Court Opinion

ID: 211134
Source: CourtListenerOpinion
Date Created: 2011-03-13 08:23:59+00
Date Added: 2024-06-11T09:48:53.813309
License: Public Domain

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.

       Lloyd R. Day, Jr., Day Casebeer Madrid & Batchelder LLP, of Cupertino, California,
argued for plaintiff-appellee. With him on the brief were Edward M. O’Toole, Howrey LLP,
of Chicago, Illinois; Michael F. Borun, Marshall, Gerstein & Borun LLP, of Chicago, Illinois;
and Stuart L. Watt, Amgen Inc., of Thousand Oaks, California. Of counsel were Renee M.
DuBord Brown, Robert M. Galvin, Jonathan Loeb, David M. Madrid, Linda A. Sasaki-
Baxley, Krista M. Carter, Courtney Towle, and Patricia L. Peden, Day Casebeer Madrid &
Batchelder LLP, of Cupertino, California; Kevin M. Flowers, Marshall, Gerstein & Borun
LLP, of Chicago Illinois; Robert R. Cook, Monique L. Cordray, Steven M. Odre, and Wendy
A. Whiteford, Amgen Inc., of Thousand Oaks, California; and Michael R. Gottfried and D.
Dennis Allegretti, Duane Morris, LLP, of Boston, Massachusetts.

      Carter G. Phillips, Sidley Austin Brown & Wood LLP, of Washington, DC, argued for
defendants-appellants. With him on the brief was Joseph R. Guerra.

Appealed from: United States District Court for the District of Massachusetts

Judge William G. Young
    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 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 judgment action against Hoechst

Marion Roussel, Inc. (now known as Aventis Pharmaceuticals Inc.) (“HMR”) and

Transkaryotic 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: (i) 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; (ii) its contingent determination that the asserted claims of the

’933 patent are invalid under section 112; (iii) its grant of summary judgment that claim

1 of the ’422 patent is 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

05-1157                                      2
(iv) its determination that claims 1, 3, 4, and 6 of the ’349 patent are infringed. Id. 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” (“the Goldwasser reference”), and the Sugimoto

patent do not anticipate claim 1 of the ’422 patent; (iii) 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. Id.

        We remanded the case to the district court to do the following: (i) construe the

term “therapeutically effective amount” in claim 1 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 1 obvious, id. at 1354, 1356, 1358; (ii)

determine 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; (iii) 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,

05-1157                                       3
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 1 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 Judgment”); Amgen, Inc. v. Hoechst Marion Roussel, Inc., 287 F. 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 1 of the ’422 patent is not invalid, Amgen III 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

equivalents, 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:

       (i) Because we hold that the district court erred in its construction of the term

“therapeutically effective amount” in claim 1 of the ’422 patent, we vacate the judgment

05-1157                                      4
of the district court that claim 1 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 equivalents. 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 infringed, it is unnecessary for us to

address HMR/TKT’s alternative argument by way of an affirmative defense that 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.1

                                      BACKGROUND

                                              I.

       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

       1
               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 III Validity &
Literal Infringement Judgment and Amgen III Doctrine of Equivalents Judgment.

05-1157                                       5
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.2 Id. col. 1, ll. 28-29. DNA is

composed of a series of subunits, called nucleotides, that are linked together to form a

linear polymeric form—a strand. Id. col. 1, ll. 33-35. Each nucleotide contains one of

four nitrogen-containing ring compounds, called bases.         The bases fall into two

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

which include adenine (“A”) and guanine (“G”). Id. col. 1, ll. 35-46; James D. Watson et

al., Molecular Biology of the Gene 98 (5th 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,

      2
             The basics of recombinant DNA technology are set forth in Amgen I and,
to a lesser extent, in Amgen II. We repeat here only the points necessary for an
understanding of the issues presented in this appeal.

05-1157                                     6
T, G, and Cs coding for a particular gene.3       ’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. Id. col. 2, ll. 4-6. The promoter is typically located upstream of the gene

to be transcribed.4    Id.   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 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, ll. 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, ll. 33-36. The expression vector incorporates itself into a host cell’s

genetic code.     The promoter then triggers the host cell to transcribe mRNA

      3
              As the name “messenger” implies, mRNA transcripts are intermediates 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.
       4
              “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.

05-1157                                     7
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.            Id.   The marker in the

expression vector enables scientists to identify the cells that successfully incorporated

the desired gene. Id. 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. Id. col. 1, l. 53–col. 2, l. 3.

       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.

Id. col. 24, l. 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.

Id. 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 to

transcribe mRNA corresponding to exogenous genes such as the EPO and DHFR

genes in Example 10. See id. col. 1, ll. 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

05-1157                                       8
’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.

                                               II.

       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 I,

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.

                                              III.

       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 1, 2, and 9 of the ’933 patent, 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 1 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).

05-1157                                        9
                                      DISCUSSION

       On this appeal, we are presented with issues relating to the ’422, ’080, ’698, and

’349 patents.5 We begin with the ’422 patent.

                                            I.

                                     The ’422 Patent

       Claim 1 is the only claim of the ’422 patent at issue in the present case. Claim 1

provides:

              A pharmaceutical composition comprising a therapeutically
              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 1 of the ’422 patent. See

Amgen II, 314 F.3d at 1320. In our remand instructions in Amgen II, we instructed the

district court to construe the limitation “therapeutically effective amount” in claim 1 and

then determine whether the Goldwasser reference or the Sugimoto patent anticipated

claim 1 or whether the Sugimoto patent rendered claim 1 obvious.

                                           A.

                                   Claim Construction

       On remand, the district court construed “therapeutically effective amount” in claim

1 of the ’422 patent to require that the claimed EPO increase hematocrit and also be

       5
            As noted above, in Amgen II, we affirmed the ruling of the district court in
Amgen I that claims 1, 2, and 9 of the ’933 patent are invalid. Amgen II, 314 F.3d at
1342.

05-1157                                     10
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, development 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 indicated 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 transfusions 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 ’422 patent found at column 33, lines 11-28.6 Id. 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. Id.

at 238–42.

       6
               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. Id. 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.

05-1157                                      11
      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 1 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 1 is

anticipated by the Goldwasser reference.

      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 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—particularly increased hematocrit—that counteract

05-1157                                    12
these anemia-like diseases are “therapeutically effective.”        Amgen buttresses 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. Id. at 1312. A claim

term has “the meaning that the term would have to a person of ordinary skill in the art. .

. .” Id. at 1313.   This meaning is ascertained “in the context of the entire patent,

including the specification.” Id. In particular, we stated in Phillips that “we must look at

the ordinary meaning in the context of the written description and the prosecution

history.” Id. (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 prosecution history,

and extrinsic evidence concerning relevant scientific principles, the meaning of technical

terms, and the state of the art.” Id. (quoting Innova/Pure Water, Inc. v. Safari Water

Filtration Sys., Inc., 381 F.3d 1111, 1116 (Fed. Cir. 2004)).

       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.”7 However, several passages of the

       7
            Claim 2 is an independent claim, which provides: “A pharmaceutically-
acceptable preparation containing a therapeutically effective amount of erythropoietin
wherein human serum albumin is mixed with said erythropoietin.” ’422 patent, col. 38,
ll. 42-44.

05-1157                                      13
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 invention
              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 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 hemoglobin C synthesis (see, Eschbach, et al.,
              supra) and, as indicated in Example 10, increasing
              hematocrit levels in mammals.

’422 patent, col. 33, ll. 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,

increasing 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 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

05-1157                                      14
four effects listed in column 33, lines 11-22, stimulation of reticulocyte response,

development of ferrokinetic effects, erythrocyte mass changes, and stimulation of

hemoglobin, 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 pharmaceutical 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 determination, 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

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). . . .” Id. col. 36,

ll. 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

05-1157                                        15
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 effects. Those effects do not

necessarily include curing disease 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 construction to the extent that it

limits the scope of claim 1 of the ’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 1 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:”

05-1157                                      16
                     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 1

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

of 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 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

05-1157                                    17
              patients had increased erythroid cells in the marrow and an
              increased plasma iron 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 Judgment, 339 F. Supp. 2d at 327–34. HMR/TKT argues

that under a revised construction of “therapeutically effective” that broadens the scope

of claim 1 to encompass EPO that “elicits any of the biological effects listed in the

specification [at column 33, lines 16-22],” Dr. Goldwasser’s study anticipates. Amgen

counters that even under a broader construction of “therapeutically effective,” Dr.

Goldwasser’s study does not anticipate claim 1 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 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.

05-1157                                     18
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. Goldwasser’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 whether

the Goldwasser reference meets the “therapeutically effective” limitation under our

construction.8

         8
             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 1 of the ’422 patent.

05-1157                                       19
                                               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 lymphoblastoids9 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, l. 55–col. 2, l. 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 . . . .” Id. col. 3, ll. 51-53.

       In Amgen I, the district court found that the Sugimoto patent did not anticipate

claim 1 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.” Id. 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. Id. After recounting Dr. Erslev’s testimony, the court discounted

HMR/TKT’s arguments. Id. HMR/TKT had put Dr. Michael 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. Id. at 108–09. The court found

that Dr. Heartlein’s experiments were not sufficient to show enablement, however,

       9
             Lymphoblastoids are cells that are typically isolated from patients with
leukemia, which is a cancer of the blood. Amgen I, 126 F. Supp. 2d at 106.

05-1157                                       20
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. Id. 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. Id. 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.

Id. 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. Id. 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 enabled . . . .” Amgen III Validity & Literal Infringement Judgment, 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 necessary to repeat the process it describes. Id. 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. Id. at 307. Second, the court found that the Sugimoto

patent was not enabled because it did not teach a person of ordinary skill in the art how

to select EPO-producing hybrid cells.      The court based its finding largely on the

05-1157                                    21
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. Id. 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. Id. 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.

Id. 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 deposited, 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 I that Dr.

Heartlein did not follow the Sugimoto patent’s disclosure.

05-1157                                     22
       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 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. Id. (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 experimentation 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. In re Wands, 858 F.2d 731, 735

(Fed. Cir. 1988).

       We established in Amgen II 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

05-1157                                     23
this presumption. Id. 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

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

05-1157                                     24
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 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 I that the Sugimoto patent did not render claim 1

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 conclusion, the court considered the scope and content of the prior art, differences

05-1157                                      25
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.” Id. 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. Id. 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.” Id. at 325. HMR/TKT appeals

the district court’s ruling.

       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.

                                             II.

                                     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 I that claims 2-4 of the

’080 patent were infringed under the doctrine of equivalents by HMR/TKT’s HMR4396

product. Id. The only issue before us on appeal is infringement under the doctrine of

equivalents. Claims 2-4 provide:

05-1157                                     26
             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
             therapeutically effective amount [of] an erythropoietin
             glycoprotein product according to claim 1, 2 or 3.

’080 patent, col. 38, ll. 39-53. Claims 2-4 of the ’080 patent each contain the limitation

that the “erythropoietin glycoprotein 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

05-1157                                    27
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 product
             not being isolated from human urinary sources having
             glycosylation which differs from that of human urinary
             erythropoietin.

             62.   An isolated human erythropoietin glycoprotein product
             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 product
             not being isolated from human urinary sources and free of
             other human proteins.

             64.     The in vivo biologically active erythropoietin product 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:

05-1157                                     28
             (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.

Claim 68, which was added in the second preliminary amendment, provided as follows:

             68.     A non-naturally occurring erythropoietin product of the
             process comprising the steps of:
             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 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.

             72.     A pharmaceutical composition comprising a
             therapeutically effective amount [of] an erythropoietin
             glycoprotein product according to claim 69, 70 or 71.

05-1157                                    29
       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 product 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 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 1 of the ’933

patent.10 126 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. Id. at

136. Therefore, the court held that Amgen was not estopped from claiming that EPO

       10
              Claim 1 of the ’933 patent provides:

              A non-naturally occurring erythropoietin glycoprotein product
              having 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 erythropoietin.

’933 patent, col. 38, ll. 18-22.

05-1157                                    30
with a 165-amino acid sequence infringed the asserted claims of the ’080 patent under

the doctrine of equivalents. Id.

       In Amgen II, citing Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 535

U.S. 722, 740–41 (2002) (“Festo II”), 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 narrow ways of rebutting the

Supreme Court’s presumption of estoppel.” Id. These “narrow ways” were first set forth

in Festo II.    They are (i) showing that an equivalent was unforeseeable; (ii)

demonstrating that the purpose for an amendment was merely tangential to the alleged

equivalent; or (iii) establishing “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 Judgment, 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. Id. 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. Id. at 152. The court found that the third preliminary

05-1157                                    31
amendment was therefore no more than tangentially related to the 165-amino acid

equivalent. Id. at 154. The court based this finding on the prosecution 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 human EPO.” 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

intention 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. Id. at 153.

       Although the district court found that the Festo presumption 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 sequence, it

set forth an alternate rationale based on the “some other reason” language in Festo II.

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. Id. at 157. In essence, the court construed the claims based on the

extrinsic record (with support from the intrinsic record). Id. The court reasoned that this

evidence reflected a “shortcoming[ ] of language” or “linguistic” limitation, which were

mentioned in Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 344 F.3d 1359,

1372 (Fed. Cir. 2003) (en banc) (“Festo III”), as possible reasons for rebuttal of the

05-1157                                     32
Festo presumption. Amgen III Doctrine of Equivalents Judgment, 287 F. Supp. 2d at

159. The court then found that those equivalents encompassed by this construction

were not surrendered, relying on the “some other reason” exception to the Festo

presumption of surrender of equivalents. Id.

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

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

encompasses only human EPO, from claim 1 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 1 of U.S. 5,547,933 in specifying that the

claimed subject matter comprises the mature human erythropoietin sequence of Figure

6. Claim 69 [currently claim 1 of the ’080 patent] (like [’933] glycoprotein claim 1) recites

05-1157                                      33
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 contends 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 presumption under the “some other reason” rationale. Amgen argues that

because a 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 patentee expected the claims to encompass this

equivalent.

                                          C.

      The burden of rebutting the Festo presumption lies with the patentee. Festo III,

344 F.3d at 1368.     Whether a patent-holder has successfully rebutted the Festo

presumption of the surrender 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

III, 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 follow, we uphold the district court’s finding that

Amgen failed to show that EPO with a 165-amino acid sequence was not foreseeable at

05-1157                                   34
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 both 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 II, 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 unforeseeable 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.” Id. Third, a patentee may demonstrate that “there [is] some other reason

suggesting that the patentee could not reasonably be expected to have described the

insubstantial substitute in question.” Id.

       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

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. Id. 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.” Id. With regard

to the tangentiality of an amendment to an equivalent, we did not set forth any concrete

05-1157                                      35
definition, but we did note that an amendment “made to avoid prior art that contains the

equivalent in question is not tangential; it is central to allowance of the claim.” Id. Thus,

an amendment is tangential when the “reason for [it] was peripheral, or not directly

relevant, to the alleged equivalent.”     Id.        The determination of whether or not an

amendment is merely tangential to the equivalent is based on the “patentee’s

objectively apparent reason for the narrowing amendment.” Id. Thus, the inquiry must

be based on the intrinsic record alone and, if necessary, expert testimony to aid in

interpretation of that record. Id. Finally, we noted that the third way to rebut the Festo

presumption, the “some other reason” route, is a narrow one. Id. at 1370. We stated

that “the third criterion may be satisfied when there was some reason, such as the

shortcomings of language, why the patentee was prevented from describing the alleged

equivalent when it narrowed the claim.” Id.

                                                1.

       With regard to the first Festo rebuttal argument, foreseeability, 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 III 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 ordinary skill in the art would understand claims 2-4 of the

’080 patent is one of claim construction, which was settled in Amgen II. 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

05-1157                                         36
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 prosecution 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

amendment would have considered the equivalent).

                                           2.

       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. Id. at 1370–71. The patented method in Insituform involved

using a vacuum to impregnate a flexible tube with resin.      Id. 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. Id. 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. Id. Thus, we ruled that the reason

for the amendment was merely tangential to the alleged equivalent using multiple cups.

05-1157                                   37
Id. Accordingly, we held that the patentee in Insituform 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 III, 344 F.3d at 1369. As seen, the third preliminary

amendment was made to avoid a double patenting 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 equivalent. As

seen, in claim 1 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 reticulocytes and red blood
               cells and having glycosylation which differs from that of
               human urinary erythropoietin.

’933 patent, col. 38, ll. 18-22. Thus, claim 1 contains no limitation pertaining to human

or non-human EPO. Claim 1 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.

05-1157                                       38
      We think Amgen’s third preliminary amendment did more than limit the scope of

the asserted claims of the ’080 patent 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, encompassed 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

because the ’556 application encompassed EPO having the incomplete amino acid

sequence set forth in Figure 6. Likewise, claim 1 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 incomplete 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 1

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 III Doctrine of Equivalents Judgment, 287 F. Supp. 2d at 152

n.36 (emphasis added) (footnote omitted). Accordingly, the limitation added in the third

05-1157                                   39
preliminary 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 tangential 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 patentee chose to

further narrow the claims in the third preliminary amendment by making reference to the

specific sequence 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 II decision in ruling that Amgen had rebutted the Festo

presumption of surrender of equivalents.        In Festo II, the Court held that the

presumption of the surrender of equivalents could be rebutted by showing that “there [is]

some other reason suggesting that the patentee could not reasonably be expected to

have described the insubstantial substitute in question.” 535 U.S. at 740–41.

05-1157                                    40
       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 Trademark 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 having either 165 or

166 amino acids at the time the third preliminary amendment was made. Id. 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. Id. 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 II, 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 III Doctrine of Equivalents 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

05-1157                                     41
reason” rebuttal argument applied when the patentee allegedly understood the claim

language to refer to the equivalent in question). Further, there were no shortcomings 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 reference

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 “fragment thereof.”    In short, there was no linguistic barrier to claiming EPO

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 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 III, 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

amendment, but still chose to claim the incorrect 166-amino acid sequence in Figure 6.

We conclude that Amgen has not rebutted 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

05-1157                                    42
court erred, however, 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.

                                              III.

                                 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 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 rejected HMR/TKT’s argument that the asserted claims

were not enabled.      Having rejected HMR/TKT’s validity challenges, 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 obviousness. Since the district court already had ruled in

Amgen I that claims 1, 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

05-1157                                       43
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 1 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 by the Goldwasser reference and for

such further proceedings as may be necessary.11 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.

       11
              See footnote 10, supra.

05-1157                                        44
                                      COSTS

     Each party shall bear its own costs.

AFFIRMED-IN-PART, REVERSED-IN-PART, VACATED-IN-PART, and REMANDED

05-1157                                     45
 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.

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 1

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 1

of this particular patent, only one of several asserted.

       At the outset, I compliment the district court for the meticulous attention it has

given to this extraordinarily complicated, 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 II.

       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 Institute 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 constructions and making

extensive findings of fact and conclusions of law; it subsequently issued two opinions,

together totaling 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, ll. 17-22, (i.e., stimulation of reticulocyte

response, development of ferrokinetic effects, erythrocyte mass changes, stimulation of

       *
              The district court's original opinion in this case contained 244 pages.

05-1157                                       2
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 disorders, such as hemophilia, sickle cell

disease, physiological anemias, and the like." '422 patent, col. 33, ll. 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

experiencing 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 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 necessarily 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

05-1157                                      3
       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 mammals, 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, ll. 6-22 (emphasis added). This disclosure 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 intention to claim EPO that (1) causes the same in vivo

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

       The subsequent disclosure strengthens my view that the district court correctly

construed the "therapeutically effective" 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 administered 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)
       µg/kg body weight of the active material.

'422 patent, col. 33, ll. 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

05-1157                                       4
cell count. Inherently, the ultimate goal is to "heal" or "cure" the disorder. That healing

is characterized by an increased red blood cell count, i.e., a higher hematocrit level.

       Significantly, I note that the words "therapeutically effective" 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 class of patients for which the product is intended to be

'therapeutically effective.'" Amgen III Validity & Literal Infringement Judgment, 339 F.

Supp. 2d at 237.

       The specification further discloses various analogs 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 fragments 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 products" of the invention is not wholly preclusive of
       therapeutic utility (see, Weiland, et. al., supra) or of utility in other
       contexts, such as in EPO assays or EPO antagonism.

'422 patent, col. 35, ll. 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 triggering any in vivo biological activity, regardless of degree. Correctly read, the

05-1157                                       5
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 "therapeutically effective" connotes

more than simply eliciting any cited in vivo biological effect.         The district court

emphasized that during prosecution of the '422 patent, the patentee differentiated 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 distinguished 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:

       [N]aturally 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.

05-1157                                     6
       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 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 erythropoietin
       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 effective
       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 effective" limitation comports with the patentee's own repeated

descriptions of the claimed invention.       It is exactly the way a skilled artisan would

interpret the patent, as the district court held.

                                               II.

       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 increase

reticulocytes, an increase in plasma iron clearance, and red cell mass changes)

demonstrated therapeutic effectiveness. HMR does not contend that the district court

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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 I think that the district court correctly rejected HMR's

proposed construction and properly construed "therapeutically effective" to mean

"healing" or "curing," HMR's validity challenge necessarily 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 1 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 1 of the '422

patent in light of its revised construction of "therapeutically 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 injunction, 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

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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 patents 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 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 1 of the '422 patent is invalid.

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