchdog claims that these are the three characteristics that Thomson revealed . . . as the bases on which to choose colonies . . . during the isolation process. Id. But Watchdog ignores the express teaching of the 913 patent that primate ES cell colonies are flatter than mouse ES cell colonies, with individual cells that, unlike in mouse, are easily distinguished. A95(col.9,ll.56-67). Accordingly, and

contrary to Watchdogs assertion (App. Br. 22), Dr. Thomson did include his recognition of the flatness of the cell colonies in the patents instructions. Watchdog also argues that the significance in the distinction between mouse and human ES cell colonies is overstated since Thomson was not required to pick a hES colony out of a sea of mouse ES colonies. Id. at 23. But this argument misses the point. Dr. Thomson was required to select a human ES cell colony out of a sea of other human cells. As Dr. Stewart explained, at this stage of the

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process, the culture dish contains a heterogeneous mixture of cells and debris and a plethora of colonies, and thus, it would not have been apparent what cells/colonies to choose for further study before Dr. Thomsons invention. A1761, 35. As described above, Dr. Bongso selected cell colonies based on the morphology of mouse ES cell colonies, and those colonies failed to give rise to stable human ES cell cultures. Only after Dr. Thomsons invention did Dr. Bongso select flat colonies of cells with the morphological appearance of . . . primate ES cells, and thus succeed in generating stable human ES cell cultures. A1479. Finally, Watchdog argues that, even [i]f the characteristic features of hES colonies didnt immediately identify the colonies as such, common sense would have guided an ordinary skilled scientist to test different colony types for those features. App. Br. 23. But, again, the actual failure reported by Dr. Bongso weighs against this hindsight supposition. Common sense might have guided scientists to pick other cell types, but there is no evidence that it would have guided them to the flat cell colonies that were ultimately successful. Because the Boards decision that Williams failed to enable human ES cell cultures is supported by substantial evidence, the Boards decision upholding the patentability of amended claims 1-4 as not anticipated by Williams should be affirmed.

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IV.

The Boards Holding that Prior Art Directed to Mouse Embryonic Stem Cell Cultures Would Not Have Rendered Obvious Claims to Human Embryonic Stem Cell Cultures Is Supported by Substantial Evidence A. The Distinct Morphology of Human Embryonic Stem Cell Colonies, the Unpredictable Nature of the Art, and the Failure of Others Provide Substantial Evidence of Nonobviousness

As this Court has explained, an invention would not have been obvious when the prior art both failed to disclose a claim limitation and failed to teach how to make that claim limitation as illustrated by the unpredictability in the art. See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1070-73 (Fed. Cir. 2012); Kinetic Concepts, Inc. v. Blue Sky Med. Grp., Inc., 554 F.3d 1010, 1019-20 (Fed. Cir. 2009); Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1086-90 (Fed. Cir. 2008). This case is a perfect example of such a situation. Human ES cell cultures as claimed in the 913 patent undisputedly did not exist in the prior art. Rather, the cited prior art teaches mouse ES cell cultures and methods of making mouse ES cell cultures. Moreover, methods of making mouse ES cell cultures failed to teach how to make the claimed human ES cell cultures. As described above, Dr. Thomson was the first to recognize that human ES cell colonies have a distinct morphology not taught in the prior art. See supra Section III.B. In selecting ES cell colonies from

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the plethora of heterogeneous cells and cell colonies at the ICM stage, the cited prior art provided just a single data pointthe morphology of mouse ES cell coloniesand thus did not teach one of ordinary skill how to achieve the claimed invention. The Board properly relied on this evidence in holding that the claims required innovation and were not just a predictable combination of the prior art. A9-10; A12. The prior art also did not teach the cell-culture conditions necessary to derive and maintain a replicating cell culture of human ES cells. The prior art contained numerous cell-culture conditions to try; it did not provide a limited and predictable set of culture conditions to apply to make human ES cell cultures. For example, following the first studies in mouse in 1981, scientists continued to develop new culture conditions for mouse ES cells, including substituting feeder cells with LIF-supplemented culture medium. A1377; A1847-58. In their attempts to derive rat ES cell cultures, researchers also developed complex culture media and optimal culture conditions, including cultures using LIF. A1384-88. But the human ES cell cultures described in the 913 patent, in contrast, are derived and maintained on a feeder layer of cells. A94(col.8,ll.53-65); A96(col.12,ll.51-63). Accordingly, the prior art directed to mouse ES cell cultures failed to render obvious claims to human ES cell cultures. See Kinetic Concepts, 554 F.3d at 1019-

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20 (affirming a holding of nonobviousness when the prior art failed to teach or suggest all the limitations of the claims). The nonobviousness of Dr. Thomsons invention is further demonstrated by the failure of others. Equipped with the prior art, those of skill in the art repeatedly failed to derive ES cell cultures from other species, including humans. Only after Dr. Thomson succeeded in primates and then humans did others succeed by following his work. And this achievement earned him numerous awards and grants as well as praise from fellow ES cell scientists. The Board properly relied on this evidence to hold the claims nonobvious. A10-11; A13. As described above, supra at pages 12, 38, 45, in 1994, Dr. Bongso applied the knowledge in the art and failed to generate stable ES cell cultures from human embryos. A1470-77. Evidence that others tried but failed to develop a claimed invention carries significant weight in an obviousness inquiry. Cyclobenzaprine, 676 F.3d at 1081. Indeed, such objective evidence of nonobviousness must be considered to help inoculate the obviousness analysis against hindsight. Mintz v. Dietz & Watson, Inc., 679 F.3d 1372, 1378 (Fed. Cir. 2012). Dr. Bongsos failure was not an isolated instance in the ES cell field. As described above, supra pages 10-12, other scientists repeatedly failed to generate ES cell cultures from certain mouse strains and from non-murine species.

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Although scientists first derived ES cell cultures from one mouse strain in 1981, by 1997 scientists were still working to obtain ES cells from additional mouse strains. A1374; A1377. And not until 2009, did researchers successfully generate ES cell cultures from the NOD mouse. A1803-07. Methods developed in mouse also failed to translate to rat, pig, or sheep. Despite a clear motivation to make ES cell cultures from rats, it took until 1994 before researchers first (though incorrectly) reported deriving rat ES cell cultures. A1384-88; A1390-94. It then took until 2008, over a quarter of a century after mouse ES cell cultures were first described, before researchers truly obtained ES cell cultures from rat. A1790-801. Similarly, in 1990, Dr. Piedrahita reported the failure to successfully produce pig or sheep ES cell cultures using techniques developed in mouse. A1431-33. And by 1995, researchers still had not reported success for pig: In spite of intense efforts by many investigators, it has not been possible to isolate stable porcine ES cell lines using conditions optimized for the mouse. A1445-47. As aptly summarized by renowned ES cell scientist Dr. McMahon in 2004, harvesting and maintaining a line of stem cells from any animal is not routine at all. A1780. Faced with such unpredictability, one of ordinary skill in the art would not have had a reasonable expectation of successfully deriving ES cell cultures from human embryos using available stem cell technology at the time of

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Dr. Thomsons invention.

See Sanofi-Synthelabo, 550 F.3d at 1090 (holding

claims nonobvious in light of evidence of unpredictability in the art). Hence the enthusiastic response to Dr. Thomsons success. Dr. Thomsons invention of human ES cell cultures receivedand continues to receivewide acclaim. As noted above, supra at pages 17-18, Dr. Thomson won numerous awards and grants from scientific and medical organizations for his invention of human ES cell cultures. See A207-08. Praise also came from individual ES cell scientists. Dr. Stewart expressed initial skepticism and later surprise at Dr.

Thomsons successful derivation of human ES cell cultures. A1324-31. And Dr. McMahon, who collaborated with Watchdogs declarant Dr. Melton, called the discovery an astounding breakthrough. A1780. Appreciation by peers supports a conclusion of nonobviousness. See Vulcan Engg Co. v. Fata Aluminium, Inc., 278 F.3d 1366, 1373 (Fed. Cir. 2002). In light of all of this evidence, the Board correctly rejected Watchdogs claim that the prior art provided step-by-step directions for the derivation and maintenance of mammalian embryonic stem cells (App. Br. 2), and instead concluded that Dr. Thomsons successful generation of human ES cell cultures took innovation (A10). The distinct morphology of human ES cell colonies, Dr. Bongsos failure to make the claimed invention, the unpredictable nature of the art, and the praise Dr. Thomson received constitute substantial evidence to support

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the Boards decision that the prior art would not have rendered claims to human ES cell cultures obvious. B. Watchdogs Arguments Fail to Undermine the Substantial Evidence Supporting the Boards Nonobviousness Decision

Watchdog attacks the Boards decision holding the claims nonobvious on several grounds. 12 None has merit. And none undermines the substantial evidence supporting the Boards decision that claims to human ES cell cultures would not have been obvious. 1. The Failure to Derive Rat Embryonic Stem Cell Cultures Until 2008 Shows the Unpredictability in the Art at the Time of the Invention

Watchdog criticizes the Board for relying on the 2008 isolation of rat ES cell cultures as evidence of nonobviousness. App. Br. 23. Specifically, Watchdog argues that the Board erred in relying on Dr. Buehrs 2008 isolation of rat ES cells rather than the 913 patents own statements about the prior art, i.e., that strong evidence of properties required of true ES cells have been published only for rodent ES cells, including rats. Id. at 24-25 (quoting A92-93(col.3,l.67col.4,l.5)). According to Watchdog, the later derivation of rat ES cells does not change what a
12

Watchdog first attacks the Boards decision holding the claims nonobvious based on the Boards finding that the isolation of human ES cells required invention in the recognition of the distinct morphology of human ES cell colonies. As described above, supra Section III.B, Watchdogs rebuttal evidence ignores the entire teaching of the 913 patent and fails to acknowledge Dr. Bongsos inability to achieve the same recognition.

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person skilled in the art, including Dr. Thomson, thought in 1995, the relevant time for the obviousness analysis. Id. at 25. The Board, however, did not rely on Dr. Buehrs work to assess obviousness from the vantage point of 2008. Rather, the Board relied on the twenty-eight-year delay between deriving ES cell cultures from mouse and from rat as evidence of the unpredictability in the art in 1995. There is no prohibition on relying on later events to show the understanding in the art at the time of the invention. See Eli Lilly & Co. v. Teva Pharms. USA, Inc., 619 F.3d 1329, 1339 (Fed. Cir. 2010). Moreover, the subjective belief of the inventor, Dr. Thomson, is legally irrelevant. The hypothetical person is not the inventor, but an imaginary being possessing ordinary skill in the art. Kimberly-Clark Corp. v. Johnson & Johnson, 745 F.2d 1437, 1454 (Fed. Cir. 1984). Finally, Watchdog cites nothing to support its

assertion that ordinarily skilled scientists would have assumed that rat ES cells could be produced with known techniques for deriving ES cells. App. Br. 25. Because scientists first reported deriving rat ES cell cultures only in 1994, thirteen years after mouse, there appears little basis for such an assumption. Importantly, regardless of whether or not those skilled in the art believed in 1995 that rat ES cells had been successfully isolated, the evidence nevertheless shows that ES cell scientists, including Dr. Thomson, did not believe that ES cell cultures had been successfully derived from any non-rodent species. As

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Watchdogs own quote from the 913 patent shows, there existed at the time strong evidence of properties required of true ES cells only for rodent ES cells. Id. at 2425 (quoting A92(col.3,l.67col.4,l.5) (emphasis added)). Watchdog extends this argument to claim that human ES cell cultures were obvious to try because there were a finite number of identified, predictable options taught in the prior art for making ES cells that would have led to anticipated success. Id. at 24 (citing KSR Intl Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007), and Bayer Schering Pharma AG v. Barr Labs., Inc., 575 F.3d 1341, 1350 (Fed. Cir. 2009)). This case is distinguishable from Bayer and KSR. In Bayer, the claimed invention was a pharmaceutical composition of micronized drospirenone for oral contraception. 575 F.3d at 1345. The Court concluded that the prior art would have funneled an ordinarily skilled formulator towards just two known and predictable options for using drospirenone in an oral formulationmicronization in a normal pill or an enteric-coated pill. Id. at 1350. Accordingly, the Court held that patent claims directed to one of those two predictable solutions would have been obvious. Id. at 1347, 1350. Similarly in KSR, all the elements of the claimed vehicle-pedal assembly existed in the prior art, and the Supreme Court held that it would have been obvious to combine them to perform their known functions. 550 U.S. at 417-18, 424-26.

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In this case, as described supra at Section IV.A, the prior art did not provide a limited number of predictable culture conditions to try and it did not provide any morphology of primate ES cell colonies to select. The art thus failed to provide a finite number of identified, predictable solutions for deriving human ES cell cultures. If it had, Dr. Bongso would have applied these solutions and obtained human ES cell cultures with anticipated success. He did not. Nor did anyone else. In fact, Watchdog repeatedly misstates the state of the art. Watchdog asserts that Piedrahita described protocols for isolating ES cells from murine, ovine (sheep) and porcine (pig) embryos. App. Br. 5; see also id. at 9. But Piedrahita failed to generate ES cell cultures from either sheep or pig embryos using protocols developed for mouse. A1416-38. Watchdog asserts that WARF has not cited any evidence of a scientist who failed to derive human ES cells. App. Br. 29. WARF, in fact, cites to Bongso, who failed to generate stable ES cell lines from human embryos. A1470-77. Watchdog also claims that [m]ultiple stem cell researchers succeeded in producing hES cells as claimed in the 913 patent following methods known in the art for mouse, rat, pig and sheep ES cells, without depend[ing] on Thomsons publication for their success. App. Br. 9 (citing Dr. Meltons

declaration). But, Dr. Thomson was the first stem-cell researcher to successfully generate human ES cells as claimed in the 913 patent. And only then did other

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researchers, including Dr. Melton in 2004, report success, citing Dr. Thomsons work. A1479-84; A1774-77. 2. The Evidence Supports the Boards Finding that Others Who Made Human Embryonic Stem Cell Cultures Did So by Following Dr. Thomsons Work, Not the Prior Art

Watchdog next criticizes the Board for relying on Dr. Meltons citation to Dr. Thomsons Science article to show that Melton followed Thomsons work and to give less weight to his conflicting testimony, relied on by Watchdog. App. Br. 9, 26, 28. According to Watchdog, Dr. Meltons declaration is not contrary to his citation to Thomsons work, as the latter was just a respectable and conventional way to credit Dr. Thomsons chronologically earlier work. Id. at 27. Watchdogs argument is undercut by the actual language of Dr. Meltons 2004 publication. That publication nowhere credits the protocols of Drs.

Robertson or Piedrahita, or, in fact, any protocols used to derive ES cells from mouse, rat, pig, or sheep. Rather, the article states that individual human

embryonic stem-cell lines . . . were derived according to [modified] published protocols, citing only to Dr. Thomsons 1998 Science paper and Dr. Bongsos work on human embryos. A1774; A1776. Watchdog argues that this does not mean that Dr. Melton relied on the publications he cites; rather, it just informs scientists reading the article that they could repeat the experiments by following the steps in the cited publications. App. Br. 27. This, however, does not explain 57

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Dr. Meltons failure to cite to protocols he purportedly relied on, if not Dr. Thomsons. 13 Accordingly, the Board did not err in giving less weight to Dr. Meltons declaration and finding instead that he, and others, had followed Dr. Thomsons work to generate additional human ES cell lines. A12-13. 3. The Acclaim for Dr. Thomsons Invention of Human Embryonic Stem Cell Cultures Is an Integral Part of the Obviousness Analysis

Watchdogs final attack on the Boards decision is directed at the Boards reliance on the acclaim Dr. Thomsons work garnered in the scientific community. Watchdog first attempts to discount this evidence of acclaim by arguing that it did not result from Dr. Thomsons patented invention. App. Br. 28. But the 913 patent claims the invention of human ES cell cultures, the exact work for which Dr. Thomson received acclaim. 14

13

Watchdog attempts to illustrate its argument with an analogy, explaining that this is the same as stating according to the Pythagorean theorem stated in Math Text X. App. Br. 27 n.2. But this analogy falls flat, as it suggests that Dr. Melton wrote according to the Robertson, Piedrahita, and Williamss methods as stated in Thomson. But Dr. Melton did not. He simply cited to work by Dr. Thomson.

14

To the extent Watchdog is suggesting that the 913 patent does not enable cultures of human ES cells (see App. Br. 8, 28), the PTO concluded otherwise during the original prosecution of the 913 patent. See U.S. Patent Application No. 09/106,390, Non-final Rejection 9-24-1999 (A5010-14); Affidavit 1-7-2000 (A5007-09); Notice of Allowance 10-16-2000 (A5019-22). Moreover, it is undisputed that no 112 challenges or rejections were made during the reexamination.

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Watchdog next argues that the acclaim resulted not from innovation, but rather from Dr. Thomsons special access to human embryos and funding. App. Br. 6, 28-29. This argument, however, lacks credibility and runs contrary to the substance of the awards, all of which recognize Dr. Thomsons scientific achievementsnot his access to human embryos. Watchdogs access argument also ignores that primate embryos were not similarly restricted, but scientists did not succeed in deriving primate ES cell cultures before Dr. Thomson. Moreover, it is undisputed that other scientists did, in fact, have access to human embryos, yet failed where Dr. Thomson succeeded. For example, Dr. Bongso had access to human embryos, but his research group was unable to obtain stable cultures of human ES cells prior to Dr. Thomsons invention. Moreover, Dr. Hogan had access to human embryos, but instead

isolated primordial germ cells rather than ES cells after concluding that [a]ttempts at isolating ES cells from other animals [than mouse] apparently have failed. A1103(col.1,ll.60-64). Watchdogs argument is also contrary to the patent laws. Section 103(a) specifically states that [p]atentability shall not be negated by the manner in which the invention was made. While Watchdog contends that their argument relates to secondary considerations instead of obviousness, evaluation of secondary considerations is an integral part of the obviousness analysis under 103(a) and

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thus also covered by the statutes prohibition. See Cyclobenzaprine, 676 F.3d at 1075-80; id. at 1077 ([T]he consideration of the objective evidence presented by the patentee is a necessary part of the obviousness determination. (quoting WMS Gaming Inc. v. Intl Game Tech., 184 F.3d 1339, 1359 (Fed. Cir. 1999))). Finally, Watchdog disregards WARFs evidence of commercial success. As described supra at page 18, as of June 2010, WARF had entered into numerous academic and commercial licenses for the use of human ES cell cultures covered by the 913 patent. See A1809-10. Thus, rather than broad and aggressive assertion of the 913 patent to completely preempt all uses of hES cells, including . . . for scientific and medical research, as Watchdog suggests (App. Br. 2), WARF has broadly licensed the 913 patent technology for the benefit of both the academic and commercial communities. This evidence of commercial success further supports the Boards finding that claims 1-4 would not have been obvious. See Al-Site Corp. v. VSI Intl, Inc., 174 F.3d 1308, 1325 (Fed. Cir. 1999). CONCLUSION For the foregoing reasons, the Court should affirm the Boards decision upholding the patentability of amended claims 1-4 of the 913 patent.

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Respectfully submitted,

August 14, 2013

/s/ Kara F. Stoll Kara F. Stoll William B. Raich Sarah E. Craven FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP 901 New York Avenue, NW Washington, DC 20001-4413 (202) 408-4000 Counsel for Appellee Wisconsin Alumni Research Foundation

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CERTIFICATE OF SERVICE I hereby certify that on August 14, 2013, the forgoing was filed via the Courts CM/ECF system. All parties or their counsel who are registered users of the CM/ECF system will receive a notice of this filing from the system. Parties may access this filing through the Courts CM/ECF system.

Daniel B. Ravicher, Esq. Public Patent Foundation 1375 Broadway, Suite 600 New York, NY 10018 ravicher@gmail.com

/s/ Kay Wylie Kay Wylie

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CERTIFICATE OF COMPLIANCE I certify that the foregoing BRIEF FOR APPELLEE WISCONSIN ALUMNI RESEARCH FOUNDATION contains 13,807 words as measured by the word-processing software used to prepare this brief.

Dated: August 14, 2013

Respectfully submitted,

/s/ Kara F. Stoll Kara F. Stoll William B. Raich Sarah E. Craven FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP Counsel for Appellee Wisconsin Alumni Research Foundation