Appendix — Amgen, Inc. v. Hoechst Marion Roussel, Inc. (No. 06-1291)

a Supr '

4 je

No. 061291542 2 2 2007

OFF OE i TH =O Cow

In the Supreme Court of the Gnited States

AMGEN INC..

Petitioner.

V.

HOECHST MARION ROUSSEL. INC.

(now known as AVENTIS PHARMACEUTICALS INC.) and

TRANSKARYOTIC THERAPIES, INC. (now known as SHIRE

HUMAN GENETIC THERAPIES. INC.).

Respondents.

On Petition for a Writ of Certiorari

to the United States Court of Appeals

for the Federal Circuit

PETITION FOR A WRIT OF CERTIORARI

APPENDIX VOLUME I OF II

LLOYD R. DAY. JR. ROY T. ENGLERT, JR. *

DAY CASEBEER MADRID & DANIEL R. WALFISH

BATCHELDER LLP ROBBINS, RUSSELL. ENGLERT,

20300 Stevens Creek Blvd. ORSECK & UNTEREINER LLP

Suite 400 1801 K Street, N.W.

Cupertino, CA 95014 Suite 41]

(408) 873-0110 Washington, D.C. 20006

AN ~ .- -

STUART L. WATT (202) 775-4500

MONIQUE L. CORDRAY

WENDY WHITEFORD

AMGEN INC.

One Amgen Center Dr.

Thousand Oaks. CA 91320

(805) 447-1000 * Counsel of Record

WILSON-EPES PRINTING CO.. INC. — (202) 789-0096 -— WASHINGTON, D.C. 20002

TABLE OF CONTENTS

Page

Appendix A: Amgen Inc. v. Hoechst Marion Roussel, Inc.

and Transkaryotic Therapies, Inc.,

457 F.3d 1293 (Fed Cir. Aug. 3, 2006) ............. la

Appendix B: Amgen Inc. v. Hoechst Marion Roussel, Inc.

and Transkaryotic Therapies, Inc.,

339 F. Supp. 2d 202 (D. Mass. 2004)................ 52a

Appendix C: Amgen Inc. v. Hoechst Marion Roussel, Inc.

and Transkaryotic Therapies, Inc.,

287 F. Supp. 2d 126 (D. Mass. 2003)................ 278a

Appendix D: Amgen Inc. v. Hoechst Marion Roussel, Inc.

and Transkaryotic Therapies, Inc.,

SUA F.3G-13 15 EOE AA BOGS) secs deivincddvnneneses 336a

Appendix E: Amgen Inc. v. Hoechst Marion Roussel, Inc.

and Transkaryotic Therapies, Inc.,

126 F. Supp. 2d 69 (D. Mass. 2001).................. 416a

A,pendix F: Amgen Inc. v. Hoechst Marion Roussel, Inc.

and Transkaryotic Therapies, Inc.,

469 F.3d 1039 (Fed. Cir. Nov. 22, 2006)........... 594a

la

APPENDIX A

UNITED STATES COURT OF APPEALS

FOR THE FEDERAL CIRCUIT

05-1157

AMGEN INC.,

Plaintiff-Appellee,

V.

HOECHST MARION ROUSSEL, INC.

(now known as Aventis Pharmaceuticals Inc.)

and TRANSKARYOTIC THERAPIES, INC.,

Defendants-Appellants.

DECIDED: August 3, 2006

Before MICHEL, Chief Judge, CLEVENGER, Senior

Circuit Judge, and SCHALL, Circuit Judge.

Opinion for the court filed by Circuit Judge SCHALL.

Dissenting-in-part opinion [p. 43a, infra] filed by Chief

Judge MICHEL.

SCHALL, Circuit Judge.

This is a patent case. Amgen, Inc. (“Amgen”) is the owner

of U.S. Patent Nos. 5,547,933 (“the °933 patent”), 5,618,698

(“the ’698 patent”), 5,621,080 (“the ’080 patent”), 5,756,349

(“the °349 patent”), and 5,955,422 (“the °422 patent”). The

patents are directed to recombinant deoxyribonucleic acid

(“DNA”) technology relating to the production of the

hormone erythropoietin (“EPO”). All five patents share a

common specification and descend from Application No.

06/561,024 (“the ’024 application’), filed on December 13,

1983. In April of 1997, Amgen brought a declaratory

2a

judgment action against Hoechst Marion Roussel, Inc. (now

known as Aventis Pharmaceuticals Inc.) (“HMR”) and Trans-

karyotic Therapies, Inc. (“TKT”) (collectively, “HMR/TKT”)

in the United States District Court for the District of

Massachusetts, alleging that HMR/TKT’s Investigational

New Drug Application (“INDA”) for an EPO product

infringed the five patents. In January of 2001, following a

Markman hearing, summary judgment proceedings, and a

bench trial, the district court issued an opinion in which it:

(1) construed the disputed claims; (ii) held the patents not

unenforceable; (iii) held the asserted claims of the ’080, °349,

and °422 patents not invalid and infringed with the exception

of claim 7 of the °349 patent, which it found not infringed;

(iv) held the asserted claims of the 698 patent not infringed;

and (v) held the asserted claims of the °933 patent not

infringed or, in the alternative, invalid for failure to satisfy 35

U.S.C. § 112. Amgen, Inc. v. Hoechst Marion Roussel, Inc.,

126 F. Supp. 2d 69, 165-66 (D. Mass. 2001) (“Amgen I’).

In Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d

1313 (Fed. Cir. 2003) (“Amgen II’), we. affirmed in toto the

district court’s claim construction. We also affirmed (i) the

court’s determination that none of the patents at issue is

unenforceable by reason of inequitable conduct; (11) its

contingent determination that the asserted claims of the 933

patent are invalid under section 112; (iii) its grant of summary

judgment that claim | of the ’422 patent ts infringed; (iv) its

determination that the °933, 698, ’080, and °349 patents are

not anticipated by U.S. Patent No. 4,377,513 (“the Sugimoto

patent”); and (iv) its determination that claims |, 3, 4, and 6

of the °349 patent are infringed. /d. at 1320.

However, we vacated (i) the district court’s determination

that the asserted claims of the 933 patent are not infringed;

(ii) its determination that Dr. Eugene Goldwasser’s clinical

study, described in Dr. Goldwasser’s grant application

entitled “Erythropoietin: Purification, Properties, Biogenesis”

3a

(“the Goldwasser reference”), and the Sugimoto patent do not

anticipate claim | of the ’422 patent; (in) its determination

that the Sugimoto patent does not render claim 1 of the °422

patent obvious; (iv) its determination that claims 2-4 of the

080 patent are not invalid and are infringed under the

doctrine of equivalents; (v) its determination that the asserted

method claims of the *698 patent are not rendered obvious by

the Sugimoto patent and are not infringed; and (vi) its

determination that the Sugimoto patent does not render claims

1, 3, 4, 6, and 7 of the °349 patent invalid and that claim 7 of

the °349 patent is not infringed. /d.

We remanded the case to the district court to do the

following: (i) construe the term “therapeutically effective

amount” in claim | of the ’422 patent and then determine

whether either the Goldwasser reference or the Sugimoto

patent anticipates claim 1 or whether the Sugimoto patent

renders claim | obvious, id. at 1354, 1356, 1358; (ii) de-

termine whether the Sugimoto patent renders claims 2-4 of

the 080 patent obvious and whether, as far as claims 2-4 are

concerned, Amgen can rebut the presumption of the surrender

of equivalents and thus assert infringement of those claims

under the doctrine of equivalents, id. at 1345, 1358; (imi)

determine whether the Sugimoto patent renders claims 4-9 of

the °698 patent obvious and whether claims 4-9 are infringed,

id. at 1357, 1358; and (iv) determine whether the Sugimoto

patent renders claims 1, 3, 4, 6, and 7 of the °349 patent

obvious and whether claim 7 of the ’349 patent is infringed,

id. at 1357, 1358.

The case is now back before us following proceedings on

remand in which the district court construed the term

“therapeutically effective amount” in claim | of the °422

patent and conducted a further bench trial. See Amgen, Inc. v.

Hoechst Marion Roussel, Inc., 339 F. Supp. 2d 202 (D. Mass.

2004) (“Amgen III Validity & Literal Infringement Judg-

ment’); Amgen, Inc. v. Hoechst Marion Roussel, Inc., 287 F.

4a

— Supp. 2d 126 (D. Mass. 2003) (“Amgen III Doctrine of

Equivalents Judgment’). Based upon various findings and

rulings, the court entered judgment in favor of Amgen as

follows: (i) claim | of the ’422 patent is not invalid, Amgen

Ill Validity & Literal Infringement Judgment, 339 F. Supp. 2d

at 334, 336; (ii)-claims 2-4 of the 080 patent are not invalid,

id. at 336, and Amgen is not estopped from asserting

infringement of claims 2-4 under the doctrine of equivalents

because it rebutted the presumption of surrender of equiva-

lents, Amgen III Doctrine of Equivalents Judgment, 287 F.

Supp. 2d at 160; (iii) claims 4-9 of the ’698 patent are not

invalid and are literally infringed, Amgen III Validity &

Literal Infringement Judgment, 339 F. Supp. 2d at 336;

(iv) claims 1, 3, 4, 6, and 7 of the ’349 patent are not rendered

obvious by the Sugimoto patent, id. at 325, 336, and claim 7

of the °349 patent is literally infringed, Amgen III Validity &

Literal Infringement Judgment, 339 F. Supp. 2d at 336.

On appeal, HMR/TKT challenges all of the above rulings.

Our disposition of the appeal is as follows:

(1) Because we hold that the district court erred in its

construction of the term “therapeutically effective amount” in

claim | of the ’422 patent, we vacate the judgment of the

district court that claim | is not invalid. We remand the case

to the district court for a determination as to whether the

Goldwasser reference anticipates claim 1 under a revised

claim construction. (ii) We reverse the judgment of the

district court that HMR/TKT’s accused product infringes

claims 2-4 of the ’080 patent under the doctrine of equiva-

lents. We do so because we hold that the district court erred

in ruling that Amgen rebutted the presumption that, during

prosecution, it surrendered coverage to EPO with a 165-

amino acid sequence, which is the sequence of HMR/TKT’s

product. Because claims 2-4 of the ’080 patent are not in-

fringed, it is unnecessary for us to address HMR/TKT’s

alternative argument by way of an affirmative defense that

5a

claims 2-4 are anticipated by the Goldwasser reference.

(iii) We affirm the judgment of the district court that claims

4-9 of the ’698 patent are not invalid and are literally

infringed. (iv) We affirm the judgment of the district court

that claim 7 of the ’349 patent is not invalid and is literally

infringed. Thus,-we affirm-in-part, reverse-in-part, vacate-in-

part, and remand.’

BACKGROUND

L.

As noted, the patents at issue relate to recombinant DNA

technology for the production of EPO. EPO, which is a

naturally occurring hormone, stimulates the production of red

blood cells in the bone marrow through a process called

erythropoiesis. Thus, the production of EPO is useful in

treating blood disorders characterized by low hematocrit,

which is a low ratio of red blood cells to total blood cells. The

production of EPO in usable amounts was made possible by

Amgen’s team led by Dr. Fu-Kuen Lin, who first successfully

identified the EPO DNA sequence. See ’422 patent, col. 20,

ll. 28-33. Amgen markets and sells its EPO product under the

brand name “Epogen.”

DNA is the genetic material of all living things.” /d. col. 1,

ll. 28-29. DNA is composed of a series of subunits, called

nucleotides, that are linked together to form a linear poly-

meric form—a strand. /d. col. 1, ll. 33-35. Each nucleotide

contains one of four nitrogen-containing ring compounds,

called bases. The bases fall into two categories: pyrimidines,

' Even though we do not agree with all of the district court’s rulings in

this case, we note the court’s careful and thorough opinions in both

Amgen Iil Validity & Literal Infringement Judgment and Amgen III Doc-

trine of Equivalents Judgment.

? The basics of recombinant DNA technology are set forth in Amgen I

and, to a lesser extent, in Amgen I/. We repeat here only the points

necessary for an understanding of the issues presented in this appeal.

6a

which include cytosine (“C”) and thymine (“T”), and purines,

which include adenine (“A”) and guanine (“G”). Jd. col. 1, Il.

35-46; James D. Watson et al., Molecular Biology of the

Gene 98 (Sth ed. 2004); Bruce Alberts et al., Molecular

Biology of the Cell 63, 120 (4th ed. 2002). The sequence of

A, T, G, and Cs on a strand of DNA forms what is known as a

“DNA sequence.” DNA is double-stranded, such that two

complimentary strands are linked together. ’422 patent, col. 1,

ll. 35-42.

Genetic information is expressed through the production of

proteins, which are molecules containing long chains of

amino acids. Alberts, supra, at 129. Ribonucleic acid

(“RNA”) determines the composition of proteins. Watson,

supra, at 31; see also Alberts, supra, at 301. During a process

called transcription, DNA is used to make messenger RNA

(“mRNA”) with the sequence corresponding to the DNA

sequence of A, T, G, and Cs coding for a particular gene.”

’422 patent, col. 1, ll. 42-43, 49-51. Transcription of the gene

is prompted by a promoter, a sequence of DNA that initiates

transcription. /d. col. 2, ll. 4-6. The promoter is typically

located upstream of the gene to be transcribed.* Jd. After

transcription is completed, the mRNA non-coding sequences,

called introns, are spliced out and the mRNA coding

sequences, called exons, are spliced together. The mRNA

sequence is then translated by ribosomes to form a protein

> As the name “messenger” implies, mRNA transcripts are interme-

diates in the process of protein synthesis. Transcription of mRNA from

DNA is completed in the nucleus of the cell. After it undergoes additional

processing in the cell’s nucleus, the complete mRNA is exported to the

cell’s cytoplasm, where it guides the synthesis of proteins. See Alberts,

supra at 304-05, 327-28.

* “Upstream” refers to the location of a particular segment of the

genetic sequence on a strand of DNA in relation to a particular gene. For

example, if a segment is “upstream” of a particular gene and transcription

proceeds in a completely linear order along the DNA sequence, then the

segment will be transcribed before the gene.

7a

composed of amino acids. Amgen III Doctrine of Equivalents

Judgment, 287 F. Supp. 2d at 145.

The common specification of Amgen’s patents describes

how Dr. Lin combined his discovery of the DNA sequence

for EPO with recombinant DNA technology to make EPO-

producing cells. In order to create these EPO-producing cells,

Dr. Lin made an expression vector carrying the EPO DNA

sequence he had discovered. °422 patent, col. 11, ll. 1-10. An

expression vector is a circular piece of DNA on which a

desired gene may be coded. See id. Figs. 2-4, col. 2, Il. 36-54.

In addition to the desired gene, an expression vector may also

contain a marker and a promoter site. See id. col. 3, ll. 35-37,

col. 25, Il. 33-36. The expression vector incorporates itself

into a host cell’s genetic code. The promoter then triggers the

host cell to transcribe mRNA corresponding to the genetic

code encoded on the vector. See id. col. 2, ll. 30-35. This

mRNA is then translated into a protein by the host cell. /d.

The marker in the expression vector enables scientists to

identify the cells that successfully incorporated the desired

gene. /d. col. 25, ll. 64-66. The DNA inserted into the genetic

code of the host cell through the expression vector is

characterized as exogenous DNA because it is not “native” to

the host cell. Genetic recombination using exogenous DNA is

referred to as heterologous recombination. /d. col. 1, 1. 53-

eo8. 24 ba

The expression vector described in Example 10 of the

common specification of Amgen’s patents contains Dr. Lin’s

EPO DNA sequence, a selectable dihydrofolate (“DHFR”)

marker, and a promoter 44 base pairs upstream of the EPO

DNA sequence. /d. col. 24, 1. 17, col. 25, 36-40. When

exposed to Chinese hamster ovary (“CHO”) cells, Dr. Lin’s

expression vectors integrate themselves into the DNA of the

host CHO cells. /d. col. 25, ll. 58-66. The general disclosures

in the background section of the °422 patent describe how

promoters, like the one used in Example 10, prompt host cells

8a

to transcribe mRNA corresponding to exogenous genes such

as the EPO and DHFR genes in Example 10. See id. col. 1, Il.

53-56, col. 25, ll. 64-66. In the invention of the five patents,

prior to production of a protein from the mRNA with the

sequence coding for EPO, the mRNA sequence is spliced to

remove introns and to connect exons. After splicing, the

mRNA is translated into the 166-amino acid protein shown in

Figure 6 of the common specification of the patents.

Prior to secretion from the cell, the 166-amino acid EPO

protein undergoes cleaving. In this process, the final amino

acid in the sequence shown in Figure 6 of the °422 patent,

arginine, is cleaved off, leaving a 165-amino acid protein.

This 165-amino acid protein is then secreted as mature human

EPO by the cell.

I.

HMR and TKT collaborated to develop a drug known as

HMR4396, HMR4396 consists of human EPO produced from

TKT’s R223 cell line grown in culture. Amgen J, 126 F. Supp.

2d at 98. The R223 cell line produces human EPO through

the use of a viral promoter that prompts transcription of the

human EPO gene. In order to create the R223 cell line,

HMR/TKT transfected human tumor cells with the viral

promoter. This viral promoter is located far upstream of the

EPO gene in the R223 cells. Because the viral promoter is not

“native” to the human tumor cells, the R223 promoter is

considered exogenous DNA. However, the R223 cells are

described as using homologous or endogenous recombination

because the human EPO gene that the viral promoter controls

is “native” to the cells.

Il.

Amgen filed suit for a declaratory judgment that HMR/

TKT’s HMR4396 infringed the °933 patent, the ’698 patent,

the ’080 patent, the 349 patent, and the °422 patent. Amgen

alleged infringement of claims |, 2, and 9 of the ’933 patent,

9a

claims 4-9 of the °698 patent, claims 2-4 of the ’080 patent,

claims 1, 3, 4, 6, and 7 of the’349 patent, and claim | of the

’422 patent. See Amgen I, 126 F. Supp. 2d at 96-98. The case

proceeded as outlined above and is again before us on appeal.

We have jurisdiction pursuant to 28 U.S.C. § 1295(a)(1).

DISCUSSION

On this appeal, we are presented with issues relating to the

°422, °080, °698, and °349 patents.” We begin with the 422

patent.

I.

The °422 Patent

Claim | is the only claim of the 422 patent at issue in the

present case. Claim | provides:

A pharmaceutical composition comprising a_thera-

peutically effective amount of human erythropoietin and

a pharmaceutically acceptable diluent, adjuvant or

carrier, wherein said erythropoietin is purified from

mammalian cells grown in culture.

"422 patent, col. 38, ll. 36-41.

HMR4396 already has been found to infringe claim | of

the °422 patent. See Amgen Il, 314 F.3d at 1320. In our

remand instructions in Amgen I/, we instructed the district

court to construe the limitation “therapeutically effective

amount” in claim | and then determine whether the Gold-

wasser reference or the Sugimoto patent anticipated claim |

or whether the Sugimoto patent rendered claim | obvious.

* As noted above, in Amgen II, we affirmed the ruling of the district

court in Amgen / that claims 1, 2, and 9 of the °933 patent are invalid.

Amgen II, 314 F.3d at 1342.

10a

A.

Claim Construction

On remand, the district court construed “therapeutically

effective amount” in claim | of the ’422 patent to require that

the claimed EPO increase hematocrit and also be useful in

healing or curing the class of patients listed at column 33,

lines 22-28 of the specification of the 422 patent:

A therapeutically effective amount is a quantity that

produces a result that in and of itself helps to heal or

cure. A therapeutically effective amount is one that

elicits in vivo biological activity of natural EPO such as

those listed in the specification, column 33, lines 24

through 28: stimulation of reticulocyte response, devel-

opment of ferrokinetic effects (such as plasma iron

turnover effects and marrow transit time effects),

erythrocyte mass changes, stimulation of hemoglobin C

synthesis (see, Eschbach, et al., supra) and, as indi-

cated in Example 10, increasing hematocrit levels in

mammals.

Therapeutically effective is to be interpreted as being

therapeutically effective with respect to the class of

patients listed in the specification, column 33 lines 31

through 36: patients generally requiring blood trans-

fusions and including trauma victims, surgical patients,

renal disease patients including dialysis patients, and

patients with a variety of blood composition affecting

disorders, such as hemophilia, sickle cell disease,

physiologic anemias, and the like.

Amgen III Validity & Literal Infringement Judgment, 339 F.

Supp. 2d at 245-46. In arriving at this construction, the

district court focused on the portion of the specification of the

lla

’422 patent found at column 33, lines 11-28.° Jd. at 232-36.

The court also pointed to statements in the prosecution

history asserting that the claimed invention of recombinant

human EPO could be used to treat anemia and other similar

disorders. /d. at 238-42.

On appeal, HMR/TKT contends that the district court erred

in construing the term “therapeutically effective” in claim 1

of the °422 patent by requiring that EPO increase hematocrit.

HMR/TKT argues that the court incorrectly read the

specification as limiting the scope of claim | to products that

increase hematocrit. HMR/TKT urges that “therapeutically

effective amount” means “an amount that elicits any of the

biological effects listed in the specification.” Under this

construction, HMR/TKT asserts, claim | is anticipated by the

Goldwasser reference. 3

Amgen responds that the district court correctly interpreted

the specification to mean that “when a ‘therapeutically

effective amount’ of EPO is used . . . it produces an increase

in hematocrit—along with any or all of the biological affects

[sic] previously attributed to natural EPO.” Appellee’s Br. 21

(quoting Amgen III Validity & Literal Infringement Judgment,

339 F. Supp. 2d at 234). Amgen points out that although the

passage at column 33, lines 11-22 does not actually use the

term “therapeutically effective,” other passages do, in fact,

use the term. For example, at column 33, lines 43-50, Amgen

notes, the patent actually uses the words “therapeutically

effective” before explaining the required dosages for patients.

According to Amgen, this indicates that “therapeutically

effective” amounts are those related to healing or curing

° The district court’s claim construction references passages of the '933

patent found at column 33, lines 24-28 and column 33, lines 31-36. /d. at

214, 236, 245. The °422 patent contains identical passages at column 33,

lines 16-20 and column 33, lines 23-28 respectively. These passages are

part of a larger portion of the specification that runs from column 33, lines

11-28.

12a

disease. Amgen also directs our attention to the portion of the

specification found at column 33, lines 22-28. This passage

states, “Included within the class of humans treatable with

products of the invention are patients generally requiring

blood transfusions . . . and patients with a variety of blood

composition affecting disorders, such as hemophilia, sickle

cell disease, physiologic anemias, and the like.” According to

Amgen, only amounts of EPO producing effects—partic-

ularly increased hematocrit—that counteract these anemia-

like diseases are “therapeutically effective.” Amgen but-

tresses this argument with citations to the prosecution history

where the patentee recounts the benefits of the claimed

invention over prior art in treating disease.

The district court’s claim construction is a matter of law,

which we review de novo. Cybor Corp. v. FAS Techs., 138

F.3d 1448, 1456 (Fed. Cir. 1998) (en banc). In Phillips v.

AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) (en banc), we

stated that claim construction must begin with the words of

the claims themselves. Jd. at 1312. A claim term has “the

meaning that the term would have to a person of ordinary

skill in the art... .” Jd. at 1313. This meaning is ascertained

“in the context of the entire patent, including the

specification.” /d. In particular, we stated in PhiHips that “we

must look at the ordinary meaning in the context of the

written description and the prosecution history.” /d. (quoting

Medrad, Inc. v. MRI Devices Corp., 401 F.3d 1313, 1319

(Fed. Cir. 2005)). When dealing with technical terms, we

noted, a court should look to “the words of the claims

themselves, the remainder of the specification, the prose-

cution history, and extrinsic evidence concerning relevant

scientific principles, the meaning of technical terms, and the

state of the art.” Jd. (quoting /nnova/Pure Water, Inc. v.

Safari Water Filtration Sys., Inc., 381 F.3d 1111, 1116 (Fed.

Cir. 2004)).

13a

Using Phillips as a guide, we turn first to the language of

the claims. Neither the language of claim 1, nor the language

of claim 2, of the °422 patent offer any guidance as to the

meaning of “therapeutically effective.”’ However, several

passages of the specification shed light on the meaning of the

term. In particular, the text found at column 33, lines 11-22

States:

[T]o the extent that polypeptide products of the inven-

tion share the in vivo activity of natural EPO isolates

they are conspicuously suitable for use in erythropoietin

therapy procedures practiced on mammals, including

humans, to develop any or all of the effects here-

fore attributed in vivo to EPO, e.g., stimulation of

reticulocyte response, development of ferrokinetic effects

(such as plasma iron turnover effects and marrow transit

time effects), erythrocyte mass changes, stimulation of

hémoglobin C synthesis (see, Eschbach, et al., supra)

and, as indicated in Example 10, increasing hematocrit

levels in mammals.

"422 patent, col. 33, Il. 11-22 (emphases added). This

language indicates that the claimed invention is used in

“therapy” to produce “any or all” of the following “effects”:

stimulation of reticulocyte response, development of

ferrokinetic effects, erythrocyte mass changes, stimulation of

hemoglobin, and increasing hematocrit levels. Thus, in-

creasing hematocrit is only one of the biological effects

produced by the claimed invention. Accordingly, we agree

with HMR/TKT that the district court misinterpreted this

passage when it read it as limiting the claimed invention to

7 Claim 2 is an independent claim, which provides: “A pharma-

ceutically-acceptable preparation containing a therapeutically effective

amount of erythropoietin wherein human serum albumin is mixed with

said erythropoietin.” ’422 patent, col. 38, Il. 42-44.

14a

products with “any or all” of the first four listed effects

ascribed in vivo to EPO and also an increase in hematocrit.

Further, in the. August 2, 1993 office action response, the

patentee cited the above language of the specification and

then stated, “It is believed that these sentences from the

specification and others provide a clear and definite

description of the uses for which the claimed erythropoietin

compositions would be therapeutically effective.” (emphasis

added). Thus, the patentee interpreted the passage at column

33, lines 11-22 of the specification as listing the therapeutic

effects of the invention disclosed in the ’422 patent. We think

the district court made an artificial distinction between the

first four effects listed in column 33, lines 11-22, stimulation

of reticulocyte response, development of ferrokinetic effects,

erythrocyte mass changes, and stimulation of hemoglo-

bin, and the fifth effect, an increase in hematocrit. The

specification lists. all five effects after stating that “any or all”

of them may be an effect of therapy with the claimed

invention. Thus, this section of the specification supports the

construction that the ’422 patent encompasses a pharma-

ceutical composition which produces “any or all” of the five

listed effects.

As seen, the district court also determined that the

specification indicates that the invention is limited to products

that are “therapeutically effective” with respect to patients

with anemia-like disorders, such as those listed at column 33,

lines 22-28 of the ’422 patent. Amgen III Validity & Literal

Infringement Judgment, 339 F. Supp. 2d at 235-36, 245-46.

For this detefmination, the court relied on a passage that

recites several diseases that may be treated by the claimed

invention. The passage begins, “Included within the class of

_ humans treatable with products of the invention . . . .” ’422

patent, col. 33, ll. 22-28. However, this passage does not state

that the claims encompass only products that treat such

patients. Rather, by using the non-limiting word “included,” it

lSa

suggests some persons, but not all persons, who may benefit

from the invention.

Moreover, an additional section of the specification states,

“It is noteworthy that the absence of in vivo activity for any

one or more of the ‘EPO products’ of the invention is not

wholly preclusive of therapeutic utility (see Weiland, et al.,

supra)... .” Jd. col. 36, Il. 9-12. We think the message of this

passage is that “therapeutic utility” is not limited to products

with “in vivo” effects. Thus, “therapeutic utility” is not

dependent on the product having an effect in a living being,

such as curing disease. Although this passage relates to a

different EPO product than the one disclosed in claim 1 of the

"422 patent, we think it illustrates the broad meaning of

“therapeutic utility” used throughout the ’422 patent. It shows

that the patentee did not use the word “therapy” in order to

limit the scope of the °422 patent to only EPO that cured

disease. Thus, products that are not necessarily effective in

actually curing disease in humans are encompassed by claim

1 of the ’422 patent. Based on a reading of the claims in light

of the specification, it appears that the patentee used the

words “therapeutically effective” in order to broadly claim

a pharmaceutical composition with a wide range of ef-

fects. Those effects do not necessarily include curing dis-

ease in humans.

During the prosecution of the *422 patent, in an office

action response filed October 23, 1997, the patentee noted

that recombinant EPO, like that found in the claimed

invention, “is the first therapeutic product which can be used

to effectively treat hundreds of thousands of patients who

suffer from anemia and other disorders involving low red

blood cell counts.” In our view, this statement merely lists

some of the uses of the invention, without restricting the

scope of the invention.

In sum, we disagree with the district court’s claim con-

struction to the extent that it limits the scope of claim | of the

l6a

’422 patent to EPO products that have one of the in vivo

effects listed at column 33, lines 16-20 and that also increase .

hematocrit. We also disagree with the district court’s

conclusion that claim | of the ’422 patent is limited to EPO

products that may be used to treat patients with the disorders

listed at column 33, lines 22-28 of the °422 patent’s

specification. On remand, the district court should utilize the

following revised construction of “therapeutically effective:”

A therapeutically effective amount is one that elicits any

one or all of the effects often associated with in vivo

biological activity of natural EPO, such as those listed in

the specification, column 33, lines 16 through 22:

stimulation of reticulocyte response, development of

ferrokinetic effects (such as plasma iron turnover effects

and marrow transit time effects), erythrocyte mass

changes, stimulation of hemoglobin C synthesis and, as

indicated in Example 10, increasing hematocrit levels in

mammals.

B.

Anticipation—The Goldwasser Reference

Based on its claim construction, the district court found in

Amgen III Validity & Literal Infringement Judgment that the

Goldwasser reference did not anticipate claim | of the *422

patent because Dr. Goldwasser’s study was not effective in

healing or curing. 339 F. Supp. 2d at 327. The parties dispute

whether the Goldwasser reference anticipates claim 1 of the

422 patent under a revised claim construction. The purpose

cf the Goldwasser study was to examine EPO and its effects

on erythropoiesis. Dr. Goldwasser acknowledged that mass

production of EPO from recombinant DNA was not yet

possible. Therefore, Dr. Goldwasser utilized EPO isolated

from urine in an attempt to discover the chemistry and mode

of action of EPO. In one portion of his study, Dr. Goldwasser

performed a “very small clinical trial” using pure urinary

17a

EPO (“uEPO”). The uEPO was administered to three anemic

patients. Two patients received injections of 520 units twice

daily for ten days. The third patient received a 1000 unit

injection every 2-3 days for three weeks. In his 1984 grant

application, Dr. Goldwasser described the results of the

clinical study as follows:

There was no significant change in hematocrit in any

patient; each patient, however[,] showed an increase in

reticulocyte count, with peaks at 9, 10[,] and 11 days.

The first two patients had increased erythroid cells in the

‘marrow and an increased plasma ifon clearance rate.

One of the first two patients showed an increase in red

cell mass. These fragmentary data, need to be reinforced

with more extensive and extended studies but they

show that epo can have a physiological effect in this type

of anemia.

In Amgen I, the district court noted that Dr. Goldwasser

testified that this “abortive, three-patient trial was a failure.”

126 F. Supp. 2d at 112.

The district court found that the Goldwasser reference did

not anticipate claim 1 of the ’422 patent because none of the

effects listed in Dr. Goldwasser’s study included healing or

curing within the court’s construction of “therapeutically

effective.” Amgen III Validity & Literal Infringement Judg-

ment, 339 F. Supp. 2d at 327-34. HMR/TKT argues that

under a revised construction of “therapeutically effective” -

that broadens the scope of claim | to encompass EPO that

“elicits any of the biological effects listed in the specification

fat column 33, lines 16-22],” Dr. Goldwasser’s study

anticipates. Amgen counters that even under a broader

construction of “theraneuzically effective,” Dr. Goldwasser’s

study does not anticipate claim | of the °422 patent because

its recombinant EPO. (“rEPO”) product differs in structure

and function from the uEPO utilized in Dr. Goldwasser’s

study. Amgen argues that a remand is not necessary because

18a

HMR/TKT admitted in its petition for a panel rehearing and

rehearing en banc following Amgen II that the rEPO disclosed

in claim 1 of the °422 patent differs in structure from

naturally occurring uEPO.

Anticipation under 35 U.S.C. § 102 is a question of fact,

which we review for clear error after a bench trial. Merck &

Co., Inc. v. Teva Pharms. USA, Inc., 347 F.3d 1367, 1369

(Fed. Cir. 2003); Alza Corp. v. Mylan Labs., Inc., 391 F.3d

1365, 1369 (Fed. Cir. 2004). The district court’s factual

findings on anticipation are clearly erroneous when

“although there is evidence to support it, the reviewing court

on the entire evidence is left with the definite and firm

conviction that a mistake has been committed.’” Merck & Co,

347 F.3d at 1369 (quoting United States v. U.S. Gypsum Co.,

333 U.S. 364, 395 (1948)). A prior art reference anticipates a_

patent if it discloses all the limitations of the claimed

invention. Oney v. Ratliff, 182 F.3d 893, 895 (Fed. Cir. 1999).

The district-court’s findings of fact on anticipation centered

on whether the effects produced on patients in Dr. Gold-

wasser’s study resulted in healing or curing. Amgen III

Validity & Literal Infringement Judgment, 339 F. Supp. 2d at

327. Under our construction of “therapeutically effective,”

however, the district court’s findings of fact as to “healing or

curing,” while relevant, do not end the anticipation inquiry.

Additional findings of fact are necessary to determine

whether the Goldwasser study anticipates under our new

construction of “therapeutically effective.” When findings of

fact are necessary under a revised claim construction, it is

appropriate for us to remand to the district court. See

Seachange Int’l, Inc. v. C-Cor Inc., 413 F.3d 1361, 1381

(Fed. Cir. 2005) (remanding for the district court to consider

anticipation after revising the claim construction). On

remand, the district court should make findings of fact as to

19a

whether the Goldwasser reference meets the “therapeutically

effective” limitation under our construction.* ae

C.

Anticipation—The Sugimoto Patent

The Sugimoto patent, filed August 10, 1981, discloses a

method for creating EPO-producing cells by creating hybrid

cells from lymphoblastoids’ and kidney tumor cells. The

Sugimoto patent suggests using recombinant techniques to

introduce the EPO genes from a human kidney tumor cell into

human lymphoblastoids. Sugimoto patent, col. 1, 1. 5S—col. 2,

1. 11. The patent involves in vivo production of EPO in which

~ human lymphoblastoid cells capable of producing EPO are

transferred to an animal body. The Sugimoto patent explains

that the EPO produced by the animal according to this

technique is then “collected easily by purification and

separation techniques using conventional procedures . . . .” /d.

col. 3, ll. 51-53.

In Amgen I, the district court found that the Sugimoto

patent did not anticipate claim | of the 422 patent because it

was not enabled. 126 F. Supp. 2d at 109. The court

considered the testimony of Amgen’s expert, Dr. Allan

Erslev, who stated that the Sugimoto procedure was “very

complex.” /d. at 108. Dr. Erslev stated that no one had used

the Sugimoto process prior to 1984, even though it would

have been highly profitable if successful. Jd After

recounting Dr. Erslev’s testimony, the court discounted

HMR/TKT’s arguments. Jd. HMR/TKT had put Dr. Michael

* If, on remand, the district court finds that the Goldwasser reference

contains the “therapeutically effective” limitation, it must then determine

whether the uEPO meets the other limitations of claim | of the ’422

patent.

* Lymphoblastoids are cells that are typically isolated from patients

with leukemia, which is a cancer of the blood. Amgen /, 126 F. Supp. 2d

at 106.

20a

Heartlein on the stand. By attempting to replicate the

Sugimoto process, Dr. Heartlein produced cells that generated

six times as much EPO as their parent cells. /d. at 108-09.

The court found that Dr. Heartlein’s experiments were not

sufficient to show enablement, however, because Dr.

Heartlein followed a different procedure than the one

disclosed in the Sugimoto patent. First, Dr. Heartlein used an

in vitro technique rather than an in vivo technique like that

disclosed in the Sugimoto patent. /d. at 109. Second, the

district court found that Dr. Heartlein used different starting

materials than the Sugimoto patent because he could not

obtain kidney tumor cells like those disclosed in the

Sugimoto patent. /d. Based on the foregoing, the district court

found that HMR/TKT had failed to demonstrate that the

Sugimoto patent was enabled by clear and convincing

evidence. /d. at 108-09.

On appeal, we ruled in Amgen II that the district court had

erred in placing the burden of proving enablement on

HMR/TKT. Id. at 1357. We indicated that the Sugimoto

patent should have been presumed enabled and that Amgen

should have had the burden of proving otherwise. /d. at 1355.

On remand, the district court affirmed its previous holding

of non-enablement, finding that “Amgen has shown by a

preponderance of the evidence that Sugimoto is not en-

abled ....” Amgen III Validity & Literal Infringement Judg-

ment, 339 F. Supp. 2d at 307. The court based its conclusion

that the Sugimoto patent was not enabled on three findings.

First, the court noted that the Sugimoto patent did not

disclose the starting materials hecessary to repeat the process

it describes. Jd. at 307-09. The Sugimoto patent required the

use of kidney tumor cells, but the inventor neither deposited

these cells publicly nor did he disclose them so that a person

of ordinary skill in the art could procure them. /d. at 307.

Second, the court found that the Sugimoto patent was not

enabled because it did not teach a person of ordinary skill in

2la

the art how to select EPO-producing hybrid cells. The court

based its finding largely on the testimony of Dr. howard

Green, a cell biologist with over forty years of experience,

who stated that although methods for selecting hybrids were

available at the time the Sugimoto patent was filed, they were

inconsistently successful and required undue experimentation

to produce results. /d. at 309. Third, the court found that the

Sugimoto patent did not enable a method for purifying EPO

even though the Sugimoto patent claimed to teach how to

produce purified EPO. Jd. at 311-12. The court found support

for this finding in the testimony of Dr. Green, id. at 311, as

well as in evidence that the Sugimoto patent’s disclosure still

had not been put into practice years after it issued in March of

1983, id. at 312. In addition, in connection with all three

findings, the court noted that Dr. Heartlein had failed to

duplicate the Sugimoto starting materials, selection methods,

or purification techniques when using the disclosure of the

Sugimoto patent. Jd. at 307-08, 311-12.

HMR/TKT makes several arguments for reversing the

district court’s finding of non-enablement. With regard to the

district court’s finding that the cells necessary for the

Sugimoto procedure were not adequately disclosed or de-

posited, HMR/TKT urges that the description of the starting

materials in the Sugimoto patent was sufficient despite the

fact that the cells were not deposited. HMR/TKT notes that

the Patent and Trademark Office found that there was an

adequate written description and that a person of ordinary

skill in the art would have understood the disclosure. HMR/

TKT asserts that the district court’s use of Dr. Heartlein’s

experiments as proof of non-enablement was flawed because -

the district court previously found in Amgen / that Dr.

Heartlein did not follow the Sugimoto patent’s disclosure.

Amgen defends the district court’s decision on remand by

arguing that the district court correctly identified deficiencies

in the Sugimoto patent’s disclosure. First, Amgen argues that

22a

the lack of starting materials is illustrated by both Amgen’s

and Dr. Heartlein’s inability to obtain the kidney tumor cells

described in the Sugimoto patent. Amgen also notes that

EPO-producing cells prior to Dr. Lin’s invention were “poor

producers.” In addition, Amgen argues that the district court

correctly found that the Sugimoto patent was not enabled

based on the lack of disclosure of a method for hybrid cell

selection or purification.

In order to anticipate, a prior art reference must not only

disclose all of the limitations of the claimed invention, but

also be enabled. Elan Pharms., Inc. v. Mayo Found., 346 F.3d

1051, 1054 (Fed. Cir. 2003). A reference is enabled when its

disclosures are sufficient to allow one of skill in the art to

make and use the claimed invention. /d. (quoting Bristol-

' Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368,

1374 (Fed. Cir. 2001)). Like a patent, a prior art reference is

_ enabled even if some “routine experimentation is required in

order to practice a claimed invention, but . . . such ex-

perimentation must not be ‘undue.’” Enzo Biochem, Inc. v.

Calgene, Inc., 188 F.3d 1362, 1371 (Fed. Cir. 1999). When

considering whether or not a prior art reference requires

“undue experimentation” we look at the reference from the

perspective of a person of ordinary skill in the art. Jn re

¥/ands, 858 F.2d 731, 735 (Fed. Cir. 1988).

We established in Amgen I] that when a piece of prior art is

a patent, like the Sugimoto patent, there is a presumption of

enablement. 314 F.3d at 1355. The patentee, Amgen, must

present persuasive evidence of non-enablement to overcome

this presumption. /d. As seen, in Amgen II, we vacated and

remanded the finding of non-enablement with regard to claim

1 of the °422 patent. On remand, the district court found that

Amgen had met its burden of proving by a preponderance of

the evidence that the Sugimoto patent was not enabled. 339 F.

Supp. 2d at 306. We review the district court’s ultimate

determination of enablement de novo while the underlying

23a

factual inquiries made by the district court are reviewed for

clear error. Enzo Biochem, 188 F.3d at 1369.

The district court’s factual finding that the Sugimoto patent

did not adequately disclose the starting materials was not

clearly erroneous. The court based its conclusion on the

testimony of several scientists with experience in the field of

erythropoeisis, including Dr. Green, Dr. Lin, and Dr. Harvey

Lodish, a research biologist at the Whitehead Institute and the

Massachusetts Institute of Technology. Dr. Green testified

that Dr. Heartlein, who attempted to duplicate the Sugimoto

disclosure, searched “for a long time and in many different

ways’ to find a suitable cell line and finally settled on a liver

tumor cell line—not a kidney tumor cell line like Sugimoto’s.

Dr. Lin testified that he had searched extensively for an EPO-

producing cell line during his research, but never acquired a

EPO-producing kidney tumor cell line. Dr. Lodish stated that

the Sugimoto patent failed to demonstrate that the kidney

tumor cells disclosed in the patent actually produced EPO. In.

addition, Amgen presented evidence that it failed to locate

any kidney tumor cells, like those described in the Sugimoto

patent, despite repeated efforts to do so. At the same time, we

do not see clear error in the court’s finding that Dr.

Heartlein’s non-conforming experiments show that a person

of ordinary skill in the art would not be able to obtain the

required kidney tumor cells based on the Sugimoto patent’s

disclosures. The failure of Dr. Heartlein to obtain the cells

disclosed by the Sugimoto patent and the expert testimony of

Drs. Green, Lin, and Lodish support this finding. Further,

Sugimoto did not deposit the EPO-producing kidney tumor

cells described in the Sugimoto patent. In sum, the Sugimoto

patent was not enabled due to the patentee’s failure to

adequately describe how to derive the starting materials or

deposit the cells. See In re Wands, 858 F.2d at 735 (“Where

an invention depends on the use of living materials such as

microorganisms or cultured cells, it may be impossible to

enable the public to make the invention (i.e., to obtain these

24a

living materials) solely by means of a written disclosure.”).

Because we discern no clear error in the district court’s

finding that the Sugimoto patent’s failure to disclose or

deposit the starting materials necessary to produce EPO

rendered the patent not enabled, it is unnecessary for us to

address Amgen’s arguments that the Sugimoto patent also did

not teach how to select hybrid cells and that the Sugimoto

patent did not disclose a means for purifying EPO.

D.

Obviousness—The Sugimoto Patent

The district court held in Amgen / that the Sugimoto patent

did not render claim | of the ’422 patent obvious because the

Sugimoto patent was not enabled. 126 F. Supp. 2d at 114 &

n.29. In Amgen II we vacated this finding and remanded

because non-enablement does not preclude a finding of

obviousness. 314 F.3d at 1357. On remand, in Amgen III

Validity & Literal Infringement Judgment, the district court

‘again concluded that the Sugimoto patent did not render

claim 1 of the ’422 patent obvious. In reaching this con-

clusion, the court considered the scope and content of the

prior art, differences between the claimed invention and the

prior art, the level of ordinary skill in the art, and reasonable

expectation of success. Amgen III Validity & Literal

Infringement Judgment, 339 F. Supp. 2d at 316-19. The court

also placed emphasis on the “objective indicia of non-

obviousness,” or “secondary considerations.” /d. at 314, 319.

Specifically, the court found that there had been a long-felt,

but unmet need for EPO-producing cells prior to Dr. Lin’s

discovery. /d. at 319. Thus, the district court concluded that

HMR/TKT “failed to persuade the Court by clear and

convincing evidence that the asserted claims of [Amgen’s

patents] were obvious in light of Sugimoto.” Jd. at 325.

HMR/TKT appeals the district court’s ruling.

25a

We have considered the various arguments made by

HMR/TKT on the obviousness issue. Having done so, we see

no reason to disturb the ruling of the district court that

HMR/TKT failed to establish that claim 1 of the ’422 patent

was obvious in view of the Sugimoto patent.

Il.

The ’080 Patent

As seen, in Amgen III Doctrine of Equivalents Judgment,

the district court ruled that claims 2-4 of the ’080 patent were

not invalid and that Amgen was not estopped from asserting

infringement under the doctrine of equivalents. 287 F. Supp.

2d at 160. Accordingly, the court reinstated its vacated

finding in Amgen / that claims 2-4 of the 080 patent were

infringed under the doctrine of equivalents by HMR/TKT’s

HMR4396 product. /d. The only issue before us on appeal is

infringement under the doctrine of equivalents. Claims 2-4

provide:

2. An isolated erythropoietin glycoprotein having the in

vivo biological activity of causing bone marrow cells to

increase production of reticulocytes and red blood cells,

wherein said erythropoietin glycoprotein comprises the

mature erythropoietin amino acid sequence of FIG. 6

and is not isolated from human urine.

3. A non-naturally occurring erythropoietin glycoprotein

having the in vivo biological activity of causing bone

marrow cells to increase production of reticulocytes and

red blood cells, wherein said erythropoietin glycoprotein

comprises the mature erythropoietin amino acid

sequence of FIG. 6. |

4. A pharmaceutical composition comprising a thera-

peutically effective amount [of] an erythropoietin gly-

coprotein product according to claim !, 2 or 3.

080 patent, col. 38, Il. 39-53. Claims 2-4 of the ’080 patent

each contain the limitation that the “erythropoietin glyco-

26a

protein comprises the mature erythropoietin amino acid

sequence of FIG. 6.” The sequence shown in Figure 6 of the

‘080 patent has a DNA sequence coding for 166 amino acids.

However, as noted above, mature human EPO actually

contains 165 amino acids, because the 166th amino acid,

arginine, is cleaved off prior to the EPO’s secretion from the

cell. The question before us is whether prosecution history

estoppel bars Amgen from claiming that claims 2-4 of the

080 patent encompass EPO with 165 amino acids under the

doctrine of equivalents. This is critical because HMR/

TKT’s EPO product, HMR4396, has only 165 amino acids.

Id. at 129.

A.

The application that resulted in the ’080 patent was filed on

June 6, 1995 as Application No. 08/468,556 (“the °556

application”). The °556 application, which contained 60

claims, was a continuation-in-part of the ’024 application. In

the first preliminary amendment of the ’556 application, the

patentee cancelled claims 1-60 and added claims 61-67. Of

the seven new claims added by amendment, claims 61-64

comprised the only independent product claims. Proposed

claims 61-64 provided as follows:

61. An isolated human erythropoietin glycoprotein prod-

uct not being isolated from human urinary sources

having glycosylation which differs from that of human

urinary erythropoietin.

62. An isolated human erythropoietin glycoprotein prod-

uct not being isolated from human urinary sources

having a higher molecular weight than human urinary

erythropoietin as measured by SDS-PAGE.

63. An isolated human erythropoietin glycoprotein prod-

uct not being isolated from human urinary sources and

free of other human proteins.

27a

64. The in vivo biologically active erythropoietin prod-

uct of the process comprising the steps of:

(a) growing, under suitable nutrient conditions, host

cells transformed or transfected with an isolated DNA

sequence selected from the group consisting of (1) the

DNA sequences set out in FIGS 5 and 6, (2) the

protein coding sequences set out in FIGS 5 and 6, and

(3) DNA sequences which hybridize under stringent

conditions to the DNA sequences defined in (1) and

(2) or their complimentary strands; and

(b) isolating said erythropoietin product therefrom.

The patentee made a second preliminary amendment to the

"556 application on December 20, 1995. In the second

preliminary amendment, claims 61-63 were cancelled, claim

64 was amended, and a new claim, claim 68, was added. The

amended version of claim 64 provided as follows:

64. The non-naturally occurring in vivo biologically

active erythropoietin product of the process comprising

the steps of:

(a) growing, under suitable nutrient conditions, host

celis transformed or transfected with an isolated DNA

sequence selected from the group consisting of (1) the

DNA sequences set out in FIGS 5 and 6, (2) the

protein coding sequences set out in FIGS 5 and 6, and

(3) DNA sequences which hybridize under stringent

conditions to the DNA sequences defined in (1) and

(2) or their complimentary strands; and

(b) isolating said erythropoietin product therefrom.

Claim 68, which was added in the second preliminary amend-

ment, provided as follows:

68. A non-naturally occurring erythropoietin product of

the process comprising the steps of:

28a

a) growing, under suitable nutrient conditions, host

cells transformed or transfected with an isolated DNA

sequence encoding the human erythropoietin amino

acid sequence set out in FIG. 6 or a fragment thereof;

and

b) isolating an erythropoietin product therefrom.

In the third and final amendment made to the °556

application for the ’080 patent, the patentee cancelled claims

64 through 68 and added claims 69-75. Claims 70-72, which

issued as claims 2-4 of the ’080 patent, provided as follows:

70. An isolated erythropoietin glycoprotein having the in

vivo biological activity of causing bone marrow cells to

increase production of reticulocytes and red blood cells,

wherein said erythropoietin glycoprotein comprises the

mature erythropoietin amino acid sequence of Figure 6

and is not isolated from human urine.

71. A non-naturally occurring erythropoietin glycopro-

tein having the in vivo biological activity of causing

bone marrow cells to increase production of reticulo-

cytes and red blood cells, wherein said erythropoietin

glycoprotein comprises the mature erythropoietin amino

acid sequence of Figure 6.

_

72. A pharmaceutical composition comprising a thera-

peutically effective amount [of] an erythropoietin gly-

coprotein product according to claim 69, 70 or 71.

As seen, after the first preliminary amendment, the claims

of the °556 application broadly encompassed an isolated

human EPO product. The application claimed an EPO pro-

duct made using the human EPO DNA sequence set out in

Figure 6 or the monkey EPO DNA sequence set out in Figure

5. With the second preliminary amendment, the patentee

added claim 68, which claimed an EPO product made using

the amino acid sequence for EPO set out in Figure 6 “or a

29a

fragment thereof.” With the third preliminary amendment, the

patentee removed all references to non-human monkey EPO

and also deleted claims for an EPO product made using “a

fragment” of the amino acid sequence of Figure 6. Instead, as

of the third preliminary amendment, the °556 application

claimed only a human EPO product having the complete

amino acid sequence of Figure 6.

B.

In Amgen I, the district court found that the amendments to

the 556 application were made to preempt a double-patenting

rejection based on claim | of the ’933 patent.'° 126 F. Supp.

2d at 135. The district court held that an amendment made to

avoid a double-patenting rejection is not an amendment

related to patentability. Jd. at 136. Therefore, the court held

that Amgen was not estopped from claiming that EPO with a

165-amino acid sequence infringed the asserted claims of the

’080 patent under the doctrine of equivalents. Jd.

In Amgen II, citing Festo Corp. v. Shoketsu Kinzoku Kogyo

Kabushiki Co., 535 U.S. 722, 740-41 (2002) (“Festo IT’), we

vacated the district court’s finding and held instead that

Amgen’s double-patenting amendment was an amendment

related to patentability that gave rise to prosecution history

estoppel. 314 -F.3d at 1345. We vacated the district court’s

finding of infringement of the ’080 patent under the doctrine

of equivalents and remanded for “an analysis under the nar-

row ways of rebutting the Supreme Court’s presumption of

estoppel.” Jd. These “narrow ways” were first set forth in

'° Claim 1 of the "933 patent provides:

A non-naturally occurring erythropoietin glycoprotein product hav-

ing the in vivo biological activity of causing bone marrow cells to

increase production of reticulocytes and red blood cells and having

glycosylation which differs from that of human urinary erythropoi-

etin.

*933 patent, col. 38, Il. 18-22.

30a

Festo II. They are (i) showing that an equivalent was unfore-

seeable; (ii) demonstrating that the purpose for an amendment

was merely tangential to the alleged equivalent; or (iii) estab-

lishing “some other reason” that the patentee could not have

reasonably been expected to have described the alleged

equivalent. 535 U.S. at 740-41.

On remand, in Amgen III Doctrine of Equivalents Judg-

ment, the district court evaluated whether any one of the three

grounds for rebutting the Festo presumption of estoppel had

been demonstrated by Amgen. 287 F. Supp. 2d at 147-59.

The court determined that Amgen had failed to show that a

165-amino acid EPO was unforeseeable at the time of the

third preliminary amendment. /d. at 149. However, the court

determined that Amgen had succeeded in showing that the

third preliminary amendment, which restricted the literal

scope of the ’080 patent to EPO having the complete amino

acid sequence shown in Figure 6, was added only to limit the

080 patent to human EPO products. /d. at 152. The court

found that the third preliminary amendment was therefore no

more than tangentially related to the 165-amino acid equiva-

lent. /d. at 154. The court based this finding on the prosecu-

tion history, noting that “the chronology and language of

the amendments support Amgen’s position that it added the

amendment in question (the third amendment) to distinguish

the 080 patent from the 933 patent on the basis that the ’080

was limited to humas: BPO.” Id. at 152 (emphasis in original).

The human EPO limitation thus was merely tangential, the

district court found, to the 165-amino acid equivalent. The

court buttressed its finding of tangentiality with a “reasonable

inference” that the amendment was not made with the inten-

tion of surrendering equivalents because, as of December of

1996, when the third preliminary amendment was made, the

Patent and Trademark Office and Amgen both were aware

that mature EPO had 165 amino acids. /d. at 153.

3la

Although the district court found that the Festo presump-

tion was rebutted because the amendment limiting the claims

of the ’080 patent to EPO with the amino acid sequence of

Figure 6 was tangential to EPO having a 165-amino acid se-

quence, it set forth an alternate rationale based on the “some

other reason” language in Festo //. The court looked to both

extrinsic and intrinsic evidence suggesting that the drafter of

the amendment, as well as those of ordinary skill in the art,

would have considered the amendment to cover all human

EPO, regardless of whether or not the EPO had 165 or 166

amino acids. /d. at 157. In essence, the court construed the

claims based on the extrinsic record (with support from the

intrinsic record). Jd. The court reasoned that this evidence

reflected a “shortcoming[ | of language” or “linguistic” limi-

tation, which were mentioned in Festo Corp. v. Shoketsu

Kinzoku Kogyo Kabushiki Co., 344 F.3d 1359, 1372 (Fed.

Cir. 2003) (en banc) (“Festo IIT’), as possible reasons for

rebuttal of the Festo presumption. Amgen III Doctrine of

Equivalents Judgment, 287 F. Supp. 2d at 159. The court then

found that those equivalents encompassed by this construc-

tion were not surrendered, relying on the “some other reason”

exception to the Festo presumption of surrender of equiva-

lents. Jd.

HMR/TKT argues on appeal that the district court erred

in finding that Amgen’s third preliminary amendment was

merely tangential to the equivalent EPO having a 165-amino

acid sequence. It contends that if the patentee had intended

solely to limit the scope of claims 2-4 of the ’080 patent to

human EPO, the patentee would have used the word “human”

to describe the EPO. Instead, according to HMR/TKT, the

third preliminary amendment uses the word “mature,” while

both of the previous amendments used the word “human” to

describe the EPO claimed. HMR/TKT urges that the district

court also erred by finding that Amgen rebutted the Festo

presumption based on “some other reason.” HMR/TKT ar-

gues that Amgen amended the claims of the ’080 patent to

32a

include only a 166-amino acid EPO out of fear of a new mat-

ter rejection, which does not fall under Festo’s “some other

reason” criterion.

Amgen counters that the district court was correct in its

conclusion because the purpose of the third preliminary

amendment was to distinguish the ’080 patent, which encom-

passes only human EPO, from claim | of the ’933 patent,

which encompasses both human and animal EPO. In support

of its argument, Amgen recites its remarks during prosecution

“that claims 69, 70, and 71 [currently claims 2-4 of the ’080

patent] all differ in scope from glycoprotein claim | of U.S.

5,547,933 in specifying that the claimed subject matter com-

prises the mature human erythropoietin sequence of Figure 6.

Claim 69 [currently claim | of the ’080 patent] (like [’933]

glycoprotein claim 1) recites carbohydrate differences in

comparison to human urinary [EPO] and claim 70 [currently

claim 2 of the 080 patent] recites a negative limitation with

respect to isolation from human urine.” (footnote omitted).

Based on the foregoing statement in the patentee’s remarks

accompanying the third preliminary amendment, Amgen con-

tends that the amendment was meant to distinguish Amgen’s

EPO from naturally-occurring EPO through differences in

glycosylation, or “carbohydrate differences.” Thus, Amgen

argues that the mention of the EPO sequence of Figure 6 was

merely tangential. Further, Amgen defends the district court’s

conclusion that Amgen successfully rebutted the Festo pre-

sumption under the “some other reason” rationale. Amgen

argues that because u person of ordinary skill in the art would

have understood the claims to encompass a 165-amino acid

equivalent, the Festo presumption was rebutted. Finally,

Amgen argues that the district court erred in finding that a

165-amino acid equivalent was foreseeable because the pat-

entee expected the claims to encompass this equivalent.

33a

a

The burden of rebutting the Festo presumption lies with the

patentee. Festo I/I, 344 F.3d at 1368. Whether a patent-holder

has successfully rebutted the Festo presumption of the surren- —

der of equivalents is a question of law, which we review

de novo. Chimie v. PPG Indus., Inc., 402 F.3d 1371, 1376

(Fed. Cir. 2005); see also Festo Ill, 344 F.3d at 1368; Biagro

W. Sales, Inc. v. Grow More, Inc., 423 F.3d 1296, 1302 (Fed.

Cir. 2005); Glaxo Wellcome, Inc. v. Impax Labs., Inc., 356

F.3d 1348, 1351 (Fed. Cir. 2004). For the reasons which fol-

low, we uphold the district court’s finding that Amgen failed

to show that EPO with a 165-amino acid sequence was not

foreseeable at the time of the amendment. However, we hold

that the district court erred when it held that Amgen had met

its burden of rebutting the Festo presumption under oth the

tangentiality and “some other reason” rationales.

The presumption that equivalents are surrendered may be

rebutted if a patentee shows that “one skilled in the art could

not reasonably be expected to have drafted a claim that would

have literally encompassed the alleged equivalent.” Festo III,

344 F.3d 1365 (quoting Festo I/, 535 U.S. at 741). As noted,

in Festo II, the Supreme Court listed three ways in which a

patentee may make this showing. First, the patentee may

demonstrate that “the equivalent [would] have been unfore-

seeable at the time of the [amendment].” 535 U.S. at 740-41.

Second, the patentee may show that “the rationale underlying

the amendment [bears] no more than a tangential relation to

the equivalent in question.” Jd. Third, a patentee may demon-

strate that “there [is] some other reason suggesting that the

patentee could not reasonably be expected to have described

the insubstantial substitute in question.” /d.

In Festo III, we offered some guidance as to what must be

shown by a patentee in order to succeed in rebutting the Festo

presumption under each of the three showings enumerated by

the Supreme Court. In order to demonstrate that an invention

34a

is not foreseeable, a patentee may utilize extrinsic evidence.

344 F.3d at 1369. We suggested that after-arising technology

is more likely to be unforeseeable than old technology, but

did not set forth any hard or fast rule on foreseeability. Jd. We

stated that “if the alleged equivalent were known in the prior

art in the field of the invention, it certainly should have been

foreseeable at the time of the amendment.” /d. With regard to

the tangentiality of an amendment to an equivalent, we did

not set forth any concrete definition, but we did note that an

amendment “made to avoid prior art that contains the equiva-

lent in question is not tangential; it is central to allowance of

the claim.” /d. Thus, an amendment is tangential when the

“reason for [it] was peripheral, or not directly relevant, to the

alleged equivalent.” Jd. The determination of whether or not

an amendment is merely tangential to the equivalent is based

on the “patentee’s obiectively apparent reason for the narrow-

ing amendment.” /d. Thus, the inquiry must be based on the

intrinsic record alone and, if necessary, expert testimony to

aid in interpretation of that record. /d. Finally, we noted that

the third way to rebut the Festo presumption, the “some other

reason” route, is a narrow one. Jd. at 1370. We stated that

“the third criterion may be satisfied when there was some

reason, such as the shortcomings of language, why the pat-

entee was prevented from describing the alleged equivalent

when it narrowed the claim.” Jd.

l.

With regard to the first Festo rebuttal argument, fore-

seeability, we see no error in the district court’s holding that,

at the time the third preliminary amendment was made, EPO

with 165 amino acids was a foreseeable equivalent. Amgen II]

Doctrine of Equivalents Judgment, 287 F. Supp. 2d at 147-49.

We reject Amgen’s assertion that the relevant inquiry is

whether it was “objectively foreseeable that the amended

claim language would not read on the accused equivalent.”

Appellee’s Br. at 74. The question of how a person of

35a

ordinary skill in the art would understand claims 2-4 of the

080 patent is one of claim construction, which was settled in

Amgen IT. 314 F.3d at 1344-45 (affirming the district court’s

construction of claims 2-4 as being limited to EPO with 166

amino acids). EPO with a 165-amino acid sequence was a

foreseeable equivalent because the patentee admittedly knew

about the 165-amino acid equivalent at the time of the third

preliminary amendment. Amgen III Doctrine of Equivalents

Judgment, 287 F. Supp. 2d at 157 (finding that during prose-

cution Amgen informed the examiner that human EPO has

165 amino acids); see Festo III, 344 F.3d at 1369 (noting that

if an equivalent is known in the field, then it is foreseeable);

Glaxo Wellcome, Inc., 356 F.3d at 1355-56 (finding that a

patentee did not rebut the presumption of surrender when a

person of ordinary skill in the art at the time of the amend-

ment would have considered the equivalent).

y A

We next examine whether Amgen has met its burden of

showing that the reason for the addition of the reference to

the “amino acid sequence of FIG. 6” was merely tangential to

the alleged equivalent.

In Insituform Technologies, Inc. v. CAT Contracting, Inc.,

385 F.3d 1360 (Fed. Cir. 2004), we were asked to review

whether a patentee had successfully rebutted the surrender of

equivalents. /d. at 1370-71. The patented method in /nsitu-

form involved using a vacuum to impregnate a flexible tube

with resin. /d. at 1362-63. During prosecution, the patentee

limited the number of suction cups that could be placed on

the tube to create the vacuum to just one cup. /d. at 1366. The

amendment that limited the number of vacuum cups was

made to overcome prior art which had a single vacuum source

located at the end of the tube a distance from the resin source.

Id. at 1370. The reason for the amendment was to clarify the

location of the vacuum source relative to the resin—not to

limit the number of vacuum cups. /d. Thus, we ruled that the

36a

reason for the amendment was merely tangential to the

alleged equivalent using multiple cups. Jd. Accordingly, we

held that the patentee in Jnsituform successfully rebutted the

Festo presumption of surrender of the equivalent in question.

Amgen was required to show that the reason for adding the

requirement in the third preliminary amendment that EPO

have 166 amino acids was peripheral to the 165-amino acid

equivalent. See Festo II], 344 F.3d at 1369. As seen, the third

preliminary amendment was made to avoid a double patent-

ing rejection in light of the ’933 patent. Amgen I, 126 F.

Supp. 2d at 135. Thus, the 165-amino acid equivalent is only

tangential if the patentee’s reason for limiting the ’080 patent

to EPO with 166 amino acids was unrelated to distinguishing

the scope of the ’080 patent from the scope of the ’933 patent.

We must reject Amgen’s argument that the sole reason for

the amendment requiring EPO with 166 amino acids was to

limit the ’080 patent to human EPO and that therefore the

amendment was merely tangential to a 165-amino acid equiva-

lent. As seen, in claim | the ’933 patent claimed:

A non-naturally occurring erythropoietin glycoprotein

product having the in vivo biological activity of causing

bone marrow cells to increase production of reticulo-

cytes and red blood cells and having glycosylation which

differs from that of human urinary erythropoietin.

’933 patent, col. 38, Il. 18-22. Thus, claim 1 contains no

limitation pertaining to human or non-human EPO. Claim |

of the ’933 patent, which covers both human and non-human

EPO, also lacks any limitation concerning the amino acid

sequence of the claimed EPO product. Accordingly, claim 1

of the 933 patent broadly encompasses EPO with any amino

acid sequence, which would include amino acid sequences

differing from that set forth in Figure 6.

We think Amgen’s third preliminary amendment did more

than limit the scope of the asserted claims of the ’080 patent

37a

to human EPO. The third preliminary amendment limited the

’556 application, and consequently the ’080 patent, to EPO

having 166 amino acids. Claim 68, which was added with the

second preliminary amendment to the °556 application, en-

compassed cells “encoding the human erythropoietin amino

acid sequence set out in FIG. 6 or a fragment thereof.” Thus,

after the second preliminary amendment, the ’556 application

and the 933 patent overlapped in claim scope. That is be-

cause the °556 application encompassed EPO having the

incomplete amino acid sequence set forth in Figure 6. Like-

wise, claim | of the °933 patent encompassed EPO having

any amino acid sequence, which would include an incomplete

amino acid sequence of Figure 6. In other words, an incom-

plete amino acid sequence of Figure 6 (a “fragment”) was

encompassed by both the °556 application and the °933

patent. The deletion of “or fragment thereof” with the third

preliminary amendment limited the °556 application to the

complete 166-amino acid sequence shown in Figure 6. This

limitation reduced the overlap between the scope of the 556

application, which encompassed only EPO with the complete

amino acid sequence of Figure 6, from the scope of claim | of

the °933 patent, which encompassed EPO with any amino

acid sequence. Indeed, as the inventor himself stated in the

remarks accompanying the third preliminary amendment, the

amended claims “all differ in scope from glycoprotein claim

1 of [the °933 patent] in specifying that the claimed subject

matter comprises the mature human erythropoietin sequence

of Figure 6.” Third Preliminary Amendment at 164 (Dec. 20,

1996), quoted in Amgen Ill Doctrine of Equivalents Judg-

ment, 287 F. Supp. 2d at 152 n.36 (emphasis added) (footnote

omitted). Accordingly, the limitation added in the third pre-

liminary amendment may have been central to overcoming a

double patenting rejection in light of claim 1 of the °933

patent. Under these circumstances we cannot say that the

reason for the addition of the limitation pertaining to the

complete amino acid sequence of Figure 6 was merely tan-

38a

gential to the alleged 165-amino acid equivalent. Thus, unlike

Insituform, where it was clear that the amendment in question

was not made to limit the number of cups and overcome the

prior art, the requirement that EPO have exactly 166 amino

acids may have been central to the allowance of claims 2-4

over a double patenting rejection.

Finally, we think that if the patentee had wished only to

limit the claims to human EPO, the patentee could have done

so by continuing to use the adjective “human” when referring

to EPO in the third preliminary amendment; instead the pat-

entee chose to further narrow the claims in the third prelimi-

nary amendment by making reference to the specific se-

quence in Figure 6 rather than human EPO. We thus hold that

Amgen has not met its burden of showing that the addition of

the “the mature amino acid sequence of FIG. 6” amendment

was tangential to a 165-amino acid equivalent.

3.

In the alternative, the district court relied on the “some

other reason” language in the Supreme Court’s Festo // deci-

sion in ruling that Amgen had rebutted the Festo presumption

of surrender of equivalents. In Festo //, the Court held that

the presumption of the surrender of equivalents could be

rebutted by showing that “there [is] some other reason sug-

gesting that the patentee could not reasonably be expected to

have described the insubstantial substitute in question.” 535

U.S. at 740-41. As previously noted, the district court based

its conclusion that Amgen had rebutted the Festo presumption

under the “some other reason” rationale on its finding that,

before the patentee made the third preliminary amendment,

the patentee disclosed information to the Patent and Trade-

mark Office concerning the fact that human EPO has 165

amino acids. Amgen III Doctrine of Equivalents Judgment,

287 F. Supp. 2d at 157. The district court also relied on

extrinsic evidence that a person of ordinary skill in the art

would understand that Amgen meant to claim human EPO

39a

having either 165 or 166 amino acids at the time the third

preliminary amendment was made. Jd. The court reasoned

that Amgen had rebutted the Festo presumption under the

“some other reason” criterion because the patentee could not

have reasonably been expected to have described the 165-

amino acid equivalent because those of skill in the art would

have interpreted the amendment to cover the 165-amino acid

equivalent. Jd. at 158.

However, the district court’s analysis does not correctly

apply the Supreme Court’s explanation of the “some other

reason” rebuttal argument: the other reason must be such that

the patentee could “not reasonably be expected” to write a

claim to encompass the equivalent, see Festo IT, 535 U.S. at

741, such as a shortcoming of language, Festo III, 344 F.3d at

1370. The patentee knew of the 165-amino acid sequence at

the time of the amendment, Amgen II] Doctrine of Equiva-

lents Judgment, 287 F. Supp. 2d at 157, but chose to limit the

claims to the 166-amino acid sequence depicted in Figure 6.

Contrary to Amgen’s argument, whether the patentee, the

examiner, or a person of skill in the art may have thought the

claims encompassed EPO with 165 amino acids does not

excuse the patentee’s failure to claim the equivalent. See

Biagro, 423 F.3d at 1307 (rejecting the patentee’s argument

that the “some other reason” rebuttal argument applied when

the patentee allegedly understood the claim language to refer

to the equivalent in question). Further, there were no short-

comings of language that might have prevented the patentee

from claiming EPO having 165 amino acids. The patentee

could have simply claimed mature human EPO without refer-

ence to Figure 6. Alternatively, the patentee could have

claimed, as it did prior to the third preliminary amendment,

EPO having the amino acid sequence disclosed in Figure 6 or

a “fragirweet thereof.” In short, there was no linguistic barrier

_ to clairing’ ©PO comprised of 165 amino acids. Amgen has |

not argued on appeal, nor do we find, that any other reason

exists that might rebut the Festo presumption. Therefore, we

40a

find that the patentee could have reasonably been expected to

accurately point out and particularly claim the 165-amino

acid sequence.

The facts in this case are analogous to those in Festo III,

where we ruled that the Festo presumption was not rebutted

by “some other reason.” In Festo Ill, we rejected Festo’s

argument that it was not estopped from asserting the doctrine

of equivalents because the patentee “could not reasonably

have been expected to have drafted a claim to cover what was

thought to be an inferior and unacceptable design.” 344 F.3d

at 1372-73. Like the patentee in Festo, who knew about the

“inferior” equivalent, the patentee of the ‘080 patent knew

about the 165-amino acid sequence at the time of the amend-

ment, but still chose to claim the incorrect 166-amino acid

sequence in Figure 6. We conclude that Amgen has not rebut-

ted the Festo presumption based on “some other reason.”

In sum, we uphold the district court’s finding that the 165-

amino acid EPO equivalent was foreseeable at the time of the

third preliminary amendment.. The district court erred, how-

ever, in finding that Amgen successfully rebutted the Festo

presumption of surrender of equivalents under both the

tangentially related rebuttal argument and the “some other

reason” rebuttal argument. This means that HMR/TKT cannot

be found to have infringed the claims 2-4 of the ’080 patent

under the doctrine of equivalents. Accordingly, the judgment

of infringement of claims 2-4 is reversed. It is unnecessary

for us to reach HMR/TKT’s alternative argument by way of

affirmative defense that claims 2-4 of the 080 patent are

invalid as anticipated by the Goldwasser reference.

Il.

The ’698 and 349 patents

The ’698 patent is directed to a process for producing EPO

in host cells using recombinant DNA techniques. On remand,

in Amgen III Validity & Literal Infringement Judgment, the

4la

district court rejected HMR/TKT’s argument that the asserted

claims of the ’698 patent (claims 4-9) are invalid because

they lack an adequate written description. The court also re-

jected HMR/TKT’s argument that the asserted claims were

not enabled. Having rejected HMR/TKT’s validity chal-

lenges, the court found claims 4-9 of the ’698 patent literally

infringed.

The °349 patent is directed to vertebrate cells capable of

producing EPO and a process for making EPO using the

claimed cells. On remand, the district court rejected HMR/

TKT’s argument that the asserted claims of the ’349 patent

(claims 1, 3, 4, 6, and 7) were invalid by reason of obvious-

ness. Since the district court already had ruled in Amgen / that

claims |, 3, 4, and 6 of the 349 patent were infringed, in

Amgen III Validity & Literal Infringement Judgment it only

was necessary for the court to address Amgen’s claim that

HMR/TKT’s HMR4396 literally infringed claim 7 of the ’349

patent. Doing so, the court found literal infringement. 339 F.

Supp. 2d at 258, 336.

On appeal, HMR/TKT argues that the district court made

various claim construction errors and also erred in its validity

and infringement rulings in the case of both the 698 and °349

patents. We have carefully considered all of HMR/TKT’s

arguments relating to the 698 and ’349 patents. Having done

SO, we see no error in the district court’s legal conclusions;

nor do we see clear error in its findings of fact. Accordingly,

we affirm in all respects the court’s rulings with respect to the

°698 and °349 patents. -

CONCLUSION

For the foregoing reasons, we vacate the district court’s

judgment that claim | of the ’422 patent is not invalid under

35 U.S.C. § 102(a) and remand to the district court for a

determination of whether, in view of our construction of the

limitation “therapeutically effective,” claim 1 is anticipated

42a

by the Goldwasser reference and for such further proceedings

as may be necessary.'' We reverse the court’s judgment that

HMR/TKT infringes claims 2-4 of the ’080 patent under the

doctrine of equivalents. We affirm the court’s judgment that

HMR/TKT infringes claims 4-9 of the °698 patent and claims

1, 3, 4, 6, and 7 of the *349 patent.

COSTS

Each party shall bear its own costs.

AFFIRMED-IN-PART, REVERSED-IN-PART, VACATED-

IN-PART, and REMANDED

" See footnote 10, supra.

43a

MICHEL, Chief Judge, dissenting-in-part.

I write separately to voice my strong disagreement with the

majority’s holdings that (1) contrary to the district court’s

construction, “therapeutically effective” in claim | of the

°422 patent means simply eliciting in vivo biological effects

even if not tending to cure certain diseases and (2) claim 1 of

the °422 patent could therefore be invalid in light of the

Goldwasser reference, which describes a prior art compound

eliciting biological activity without curing. Because the

majority concludes that the district court erred in construing

“therapeutically effective” to mean having a disease-curing

effect, it remands the case for a re-adjudication of whether the

Goldwasser reference anticipates claim | of this particular

patent, only one of several asserted.

At the outset, [ compliment the district court for the me-

ticulous attention it has given to this extraordinarily comphi-

cated, highly-technical, and very difficult case. The district

court’s two opinions on remand, the subject of our present

review, were well-reasoned, well-grounded in the evidence,

and well-written. The trial court clearly exerted tremendous

effort to carefully consider all the issues raised by the parties

as well as our remand instructions in Amgen I].

After discovery, the district court conducted a three-day

Markman hearing and a bench trial spanning twenty-

three days in 2000 and then, following our remand, a second

Markman hearing and second bench trial spanning nine days

in 2003. The district court also took the creative steps of

employing Professor Chris Kaiser of the Massachusetts Insti-

tute of Technology as a technical advisor on the underlying

technology and Michele D. Beardslee as a special master to

aid in researching the law, analyzing the issues, and drafting

the remand opinion. Assisted by them, the district court spent

more than ten months rendering its revised claim construc-

tions and making extensive findings of fact and conclusions

of law; it subsequently issued two opinions, together totaling

44a

over 360 pages. Plainly, these decisions were not reached in

a haphazard or hurried manner by a court intimidated by

either the science or the law. On the contrary, the district

court’s management and resolution of this case is, I think, a

model for all trial courts confronted with such patent suits.

I.

The district court construed “therapeutically effective

amount” to mean “a quantity that produces a result that in and

of itself helps to heal or cure.” Amgen III Validity & Literal

Infringement Judgment, 339 F. Supp. 2d at 245. It further

elaborated that a therapeutically effective amount would elicit

certain in vivo biological effects, such as those described

in the specification, col. 33, Il. 17-22, (i.e., stimulation of

reticulocyte response, development of ferrokinetic effects,

erythrocyte mass changes, stimulation of hemoglobin C

synthesis, and increasing hematocrit levels), which reflect a

“healing” or “curing” effect in “patients generally requiring

blood transfusions and including trauma victims, surgical

patients, renal disease patients including dialysis patients, and

patients with a variety of blood composition affecting dis-

orders, such as hemophilia, sickle cell disease, physiological

anemias, and the like.” °422 patent, col. 33, Il. 23-28. I

believe the court correctly recognized that merely eliciting a

biological effect is not the same as being therapeutically

effective.

Indeed, prior art compounds could trigger the very in vivo

biological effects enumerated in the specification but were

utterly incapable of “healing” or “curing” the class of patients

described in the °422 patent. Notably, an article published in

the Renal Extrarenal Sources of Erythropoietin Journal in

1971 revealed that a patient suffering from renal anemia was

treated with an urinary EPO preparation but, despite experi-

encing an increase in reticulocytes, died five days later. The

district court was particularly aware of this article and even

mentioned it when addressing the issue of obviousness after

45a

the first bench trial. See Amgen I, 126 F. Supp. 2d at 116. Had

this uEPO or any other prior art EPO product been shown to

“heal” or “cure” anemia or similar blood disorders, there

would have been little need for the claimed invention.

When a compound is truly “therapeutically effective,” that

is, when it “heals” or “cures” such a blood disorder, it nec-

essarily increases hematocrit as well as causes one or more of

the other listed in vivo biological effects. Reading lines 17-22

of column 33 in context, the patentee clearly recognized this.

As previously indicated, recombinant-produced and

synthetic products of the invention share, to varying

degrees, the in vitro biological activity of EPO isolates

from natural sources and consequently are projected to

have utility as substitutes for EPO isolates in culture

media employed for growth of erythropoietin cells in

culture. Similarly, to the extent that polypeptide products

of the invention share the in vivo activity of natural EPO

isolates they are conspicuously suitable for use in

erythropoietin therapy procedures practiced on mam-

mals, including humans, to develop any or all of the

effects herefore attributed in vivo to EPO, e.g., . . . and,

as indicated in Example 10, increasing hematocrit levels

in mammals. -

’422 patent, col. 33, Il. 6-22 (emphasis added). This disclo-

sure clarifies three aspects of the claimed invention. First, the

claimed EPO shares the in vitro biological activity of natural

EPO. Second, the claimed EPO elicits the very same in vivo

activity as natural EPO and, therefore, is suitable for use in

EPO therapy procedures. Third, the claimed EPO increases

hematocrit in mammals, as exemplified in Example 10 of the

‘422 patent. By reciting “therapeutically effective amount of

human erythropoietin,” the patentee thus demonstrated an in-

tention to claim EPO that (1) causes the same in vivo

biological effects as the natural EPO; and also (2) increases

hematocrit.

46a

The subsequent disclosure strengthens my view that the

district court correctly construed the “therapeutically effec-

tive” limitation.

A preferred method for administration of polypeptide

products of the invention is by parenteral (e.g., IV,

IM, SC, or IP) routes and the compositions adminis-

tered would ordinarily include therapeutically effective

amounts of product in combination with acceptable

diluents, carriers and/or adjuvants. . . . Effective dosages

are expected to vary substantially depending upon the

condition treated but therapeutic doses are presently

expected to be in the range of 0.1 (~70) to 100 (~7000

U) pg/kg body weight of the active material.

°422 patent, col. 33, Il. 41-52 (emphasis added). In the only

part of the specification where the term “therapeutically

effective” actually appears, the patentee uses the term in the

ordinary sense of the phrase to mean promoting “healing” or

“curing.” That is, the patentee teaches the preferred amount

of EPO product and a preferred method of administration for

a patient suffering from a disorder characterized by a low red

blood cell count. Inherently, the ultimate goal is to “heal” or

“cure” the disorder. That healing is characterized by an in-

creased red blood cell count, i.e., a higher hematocrit level.

Significantly, I note that the words “therapeutically effec-

tive” are conventionally employed in the pharmaceutical arts

to indicate that the claimed pharmaceutical product has utility

in the treatment of a human disease where such treatment

tends to cause the “healing” or “curing” of the disease. The

patentee, I think, intended to invoke that very convention.

While the majority might be correct that the ’422 patent is not

necessarily limited to the exact class of patients described

in the specification (as opposed to other blood disorders

associated with low hematocrit levels), the district court

correctly recognized that it would be “foolish to construe a

term such as ‘therapeutically effective,’ without reference to a

47a

class of patients for which the product is intended to be

‘therapeutically effective.” Amgen Ill Validity & Literal

Infringement Judgment, 339 F. Supp. 2d at 237.

The specification further discloses various ey of EPO

at columns 35-36:

In addition to naturally-occurring allelic forms of mature

EPO, the present invention also embraces other “EPO

products” such as polypeptide analogs of EPO and frag-

ments of “mature” EPO. . . . Especially significant in this

regard are those potential fragments of EPO which are

elucidated upon consideration of the human genomic

DNA sequence of FIG. 6, i.e., “fragment” of the total

continuous EPO sequence which are delineated by intron

sequences and which may constitute distinct “domains”

of biological activity. It is noteworthy that the absence of

in vivo activity for any one or more of the “EPO pro-

ducts”’ of the invention is not wholly preclusive of thera-

peutic utility (see, Weiland, et. al., supra) or of utility in

other contexts, such as in EPO assays or EPO anta-

gonism.

422 patent, col. 35, Il. 34-37; col. 36, ll. 4-14. The majority

mistakenly relies on this disclosure to support its view that

the “therapeutically effective” means merely capable of trig-

gering any in vivo biological activity, regardless of degree.

Correctly read, the emphasized passage plainly concerns only

analogs of EPO, not the EPO of claim 1. That is, the full

disclosure teaches that analogs of EPO may offer therapeutic

utility even though they may not have in vivo activity. The

emphasized sentence says nothing about the claimed EPO and

hence cannot be relied upon to construe the “therapeutically

effective” limitation.

The prosecution history further confirms that “therapeuti-

cally effective” connotes more than simply eliciting any cited

in vivo biological effect. The district court emphasized that

48a

during prosecution of the ’422 patent, the patentee differenti-

ated its invention from natural EPO, which also elicits the

aforementioned biological activity, on the basis that the latter

was not available in large enough quantities to treat patients,

i.e., help cure their diseases. Amgen III Validity & Literal

Infringement Judgment, 339 F. Supp. 2d at 239. Likewise,

during the prosecution of the Application No. 07/113,178, a

parent application of the °422 patent which itself issued as

United States Patent No. 5,441,868, the patentee distin-

guished the claimed EPO from the prior art, emphasizing that

the claimed EPO could be used as a therapeutic product to

treat humans with blood disorders characterized by a low red

blood cell count whereas the prior art EPO could not. In

particular, the patentee stated:

{Njaturally occurring human erythropoietin is not a

viable human therapeutic product; human recombinant

erythropoietin, on the other hand, has been proved to be

clinically effective, and is the first therapeutic product

which can be used to effectively treat the hundreds of

thousands of patients who suffer from anemia and other

disorders involving low red blood cell counts.

In so differentiating the claimed EPO from the prior art, the

patentee said that the claimed EPO is capable of doing more,

i.e., the claimed EPO “heals” or “cures” anemia and other

such disorders by raising a patient’s red blood cell count.

Thereafter, during the prosecution of the Application No.

08/100,197, a continuation of Application No. 07/113,178

discussed above, the examiner objected that “Claim 62 is

vague and indefinite because it is unclear what the claimed

composition is required to be ‘effective’ for.” In response,

after quoting column 33, lines 11-28, which includes a

description of the in vivo biological effects, the “increasing

hematocrit” language, and various diseases treatable with the

claimed invention, the patentee again explained that the

49a

claimed EPO could be used to treat, (i.e., “heal” or “cure”),

various blood disorders:

It is believed that these sentences from the specification

and others provide a clear and definite description of the

uses for which the claimed erythropoietin compositions

would be therapeutically effective. A person of skill in

the art would understand that the amount of erythropoi-

etin necessary to achieve these defined therapeutic results

would vary for each use. However, clinicians can readily

determine the “therapeutically effective” amounts for

each condition, and indeed for each patient. Application

submits that the claim language “therapeutically effec-

tive amount” is commonly used in this type of case

where the product is usable to treat various conditions.

(emphasis added). Accordingly, I must conclude that the

district court’s construction of the “therapeutically eftective”

limitation comports with the patentee’s own repeated descrip-

tions of the claimed invention. It is exactly the way a skilled

artisan would interpret the patent, as the district court held.

I.

Regarding possible anticipation of the invention of the’422

patent by the Goldwasser reference, the district court set forth

very specific reasons why none of the in vivo biological

effects mentioned in the Goldwasser reference (i.e., an in-

crease reticulocytes, an increase in plasma iron clearance, and

red cell mass changes) demonstrated therapeutic effective-

ness. HMR does not contend that the district court clearly

erred. Rather, it merely asserts that all of these biological

results fall under its proposed claim construction for the term

“therapeutically effective amount,” which is any amount of

EPO that elicits any in vivo biological effect, even if not

accompanied by an increased hematocrit. Because | think that

the district court correctly reyected HMR’s proposed con-

struction and properly construed “therapeutically effective” to

50a

mean “healing” or “curing,” HMR’s validity challenge nec-

essarily fails. While all of the results described in the

Goldwasser reference represent in vivo biological responses,

none demonstrate that the subject anemic patients were even

partially “healed” or “cured.” In fact, Dr. Goldwasser himself

considered his study a failure because the patients’ hematocrit

levels did not increase. I therefore conclude that the district

court correctly found that the Goldwasser reference does not

anticipate claim | of the ’422 patent. Clear error has not been

shown. We should therefore affirm the judgment as to

validity.

III.

This litigation has already dragged on for almost ten years,

yet the end is nowhere in sight. The majority again remands

this case to the district court, this time for a re-adjudication of

whether the Goldwasser reference anticipates claim | of the

°422 patent in light of its revised construction of “therapeuti-

cally effective.” The district court, as a result, will conduct

further proceedings and render a third opinion. Inevitably, at

least one party will appeal that judgment, prompting a third

review by this Court. We, in turn, will issue another opinion,

perhaps even remanding the case a third time. The district

court, however, has yet to decide whether to grant an injunc-

tion, the specific relief sought by the patentee. Presumably,

after our decision in that potential third appeal, the district

court would conduct a trial or hearing on that issue and reach

another decision, which will likely be appealed by one or

both of the parties. We consequently would hear a fourth

appeal and issue a fourth decision, which could involve yet

another remand. When will it end? Ironically, the patents in

dispute may expire before this litigation concludes.

Moreover, since the majority holds that other asserted pat-

ents are not invalid and are literally infringed by HMR 4396,

(and here I agree), the district court likely will enter an

injunction precluding appellants from marketing HMR 4396

S5la

until the expiration of at least the 698 and °349 patents.

Prolonging this litigation seems futile when, in the end, an

injunction will likely issue regardless of how “therapeutically

effective” is construed or whether claim | of the ’422 patent

is invalid.

52a

APPENDIX B

UNITED STATES DISTRICT COURT

DISTRICT OF MASSACHUSETTS

CIVIL ACTION NO. 97-10814-WGY

AMGEN, INC.,

Plaintiff,

Vv.

HOECHST MARION ROUSSEL, INC. and

TRANSKARYOTIC THERAPIES, INC.,

Defendants.

MEMORANDUM AND ORDER

YOUNG, C.J. October 15, 2004

J. INTRODUCTION

This patent infringement action concerns patents held by

Amgen, Inc. (“Amgen”), relating to the manufacture of a

recombinant (genetically engineered) DNA! product, known

as epoietin alfa,’ that is similar to natural erythropoietin

(“EPO”), a hormone that stimulates production of red blood

cells, and is useful in, among other. things, treating patients

who need of blood transfusions and suffer from blood

composition disorders such as hemophilia, anemia, and sickle

cell disease. This product and this case are not new to the

public or to this Court. The case began brewing in 1997,

when Amgen filed a declaratory judgment in the United —

States District Court for the District of Massachusetts against

' “DYNA” is short for “deoxyribonucleic acid.”

? This product is sold under the trademark EPOGEN”.

53a

Defendants Hoechst Marion Roussel, Inc.’ and Transkaryotic

Therapies, Inc. (collectively “HMR/TKT”) claiming that

three of its patents were infringed by HMR/TKT’s human

EPO product, “HMR 4396,” produced from the R223 cell line

grown in culture. See Amgen, Inc. v. Hoechst Marion Rous-

sel, Inc., 3 F. Supp. 2d 104, 106 (D. Mass. 1998). In 1999,

Amgen amended the complaint to include two other patents.

Amgen, Inc. v. Hoechst Marion Roussel, Inc., 126 F. Supp. 2d

69, 96-98 (D. Mass. 2001) (“Amgen I’). A lengthy jury-

waived trial ensued. It commenced in May 2000 and lasted

twenty-three days over the course of four months. Jd. at 78.

Not surprisingly, HMR/TKT appealed this Court’s decision,

Amgen I, 126 F. Supp. 2d 69. In Amgen Inc. v. Hoechst

Marion Roussel, Inc., 314 F.3d 1313 (Fed. Cir. 2003)

(“Amgen IT’), the Federal Circuit affirmed a majority of this

Court’s findings and rulings but vacated and remanded a few

issues to this Court. Jd. at 1358. This memorandum and order

addresses those issues on remand, some of which have

already been decided by the Court and announced to the

parties, thus requiring only a brief review.

ll. BACKGROUND: PROCEDURAL AND SUBSTAN-

TIVE HISTORY

A. The Patents at Issue

There were originally five patents at issue in this case.

Only four, however, remain on remand. The patents and

claims now at issue are: Claim | of U.S. Patent No. 5,955,422

(issued Sept. 21, 1999) (“’422 patent”); Claims 2-4 of U.S.

Patent No. 5,621,080 (issued Apr. 15, 1997) (“’080 patent”);

Claims 4-9 of U.S. Patent No. 5,618,698 (issued Apr. 8,

1997) (“698 patent”); and Claims 1, 3, 4, 6, and 7 of U.S.

> Hoechst Marion Roussel, Inc. is now known as Aventis Pharma-

ceuticals, Inc.

54a

Patent No. 5,756,349 (issued May 26, 1998) (“°349 patent”).

Amgen I, 126 F. Supp. 2d at 79; Amgen II, 314 F.3d at 1320.4

Although the patents vary, they all share a common dis-

closure and identical specifications. Amgen J, 126 F. Supp. 2d

at 79. For ease of reference, the Court cites to the spe-

cification found in the ’933 patent, which is identical to the

specification of the patents in dispute on remand. ’933 Patent,

Ex. 1.

B. The Technology

As Amgen I set out the basics of the underlying technology

in detail, only a brief summary is provided here. EPO is a

naturally occurring hormone that controls erythropoiesis, the

production of red blood cells in bone marrow. ’933 Patent,

Ex. 1,-col. 5: 39-67. Erythropoiesis occurs continuously to

offset cell destruction. Jd. It enables a sufficient (but not

excessive) amount of red blood cells to be available in the

blood to provide tissue oxygenation. /d. Hemoglobin is the

protein in the red blood cells that actually transports the oxy-

gen. Amgen I, 126 F. Supp. 2d at 98. The amount of hemo-

globin correlates to the amount of oxygen. /d. Hematocrit,

which indicates the relative proportion of red blood cells to

the total volume of blood, measures the ability of the blood to

supply oxygen to the body. /d. Thus, generally an increase or

* The fifth patent involved in Amgen | was U.S. Patent No. 5,547,933

(issued Aug. 20, 1996) (“933 patent”). Since this Court’s ruling that the

”933 patent was invalid for indefiniteness under 35 U.S.C. § 112, 4 2 was

upheld on appeal, Amgen //, 314 F.3d at 1342, that patent will not be

addressed in this memorandum and order.

> Because many of the exhibits from the first trial were used in the

second trial and the numbering system was simply continued in the sec-

ond tnal, the Court will not designate from which trial the exhibits came

but instead simply refer to the trial exhibit number. When citing testi-

mony, however, the Court will refer to the second trial as the “remand

trial” and cite it as “R. Trial,” while the first trial will simply be cited as

“Trial.”

55a

decrease in hematocrit equates with an increase or decrease in

the ability to supply oxygen to the body. /d. Under normal

conditions, a person has a hematocrit of about forty-five to

fifty, which means forty-five to fifty percent of the blood is

made up of red blood cells. /d.

EPO is produced in the kidney and liver. Therefore,

patients with chronic renal failure lack normal levels of EPO

and suffer from anemia. Amgen II, 314 F.3d at 1321.

Introduction of additional EPO into the patient’s body can

increase a patient’s hematocrit level and sustain it at or near

normal levels. /d. In other words, the blood is able to provide

a steady supply of sufficient oxygen to the tissues. /d.; Amgen

I, 126 F. Supp. 2d at 99.

Early attempts to obtain EPO from plasma or urine proved

unsuccessful because the body only produces human EPO in

very small amounts, ’933 Patent, Ex. 1, col. 5: 54-58, and the

techniques were very complicated and resulted in the col-

lection of very small amounts of impure and unstable

amounts of EPO, id. at col. 6: 60-65. Amgen is recognized as

the pioneer in the production of a therapeutically effective

amount of EPO via recombinant EPO (“rEPO”) techniques.

See, e.g., Molecular Biology and Biotechnology: A Compre-

hensive Desk Reference 108 (Robert A. Meyers ed., VCH

Publishers 1995).

Dr. Fu-Kuen Lin (“Lin”), the named inventor of all the

patents in issue, isolated and characterized DNA sequences

encoding EPO from humans and monkeys. ’933 Patent, Ex. 1,

col. 13: 50-53. Lin determined the DNA sequence of human

EPO and its predicted amino acid sequence. °933 Patent, Ex.

1, col. 10: 65-11: 2. Lin then produced large amounts of EPO

by using recombinant DNA technology. /d. at col. 14: 23-29.

In the patent specification, many methods of producing EPO

are described. EPOGEN® is produced by the method

described in Example 10, wherein human EPO is produced by

introducing exogenous DNA into host Chinese hamster ovary

56a

(“CHO”) cells. Jd. at col. 25: 30-29: 7.° The rEPO-that is

produced has the same or similar amino acid sequences or

primary structural conformation as that of naturally-occurring

EPO. Id. at col. 29:-1-7. As a result, it possesses one or more

the biological properties of naturally-occurring EPO but

differs from natural EPO in its “glycosylation,” that is, it has

a different average carbohydrate composition. /d. at col. 10:

35-41.

HMR/TKT, in producing its human erythropoietin, HMR

4396 (also called Gene-Activated EPO “GA-EPO”), also uses

recombinant technology. HMR/TKT, however, does not use a

host cell from a non-human species but manipulates the

ordinarily unexpressed human EPO gene where it naturally

resides. Amgen I, 126 F. Supp. 2d at 102. In that way, the

human EPO DNA material is endogenous to the human cell.

Id. After introducing a promoter sequence, human EPO is

expressed in a human rather than a hamster cell. /d.

C. The Federal Circuit’s Decision i

A brief review of the key rulings and findings that were

affirmed and remanded on appeal follows:

1. Claim Construction

a. Affirmed

The Federal Circuit upheld all of the Court’s claim con-

structions. Amgen II, 314 F.3d at 1320. Specifically, the

Federal Circuit upheld this Court’s construction that Amgen’s

claims do not limit the invention to using only exogenous

° Amgen transfects CHO cells with a vector that contains both viral

promoter DNA and the human EPO gene. ’933 Patent, Ex. 1, col. 25: 58-

61; Amgen I, 126 F. Supp. 2d at 102. Therefore, the human EPO DNA

material is exogenous to the hamster host cell because it was removed

from the cell in which it originated, placed in a vector, and reintroduced

into a host cell. Amgen I, 126 F. Supp. 2d at 102. This is called

heterologous recombination. /d.

57a

DNA (as opposed to endogenous DNA). Jd. at 1327. It also

upheld this Court’s determinations that (1) non-naturally |

occurring means “‘not occurring in nature’”; (2) vertebrates

are anything with “‘a segmented bony or cartilaginous spinal

cord’ which obviously includes humans”; and (3) humans are

a subset of mammals and mammals are a subset of verte-

brates. Jd. at 1327-28 (quoting Amgen I, 126 F. Supp. 2d at

85, 90-91). To that end, the Federal Circuit agreed that the

specification indicates that the invention uses human DNA in

human host cells in culture. /d.

The Federal Circuit also upheld the Court’s determination

that claim | of the ’422 patent, claims 2, 3, and 4 of the "080

patent, and claims 1, 3, 4, and 6 of the °349 patent are product

claims (not process claims) and thus are not restricted or

defined by any method of production or any particular source,

other than what is specifically excluded. Amgen II, 314 F.3d

at 1329-30.

b. Remanded

Although all the terms that this Court construed in Amgen I

under the principles of Markman v. Westview Instruments,

Inc., 517 U.S. 370 (1996), were upheld, the Federal Circuit re-

manded to this Court the construction of the term “therapeut-

ically effective.”’ Amgen II, 314 F.3d at 1354. This phrase was

not considered by the Court to be in dispute during the first

trial. In its written analysis, however, this Court interpreted the

term. Amgen I, 126 F. Supp. 2d at 112; see also id. at 99.

While interpreting a term to provide context for the discussion

is proper when the term is not in dispute, the Federal Circuit

determined that the term “therapeutically effective” actually

was in dispute “because it is central to whether Goldwasser is

properly considered prior art.” Amgen IJ, 314 F.3d at 1353.

Therefore, it remanded so this Court could construe “thera-

’ The term “therapeutically effective” is found in claim 1 of the 422

patent and in claim 4 of the ‘080 patent.

58a

peutically effective” pursuant to Markman. Id. at 1358. Since

claim construction is matter of law, Markman, 517 U.S. at 386;

but see Arthur R. Miller, The Pretrial Rush to Judgment: Are

the “Litigation Explosion,” “Liability Crisis,” and Efficiency

Clichés Eroding Our Day in Court and Jury Trial Com-

mitments?, 78 N.Y.U. L. Rev. 982, 1087 (2003) (criticizing

the decision in Markman), the Federal Circuit could have

proceeded to construe the phrase itself. Where a word or

phrase has not been first construed in the district court, the

Federal Circuit follows the courteous and prudential path of

first seeking claim construction below. Hon. Pauline Newman,

Remarks at the American Law Inst.-Am. Bar Assoc. Panel on

the Trial of a Patent Case (Sept. 18, 2003).

2. Infringement

a. Affirmed

The Federal Circuit affirmed this Court’s ruling on sum-

mary judgment that claim 1 of the ’422 patent is literally

infringéd. Amgen II, 314 F.3d at 1348. It also affirmed this

Court’s ruling that the ’080 patent is not literally infringed by

HMR/TKT’s HMR 4396, id. at 1344-45, but that claims 1, 3,

4, and 6 of the °349 patent are literally infringed by it, id. at

1351-52. 3

b. Remanded

(1) The ’080 Patent

After finding that HMR 4396 did not literally infringe

claims 2, 3, and 4 of the ’080 patent because HMR 4396

comprised only 165 amino acids, Amgen I, 126 F. Supp. 2d at

99-101, this Court held that HMR 4396 performed sub-

stantially the same function in substantially the same way to

obtain substantially the same result as the EPO glycoprotein

of claims 2 and 3 of the ’080 patent, id. at 133. Therefore, it

ruled that Amgen’s ’080 patent was infringed by HMR/

TKT’s product under the doctrine of equivalents. /d.

59a

In response to HMR/TKT’s argument that Amgen should

be estopped from arguing equivalent infringement, this Court

ruled that prosecution history estoppel did not apply because

Amgen did not add the “mature amino acid sequence of

Figure 6” limitation “in an attempt to ov rcome a rejection

[or] to avoid prior art,” but, instead, to “demonstrate that

‘same invention’ type double patenting did not apply,’—that

is, to distinguish the ’080 patent from the ’933 patent. /d. at

134-35.

The Federal Circuit agreed that the amendment was made

for this purpose but made clear that under Festo Corp. v.

Shoketsu _Kinzoku Kogyo Kabushiki, 535 U.S. 722, 731

(2002) (““Festo IT’), “‘a narrowing amendment to satisfy any

requirement of the Patent Act may give rise to an estoppel.’”

Amgen II, 314 F. 3d at 1345 (quoting Festo II, 535 U.S. at

736) (emphasis added). Therefore, it held that the pre-

sumption of prosecution history estoppel applied. /d. at 1345.

The Federal Circuit then vacated this Court’s finding of

equivalent infringement and remanded for an analysis based

on the “narrow ways of rebutting the Supreme Court’s

presumption of estoppel” outlined in Festo II. Id. at 1345.

(2) The ’698 Patent

On appeal, the Federal Circuit vacated and remanded this

Court’s ruling regarding infringement of the °698 patent

because this Court had compared the accused device to the

preferred or commercial embodiments of the patent instea of

to the properly construed claims themselves. Amgen II, 314

F.3d at 1347. Therefore, it remanded to this Court the ques-

tion whether claims 4-9 of the 698 patent are infringed. /d.

(3) The ’349 patent

Although this Court found that claims 1, 3, 4, and 6 of the

’349 patent are literally infringed by HMR/TKT’s 4396, it

held that HMR/TKT did not literally or equivalently infringe

claim 7, the process claim, of the *349 patent. Amgen I, 126

60a

F. Supp. 2d at 122. The Court compared the accused process

to the preferred embodiment in the claim and concluded that

_HMR/TKT’s “process for producing erythropoietin differs

markedly from that disclosed by Amgen’s specification.” Jd.

The Federal Circuit, as it did with the Court’s holding of

infringement of the °698 patent, vacated this ruling ‘and

remanded so that the Court could analyze infringement by

comparing the accused process to the properly construed

claims themselves. Amgen II, 314 F.3d at 1350-51.

3. Inequitable Conduct

The Court’s determination that HMR/TKT had not proven

by clear and convincing evidence that the 933, 080, °349

and *422 patents were unenforceable due to inequitable con-

duct was affirmed on appeal. Amgen II, 314 F.3d at 1357-58.

4. Whitten Description, Definiteness, and Enablement

a. Affirmed

The Federal Circuit affirmed this Court’s rulings that the

"422, *080, and °349 patents are adequately described and

enabled. /d. at 1337. In so ruling, the Federal Circuit ex-

plained that this Court “carefully considered these issues,

finding in the end that HMR/TKT had not met its clear and

convincing burden of proof.” /d. Because the Federal Circuit

found “no clear error in these factual determinations,” and the

parties did not allege any legal error, it reasoned that it would

“not disturb [this Court’s] holding that the asserted patents

are not invalid for failure to meet the enablement requirernent

of § 112 4 1.” Id.

As mentioned in an earlier footnote, see note 3, supra, this

Court held and the Federal Circuit affirmed that the °933

patent (specifically the claims requiring “glycosylation which

differs”) was invalid for indefiniteness under section 112.

Amgen I, 126 F. Supp. at 156-57. Therefore, the 933 patent is

not at issue on remand.

6la

5. Anticipation and Obviousness

a. Affirmed

The Court’s ruling that the asserted claims of the ’080,

”349, and °933 patents are not anticipated under 35 U.S.C.

§ 102 by the Sugimoto reference was affirmed by the Federal

Circuit. /d. at 1320, 1356.° In affirming, however, the Federal

Circuit’ made clear that the Court’s determination that

Sugimoto was not enabled was an error, though harmless,

because the Court put the burden of proving enablement of

Sugimoto on HMR/TKT when the burden of proving non-

enablement should have been put on Amgen. /d. at 1356.

‘b. Remanded

The Federal Circuit remanded, however, the Court’s

findings that Sugimoto does not anticipate claim | of the ’422

patent stating that the “district court should consider whether

claim 1 of the ’422 patent is novel over Sugimoto in light of

the court’s new definition of ‘therapeutically effective’” and

be “mindful of the principle that source limitations cannot

impart novelty to old compositions.” /d. at 1356.'° Addi-

* In its opinion, the Federal Circuit affirmed this Court’s finding that

Sugimoto did not anticipate the ’080, °933, °349, and ’698 patents. Amgen

IT, 314 F.3d at 1320, 1356. This Court, however, never addressed the

validity of the °698 patent. It concluded that the °698 patent was not

infringed literally or equivalently at the close of Amgen’s direct case.

Amgen I, 126 F. Supp. 2d at 101. Therefore, whether Sugimoto anticipates

the °698 patent is one of the issues addressed in this memorandum and

order.

* The error was harmless because the Court, despite having concluded

that Sugimoto was not enabled, “nevertheless conducted a full antici-

pation analysis” and found that “‘none of the cited references disclose({s]

each and every limitation of any of Amgen’s individual claims’” of the

080, ’933 and °349 patents. Amgen II, 314 F.3d at 1356 (quoting Amgen

T, 126 F. Supp. 2d at 109).

' It is clear from Amgen I] that Amgen may on remand argue that the

422 patent is not anticipated because Sugimoto is not enabled. See

62a

tionally, the Federal Circuit remanded this Court’s finding

that the °422, 080, and 349 patents were not obvious in light

of Sugimoto because this Court based its decision, in part, on

the fact that it concluded that Sugimoto was not enabled. Jd.

at 1357. The Federal Circuit explained that under section 103,

a reference need not be enabled to qualify as prior art. /d.

In Amgen I, this Court found that the asserted claims of the

080, °422 and °349 patents were not anticipated or rendered

obvious by the Goldwasser reference. Amgen I, 126 F. Supp.

2d 112-17. The Federal Circuit remanded these findings for

further proceedings given that “therapeutically effective” was

not construed in accordance with Markman. Amgen II, 314

F.3d at 1354. As mentioned above, it directed the Court to

construe the term and determine whether Goldwasser invali-

dates any of the asserted patents under 35 U.S.C. § 102(a) or

§ 103 in light of the Court’s construction. /d. at 1354.

D. Procedural and Substantive History Since Amgen IT

The Federal Circuit’s decision issued on January 6, 2003.

This Court received the action on remand on March 13, 2003

[Doc. No. 653], and it held a status conference on April 16,

2003 [Doc. No. 657]. On May 16, 2003, Amgen moved for:

(1) judgment under Federal Rule of Civil Procedure 52(c) that

claims 2-4 of the °080 patent were infringed under the

doctrine of equivalents [Doc. No. 659]; (2) summary judg-

ment of infringement of claims 4-9 of the 698 patent [Doc.

No. 663]; (3) judgment pursuant to Rule 52(c) that claim | of

the ’422 patent and claim 4 of the ’080 patent are valid [Doc.

No. 670]; and (4) judgment pursuant to Rule 52(c) that claims

1, 3, 4, 6, and 7 of the 349 patent are valid and that claim 7

Amgen IT, 314 F.3d at 1354-57. The burden of proving Sugimoto’s non-

enablement, however, rests with Amgen. Moreover, Amgen must present

more evidence than that adduced in the first trial as the Federal Circuit

made clear that the evidence from the first trial was insufficient to prove

non-enablement.

63a

of the *349 patent is infringed [Doc. No. 674]. HMR/TKT

simultaneously moved for: (1) judgment that Amgen is

estopped from asserting infringement of the ’080 patent

pursuant to the doctrine of equivalents [Doc. No. 678]; (2)

judgment that claim 1 of the ’422 patent is invalid as antic-

ipated [Doc. No. 682]; (3) judgment pursuant to Rule 52(c)

that the asserted process claims of the ’698 patent and ’349

patents are not infringed [Doc. No. 686]; and (4) judgment

that the ’422, ’080, and ’349 claims are invalid for obvious-

ness [Doc. No. 690}.

The memoranda in support of and in opposition to these

motions raised additional issues that are reviewed in this

opinion. They are described briefly below.

In its opposition to Amgen’s renewed motion for summary

judgment of infringement of the ’698 patent,'' HMR/TKT

argued, among other things, that Amgen’s proposed construc-

tion of the words “DNA encoding” found in claims 4 and 6 of

the *698 patent is incorrect. HMR/TKT’s Mem. in Opp’n re

698 [ Doc. No. 700] at 7-8. Second, HMR/TKT argued that in

claims 4 and 6 of the ’698 patent, Amgen set forth a step-plus-

function claim in referring to the “steps of . . . growing, under

suitable nutrient conditions” and that an assessment of whether

HMR/TKT infringed this aspect of the claim must focus on a

comparison between HMR/TKT’s process for growing and the

process for growing described by Amgen in the specification.

Id. at 9. Finally, HMR/TKT argued that even if there is literal

infringement here, it can justifiably invoke the defense of the

reverse doctrine of equivalents. Jd. at 13.'

'’ During the first trial, this Court found in favor of HMR/TKT on

equivalent and literal infringement of the °698 patent after Amgen pre-

sented its case but before HMR/TKT had the opportunity to present its

case on this issuc.

'* HMR/TKT also attempted to argue that the ’698 patent should be

declared unenforceable because it was obtained as a result of inequitable

conduct. This Court, during the pretrial conference on September 24,

64a

With regard to claim 7 of the °349 patent, HMR/TKT made

four “new” arguments, two of which are very similar to those

made in conjunction with the °698 patent. First, HMR/TKT

contended that its process does not infringe claim 7 of the

°349 patent when considered in light of its proposed claim

construction of “DNA encoding.” HMR/TKT’s Mem. in

Support re ’698/°349 [Doc. No. 687] at 8-9. Second, HMR/

TKT argued that its process does not infringe claim 7 of the

*349 patent because claim 7 is a step-plus-function limitation;

and, as such, HMR/TKT’s process does not literally infringe

the “step of culturing” found in claim 7 because it does not

involve the culturing procedures set forth in Amgen’s

specification. /d. at 12-15. Third, HMR/TKT claimed that its

process does not infringe the process claim under the reverse

doctrine of equivalents. /d. at 15-18. Fourth and lastly,

HMR/TKT argued that if the Court construes the term “DNA

encoding” as Amgen urges, then the validity of the asserted

claim of the 349 patent is called into question. /d. at 12.

Amgen, in response, did not dispute that “DNA encoding”

needs to be construed by the Court. See, e.g., Amgen’s Reply

re °698 [Doc. No. 731] at 6-10. It did, however, assert that

HMR/TKT should not be allowed to make its “new” argu-

ments relating to step-plus-function and the reverse doctrine

of equivalents given the procedural posture of the case.'* See,

e.g., id. at 10-15.

2003, ruled that HMR/TKT could not put on any evidence of inequitable

conduct relating to the °698 patent because it was “satisfied that the

pleadings, the pretrial documents early on as to *698 did not frame that

issue for trial.” 9/24/03 Pretrial Conf. Tr. at 26: 4-9.

'3 Therefore, these memos requested that the Court (1) construe “DNA

encoding”; (2) decide whether HMR/TKT is allowed to make its step-

plus-function arguments at this stage and if yes, determine whether the

asserted claims of the 349 and °698 patents are step-plus-function claims;

and (3) determine whether HMR/TKT can argue the reverse doctrine of

equivalents with respect to the 698 and °349 patents for the first time on

remand and if so, whether this argument has merit.

65a

On July 29, 2003, this Court held a Markman hearing

regarding those terms in dispute and in need of construction

and considered other pending motions, including motions for

summary judgment. At the end of the Markman portion of the

hearing, the Court tentatively construed the terms “DNA

encoding” and “therapeutically effective,” providing two

constructions for the latter, one being an alternate. 7/29/03

Hr’g Tr. at 55: 1-56: 23. It then continued to hear argument.

At the end of the day, the Court noted that it would determine

whether the asserted claims of the °698 and ’349 patents were

step-plus-function claims at a later date. Jd. at 176: 1-10. It

then continued the motion hearing to July 31, 2003. /d. at

176: 11-15.

During a hearing two days later, the Court retracted the

alternative construction and reiterated its primary “working

construction,” retaining its right to revise it after a more care-

ful review of the claims, specification, and prosecution his-

tory. 7/31/03 Hr’g Tr. at 87: 5-88: 7. Additionally, it ruled

that claims 4 and 6 of the ’698 patent and claim 7 of the ’349

patent were not step-plus-function claims pursuant to 35

U.S.C. § 112. /d. at 88: 8-89: 9. It then denied Amgen’s mo-

tion for summary judgment of infringement of the 698 pa-

tent, citing Arthur Miller’s recent article, The Pretrial Rush to

Judgment. Id. at 89: 23-90: 25; see Miller, supra. The Court

took everything else under advisement and set the final pre-

trial conference for September 18, 2003. /d. at 91: 25-92: 2.

On August 5, 2003, the Court entered an order regarding

the pending motions. [Doc. No. 740]. It denied HMR/TKT’s

motions for summary judgment with respect to the validity of

the asserted claims of the ’422, ’080 and °349 patents. Order

of 8/5/03 at 1. It denied in part and allowed in part Amgen’s

motions, under Rule 52(c), for judgment that claim 1 of the

°422 patent and claim 4 of the 080 patent are valid and that

claims 1, 3, 4, 6, and 7 of the °349 patent are valid. Jd. Be-

cause HMR/TKT did not dispute that the ’080 and °349

66a

patents are not anticipated by Goldwasser and that the °349

patent is not rendered obvious by Goldwasser, the Court

allowed Amgen’s motions with respect to these matters. /d. at

1-2. Specifically, the Court held that claim 4 of the ’080

patent is not anticipated by Goldwasser and that claims 1, 3,

4, 6, and 7 of the ’349 patent are not anticipated or rendered

obvious by Goldwasser. /d. at 2. Because Amgen did not

have the opportunity to rebut HMR/TKT’s remaining validity

arguments concerning the °422, 080, and ’349 patents during

trial in 2000, the Court stated that Amgen would have that

opportunity at the October trial. /d.

On September 18, 2003, the Court held a final pretrial

conference. After explaining that this case will not “turn into

a patent version of Penelope’s robe,” in other words, that the

Court and the parties were “not going to unravel anything

[that the Court has] woven thus far which has not been

unraveled by a higher court,” the Court made the following

findings and rulings. First, it ruled that it would hear and take

evidence on the reverse doctrine of equivalents as it related to

the *698 patent and that HMR/TKT could address other

patent defenses. 9/18/03 Final Pretrial Conf. Tr. at 6: 4-16.

Second, it ruled that Amgen had met its burden (outlined in

Festo II) of proving that the prosecution history does not

estop it from arguing equivalent infringement with regard to

the *080 patent and it affirmed its earlier finding that

HMR/TKT infringes claims 2-4 of the ’080 patent. /d. at 7:

17-8: 5. It explained that it would issue a full opinion at a

later date but that it might have to revisit the Festo issue due

to the rapidly developing law in that area. /d. at 7: 19-25. The

Court then turned to the ’349 patent and explained that it

would allow Amgen to put on rebuttal evidence as to the

matter of obviousness and Sugimoto only and it made clear

that the Court would not accept other evidence from HMR/

TKT regarding the °349 patent. /d. at 8: 12-19, 16: 5-6 (“As

far as evidence goes, °349 is in the can and I’m done with

it.”). The Court then issued a revised claim construction of

67a

“therapeutically effective” based on a more thorough analysis

of the claims, specification, and prosecution history. /d. at 9:

3-10: 25. The Court mentioned, however, that this revision

may have made the third sentence of the construction unnec-

essary and, therefore, reserved its right to further consider the

proper construction. /d. at 10: 21-25. It directed the parties to

try the case based on the construction it had just issued along

with a construction that eliminated the third sentence. Jd.

at 11: 1-5. The pretrial conference was continued until

September 24, 2003. Jd. at 30: 22-23.

During the further pretrial conference, the Court reviewed

the issues to be tried and outlined the procedure for trial and

the parameters for the introduction of evidence and expert

testimony. See 9/24/03 Final Pretrial Conf. Tr. After the

Court provided both parties with an opportunity to be heard

on the subject, pursuant to Federal Rule of Civil Procedure

53(b)(1), the Court appointed Michele D. Beardslee as —

Special Master, beginning January 1, 2004, to assist the Court

in research, analysis, and drafting of the forthcoming opinion.

Order re Special Master [Doc. No. 801]; see also 11/07/03

Beardslee Aff. [Doc. No. 799].'* The trial.on remand was set

to commence on October 7, 2003. 9/24/03 Final Pretrial Conf.

Tr. at 40: 23.

On October 30, 2003, the Court issued an opinion

supporting its ruling that Amgen had successfully rebutted the

presumption of prosecution history estoppel as outlined in

Festo II and, therefore, was not estopped from asserting

'4 See generally Hon. Shira A. Scheindlin & Jonathan M. Redgrave,

Revisions in Federal Rule 53 Provide New Options for Using Special

Masters in Litigation, N.Y. St. B.A.J., Jan. 2004, at 10, reprinted sub.

nom. The Evolution and Impact of the New Federal Rule Governing

Special Masters, Fed. Law., Feb. 2004, at 35.

68a

equivalent infringement of the ’080 patent. Amgen, Inc. v.

Hoechst Marion Roussel, Inc., 287 F. Supp. 2d 126 (D. Mass.

2003) (“Amgen IIT’)."°

The remanded trial lasted nine days over the course of four

and a half weeks.'® All the remaining issues—those remanded

to the Court from the Federal Circuit and those raised by the

parties in the course of this remanded trial—are addressed

herein.”

Ill. CLAIM CONSTRUCTION

As expounded in great detail in Amgen I, this Court

strongly believes in the importance of construing patent

claims without regard to the alleged infringement issues.

Amgen I, 126 F. Supp. 2d at 80-81; MediaCom Corp. v. Rates

Tech., Inc., 4 F. Supp. 2d 17, 21-24 (D. Mass. 1998); see also

Anthony R. Zeuli & Rachel Clark Hughey, Avoiding Patent

Claim Construction Errors: Determining the Ordinary and

Customary Meaning Before Reading the Written Description,

'S While the reasoning need not be rehashed in this memorandum and

opinion, the Court takes this opportunity to note a few typographical

errors in the decision. At the following pages, the word “urinary” was

inadvertently added where it should not have been: 154 (“urinary” is used

five times in note 39 and should be deleted); 157 (the word “urinary” is

used right before note 41 and should be deleted). As will be noted, the

word “urinary” is used in many other places throughout the opinion.

These uses of the word should remain. These errors do not in any way

change the result of that opinion. Correction of them, however, makes the

opinion more accurate.

'© During the remanded trial, Amgen moved for Judgment Pursuant to

Rule 52(c) that claims 4-9 of the °698 patent were infringed and not

invalid under 35 U.S.C. § 112 [Doc. No. 778]. The Court did not rule on

this motion but instead deferred entering judgment until all of the

evidence had been presented. See Fed. R. Civ. P. 52(c). The Court’s final

decisions regarding infringement and validity of the °698 patent will be

explained in detail below.

'? Previous decisions by the Court, such as claim constructions, will be

explained in this memorandum.

69a

Fed. Law., June 2004, at 29. One way to avoid conflating

issues of fact and law and to ensure division between the fact

finding and law explaining roles in a patent case is to hold the

Markman hearing prior to and separate from the summary

judgment motion hearing. Although (as mentioned above)

this Court held the Markman hearin~ for the trial on remand

on the same day as the summary judgment motions hearing, it

kept the hearings independent of one another by separating

the hearing into two parts. The first part dealt with claim

construction. Then the Court held a recess, issued its pre-

liminary constructions, and moved on to the summary judg-

ment motions hearing.

The Court followed its usual procedure in conducting the

Markman hearing. The Court entertained oral argument from

counsel for each party. Counsel referred the Court to the

relevant portions of the patent, specification, and prosecution

history. Demonstrative exhibits were presented and refer-

ences were made to certain expert testimony, but extrinsic

evidence was not admitted.

At the conclusion of the Markman portion of the hearing

the Court interpreted “therapeutically effective” and “DNA

encoding”—cautioning that they were “working construc-

tions”—and held off deciding whether the asserted claims of

the 349 and ’698 patent were step-plus-function claims. The

Court then announced during the July 31, 2003 hearing that it

did not construe the asserted claims of the °349 and °698

patents as step-plus-function claims. During the pretrial con-

ference on September 18, 2003, after the Court had engaged

in a more careful review of the patents, specification, and

prosecution history, the Court issued a revised claim con-

struction for “therapeutically effective.” The final claim con-

structions are reproduced and explained below.'®

'* While the focus of the Markman hearing was on the patents, spe-

cification, and prosecution history, the Court writes now with the benefit

70a

A. “Therapeutically Effective”

1. Background

The term “therapeutically effective” is contained in claim 1

of the ’422 patent and claim 4 of the ’080 patent.'? As men-

tioned above, although this phrase was not construed during

the first trial, in determining whether prior art anticipated the

°422 and ’080 patents, the Court interpreted the term to mean

an increase in hematocrit:

Such evidence [of e.g., increased erythroid marrow

stimulation} should be outweighed by the fact that the

actual production of mature red blood cells was not

achieved and, as a result, hematocrit levels were un-

changed. Because an increase in hematocrit and hemo-

globin levels is the true mark of therapeutic effective-

ness, Dr. Goldwasser’s study, which revealed only

inchoate indicators of red blood cell production, falls far

short of anticipating claims requiring a_ therapeutic

amount of human EPO.

Amgen I, 126 F. Supp. 2d at 112; see also id. at 99 (“The

therapeutic effectiveness or benefit of an erythropoietin prep-

aration is shown by demonstrating a correction in anemia by

increasing and maintaining the hematocrit of a patient to

normal or near normal levels.”).

of having presided over the entire second tnal. Unsurprisingly, both

parties continued to present arguments regarding construction throughout

the tnal, weaving in arguments regarding validity. The Court, however,

construcd the terms before the re-trial and, therefore, the arguments and

intrinsic evidence addressed in this memorandum regarding construction

of these terms stem from these data provided before the re-trial.

'° The Federal Circuit refers to the term “therapeutically effective.”

The Court notes, however, that claim | of the *422 patent and claim 4 of

the ’080 patent actually recite a “therapeutically effective amount” of

either “human erythropoietin” or “an erythropoeitin glycoprotein prod-

uct,” respectively. 422 and ’080 Patents, Ex. | (emphasis added).

Tla

The Federal Circuit, in addition to remanding so that the

Court could construe the term pursuant to Markman, provided

some guidance. It agreed that the “endgame in the treatment of

chronically anemic patients is to increase the hematocrit,” but

pointed out that the term should be construed in light of the

specification. Amgen IT, 314 F.3d at 1353. It stated, however,

that the “specification appears to teach that results in addition

‘to simply an increase in hematocrit can provide effective

therapy.” Jd. (citing 933 Patent, col. 33: 19-31). It pointed out

that Amgen was arguing that one skilled in the art would

construe “therapeutically effective” as “increasing and main-

taining the patient’s hematocrit to normal or near normal

levels,” but that “the relevant question is not whether one of

ordinary skill would so understand the term, but whether that

term should be limited based upon the express disclosure in the

specification.” Jd. at 1353-54 (citing CCS Fitness v. Brunswick

Corp., 288 F.3d 1359, 1367 (Fed. Cir. 2002) (“[A] claim term

will not carry its ordimary meaning if the intrinsic evidence

shows that the patentee distinguished that term from prior art

on the basis of a particular embodiment, expressly disclaimed

subject matter, or described a particular embodiment as

important to the invention.”’)). The Federal Circuit stated that it

appeared that the term ‘‘therapeutically effective” encompassed

the list of effects described in the specification and noted that if

the Court also held this to be true, then the Goldwasser study

may indeed invalidate some of the claims at issue in this case

under 35 U.S.C. § 102¢a) or § 103. /d. at 1354 (“If the claim

term ‘therapeutically effective’ encompasses the patient re-

sponses described in the specification, as it appears to us it

does, then the Goldwasser study may constitute invalidating

prior art under § 102(a) or § 103 even if he did not achieve his

intended result.”) (emphasis added)). Therefore, it vacated this

Court’s determination that Goldwasser did not constitute prior

72a

art’’ and ordered this Court to construe the term and thereafter

determine whether Goldwasser invalidates any of the asserted

patents. Jd.

2. The Claims at Issue

The actual words of the claims are as follows:

‘422 Claim I: A pharmaceutical composition comprising

a therapeutically effective amount of human erythro-

poietin and a pharmaceutically acceptable diluent, adju-

vant or carrier, where insaid erythropoietin is purified

from mammalian cells grown in culture.

’422 Patent, Ex. 1, col. 38: 36-41 (emphasis added).”!

‘080 Claim 4: A pharmaceutical composition compris-

ing a therapeutically effective amount of an erythro-

poietin glycoprotein product according to Claim 1, 2, or 3.

’080 Patent, Ex. 1, col. 38: 51-53 (emphasis added).

3. Summary of the Parties’ Arguments

Amgen urges adoption of the ordinary meaning of

“therapeutically effective” given by those skilled in the art.

Amgen’s Mem. in Support re ’422/’080 [Doc. No. 671] at 7.

Specifically, it argues that (1) expert testimony shows that the

ordinary meaning of “therapeutically effective” is “sufficient

to produce a sustained increase in hematocrit,” and that the

term requires a therapeutic—not merely biological—effect;

(2) the other effects listed in the specification, to which the

Federal Circuit referred, are known biological effects of EPO,

not the intended therapeutic effects; (3) the specification

2° The Court came to this conclusion because it found that the Gold-

wasser study was a failure.

*! Although the Court did not receive evidence during the Markman

hearing, for the sake of unity throughout this decision, citations to the pa-

tents are made to what was identified as Trial Exhibit | (“Ex. 1”) (which

contains the common specification and recitation of all the claims).

73a

taken as a whole supports the plain meaning of “thera-

peutically effective,” and that no special meaning was given

to the term; (4) the prosecution history shows that Amgen

specifically noted that its invention shares the same in vivo

biological activity as naturally occurring human EPO, but

differentiated its invention from prior art by pointing out that

human recombinant EPO (unlike naturally-occurring human

EPO) is not a viable, effective human therapeutic product;

and (5) the doctrine of claim differentiation requires that this

term have a different meaning than the recitation of EPO’s

biological activities. Jd. at 8-17. In its reply memorandum,

Amgen also argues that the dictionary definition of the term

supports its asserted meaning. Amgen’s Reply re *422/°080

[Doc..No. 730] at 5-6.

HMR/TKT, on the other hand, argues that the Federal

Circuit made clear that it believed that the term “thera-

peutically effective” encompasses all of the effects set forth

in the specification described. HMR/TKT’s Mem. in Opp’n re

"422/080 [Doc. No. 702] at 5. Thus, it argues, the term

encompasses those effects observed in the Goldwasser study.

Id. at 6. Moreover, it asserts that Amgen is trying to import

limitations from the specification to make the claims require

an increase in the hematocrit levels when the claims contain

no language indicating such a requirement and the specifi-

cation language itself is actually inconsistent with such a

requirement. HMR/TKT points to the same section of the

specification as did the Federal Circuit did to make its point:

[T]o the extent that polypeptide products of the inven-

tion share the in vivo activity of natural EPO isolates

they are conspicuously suitable for use in erythropoietin

therapy procedures practiced on mammals, including

humans, to develop any or all of the effects herefore at-

tributed in vivo to EPO, e.g., stimulation of reticulocyte

response, development of ferrokinetic effects .. .

erythrocyte mass changes, stimulation of hemoglobin

74a

C syntheses . . . and, as indicated in Example 10, in-

creasing hematocrit levels in mammals.

Id. at 13 (quoting ’933 Patent, Ex. 1, col. 33: 19-31). This,

HMR/TKT asserts, makes clear that “erythropoietin therapy

procedures” include procedures that “develop any or all of the

effects heretofore attributed in vivo to EPO,” and, therefore,

“therapeutically effective amount” includes any or all of the

effects listed in this portion of the specification—which,

HMR/TKT argues, are defined in terms of biological effects.

Id. at 14. HMR/TKT further argues that Amgen is trying to

rely on isolated references of the specification to restrict the

term meaning when these restrictions are not apparent in the

plain language, and when the intrinsic record, as a whole,

supports a broader interpretation. /d. at 16.

4. Discussion

While the Federal Circuit indeed mentioned that the term

“therapeutically effective” appeared to encompass the bio-

logical effects listed within lines 19-31 of column 33, the

Court notes that the Federal Circuit did not, in Amgen I],

actually construe the term “therapeutically effective.” See

Amgen IT, 314 F.3d at 1324 (noting that the Federal Circuit

considers claim construction “afresh” on appellate review);

Bayer AG v. Biovail,Corp., 279 F.3d 1340, 1349 (Fed. Cir.

2002) (noting that, notwithstanding its de novo review, “it

would be premature for this court to engage in its own claim

construction without . . . evidence of the meaning of the terms

to one of skill in the art at the time of the invention”). On the

contrary, the Federal Circuit remanded that task to this Court.

To perform it properly, however, the Court must consider the

prosecution history in addition to the claims and the

specification—something that the Federal Circuit did not do.

See Amgen II, 314 F.2d at 1324 (“To properly construe the

claims, a court must examine the claims, the rest of the

specification, and if in evidence, the prosecution history.”’);

Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582

75a

(Fed. Cir. 1996) (“[I]t is well-settled that, in interpreting an

asserted claim, the court should look first to the intrinsic

evidence of record, i.e., the patent itself, including the claims,

the specification and, if in evidence, the prosecution his-

tory.”); SRI Int'l v. Matsushita Elec. Corp. of Am., 775 F.2d

1107, 1118 (Fed. Cir. 1985) (noting that a claim is construed

in light of its language, the specification, and the prosecution

history). Moreover, the Court must begin by determining

what the plain and ordinary meaning of “therapeutically

effective” is in order to determine whether Amgen has

become its own lexicographer. /niellectual Prop. Dev., Inc. v.

UA-Columbia Cablevision of Westchester, Inc., 336 F.3d

1308, 1315 (Fed. Cir. 2003) (“Consulting the written de-

scription and prosecution history as a threshold step in the

claim construction process, before any effort is made to

discern the ordinary and customary meanings attributed to the

words themselves, invites a violation of our precedent

counseling against importing limitations into the claims.”

(quoting Texas Digital Systems, Inc. v. Telegenix, Inc., 308

F.3d 1193, 1204 (Fed. Cir. 2002)) (internal quotation marks

omitted)).

a. The Plain and Ordinary Meaning

Generally, it is the plain and ordinary meaning of the

words—as defined by one skilled in the relevant art—that

governs. Vitronics, 90 F.3d at 1582; Enk Paul Belt, Federal

Circuit Stresses Ordinary Meaning, Natl] L.J., Sept. 22,

2003, at S1. Amgen argues that the plain and ordinary mean-

ing of the term “therapeutically effective” is “sufficient to

produce a sustained increase in hematocrit.” HMR/TKT

argues, on the other hand, that the plain and ordinary meaning

of “therapeutically effective” is not so restricted.” Inter-

2 HMR/TKT argues that Amgen’s position on this claim construction

is inconsistent with its position on claim construction for all the other

terms the Court has construed in the previous trial because Amgen here is

secking to limit the term’s definition via the specification and prosecution

76a

estingly, HMR/TKT never states what it believes the plain

and ordinary meaning of the term to be—it only discusses the

meaning of the term with reference to how it believes Amgen

has so defined it in the specification and prosecution history.

Amgen, on the other hand, grounds its assertion of the

plain and customary meaning of the disputed term upon

expert testimony. This, however, is extrinsic evidence to

which resort ought be had only “if necessary.” Vitronics, 90

F.3d at 1583 (quoting Hormone Research Foundation, Inc. v.

Genentech, Inc., 904 F.2d 1558, 1562 (Fed. Cir. 1990)).

Therefore, the Court does not begin by considering this evi-

dence. Instead, it turns first to the dictionary and to technical

treatises to decipher the plain and ordinary meaning of

“therapeutically effective.” See id. at 1584 & n.6 (noting that

judges are free to consult technical treatises and dictionaries

history. HMR/TKT’s Mem. in Opp’n re ’422/°080 at 12. While it is true

that Amgen has previously argued to the Court that the terms of the claims

were entitled to their broadest possible scope, it also consistently argued

that the words of the claim should prevail. Amgen J, 126 F. Supp. 2d at 82.

In essence, it is here arguing this again. The difference is that, here,

Amgen is arguing that the claim language itself contains a term that hasa .

limited definition and that resort to the specification and prosecution

history is not necessary since the plain meaning of the term prevails.

HMR/TKT, on the other hand, is secking to “broaden” what Amgen

argues is the plain meaning by pointing to the specification and pros-

ecution history.

Ultimately, how the issue has been framed will not change the analysis

because it is clear from the principles of claim construction that claims are

construed in light of the specification and prosecution history. Southwall

Techs., Inc. v. Cardinal IG Co., 54 F.3d 1570, 1576 (Fed. Cir. 1995)

(“The prosecution history limits the interpretation of claim terms so as to

exclude any interpretation that was disclaimed during prosecution.”)

(emphasis added) (citations omitted)). Whether the Court determines that

the term is limited or broadened is irrelevant. The important determi-

nations instead are: What is the plain and ordinary meaning of “thera-

peutically effective,” and does the intrinsic evidence define the term

differently than its plain and ordinary meaning?

77a

in order to gain a better understanding of the claims and to

interpret them, “so long as the dictionary definition does not

contradict any definition found in or ascertained by a reading

of the patent documents.”).”°

*> At first glance, the extrinsic evidence rule in Vitronics appears to’

create somewhat of a conundrum, in that it discourages resort to extrinsic

evidence while at the same time urging courts to begin claim construction

by considering the plain and customary meaning of a term as understood

by one skilled in the art. How does a Court decipher the plain and

customary meaning of a term as understood by one skilled in the art

without resorting to extrinsic evidence about how one skilled in the art

would construe the term?

The Federal Circuit is currently considering this question en banc. In

granting a petition for rehearing en banc in Phillips v. AWH Corp., 03-.

1269, -1286, the Federal Circuit asked for bricfing on the following

questions:

1. Is the public notice function of patent claims better served by

referencing primarily to technical and general purpose dictionaries

and similar sources to interpret a claim term or by looking primarily

to the patentee’s use of the term in the specification? If both sources

are to be consulted, in what order?

2. If dictionaries should serve as the primary source for claim

interpretation, should the specification limit the full scope of the

claim language (as defined by the dictionaries) only when the

patentee has acted as his own lexicographer or when the specifi-

cation reflects a clear disclaimer of claim scope? If so, what

language in the specification will satisfy those conditions? What use

should be made of general as opposed to technical dictionaries?

How does the concept of ordinary meaning apply if there arc

multiple dictionary definitions of the same term? If the dictionary

provides multiple potentially applicable definitions for a term, is it

appropriate to look to the specification to determine what definition

or definitions should apply?

3. If the primary source for claim construction should be the

specification, what use should be made of dictionaries? Should the

range of the ordinary meaning of claim language be limited to the

scope of the invention disclosed in the specification, for example,

when only a single embodiment is disclosed and no other indi-

cations of breadth are disclosed?

78a

4. Instead of viewing the claim construction methodologies in the

majority and dissent of the now-vacated panel decision as al-

ternative, conflicting approaches, should the two approaches be

treated as complementary methodologies such that there is a dual

restriction on claim scope, and a patentce must satisfy both limiting

methodologies in order to establish the claim coverage it secks?

5. When, if ever, should claim language be narrowly construed

for the sole purpose of avoiding invalidity under, e.g., 35 U.S.C.

§§ 102, 103 and 112?

6. What role should prosecution history and expert testimony by one

of ordinary skill in the art play in determining the meaning of the

disputed claim terms?

7. Consistent with the Supreme Court’s decision in Markman v.

Westview Instruments, Inc., 517 U.S. 370 (1996), and our en banc

decision in Cybor Corp. v. FAS Technologies, Inc., 138 F.3d 1448

(Fed. Cir. 1998), is it appropriate for this court to accord any

deference to any aspect of trial court claim construction rulings? If

so, in what circumstances, and to what extent?

Phillips, Order of July 21, 2004. Judge Rader, concurring in the granting

of the petition, added the following:

Is claim construction amenable to resolution by resort to strictly

algorithmic rules, e.g., specification first, dictionaries first, etc.? Or

is claim construction better achieved by using the order or tools

relevant in each case to discern the meaning of terms according to

the understanding of one or ordinary skill in the art at the time of the

invention, thus entrusting trial courts to interpret claims as a

contract or statute?

Id. (Rader, J., concurring).

This Court’s approach is first to consider the plain and ordinary

meaning as defined by dictionaries and technical treatises, and then to

consider the file wrapper to determine what it communicates to the reader

about the plain and customary definition of the term. It may provide clues

as to how one skilled in the art would define the term or which dictionary

or technical definition is adopted by those skilled in the art. Then again, it

may clearly redefine the term and thus overrule the plain and ordinary

meaning deciphered by the Court. Regardless, since the patent process is a

public one, whatever definition is c/early supported in the file wrapper is

the one that ought prevail, since this is the one on which the public relies.

Thus, if a term supposedly has a specific technical meaning that cannot be

79a

gleaned from general dictionaries and treatises or the file wrapper, but can

only be ascertained from expert testimony, this specific meaning will not

be adopted, given the Vitronics rule against resort to extrinsic evidence.

This Court’s approach resolves the apparent conundrum by drawing a

line between cognitive and investigative tasks. One can understand this

process by analogizing claim construction to contract interpretation. When

a judge interprets the meaning of a term in a run-of-the-mill contract, she

is determining how an ordinary speaker of English would understand the

term, in context, and she cannot look to extrinsic evidence unless there is

some ambiguity. A dictionary constitutes extrinsic evidence of the “plain

and customary” meanings that members of the relevant language com-

munity ascribe to various words, but it is also serves as a tool to enhance

the judge’s cognitive capacities, which capacities are then applied to the

task of interpretation. In theory, at least, a judge interpreting a contract

written in a forcign language would follow the same process, though she

might want to gain some background understanding of the language from

experts. Having acquired such background, she could then use foreign

language dictionaries the same way she would use an English dictionary.

Having acquired the additional cognitive capacity, the judge might find

that a term’s meaning is ambiguous, in which case the judge could tum

to extrinsic evidence, say, of industry custom. In other words, the

judge would then conduct an empirical investigation of the behavior of

relevant actors.

One could thus regard the task of judges in patent cases as one of

learning a number of “difficult” words in the English language, or as one

of entering a new community of language. In either case, seeking “flu-

ency” is different from determining what customs prevail in a particular

“art,” even if those customs involve the use of an otherwise ambiguous

term. Having learned to “speak” the relevant “language” by consulting lay

and technical dictionaries (and perhaps having acquired background

understanding from experts), the judge can then apply these new cognitive

capacities to determine whether, in context, the patent term is ambiguous.

Finding that meaning, then, involves an application of the judge’s

enhanced cognitive abilities, not an investigation of empirical facts.

In reality, construction of patent claims does not work the same way

that interpretation of foreign-language contracts does. In practice, judges

interpreting foreign language contracts rely on experts to interpret them.

See, e.g., Ist Cir. R. 30(d) (“The court will not receive documents not in

the English language unless translations are furnished.”); Ramos-Bdez v.

Bossolo-Lopéz, 240 F.3d 92, 94 (1st Cir. 2001) (similar); cf 35 U.S.C.

80a

The dictionary definition of “therapeutic” is “[hjaving

healing or curative powers,” or “[o]f or relating to the treat-

ment of disease or disorders by remedial agents or methods.”

The American Heritage Dictionary 1260 (2d college ed.

1985); Webster’s Ninth New Collegiate Dictionary 1223

(1984), attached as Tab X to Supp. App. [Doc. No. 735] to

Amgen’s Reply re °422/’080; see also Chamber's Technical

Dictionary 844 (3d ed. 1961), attached as Tab W to Supp.

App. to Amgen’s Reply re *422/’080 (“Of, or pertaining to,

the medical treatment of disease: remedial: curative”). The

definition of therapeutics is “{t]he medical treatment of

disease.” The American Heritage Dictionary, supra, at 1260.

The dictionary definition of “effective” is “[h]aving an in-

tended or expected effect” or “[p]roducing or designed to

produce the desired impression or response.” /d. at 439.

Based on these definitions alone, one would surmise that a

“therapeutically effective” amount is one that produces heal-

§ 371(c)(2) (requiring that an applicant filing a national stage application

submit a copy of the international application (with certain exceptions), as

well as translation into the English language of the international appli-

cation). Every foreign language contract is treated as “ambiguous,”

because learning a new language would involve too dramatic an expan-

sion of a judge’s cognitive capacities, and an empirical investigation is the

best that she can do (although once that investigation reveals which

English translation is correct, the judge can then determine whether that

translated document is ambiguous). The Federal Circuit has decided, how-

ever, that learning the meaning of technical terms in English, or mastering

the language used by members of a community of English-speaking

persons of ordinary skill in a particular art, does not reach that level. The

task of claim construction falls on the “cognitive” side of the divide

between expanding and applying cognitive capacities, on the one hand,

and investigating empirical facts, on the other. Thus, only when applica-

tion of the judge’s newly acquired cognitive capacities determines that a

term’s meaning is ambiguous does she then turn to empirical investigation

of the behavior of persons skilled in the art. She then uses dictionaries,

expert testimony, and so on not as a cognitive tool, but as evidence.

8la

ing or curing as it relates to medical treatment of disease.”

This is, in essence, consistent with the definition that Amgen

proposes. See Amgen’s Mem. in Support re ’422/’080 [Doc.

No. 671] at 14 (arguing that the ordinary meaning is an

amount sufficient to “cure or relieve a disease state” and

“require[s] a meaningful benefit to the health of patients”).

Amgen, however, goes further, asserting that the plain and

ordinary meaning of “therapeutically effective amount,” to

one skilled in the art, taken in the context of this patent, is an

amount that provides more than the biological effects of EPO

and “produce[s] a sustained increase in hematocrit,” because

only this result provides a meaningful benefit to the health of

patients suffering from anemia.” Jd. at 7-8, 14. Neither the

claims, the specification, nor the prosecution history, how-

ever, demonstrate clearly that the plain and ordinary meaning

of the term to one skilled in the art involves an increase in

hematocrit. Therefore, the Court begins with the assumption

that the plain and ordinary meaning of “therapeutically

effective amount” is one in line with that found in the

dictionaries and treatises noted above—i.e., one that heals or

cures as it relates to medical treatment of disease.

The next step is to look to the claims, specification, and

prosecution history to see if Amgen redefined the term in the

file wrapper. In addition, the Court will look to these sources

to determine whether the file wrapper indicates clearly the

types of patients for which this product is “therapeutically

effective” and thus infuses the term with real meaning. In-

* To heal means “[t]o restore to health, or soundnes

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