CW v WARF - Appellee Brief (ECF)

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

Case: 13-1377 Document: 17 Page: 1 Filed: 08/14/2013

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


i

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. Embryonic Stem Cells ..................................................................................... 5

II. Robertson and Williams: Discovery of Mouse Embryonic Stem Cell Cultures .................................................................................................... 6

III. Piedrahita and Bongso: Methods Developed for Mouse Embryonic Stem Cells Proved Unsuccessful in Deriving Embryonic Stem Cell Cultures from Other Species, Including Humans .......................................... 11

IV. Dr. James Thomson’s Successful Invention of Primate and Human Embryonic Stem Cell Cultures ...................................................................... 13

V. The ’913 Patent .............................................................................................. 18

VI. Inter Partes Reexamination ........................................................................... 20

SUMMARY OF THE ARGUMENT ...................................................................... 27

ARGUMENT ........................................................................................................... 30

I. Standard of Review........................................................................................ 30

II. Watchdog’s Newly Raised § 101 Challenge Is Improper in Inter Partes Reexamination Proceedings and, in Any Event, Was Waived ........................................................................................................... 31

A. Watchdog’s § 101 Challenge Is Not Properly Before This Court .................................................................................................... 31

B. Watchdog Waived Its Newly Raised § 101 Challenge ....................... 32


ii

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

B. Williams Also Does Not Describe the Distinct Morphology of Human Embryonic Stem Cell Colonies .......................................... 44

IV. The Board’s 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

B. Watchdog’s Arguments Fail to Undermine the Substantial Evidence Supporting the Board’s 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

2. The Evidence Supports the Board’s Finding that Others Who Made Human Embryonic Stem Cell Cultures Did So by Following Dr. Thomson’s Work, Not the Prior Art ....................................................................... 57

3. The Acclaim for Dr. Thomson’s Invention of Human Embryonic Stem Cell Cultures Is an Integral Part of the Obviousness Analysis ......................................................... 58

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


iii

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


iv

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


v

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


vi

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 Court’s decision in this appeal.


1

STATEMENT OF ISSUES PRESENTED

Whether this Court should hear Consumer Watchdog’s 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 Board’s 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.


2

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 Parkinson’s 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


3

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. Thomson’s 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.


4

Dr. Thomson’s 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. Thomson’s 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. Thomson’s work on human ES cells earned him the McEwen Award for

Innovation from The International Society of Stem Cell Research.

Based on Dr. Thomson’s 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


5

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). Watchdog appealed the Board’s

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. See A91(col.1,ll.29-30);

A92(col.3,ll.62-67).

Stem cells exist in both developing and mature animals. In the adult

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 blood-

cell types, such as red blood cells, but not to any other cell type in the body.

A91(col.1,ll.30-32).


6

Embryonic stem cells (ES cells), in contrast, are pluripotent. Id.(col.1,ll.33-

36). 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). See

A94(col.8,ll.53-55).


7

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.


8

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. Williams’s first method, isolated mouse blastocysts were plated

directly onto culture dishes in LIF-containing culture medium without a feeder


9

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.66–col.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).

Williams’s ’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


10

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.

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


11

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. A1390-

94. 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


12

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. Bongso’s 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.


13

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 post-

implantation 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 Thomson’s 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 species—the

common marmoset and the rhesus monkey. A93(col.6,ll.11-15); A94(col.8,ll.11-

44). 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


14

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 ICM-

derived 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.65–col.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).


15

Primate ES cells also differ from those of mouse in their expression of

certain cell-surface proteins, or markers (A95-96(col.10,l.1–col.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.64–col.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. Thomson’s 1998 publication, other researchers soon succeeded in

deriving human ES cell cultures using Thomson’s method. In early 2000,

Dr. Bongso, who had previously failed to obtain stable human ES cell cultures,

now reported success. A1479-84. His research group’s 2000 publication

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


16

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. Bongso’s 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. Bongso’s

2000 publication cited Dr. Thomson’s 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. Thomson’s 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.


17

Dr. Thomson’s invention of human ES cell cultures earned him significant

acclaim in the scientific community, including from scientists active in the stem-

cell field. Interviewed by Harvard Magazine for a 2004 article on stem cells

(A1779), Dr. Melton’s 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. Thomson’s 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. Thomson’s

work won him the World Technology Summit Award in Health & Medicine

sponsored by the World Technology Network. A208. In 2005, the AAAS

identified Dr. Thomson’s derivation of human ES cells as one of the most

significant “Milestones of Science.” A207. More recently, in 2013, Dr.

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


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

18

Thomson’s 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. Thomson’s 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 at http://www.isscr.org/home/awards/mcewen-award-for-innovation.


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

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

19

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


20

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.

5 Watchdog contends that claims 1-3 are the only claims before this Court (App. Br. 7 n.1), because the Board’s 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 Examiner’s determination” of November 23, 2011, finding “that claims 1-3 and new claim 4 are patentable over the cited prior art.” A5. Accordingly, contrary to Watchdog’s 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. 6 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.


21

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. Thomson’s 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 Williams’s 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. Thomson’s publications or patents.” A337-42; A451-56. As noted above,

however, Drs. Melton and Cowan’s 2004 publication reported deriving human ES

cell lines according to protocols in Dr. Thomson’s published work. A1774;

A1776.


22

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 Cowan’s declarations that they had successfully isolated ES cells by

following the methods taught for mouse, rat, pig, and sheep. A76-77.


23

WARF moved to reopen prosecution. A1713. WARF then amended claims

2 and 3—but only to rewrite them in independent form—and 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. A1755-

62. 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


24

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 Cowan’s

declarations. Specifically, WARF submitted the 2004 publication by these very

researchers, which, as discussed above, credited Dr. Thomson’s 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. Melton’s

team, stated that harvesting ES cells from any animal is “not routine at all,” and

that Dr. Thomson’s 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.


25

The Examiner again found pending claims 1-4 patentable. A14-18. The

Examiner found that, based on Dr. Stewart’s 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. Williams’s statements in Cherny acknowledging the murine

model’s failure in other domestic animals, and (2) the prosecution history of

Williams’s 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


26

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. Thomson’s

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 WARF’s 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. McMahon’s statement that deriving ES cells from any animal is “not routine at

all,” and the accolades Dr. Thomson’s work received in the scientific community.

A10-11. Finally, the Board gave less weight to Dr. Melton’s declaration in light of

his 2004 publication crediting Dr. Thomson’s published work. A11-12. The


27

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

Watchdog’s 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 PTO’s 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 Court’s 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 Board’s decision in this case.

Regardless, Watchdog’s argument fails on the merits. All the claims recite a

non-naturally occurring in vitro cell culture of human ES cells. These cultured ES


28

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-in-

suit 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 Board’s 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. Thomson’s work, no one knew which

cell colonies to select. And only after Dr. Thomson’s 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


29

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 Board’s 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 Board’s decision upholding the patentability of amended claims 1-4 is

supported by substantial evidence and should be affirmed.


30

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.


31

II. Watchdog’s Newly Raised § 101 Challenge Is Improper in Inter Partes Reexamination Proceedings and, in Any Event, Was Waived

A. Watchdog’s § 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

proceeding—and WARF is aware of none—where the PTO considered § 101 in a


32

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 court’s review of an issue may be, it is still no

more than that—a review.”). Accordingly, an appeal from an inter partes

reexamination is an inappropriate forum for resolving a newly raised challenge

under § 101, and Watchdog’s 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 Int’l 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


33

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. Comm’n 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,


34

1380 (Fed. Cir. 2008) (declining to hear a challenge on appeal that was not raised

before the Board).

Watchdog also argues that the Supreme Court’s 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 cultures—an 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, Watchdog’s 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.


35

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 Watchdog’s 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.


36

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% Dulbecco’s modified Eagle’s

medium, 20% fetal bovine serum, 0.1 mM β-mercaptoethanol, and 1% non-

essential 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


37

“the basis of the rejection.”7 Thus, the PTO expressly found that the claims were

directed to patent-eligible subject matter.8

Watchdog’s § 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. Thomson’s

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

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 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). 8 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).


38

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 reference’s 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 Board’s 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) 9 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.


39

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 Board’s decision is also supported by Dr. Bongso’s 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. Bongso’s failure to make the claimed

invention in 1994 is strong evidence that Williams’s earlier disclosure was

nonenabling. See Donohue, 766 F.2d at 533.

The Board’s decision is further supported by the PTO’s 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; A5074-77); 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).


40

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.

Watchdog’s sole challenge to the Board’s nonenablement decision is the

Board’s 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 Watchdog’s claim of bias misplaced, but its selective and unsupported

reading of Williams fails to undermine the substantial evidence supporting the

Board’s 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. Stewart’s second declaration after the reopening of prosecution.


41

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 conclusion—that the definition of

culture medium relates only to isolation—through 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 Watchdog’s “isolation portion” of the specification.


42

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 Watchdog’s interpretation, Dr. Stewart’s 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.59–col.7,l.3; col.8,ll.9-31).


43

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 Board’s 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. Stewart’s testimony

that Williams’s 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.


44

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 Board’s 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. Thomson’s 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 mouse—it “took

innovation by Dr. Thomson.” A9-10.


45

This finding is supported by Dr. Bongso’s 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. Bongso’s 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


46

“compact colony structure” as reported for other stem-cell lines, citing Thomson’s

initial and Bongso’s subsequent derivation of human ES cells. A1775-76.

Watchdog argues that Dr. Stewart’s 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 Watchdog’s assertion (App. Br. 22), Dr. Thomson did include his

recognition of the flatness of the cell colonies in the patent’s 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


47

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. Thomson’s 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. Thomson’s 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 didn’t 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 Board’s decision that Williams failed to enable human ES cell

cultures is supported by substantial evidence, the Board’s decision upholding the

patentability of amended claims 1-4 as not anticipated by Williams should be

affirmed.


48

IV. The Board’s 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


49

the plethora of heterogeneous cells and cell colonies at the ICM stage, the cited

prior art provided just a single data point—the morphology of mouse ES cell

colonies—and 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-


50

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. Thomson’s 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. Bongso’s 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.


51

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


52

Dr. Thomson’s 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. Thomson’s success. Dr. Thomson’s

invention of human ES cell cultures received—and continues to receive—wide

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.

Thomson’s successful derivation of human ES cell cultures. A1324-31. And Dr.

McMahon, who collaborated with Watchdog’s declarant Dr. Melton, called the

discovery “an astounding breakthrough.” A1780. Appreciation by peers supports

a conclusion of nonobviousness. See Vulcan Eng’g Co. v. Fata Aluminium, Inc.,

278 F.3d 1366, 1373 (Fed. Cir. 2002).

In light of all of this evidence, the Board correctly rejected Watchdog’s

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. Thomson’s successful generation of human ES cell cultures

“took innovation” (A10). The distinct morphology of human ES cell colonies,

Dr. Bongso’s failure to make the claimed invention, the unpredictable nature of the

art, and the praise Dr. Thomson received constitute substantial evidence to support


53

the Board’s decision that the prior art would not have rendered claims to human ES

cell cultures obvious.

B. Watchdog’s Arguments Fail to Undermine the Substantial Evidence Supporting the Board’s Nonobviousness Decision

Watchdog attacks the Board’s decision holding the claims nonobvious on

several grounds.12 None has merit. And none undermines the substantial evidence

supporting the Board’s 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. Buehr’s 2008 isolation of rat ES cells

rather than the ’913 patent’s 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.67–col.4,l.5)).

According to Watchdog, the later derivation of rat ES cells does not change what a

12 Watchdog first attacks the Board’s decision holding the claims nonobvious based on the Board’s 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, Watchdog’s rebuttal evidence ignores the entire teaching of the ’913 patent and fails to acknowledge Dr. Bongso’s inability to achieve the same recognition.


54

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. Buehr’s 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


55

Watchdog’s 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 24-

25 (quoting A92(col.3,l.67–col.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 Int’l 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 formulation—micronization

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.


56

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

Thomson’s publication for their success.” App. Br. 9 (citing Dr. Melton’s

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


57

researchers, including Dr. Melton in 2004, report success, citing Dr. Thomson’s

work. A1479-84; A1774-77.

2. The Evidence Supports the Board’s Finding that Others Who Made Human Embryonic Stem Cell Cultures Did So by Following Dr. Thomson’s Work, Not the Prior Art

Watchdog next criticizes the Board for relying on Dr. Melton’s citation to

Dr. Thomson’s Science article to show that Melton “followed Thomson’s work”

and to give less weight to his conflicting testimony, relied on by Watchdog. App.

Br. 9, 26, 28. According to Watchdog, Dr. Melton’s declaration is not contrary to

his citation to Thomson’s work, as the latter was just a respectable and

conventional way to credit Dr. Thomson’s chronologically earlier work. Id. at 27.

Watchdog’s argument is undercut by the actual language of Dr. Melton’s

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. Thomson’s 1998 Science paper and Dr. Bongso’s

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


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Dr. Melton’s failure to cite to protocols he purportedly relied on, if not

Dr. Thomson’s.13

Accordingly, the Board did not err in giving less weight to Dr. Melton’s

declaration and finding instead that he, and others, had followed Dr. Thomson’s

work to generate additional human ES cell lines. A12-13.

3. The Acclaim for Dr. Thomson’s Invention of Human Embryonic Stem Cell Cultures Is an Integral Part of the Obviousness Analysis

Watchdog’s final attack on the Board’s decision is directed at the Board’s

reliance on the acclaim Dr. Thomson’s work garnered in the scientific community.

Watchdog first attempts to discount this evidence of acclaim by arguing that

it did not result from Dr. Thomson’s 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 Williams’s 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. Thomson’s 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. Thomson’s scientific

achievements—not his access to human embryos.

Watchdog’s 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. Thomson’s

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).

Watchdog’s 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 statute’s 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. Int’l Game Tech., 184 F.3d 1339, 1359 (Fed. Cir. 1999))).

Finally, Watchdog disregards WARF’s 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 Board’s finding

that claims 1-4 would not have been obvious. See Al-Site Corp. v. VSI Int’l, Inc.,

174 F.3d 1308, 1325 (Fed. Cir. 1999).

CONCLUSION

For the foregoing reasons, the Court should affirm the Board’s decision

upholding the patentability of amended claims 1-4 of the ’913 patent.


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August 14, 2013

Respectfully submitted, /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


CERTIFICATE OF SERVICE

I hereby certify that on August 14, 2013, the forgoing was filed via the

Court’s 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 Court’s CM/ECF system.

Daniel B. Ravicher, Esq. Public Patent Foundation 1375 Broadway, Suite 600 New York, NY 10018 [email protected]

/s/ Kay Wylie Kay Wylie


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


CW v WARF - Appellee Brief (ECF)

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