Court Opinion

ID: 1038335
Source: CourtListenerOpinion
Date Created: 2013-08-24 00:02:48.982815+00
Date Added: 2024-06-11T12:05:23.091473
License: Public Domain

United States Court of Appeals
      for the Federal Circuit
                ______________________

                 SKINMEDICA, INC.,
                  Plaintiff-Appellant,

                           v.

 HISTOGEN INC., HISTOGEN AESTHETICS LLC,
         AND GAIL K. NAUGHTON,
             Defendants-Appellees.
            ______________________

                      2012-1560
                ______________________

   Appeal from the United States District Court for the
Southern District of California in No. 09-CV-0122, Judge
Janis L. Sammartino.
                ______________________

               Decided: August 23, 2013
                ______________________

    RICHARD P. BRESS, Latham & Watkins, LLP, of Wash-
ington, DC, argued for plaintiff-appellant. With him on
the brief were GABRIEL K. BELL, of Washington, DC, and
STEPHEN P. SWINTON, ALEXANDER E. LONG, and LISA
LIMOR RABIE, of San Diego, California.

    GREGORY A. CASTANIAS, Jones Day, of Washington,
DC, argued for defendants-appellees. With him on the
brief were ANDREW A. PINSON, of Washington, DC, and
RANDALL E. KAY, of San Diego, California.
2                             SKINMEDICA INC   v. HISTOGEN INC
                    ______________________

    Before RADER, Chief Judge, CLEVENGER and PROST, Cir-
                         cuit Judges.
    Opinion for the court filed by Circuit Judge PROST. Dis-
         senting opinion filed by Chief Judge RADER.
PROST, Circuit Judge.
     SkinMedica, Inc. (“SkinMedica”) appeals from the de-
cision of the United States District Court for the Southern
District of California granting Histogen, Inc., Histogen
Aesthetics, and Gail Naughton (collectively “Histogen”)
summary judgment of noninfringement of the asserted
claims of U.S. Patent Nos. 6,372,494 (’494 patent) and
7,118,746 (’746 patent) after construing a phrase common
to both patents. Because we find no legal error in the
district court’s construction, we affirm the grant of sum-
mary judgment.
                       I. BACKGROUND
     SkinMedica owns the ’494 and ’746 patents. In 2009,
it filed a patent infringement suit against Histogen for
producing dermatological products according to methods
covered by the claims of those patents. 1 Those claims
generally relate to methods for producing pharmaceutical
compositions containing “novel conditioned cell culture
medium compositions, . . . [and] uses for the[m].” ’494
patent col. 4 ll. 40–45. 2 A cell culture medium is an
artificial environment, such as a liquid, that is outside the

      1 The suit included allegations of trade secret mis-
appropriate and violations of several state laws. Only the
infringement claims are at issue on appeal.
      2 We cite only to the written description of the ’494
patent because it is the parent of the ’746 patent and uses
an identical written description.
SKINMEDICA INC   v. HISTOGEN INC                              3
body (“in vitro”) and “suppl[ies] the components necessary
to meet the nutritional needs required to grow cells.” Id.
at col. 1 ll. 24–25. A “conditioned” cell culture medium is
one which has been incubated with cells. Id. at col. 1 ll.
30–32 (“Once the culture medium is incubated with cells,
it is known to those skilled in the art as . . . ‘conditioned
medium.’”). In addition to the nutritional compounds that
are present in the unconditioned medium for feeding cells,
a conditioned medium commonly includes “a variety of
cellular metabolites and secreted proteins” produced by
cells in the culture, including “biologically active growth
factors, inflammatory mediators and other extracellular
proteins.” Id. at col. 1 ll. 34–37; see also id. at 8 l. 64–col.
9, l. 30. According to the patentees, those “extracellular”
proteins may be useful in the treatment of many condi-
tions, including “wrinkles, frown lines, scarring and . . .
other skin conditions.” Id. at col. 5 l. 50.
           A. The Asserted Patents and Claims
    Originally, the inventors of the ’494 patent proposed
claims related to a pharmaceutical composition compris-
ing any cell culture medium conditioned by animal cells
(or “eukaryotic” cells), including those cultured in either
“two-dimensions” or “three-dimensions.”        Indeed, the
written description explains that the invention “relates to
compositions comprising cell culture medium conditioned
by cells grown in two-dimensional culture (i.e., a mono-
layer), or in three-dimensional culture.” Id. at col. 1 ll. 5–
8. The written description also states the cells that
condition the medium used in the invention “are cultured
in monolayer, beads (i.e., two-dimensions) or, preferably,
in three-dimensions” and “may be cultured in any manner
known in the art including in monolayer, beads or in
three-dimensions and by any means.” Id. at col. 7 ll. 28–
29; col. 9 ll. 66–col. 10 l. 1.
    During prosecution of the ’494 patent, the inventors
limited their claimed inventions to pharmaceutical com-
4                            SKINMEDICA INC   v. HISTOGEN INC
positions comprising cell culture medium conditioned by
animal cells cultured only in three-dimensions. They did
so to overcome an anticipation rejection based on prior art
(the “Shipley” reference) that disclosed the use in a phar-
maceutical composition of cell culture medium condi-
tioned by animal cells grown in two-dimensions.
    In their final form, the claims of the ’494 patent—and,
correspondingly, the ’796 patent—include the limitation
that the cell culture medium used in the inventions must
be conditioned by “culturing . . . cells in three-
dimensions.” Claim 1 of the ’494 patent is representative.
    1. A method of making a composition comprising:
        (a) culturing fibroblast cells in three-
        dimensions in a cell culture medium suffi-
        cient to meet the nutritional needs re-
        quired to grow the cells in vitro until the
        cell culture medium contains a desired
        level of extracellular products so that a
        conditioned medium is formed;
        (b) removing the conditioned medium from
        the cultured cells; and
        (c) combining the conditioned medium
        with a pharmaceutically acceptable carrier
        to form the composition.
Id. at claim 1 (emphases added).
    According to the patentees, a novel and important as-
pect of their invention is the difference between the
conditioned medium produced by cells cultured in two-
dimensions and in three-dimensions. “While growth of
cells in two dimensions is a convenient method for prepar-
ing, observing and studying cells in culture,” two-
dimensional cultures lack “characteristic[s] of whole
tissue in vivo.” Id. at col. 2 ll. 15–18. In a section titled
SKINMEDICA INC   v. HISTOGEN INC                           5
“Background of the Invention,” the inventors detail the
relevance of that deficiency.
    Cell lines grown as a monolayer or on beads, as
    opposed to cells grown in three-dimensions, lack
    the cell-cell and cell-matrix interactions charac-
    teristic of whole tissue in vivo. Consequently,
    such cells secrete a variety of cellular metabolites
    although they do not necessarily secrete these me-
    tabolites and secreted proteins at levels that ap-
    proach physiological levels.           Conventional
    conditioned cell culture medium, medium cultured
    by cell-lines grown as a monolayer or on beads, is
    usually discarded or occasionally used in culture
    manipulations such as reducing cell densities.
Id. at col. 1 ll. 37–47.
     The inventors explain in the written description that
some researchers have attempted to create cell cultures
that replicate the valuable characteristics of whole tissue
in vivo. As they say, a “few investigators have explored
the use of three-dimensional substrates” to grow cells
with such characteristics. Id. at col. 2 ll. 19–20. In such
systems, “three-dimensional substrates are inoculated
with the cells to be cultured,” and those cells “penetrate
the matrix and establish a ‘tissue-like’ histology.” Id. at
col. 2 ll. 30–33. “Additionally,” according to the inventors,
“various attempts have been made to regenerate tissue-
like architecture from dispersed monolayer cultures,”
which “could grow to more than ten cells deep” and could
develop “organoid structures.” Id. at col. 2 ll. 37–41. The
inventors also detail how certain skin cell lines could form
“friction ridges if kept for several weeks without transfer,”
and other cell lines could form “capillary tubules” in the
presence of certain growth factors. Id. at col. 2 ll. 45–51.
“However,” the inventors state, “the long term culture and
proliferation of cells in such systems has not been
achieved.” Id. at col. 2 ll. 55–57.
6                             SKINMEDICA INC   v. HISTOGEN INC
    As part of the written description, the inventors dis-
cuss a system that is closer to achieving the goal of long
term culture and proliferation of cells and that more
closely replicates the valuable characteristics of whole
tissue in vivo. They indicate that a three-dimensional cell
culture system “will sustain active proliferation of . . .
cells in culture for much longer time periods than will
monolayer systems” and “supports the maturation, differ-
entiation, and segregation of cells in culture in vitro to
form components . . . analogous to counterparts found in
vivo and . . . proteins [in] the condition[ed] medium more
closely resembling physiological ratios.” ’ Id. at col. 11 ll.
11–19.
    As the inventors describe them in the specification,
three-dimensional cell cultures are created by inoculating
a “three-dimensional framework” with cells. That frame-
work is expressly defined as “a three-dimensional scaf-
fold” that is “inoculated with stromal cells” and is
“composed of any material and/or shape that (a) allows
cells to attach to it . . . and (b) allows cells to grow in more
than one layer.” ’ Id. at col. 6 ll. 42–47. The inventors
explain that a number of non-exhaustive factors may
contribute to the success of such a three-dimensional
culture system, including, for example, that the “three-
dimensional framework provides a greater surface area
for protein attachment”; the three-dimensionality of the
framework permits “stromal cells [to] continue to grow
actively, in contrast to cells in monolayer cultures, which
grow to confluence, exhibit contact inhibition, and cease to
grow and divide”; “[t]he three-dimensional framework
allows for a spatial distribution of cellular elements which
is more analogous to that found in the counterpart tissue
in vivo”; “[t]he elaboration of growth and regulatory
factors by replicating stromal cells” in a three-
dimensional culture may stimulate “proliferation” and the
“regulat[ion] [of] differentiation of cells in culture”; “[t]he
increase in potential volume for cell growth in the three-
SKINMEDICA INC   v. HISTOGEN INC                           7
dimensional system may allow the establishment of
localized microenvironments conducive to cellular matu-
ration”; and “[t]he three-dimensional framework maxim-
izes cell-cell interactions by allowing greater potential for
movement of migratory cells . . . in the adherent layer.”
Id. at patent col. 11 ll. 20–53.
    In addition, the patentees highlight the importance of
maintaining and maximizing “proliferative activity”
during three-dimensional culturing and describe ways to
do so. For example, they teach that “proliferating cells
may be released from the matrix” used in a three-
dimensional culture and “stick to the walls of the culture
vessel where they may continue to proliferate and form a
confluent monolayer.” Id. at col. 14 ll. 20–24. That
“should be prevented or minimized” by “[r]emoval of the
confluent monolayer or transfer of the culture to fresh
media in a new vessel” because the presence of confluent
monolayers in the culturing vessel will “shut down”
continued proliferation in a three-dimensional culture
system. Id. at col. 14 ll. 24–31.
    During prosecution of the ’494 patent, the patentees
also discussed the importance of sustained proliferation of
cells in three-dimensional cultures and the importance of
the components in the culture medium for achieving such
growth. At one point, the examiner of the ’494 patent
rejected a set of proposed claims, which included the
three-dimensional culturing limitation, over Shipley
combined with U.S. Patent No. 5,032,508 (’508 patent)
(issued to Naughton, et al.). 3 That patent discloses a
“three-dimensional skin culture system” that uses a
“three-dimensional matrix” to culture a variety of cells
and that “allow[s] for normal cell-cell interactions and the

    3    Gail Naughton, a defendant in this case and an
inventor of the ’494 and ’796 patents, was also an inventor
of the ’508 patent.
8                            SKINMEDICA INC   v. HISTOGEN INC
secretion of natural growth factors, and the establishment
of a connective tissue network virtually identical to that
found in vivo.” ’508 patent col. 27 ll. 10–35. The written
description of the ’508 patent additionally explained that
“three-dimensional skin cultures have applicability to
many fields of industry including use . . . as a source of
naturally secreted pharmacologic agents.” Id. at col. 27 l.
68–col. 28 l. 4. To overcome the obviousness rejection, the
inventors of the ’494 patent argued that “the conditioned
medium from cells cultured in three-dimensions has
desirable properties not exhibited by medium conditioned
by cells cultured [in] two dimensions” and that “nowhere
in Naughton et al., is there a teaching or suggestion that
sustained proliferation of the cells in culture is a result of
factors or components of the conditioned medium.” 4
Response to Office Action, Exhibit to Response to Claim
Construction Brief, SkinMedica v. Histogen, No. 3:09-cv-
122, (S.D. Cal. July 21, 2009), ECF No. 47-1 at 30 (second
emphasis added).
                B. District Court Proceedings
    In May 2011, the United States District Court for the
Southern District of California construed the phrase
“culturing . . . cells in three-dimensions” as “growing . . .
cells in three dimensions (excluding growing in monolay-
ers or on microcarrier beads).” 5 J.A. 49. The court rea-
soned that “the inventors acted as their own
lexicographers, defining ‘culturing . . . cells in three-
dimensions’ away from its ordinary meaning,” by consist-
ently distinguishing beads from three-dimensional cul-

    4    The prosecution of the ’494 patent was prior to
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007), a time
during which the teaching, suggestion, and motivation
test reigned supreme.
    5     The parties do not dispute the exclusion of mono-
layers.
SKINMEDICA INC   v. HISTOGEN INC                          9
tures in the specification. J.A. 21. That conclusion was
evident from the written description, according to the
court, because the inventors used the disjunctive “or” and
the disjunctive phrase “as opposed to” as coordinating
conjunctions when they listed monolayer, beads, and
three-dimensions as the methods used in the invention to
culture cells. Id. The court noted that there was only one
other reference to culturing with beads in the specifica-
tion: a statement by the inventors that the conditioned
medium created from bead cultures was “conventional”
and “usually discarded.” Id. The court also concluded
that the patentees “explicitly defined beads as a two-
dimensional culture method” by using the phrase “beads
(i.e. two-dimensions).” J.A. 22.
    The district court stated, however, that it would have
found otherwise if “the intrinsic evidence disclosed even a
single reference to culturing cells in three dimensions
using beads.” J.A. 22. To that point, SkinMedica had
argued that a document referenced in the written descrip-
tion provided such disclosure. That reference, Cell &
Tissue Culture: Laboratory Procedures (“Doyle”), is a
voluminous technical treatise that the written description
states to be “incorporated by reference” in its “entirety,”
without further relevant citation to specific contents. ’494
patent col. 7 ll. 50–53. Doyle states that microcarriers
(beads) commonly formed “aggregates made up of as
many as 10 or more microcarriers” that “are joined by
cellular bridges.” J.A. 100974. The court concluded that
the relevant discussion in Doyle was not identified with
enough particularity to be adequately incorporated into
the intrinsic record.
    The district court also gave no weight to the testimo-
ny provided by SkinMedica’s expert, Dr. Salomon, during
claim construction proceedings. Dr. Salomon had testified
that beads should not be excluded from the meaning of
“culturing . . . cells in three-dimensions.” The court found
10                            SKINMEDICA INC   v. HISTOGEN INC
his testimony to be “inconsistent with the intrinsic patent
record” and erroneously reliant on Doyle. J.A. 23.
     Following claim construction, Histogen moved for
summary judgment on the infringement claims. Based on
its construction of the phrase “culturing . . . cells in three-
dimensions,” the district court granted Histogen’s motion
in November 2011. In its summary judgment opinion, the
court first dismissed an argument by SkinMedica in
opposition to the summary judgment motion that the
phrase “excluding grown . . . on microcarrier beads” only
excluded “two-dimensional growth on beads,” not three-
dimensional growth “using” beads. J.A. 53 (emphases
added). The court clarified that its “use of the preposition
‘on’ as opposed to the preposition ‘between’ or the gerund
‘using’” was “nothing more than the Court’s dictional
preference” and that its definition of “culturing cells in
three-dimensions” would also exclude three-dimensional
growth using beads. J.A. 52. After that explanation, the
court determined there was no genuine dispute that
Histogen’s culturing method begins as “one- or two-
dimensional growth” on beads that then “evolves into a
three-dimensional growth phase in which the cells crawl
off the beads.” J.A. 54. The court held that summary
judgment of noninfringement was appropriate because
“Histogen’s cell growth process, which uses beads, cannot
infringe the disputed claim element as construed.” J.A.
56.
   SkinMedica filed a timely appeal of the district court’s
grant of summary judgment. We have jurisdiction under
28 U.S.C. § 1295(a)(1).
                       II. DISCUSSION
    SkinMedica raises a single point of error on appeal. It
argues that the district court erroneously excluded beads
from the definition of “culturing . . . cells in three-
dimensions.” According to SkinMedica, those of ordinary
skill in the art would understand the ordinary meaning of
SKINMEDICA INC   v. HISTOGEN INC                        11
the phrase “culturing . . . cells in three-dimensions” to
include the use of beads because they would have under-
stood that beads could be used to grow cells in three
dimensions. It believes that the inventors did not act as
their own lexicographers because they did not expressly
define culturing cells in three-dimensions nor disclaim the
use of beads in such culturing. They argue that point is
particularly clear given that: (1) the definition of three-
dimensional framework provided by the inventors is
broad enough to include beads; (2) Doyle is incorporated
in the specification and discloses three-dimensional cell
culturing with beads; (3) a published international patent
application, WO 98/21312 (“Seldon”), which is listed
among the “References Cited ” on the cover page of
the ’746 patent, discloses that cells in bead cultures are
“reminiscent” of those in vivo; and (4) Dr. Salomon testi-
fied that that beads could be used to grow cells in three
dimensions and such cultures would exhibit the benefits
of three-dimensional cultures described by the patentees.
    We find no basis to disturb the district court’s con-
struction of the phrase “culturing . . . cells in three-
dimensions.” The specification clearly proves that the
patentees defined the three-dimensional culturing re-
quired by the claims to exclude culturing with beads,
because the patent expressly confines culturing with
beads to two-dimensional culturing. Whether viewed as a
matter of disclaimer or of lexicography, the result is the
same: the kind of three-dimensional culturing protected
by the patent excludes use of beads. Because the accused
method employs beads, it cannot infringe the patents in
suit. We therefore affirm the district court’s grant of
summary judgment of noninfringement to Histogen.
                    A. Legal Background
   A grant of summary judgment is appropriate “if the
movant shows that there is no genuine dispute as to any
material fact and the movant is entitled to judgment as a
12                            SKINMEDICA INC   v. HISTOGEN INC
matter of law.” Fed. R. Civ. P. 56(a). The law of the
regional circuit, here the Ninth Circuit, controls our
review of a district court’s grant or denial of a motion for
summary judgment. Bayer Healthcare Pharm., Inc. v.
Watson Pharm., Inc., No. 2012-1397, 2013 WL 1606014
(Fed. Cir. Apr. 16, 2013); Teva Pharm. Indus. v. Astra-
Zeneca Pharm. LP, 661 F.3d 1378, 1381 (Fed. Cir. 2011).
The Ninth Circuit reviews grants of summary judgment
rulings without deference. Id.; see also Burke v. Cnty. of
Alameda, 586 F.3d 725, 730–31 (9th Cir. 2009).
    The dispute in this case rests on the district court’s
construction of a single phrase in the asserted claims.
Our review of that construction is de novo. Cybor Corp. v.
FAS Techs., Inc., 138 F.3d 1448, 1455–56 (Fed. Cir. 1998)
(en banc).
    “The words of a claim are generally given their ordi-
nary and customary meaning as understood by a person
of ordinary skill in the art when read in the context of the
specification and prosecution history.” Thorner v. Sony
Computer Entm’t Am. LLC, 669 F.3d 1362, 1365–67 (Fed.
Cir. 2012) (citing Phillips v. AWH Corp., 415 F.3d 1303,
1313 (Fed. Cir. 2005) (en banc)). When construing claim
terms, we first look to, and primarily rely on, the intrinsic
evidence, including the prosecution history and the speci-
fication—which is usually dispositive. Phillips, 415 F.3d
at 1315 (“The claims, of course, do not stand alone. Ra-
ther, they are part of a fully integrated written instru-
ment . . . . For that reason, claims must be read in view of
the specification, of which they are a part. . . . Usually, it
is dispositive . . . .” (citations omitted) (internal quotation
marks omitted)). When interpreting the claims, the
written description is of particular import, and it is “en-
tirely appropriate for a court, when conducting claim
construction, to rely heavily on [it] for guidance as to the
meaning of the claims.” Phillips, 415 F.3d at 1317; see
also id. at 1316 (“The close kinship between the written
description and the claims is enforced by the statutory
SKINMEDICA INC   v. HISTOGEN INC                          13
requirement that the specification describe the claimed
invention in ‘full, clear, concise, and exact terms.’” (quot-
ing 35 U.S.C. § 112)).
    When construing claim terms, “extrinsic evidence in
the form of expert testimony can be useful to a court for a
variety of purposes, such as to provide background on the
technology at issue, to explain how an invention works, to
ensure that the court’s understanding of the technical
aspects of the patent is consistent with that of a person of
skill in the art, or to establish that a particular term in
the patent or the prior art has a particular meaning in the
pertinent field.” Phillips, 415 F.3d at 1318. However,
“extrinsic evidence in general” is “less reliable than the
patent and its prosecution history in determining how to
read claim terms.” Id. Expert testimony, in particular, is
less reliable because it “is generated at the time of and for
the purpose of litigation and thus can suffer from bias
that is not present in intrinsic evidence.” Id. For that
reason, “conclusory, unsupported assertions by experts as
to the definition of a claim term are not useful to a court.”
Id. Thus “a court should discount any expert testimony
that is clearly at odds with the claim construction man-
dated by the claims themselves, the written description,
and the prosecution history.” Id. (internal quotation
marks omitted).
    During claim construction, terms are not always af-
forded their ordinary meaning. In this case, the ordinary
meaning of “culturing . . . cells in three-dimensions” would
reach the use of beads. The question is whether the
patentees here instead defined “culturing . . . cells in
three-dimensions” to exclude the use of beads. If the
specification reveals “a special definition given to a claim
term by the patentee that differs from the meaning it
would otherwise possess[,] . . . the inventor’s lexicography
governs.” Id. at 1316; see Helmsderfer v. Bobrick Wash-
room Equip., Inc., 527 F.3d 1379, 1381 (Fed. Cir. 2008)
(explaining that inventors’ definition of a claim term
14                           SKINMEDICA INC   v. HISTOGEN INC
controls when they “clearly express an intent” to redefine
a term used in the claims). And if the specification re-
veals “an intentional disclaimer, or disavowal, of claim
scope by the inventor,” the scope of the claim, “as ex-
pressed in the specification, is regarded as dispositive.”
Phillips, 415 F.3d at 1316 (citing SciMed Life Sys., Inc. v.
Advanced Cardiovascular Sys., Inc., 242 F.3d 1337, 1343–
44 (Fed. Cir. 2001)).
    Disclaiming the ordinary meaning of a claim term—
and thus, in effect, redefining it—can be affected through
“repeated and definitive remarks in the written descrip-
tion.” Computer Docking Station Corp. v. Dell, Inc., 519
F.3d 1366, 1374 (Fed. Cir. 2008) (citing Watts v. XL Sys.,
232 F.3d 877, 882 (Fed. Cir. 2000)); see SafeTCare Mfg.,
Inc. v. Tele-Made, Inc., 497 F.3d 1262, 1270 (Fed. Cir.
2007) (finding disclaimer of “pulling force” where “the
written description repeatedly emphasized that the motor
of the patented invention applied a pushing force”);
SciMed, 242 F.3d at 1344 (“[T]he written description can
provide guidance as to the meaning of the claims, thereby
dictating the manner in which the claims are to be con-
strued, even if the guidance is not provided in explicit
definitional format.”); Bell Atl. Network Servs., Inc. v.
Covad Commc’ns Grp., Inc., 262 F.3d 1258, 1268 (Fed.
Cir. 2001) (“[A] claim term may be clearly redefined
without an explicit statement of redefinition. . . . In other
words, the specification may define claim terms by impli-
cation such that the meaning may be found in or ascer-
tained by a reading of the patent documents.” (citations
omitted) (internal quotation marks omitted)); Vitronics
Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir.
1996) (“The specification acts as a dictionary when it
expressly defines terms used in the claims or when it
defines terms by implication.”). We do, though, “recognize
that the distinction between using the specification to
interpret the meaning of a claim and importing limita-
tions from the specification into the claim can be a diffi-
SKINMEDICA INC   v. HISTOGEN INC                          15
cult one to apply in practice.” Phillips, 415 F.3d at 1323.
However, we can rely on the specification “to understand
what the patentee has claimed and disclaimed.”
SafeTCare Mfg., 497 F.3d at 1270.
                        B. Analysis
     The district court found that “the inventors defined
‘culturing . . . cells in three-dimensions’ by implication to
exclude culturing on beads,” even though “culturing cells
in three dimensions on beads was known in the art at the
time the patent was filed.” J.A. 50. We agree with the
court’s exclusion of beads from the construction of the
disputed phrase. In the written description, the patentees
plainly and repeatedly distinguished culturing with beads
from culturing in three-dimensions.          They expressly
defined the use of beads as culturing in two-dimensions.
And they avoided anticipatory prior art during prosecu-
tion by asserting that the conditioned medium produced
by two-dimensional cultures was inferior and chemically
distinct from the conditioned medium produced by three-
dimensional cultures. Because none of the evidence called
to our attention by SkinMedica would reasonably lead to a
different reading of the intrinsic evidence, we find that
the inventors clearly redefined the scope of “culturing . . .
cells in three dimensions” by disclaiming the use of
beads—which would otherwise be included in the ordi-
nary meaning of that phrase. 6

    6   While Histogen appears to dispute on appeal
whether the ordinary meaning of three-dimensional cell
culture can include the use of beads, it appears to have
conceded the point to the district court. Def.’s Responsive
Claim Construction Br. 11, SkinMedica v. Histogen, No.
3:09-cv-122, (S.D. Cal. July 21, 2009), ECF No. 48 (“When
the ‘494 patent application was filed, culturing three-
dimensional tissues on beads was known in the art. . . .
16                           SKINMEDICA INC   v. HISTOGEN INC
                   1. The Intrinsic Record
    The patentees refer to “beads” five times in the intrin-
sic record. All of those references appear in the written
description, and four concern the use of beads in cell
culturing. 7 In each and every one of those four references,
the patentees clearly distinguish culturing with beads
from culturing in three-dimensions.
     a. Beads “as opposed to” Three-Dimensional Cultures
     The patentees’ first use of the term “beads” comes
during their discussion of the characteristics of the cells
grown by methods known in the art. In a subsection
titled “Conditioned Cell Media” that appears in the back-
ground section of the written description, the patentees
state:
      Conditioned medium contains many of the origi-
      nal components of the medium, as well as a varie-
      ty of cellular metabolites and secreted proteins,
      including, for example, biologically active growth
      factors, inflammatory mediators and other extra-
      cellular proteins. Cell lines grown as a monolayer
      or on beads, as opposed to cells grown in three-
      dimensions, lack the cell-cell and cell-matrix in-
      teractions characteristic of whole tissue in vivo.
’494 patent col. 1 ll. 33–44 (emphasis added).

[T]he . . . inventors would have understood that beads
could be used in three-dimensional culture systems.”).
      7 The fifth reference to beads appears in a section of
the written description discussing the use of “[r]igid
spherical beads suspended in a Newtonian fluid” as part
of “formulations for dermal augmentation.” ’494 patent
col. 26 ll. 35-50. Neither of the parties contends that
reference is somehow relevant here.
SKINMEDICA INC   v. HISTOGEN INC                          17
     It is quite apparent from the use of the disjunctive
phrase “as opposed to” that the patentees considered cells
grown on beads to be different and distinct from cells
grown in what they considered to be three-dimensions.
The plain meaning of the disjunctive phrase, “as opposed
to,” is “contrary or opposite to” or “standing in opposition,
contrast, or conflict.” Oxford English Dictionary 867, vol.
X (2d ed. 1989).
    SkinMedica, however, would like to limit the import of
the disjunctive phrase by reading the passage as: “Cell
lines grown as a monolayer or ‘on [the surface of the]
beads,’ as opposed to cells grown in three-dimensions.”
Appellant’s Br. 38 (alteration in original) (emphasis
added). The addition of the phrase “the surface of the” is
necessary, according to SkinMedica, to clarify that “the
text is addressing only two-dimensional culturing” with
beads. Id. That clarification is important in SkinMedi-
ca’s view because beads can be used to culture cells in
both two- and three-dimensions, and the “specification’s
mentions of beads simply emphasize that beads can be
used for purely ‘two-dimensional’ culturing (i.e., a single
layer of cells cultured on the surface of the beads) and
when so used are not sufficient to practice the invention.”
Id.
    We do not see any reason to add additional language
to the passage—especially the phrase proposed by
SkinMedica. The plain words selected by the inventors
exhibit a clear intent to distinguish between three-
dimensional culturing and culturing in monolayer and on
beads. Nowhere do the inventors indicate otherwise. Nor
at any point—in the written description or in the entire
prosecution history—do the inventors ever mention the
“surface” of beads. And there is no indication in the
specification or prosecution history that the inventors
believed beads could be used for both two- and three-
dimensional culturing—as they used those terms in their
patents. Rather, as the patentees stated to avoid prior art
18                           SKINMEDICA INC   v. HISTOGEN INC
during prosecution, “conditioned medium obtained
from . . . cells cultured in two-dimensions . . . [is] not
identical, expressly or inherently” to “medium obtained
from the same cells cultured in three-dimensions.” J.A.
101245–46 (emphasis added).          The patentees clearly
distinguished two-dimensional and three-dimensional
cultures as distinct and different methods to culture cells
with distinct and different results.
    The plain import of the phrase “[c]ell-line grown as a
monolayer or on beads, as opposed to cells grown in three-
dimensions” is that, in context of the patents, cultures in
which cells are grown on beads are distinct and different
from cultures in which cells are grown in three-
dimensions. In light of the specification and prosecution
history, that means cells grown on beads are cells grown
in a two-dimensional culture.
      b. Beads Produce Inferior Cell Culture Medium
   The second reference to beads made by the patentees
immediately follows the first.
     Cell lines grown as a monolayer or on beads, as
     opposed to cells grown in three-dimensions, lack
     the cell-cell and cell-matrix interactions charac-
     teristic of whole tissue in vivo. Consequently,
     such cells secrete a variety of cellular metabolites
     although they do not necessarily secrete these me-
     tabolites and secreted proteins at levels that ap-
     proach      physiological   levels.    Conventional
     conditioned cell culture medium, medium cultured
     by cell-lines grown as a monolayer or on beads, is
     usually discarded or occasionally used in culture
     manipulations such as reducing cell densities.
’494 patent col. 1 ll. 33–44 (emphasis added).
    In that passage, the inventors unmistakably differen-
tiate culturing on beads from culturing in three-
dimensions by distinguishing the chemical composition of
SKINMEDICA INC   v. HISTOGEN INC                         19
the medium conditioned by cells grown by each method.
The patentees first mention why the “metabolites and
secreted proteins” in medium conditioned by cells grown
“as a monolayer or on beads” are different than those in
medium conditioned by “cells grown in three-dimensions”:
because the latter have “cell-cell and cell-matrix interac-
tions characteristic of whole tissue in vivo.” Id. They
then declare that the “conventional” medium conditioned
by cells “grown as a monolayer or on beads” is “usually
discarded.” Id. There is a logical and plain conclusion
from the passage. It is that “cell-lines grown as a mono-
layer or on beads” are distinct from three-dimensional
cultures because they produce “conventional” media with
inferior chemical compositions.
     The prosecution history supports this conclusion.
During prosecution of the ’494 patent, the patentees
juxtaposed the chemical composition of the medium
produced by three-dimensional cultures with the medium
produced by “conventional” means to demonstrate that
the medium used in their patents was part of a novel and
patentable invention. To overcome an anticipation rejec-
tion, the patentees argued that “[c]ulturing cells in three-
dimensions results in the production of a conditioned
medium having a different chemical composition than
that of cells cultured by conventional means.” J.A. 101245
(first emphasis altered) (second emphasis added). They
also explained that the two media were “not identical,
expressly or inherently” and differed, in part, by the
abundance of growth factors and other cell metabolites.
J.A. 101245–46; see also J.A. 101284-91 (a declaration
submitted by patentees’ expert during prosecution de-
scribing the differences between the media in specific
detail).
    In its briefing on appeal, SkinMedica even acknowl-
edges that “a key advantage of culturing in three dimen-
sions” is the chemical composition of the medium
conditioned by cells grown in such cultures. They agree
20                           SKINMEDICA INC   v. HISTOGEN INC
with the district court that “cells cultured in three dimen-
sions secrete growth factors and other proteins in [higher]
ratios” and that the medium conditioned by them are
accordingly “superior.” Appellant’s Br. 31 (internal quota-
tion marks omitted).
    We therefore read the second reference to beads in the
written description as another clear and unmistakable
statement that bead cultures are not the three-
dimensional cultures the inventors require in their
claimed methods. 8 The inventors argued during prosecu-
tion that the chemical composition of the medium pro-
duced by cells cultured in three-dimensions was a novel
and patentable aspect of their invention (an argument
with which SkinMedica agrees), and they clearly stated in
the written description that cultures of cells grown on
beads do not produce such novel and patentable results
(they are “usually discarded”). Such emphasis on a par-
ticular mode of operation, especially to avoid prior art, can
operate as a disclaimer of the otherwise broad scope of a
claim term. See SafeTCare Mfg., Inc. v. Tele-Made, Inc.,
497 F.3d 1262, 1270 (Fed. Cir. 2007) (finding disclaimer
when a feature was repeatedly emphasized in contradic-
tion to another and that particular “attribute of the
invention [was] important in distinguishing the invention
over the prior art”).

     8  The only reason presented by SkinMedica to read
the second reference to beads differently is because they
believe that “the advantages of three-dimensional cultur-
ing apply equally to bead-based three-dimensional cultur-
ing.”   Appellant’s Br. 31.    That belief, however, is
premised on Dr. Salomon’s opinion, Doyle, and Seldon—
evidence we find unpersuasive in light of the clear dis-
claimers in the written description. See discussion infra
Section II(B)(2).
SKINMEDICA INC   v. HISTOGEN INC                            21
              c. Beads (i.e., Two-Dimensions)
    The third reference to beads made by the patentees
occurs at the beginning of a section titled “Detailed De-
scription of the Invention.” It states that:
    The present invention relates to novel composi-
    tions comprising any conditioned defined or unde-
    fined medium, cultured using any eukaryotic cell
    type or three-dimensional tissue construct and
    methods for using the compositions. The cells are
    cultured in monolayer, beads (i.e., two-dimensions)
    or, preferably, in three-dimensions.
’494 patent col. 7 ll. 24–29 (emphasis added).
    Here, the patentees once again list cell culture meth-
ods that can be used in their invention, 9 and once again,
clearly differentiate between cells cultured using beads
and those cultured in three-dimensions. They list meth-
ods for culturing cells, include beads and three-
dimensions in that list, and use a disjunctive (“or”) as the
coordinating conjunction that reveals the relationship of
the members in the list. The disjunctive “or” plainly
designates that a series describes alternatives. See Kus-
tom Signals, Inc. v. Applied Concepts, Inc., 264 F.3d 1326,
1331 (Fed. Cir. 2001) (explaining that “or” designates
alternatives); see also Oxford English Dictionary 882, vol.
X (2nd ed. 1989) (defining “or” as a particle “coordinating
two (or more) words, phrases, or clauses, between which
there is an alternative”). In Thorner, we recognized that
the “use of two terms as alternatives” functions as a
redefintion of a term if that redefinition is “so clear that it
equates to an explicit one.” 669 F.3d at 1368. The pa-

    9   The “invention” referenced by the patentees here
is that which they originally envisioned, one not restricted
to use of conditioned medium formed by cells cultured in
three-dimensions.
22                              SKINMEDICA INC   v. HISTOGEN INC
tentees’ distinction between bead and three-dimensional
cultures is that clear. They not only repeated such a
disjunctive listing of culturing methods elsewhere in the
specification, but also expressly chose to define beads as
culturing in “two-dimensions”—a definition that places
beads in stark contrast to another method immediately
following it in the list, “three-dimensions.” And, unlike in
their first reference to beads, the inventors here do not
distinguish cells “grown” in three-dimensions from cells
“grown” “on” beads; they broadly distinguish cells “cul-
tured in” three-dimensions from cells “cultured in . . .
beads.”
     Furthermore, we agree with the district court that the
“phrase ‘beads (i.e, two-dimensions)’ explicitly define[s]
beads as a two-dimensional culture method, despite that
culturing cells in three-dimensions on beads was known
in the art.” J.A. 22. A plain reading of that phrase indi-
cates that the patentees considered beads a form of two-
dimensional culturing that was not akin to the three-
dimensional culturing used in their invention. In a speci-
fication, a patentee’s “use of ‘i.e.’ signals an intent to
define the word to which it refers.” Edwards Lifesciences
LLC v. Cook Inc., 582 F.3d 1322, 1334 (Fed. Cir. 2009); see
also Abbott Labs. v. Novopharm Ltd., 323 F.3d 1324, 1330
(Fed. Cir. 2003) (holding that a patentee “explicitly de-
fined” a term by using “i.e.” followed by an explanatory
phrase). The inventors also used the phrase “i.e.” else-
where in the specification (twelve other times in total) to
introduce an explanation or definition of a word or phrase.
See ’494 patent col. 1 l. 7; col. 7 l. 44; col. 8 l. 65; col. 10 l.
1; col. 15 l. 16; col. 18 l. 52; col. 19 l. 20; col. 20 l. 16; col.
22 l. 40; col. 26 l. 15; col. 27 l. 36; col. 30 l. 58. Based on
the plain meaning of the term “i.e.” and the patentees’
consistent use of it throughout the specification, there is
no reason to believe that the inventors did not intend for
the abbreviation to signal an intent to define the word it
followed when they stated “[t]he cells are cultured in . . .
SKINMEDICA INC   v. HISTOGEN INC                           23
beads (i.e., two-dimensions) or, preferably, in three-
dimensions.”
     SkinMedica, however, argues that the inventors did
not explicitly define beads as a two-dimensional culture
method. It asserts that our cases indicate that the “mere
use of ‘i.e.’ does not act as an express definition or limita-
tion” and “must be read in the context of the patent as a
whole.” Appellant’s Br. 41. Read in context, SkinMedica
believes that the phrase “beads (i.e., two-dimensions)”
merely represents the inventors’ recognition of the ability
to use beads in both two- and three-dimensional cultures.
To SkinMedica, the phrase simply clarifies culturing
beads in two-dimensions is different from culturing beads
in three-dimensions. Any other reading, in SkinMedica’s
view, would be inconsistent with the ordinary meaning of
three-dimensional cultures, which includes the use of
beads.
      We agree with SkinMedica that our reading of “beads
(i.e., two-dimensions)” is “inconsistent” with the ordinary
meaning of three-dimensional culturing; but that result is
inescapable in context of the entire specification. Read as
a whole, the specification provides no distinction between
culturing with beads in two- versus three-dimensions in
the specification. We do not believe that the patentees
used the phrase “beads (i.e., two-dimensions)” to signal
that beads “can” be a two-dimensional culturing method.
That is a not a natural reading. The inventors go to great
lengths (in over twenty-five columns of text in the specifi-
cation) to explain dozens upon dozens of different ways to
culture cells in three-dimensions, yet do not mention
beads once in any of them. See ’494 patent cols. 7–32.
And in the only places where the inventors mention
culturing with beads in the specification, they clearly
distinguish such culturing from growing or culturing cells
in three-dimensions. During prosecution, the patentees
disclaimed medium conditioned by “conventional means”
and taught in the written description that cells grown on
24                           SKINMEDICA INC   v. HISTOGEN INC
beads produce such “conventional” medium. Reading
“beads (i.e., two-dimensions)” as definitional comports
with the plain language of the specification as a whole
and the inventors clearly expressed intent to differentiate
the use of beads from three-dimensional culturing. While
that result might be “inconsistent” with the ordinary
meaning of three-dimensional culturing, it is one that the
intrinsic record here plainly demonstrates to be correct.
    In addition, the import we assign to the term “i.e.”
here aligns with our case law. We have held—as dis-
cussed above—that a “specification’s use of ‘i.e.’ signals an
intent to define the word to which it refers.” Edwards
Lifesciences, 582 F.3d at 1334. As SkinMedica correctly
points out, such use of “i.e.” is not absolute. It identifies
several cases in which we did not give “i.e.” its plain
meaning and import. But the reasoning of those cases
does not apply here.
     SkinMedica first points to Toshiba Corp. v. Imation
Corp., 681 F.3d 1358 (Fed. Cir. 2012). In that case, which
concerned DVD technology, we were unconvinced that a
patentee’s use of the term “i.e.” clearly expressed an
intent to define a term and affect a prosecution history
disclaimer. A patentee had responded to an office action
and when describing a figure had stated: “As illustrated
in FIG. 2 . . . [disc number and side] information must be
provided on each side of the disc—i.e., each recording
plane—in order for the disc side identifier 3 to serve its
purpose of identifying which side is being record-
ed/reproduced.” Id. at 1370 (emphasis added). We rea-
soned that the patentee’s statement did not limit the
claim term “recording plane” to a “disc side.” Id. That
was because the patentee was “merely explaining that, in
the example in figure 2, a side of the disc constitutes a
recording plane”—which did not mean “a recording plane
is to be equated with a disc side in all instances.” Id.
SKINMEDICA INC   v. HISTOGEN INC                         25
     In contrast, the patentees here did not use the term
“i.e.” to discuss how an aspect of one particular embodi-
ment of their invention depicted in a figure satisfied a
claim limitation. They were providing a list of different
alternative methods by which cells could be cultured, and
they used the term “i.e.” to describe how one of those
methods did not satisfy a claim limitation. And, unlike in
Toshiba, the definition that follows “i.e.” here directly
contrasts the term it is defining with another listed alter-
native (two- versus three-dimensions).
     Moreover, we are not assigning definitional intent to
“i.e.” in order to directly assign meaning to a claim term.
“Two-dimensions” appears nowhere in the allowed claims.
And we are not proposing that the definition of “two-
dimensions” (the term that follows “i.e.” here) be restrict-
ed to or defined as only “beads” (the word that precedes
“i.e.”). We do the opposite: we read “beads” (the word that
precedes “i.e.”) to be defined by “two-dimensions” (the
term that follows “i.e.”). That is a natural interpretation
of “i.e.”
    The other cases SkinMedica relies on are similarly
distinguishable. In Dealertrack, Inc. v. Huber, we refused
to read “i.e.” as showing intent to define because doing so
would exclude multiple embodiments clearly discussed
throughout the claims. 674 F.3d 1315, 1326 (Fed. Cir.
2012) (“The only way that the “i.e.” in this patent could be
read definitionally is if it excluded from the claim scope
the embodiments discussed throughout the claim where
only a single funding source is selected. This is rarely, if
ever, correct.” (internal quotation marks omitted)). Here,
the use of beads is mentioned nowhere in the claims. And
in Pfizer, Inc. v. Teva Pharmaceuticals, USA, Inc., we
refused to limit a disputed claim term to a narrow defini-
tion introduced by “i.e.” in a patent specification because
the specification expressly included a broader definition of
the term in a different section that the “patentee clearly
intended . . . to address the meaning of the same term.”
26                             SKINMEDICA INC   v. HISTOGEN INC
429 F.3d 1364, 1373 (Fed. Cir. 2005). Here, there is no
other section of the specification in which the patentees
have defined “beads” as being broader than “two-
dimensions.”
    Thus, we give the term “i.e.” here its plain meaning—
that it “signals an intent to define the word to which it
refers.” Edwards Lifesciences, 582 F.3d at 1334. That
reading comports with the inventors’ other uses of the
abbreviation in the specification and with each and every
other reference to culturing with beads. We therefore
conclude that the patentees expressly defined culturing in
beads as a two-dimensional culturing method. Because it
is defined as two-dimensional, culturing in beads cannot
be the three-dimensional culturing required by the claims.
     d. Cells Cultured in Beads or in Three-Dimensions
    The fourth reference to beads made by the patentees
occurs in the same section as the third, “Detailed Descrip-
tion of the Invention,” but under the subheading, “The
Cell Cultures.” There the patentees state:
     The cells may be cultured in any manner known
     in the art including in monolayer, beads or in
     three-dimensions and by any means . . . .
’494 patent col. 9 ll. 66–col. 10 l. 1.
    Once again, the patentees list cell culture methods
that can be used in their originally-claimed invention, and
again use the disjunctive “or” to differentiate between
cells cultured using beads and those cultured in three-
dimensions. As we concluded from such evidence previ-
ously, the use of the disjunctive in context of the entire
specification and prosecution history in evidence plainly
evinces an intent of the inventors to classify culturing
with beads as a non-three-dimensional cell culturing
method.
SKINMEDICA INC   v. HISTOGEN INC                          27
         e. Conclusion From the Intrinsic Record
     In sum, although the inventors never explicitly rede-
fined three-dimensional cultures to exclude the use of
beads, their implicit disclaimer of culturing with beads
here was even “so clear that it equates to an explicit one.”
Thorner, 669 F.3d at 1368. Without fail, each time the
inventors referenced culturing with beads in the specifica-
tion, they unambiguously distinguished that culture
method from culturing in three-dimensions. Every time
they included beads in a list of methods for culturing cells,
the inventors indicated that bead cultures were an alter-
native to three-dimensional cultures (by using the dis-
junctive “or”) or distinct from three-dimensional cultures
(by using the disjunctive phrase “as opposed to”). The
inventors also discussed beads in order to explain how the
conditioned medium created from cells grown in three-
dimensions was chemically distinct and superior to the
conventional conditioned medium created from cells
grown on beads—a point of novelty the patentees relied
upon during prosecution to avoid anticipatory prior art.
And the patentees expressly defined culturing in beads as
culturing cells in “two-dimensions,” which excludes that
method from the three-dimensional culturing required by
the claims. The patentees repeated and definitive state-
ments clearly indicate that they disclaimed the ordinary
meaning of “culturing . . . cells in three-dimensions.” See,
e.g., Computer Docking Station Corp., 519 F.3d at 1374
(citing Watts, 232 F.3d at 882) (“[R]epeated and definitive
remarks in the written description could restrict a claim
limitation to a particular structure.”); Innova/Pure Water,
Inc. v. Safari Water Filtration Sys., Inc., 381 F.3d 1111,
1117 (Fed. Cir. 2004) (“All that is required is that the
patent applicant set out the different meaning in the
specification in a manner sufficient to give one of ordinary
skill in the art notice of the change from ordinary mean-
ing. Because the inquiry into the meaning of claim terms
is an objective one, a patentee who notifies the public that
28                           SKINMEDICA INC   v. HISTOGEN INC
claim terms are to be limited beyond their ordinary mean-
ing to one of skill in the art will be bound by that notifica-
tion, even where it may have been unintended.”); In re
Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994) (“Where an
inventor chooses to be his own lexicographer and to give
terms uncommon meanings, he must set out his uncom-
mon definition in some manner within the patent disclo-
sure so as to give one of ordinary skill in the art notice of
the change.” (internal quotation marks omitted)); see also
Philips, 415 F.3d at 1312 (“reaffirm[ing] the “basic princi-
ples of claim construction outlined” in several cases,
including Innova/Pure Water).
    Our holding comports with our cases in which we
have found similar implicit disclaimers. For example, in
Bell Atlantic, a patent holder argued for a plain meaning
of the word “mode,” which would “encompass[] different
methods of altering . . . transmission rates.” 262 F.3d at
1269 (emphasis added). We held, however, that the
patentees redefined the broad term “mode” and excluded
“rates” by “implication.” Id. at 1273. Even though the
patentees did not provide an “explicit definition[]” of
“mode” that excluded “rates,” we explained that they used
“the claim term ‘throughout the entire patent specifica-
tion, in a manner consistent with only a single meaning,’
one that was a ‘different and distinct concept[]’ than
‘rate.’” Id. at 1271 (quoting SciMed, 242 F.3d at 1344 and
Vitronics, 90 F.3d at 1582). As we found, the patentees
had consistently described transmission “mode” and
transmission “rate” as possessing different characteristics
and had distinguished between them repeatedly by ex-
plaining that either transmission “rate or mode” could be
independently altered. Id. at 1271–73. Thus, because
there was no “[v]aried use of [the] disputed term,” we held
that the repeated explicit differentiation between the
terms constituted a disclaimer. Id. at 1273 (quoting and
distinguishing Johnson Worldwide Assocs. v. Zebco Corp.,
SKINMEDICA INC   v. HISTOGEN INC                         29
175 F.3d 985, 992 (Fed. Cir. 1999)) (internal quotation
marks omitted).
    As in Bell Atlantic, the patentees in this case have,
without express redefinition, disclaimed a potential
embodiment from the ordinary scope of a claim term
through clear, repeated, and consistent statements in the
specification that describe how culturing with beads is
different and distinct from culturing in three-dimensions.
Like the Bell Atlantic inventors, the patentees here
repeatedly used the disjunctive “or” in the specification to
carve out a disclaimed embodiment (“beads”) from the
ordinary meaning of a broad term (“culturing in three-
dimensions”). And like the Bell Atlantic inventors, they
also describe how the characteristics of the disclaimed
embodiment were different from those of the claimed
feature (that culturing on beads produces chemically
different and inferior conditioned medium).
    Furthermore, the patentees here have done even more
than the inventors in Bell Atlantic to distinguish their
disclaimed embodiment from the ordinary scope of a claim
term. In addition to the disjunctive “or,” they used the
unambiguous disjunctive phrase “as opposed to” when
differentiating between bead and three-dimensional
cultures. They also expressly defined culturing with
beads as culturing cells in “two-dimensions”—a definition
that plainly excludes culturing with beads from three-
dimensional cultures.
    Thus, the patentees here have affected an even clear-
er implicit redefinition of a term than the inventors in
Bell Atlantic. We stated in Thorner that an “‘implied
redefinition must be so clear that it equates to an explicit
one.” 669 F.3d at 1368. The implicit redefinition here
satisfies even that hurdle. We are left with “no question
that the . . . patent specification uses the terms [“cultur-
ing with beads”] and [“culturing in three dimensions”] to
30                            SKINMEDICA INC   v. HISTOGEN INC
refer to two different and distinct concepts.” Bell Atlantic,
262 F.3d at 1272.
    We also reached a similar result in SafeTCare. 497
F.3d 1262. In that case, we held that an inventor of an
adjustable hospital bed disclaimed the full scope of the
phrase, “pushing force on said plurality of deck sections.”
497 F.3d at 1270 (emphasis added). The patent holder
had argued for a broad construction to cover any bed that
adjusted through a directional force applied to a “deck
section.” Id. at 1268-69. However, because the patentee
“repeatedly emphasize[d]” in the written description that
“the patented invention applies a pushing force . . .
against a lift dog [a support member],” not the deck sec-
tion, we limited the scope of the asserted claim to a pull-
ing force exerted on a lift dog. Id. at 1270 (emphasis
added). We felt additional comfort in reaching that result
because the patentee had distinguished “conventional”
adjustable bed frames in the written description by ex-
plaining: “[E]ach of the shafts . . . of bed lift motors [in the
invention] . . . apply pushing forces against their respec-
tive lift dogs . . . . This is in contrast to conventional bed
frames in which lift motors exert a pulling force against
the frame.” Id. (emphasis added).
    Like the SafeTCare inventors, the inventors here af-
fected a disclaimer by repeatedly emphasizing in the
written description that culturing with beads is a method
of culturing distinct from three-dimensional culturing—a
point we have discussed extensively above. As we were in
SafeTCare, we are reassured here of that disclaimer
because the inventors distinguished their invention over
the prior art by clearly differentiating between the medi-
um produced by culturing with conventional means and
the medium produced by culturing in three-dimensions.
They did that not only in the specification—as the patent-
ees in SafeTCare did—but also during prosecution to
overcome anticipation and obviousness rejections.
SKINMEDICA INC   v. HISTOGEN INC                           31
    It is therefore clear from the intrinsic record that, alt-
hough the inventors never explicitly redefined “cultur-
ing . . . cells in three-dimensions” to exclude the use
beads, they affected a clear implicit disclaimer of cultur-
ing with beads from the scope of their claimed invention.
      2. Further Arguments Raised by SkinMedica
    SkinMedica asserts four additional reasons not to find
a disclaimer of beads. First, it asserts that the inventors
“expressly defin[ed] the term ‘three-dimensional frame-
work,’” which is “used in ‘culturing . . . in three-
dimensions,” to be “broad enough to include a three-
dimensional structure formed using beads.” Appellant’s
Br. 26. Second, it stresses that the specification incorpo-
rated and referenced Doyle, “which expressly discusses
the use of beads to culture cells in three dimensions.”
Appellant’s Br. 26. Third, it claims that Seldon “expressly
acknowledges that three-dimensional culturing with
beads provides the same inherent advantages—i.e.,
mimicking an in vivo environment—as other three dimen-
sional culturing.” Reply Br. 30. And, fourth, it asserts
that Dr. Salomon “testified without contradiction that
skilled practitioners understood that three-dimensional
culturing could be performed using beads” and that
“culturing using beads in three-dimensions produces the
same benefits over two-dimensional culturing that the
patents describe.” Appellant’s Br. 33. We take each
argument in turn.
            a. Three-Dimensional Framework
    SkinMedica’s first argument, that the patentees de-
fined “three-dimensional framework” broadly enough to
encompass the use of beads, is straightforward, but
unhelpful. SkinMedica’s argument is simple: “The inven-
tors knew that beads could be used in three-dimensional
culturing. Their definition of a three-dimensional frame-
work broadly encompassed ‘any material and/or shape.’
Beads are of any material or shape. Therefore, the inven-
32                           SKINMEDICA INC   v. HISTOGEN INC
tors intended that beads could be used in three-
dimensional culturing.” See Appellant’s Br. 25-26.
    SkinMedica’s theory misses the mark. It focuses on
the three-dimensional framework being “any material
and/or shape” and ignores that the inventors expressly
restricted the definition of a “three-dimensional frame-
work” to a “three-dimensional scaffold.” The written
description defines three-dimensional framework as:
     [A] three-dimensional scaffold composed of any
     material and/or shape that (a) allows cells to at-
     tach to it (or can be modified to allow cells to at-
     tach to it); and (b) allows cells to grow in more
     than one layer.
’494 patent col. 6 ll. 43–47 (emphasis added).
     Beads obviously are “any material and/or shape,” but
that does not mean that they are also a “three-
dimensional scaffold.” Without explaining how beads are
a “three-dimensional scaffold,” SkinMedica’s reliance on
the definition of “three-dimensional framework” is incom-
plete. If we were to simply ignore the scaffold restriction,
any structure of any material and/or shape that allows for
cell attachment and for cell growth in more than one layer
would be swept into the definition. That could not have
been the inventors’ understanding. For example, the
patentees discuss in the written description that some
“monolayer cultures . . . could grow to more than ten cells
deep.” Id. at col. 2 ll. 40–41. Without the scaffold re-
striction, the structure used to grow those types of mono-
layer cultures would meet the definition of a three-
dimensional framework (cells attach and grow in more
than one layer). See id. at col. 2 ll. 37–42. According to
SkinMedica’s theory, those cultures would therefore be
three-dimensional. But no one contends that a monolayer
culture should qualify as three-dimensional.
SKINMEDICA INC   v. HISTOGEN INC                       33
    Because it is unclear how beads could be a three-
dimensional scaffold, we are unconvinced by SkinMedica’s
argument that the inventors broadly defined “three-
dimensional framework” to indicate their intent to include
culturing with beads as a three-dimensional culturing
method.
                          b. Doyle
    According to SkinMedica, the inventors also could not
have disclaimed the use of beads because they stated in
the written description that “cells may be cultured in any
manner known in the art” and incorporated Doyle into the
specification, 10 which “expressly discusses the use of
beads to culture cells in three dimensions.” Appellant’s
Br. 26–30. In other words, according to SkinMedica, the
inventors stated that any three-dimensional culturing
method would work with their invention and listed cultur-
ing with beads as such a three-dimensional culturing
method by incorporating Doyle. That argument fails for
several reasons.
    First, SkinMedica reads the phrase “cells may be cul-
tured in any manner known in the art” out of context.
The sentence from which SkinMedica plucked that phrase
states that “[t]he cells may be cultured in any manner
known in the art including in monolayer, beads or in
three-dimensions and by any means.” ’494 patent col. 9 ll.
66–col. 10 l. 2. That statement described the scope of the
invention covered by the original proposed claims, which
were written to include any culture method. Those claims
were rejected. The patentees restricted them to a single
method of culturing—three-dimensional culturing—in
order to avoid prior art. Therefore, while the original
proposed invention could have used cells cultured in any

   10   The patentees stated in the written description
that Doyle was “incorporated by reference . . . in [its]
entirety.” ’494 patent col. 7 ll. 51-52.
34                           SKINMEDICA INC   v. HISTOGEN INC
manner known in the art, the claimed invention is limited
to cells cultured only in three-dimensions. Accordingly, it
is impossible to know whether any discussion of beads in
Doyle was intended to be an example of the culturing
methods covered by the broad original claims (which
covered two- and three-dimensional cultures) or the
narrow final claims (which was restricted to three-
dimensional cultures).
    Second, Doyle does not “expressly discuss[] the use of
beads to culture cells in three dimensions,” as claimed by
SkinMedica.     Appellant’s Br. 26 (emphasis added).
SkinMedica identifies one paragraph in that voluminous
reference to support its assertion.
     A common occurrence in microcarrier culture is
     the formation of large microcarrier aggregates in
     which the microcarriers are joined by cellular
     bridges. Microcarrier aggregates made up of as
     many as 10 or more microcarriers are not uncom-
     mon. Microcarrier bridging occurs mainly during
     the growth phase of the culture, with little addi-
     tional bridging occurring after cell growth has
     ceased (Borys & Papoutsakis 1992). This study
     also showed that there is an inverse relationship
     between the rate of microcarrier bridging and agi-
     tation intensity. Thus, it may be of interest to op-
     erate at higher agitation intensities during the
     growth phase of the culture to minimize microcar-
     rier aggregation, and to slow down the agitation
     as cell growth slows to minimize cell detachment
     during the later stages of the culture. In certain
     cases, such as to promote bead-to-bead transfer of
     cells to bare microcarriers, low agitation rates
     would be desirable during the culture growth
     phase.
J.A. 100974. Nowhere does that portion of Doyle “ex-
pressly discuss” culturing with beads in “three dimen-
SKINMEDICA INC   v. HISTOGEN INC                           35
sions.” The phrase “three dimensions” does not even
appear in the passage. 11
     Third, even if we assume that the passage from Doyle
discusses what one of ordinary skill in the art might
understand to be three-dimensional culturing with beads,
the inventors’ general citation of Doyle does not indicate
any reliance on that particular passage to define “cultur-
ing in three-dimensions” and to abandon the otherwise
clear disclaimer of beads in the specification. When
discussing cell culture methods, the patentees make the
following reference to Doyle:
    The cells may be cultured in any manner known
    in the art including in monolayer, beads or in
    three-dimensions and by any means . . . . Meth-
    ods of cell and tissue culturing are well known in
    the art, and are described, for example, in [Doyle],
    supra; Freshney (1987), Culture of Animal Cells:
    A Manual of Basic Techniques, infra.
’494 patent col. 10 ll. 2–6.
    It is clear from that passage that the inventors did not
refer to Doyle in order to define what they meant by
“three-dimensional culturing” in their patent. They did
not indicate their reference to Doyle was for that purpose;
nor did they even refer with any detailed particularity to
the passages in Doyle that, according to SkinMedica, may

    11  Histogen’s counsel stated at oral argument that
Doyle does, in fact, reference culturing cells in three-
dimensions. He asserted, however, that the reference is
in the index and points readers to sections of the book
that do not discuss culturing cells with beads. Oral
Argument available at http://www.cafc.uscourts.gov/oral-
argument-recordings/2012-1560/all 28:51-29:08. But the
index of Doyle is not in the record. We therefore give no
weight to counsel’s statements.
36                           SKINMEDICA INC   v. HISTOGEN INC
have discussed three-dimensional culturing with beads.
When the inventors wanted to use Doyle to explain the
potential scope of terms they used, they did so specifically.
See ’494 patent col. 20 ll. 21–26 (“[I]t may be necessary to
further process the resulting supernatant. Such pro-
cessing may include . . . the methods described in [Doyle],
supra, pp 29 D:0.1-29D:0.4.”). But when describing cell
culturing methods, the inventors generally referred to
Doyle and another reference to support their assertion
that many methods of cell culturing were well known in
the art. 12 We see no reason for such a non-specific refer-
ence to trump the clear disclaimer in the specification of
culturing with beads. See Advanced Display Sys., Inc. v.
Kent State Univ., 212 F.3d 1272, 1282 (Fed. Cir. 2000)
(discussing how a host document must “identify with
detailed particularity what specific material it incorpo-
rates” to properly incorporate such material by refer-
ence). 13

     12 That one of those methods known in the art could
have been three-dimensional culturing with beads is of no
import here. We assumed the patentees already knew
that fact when we found a clear disclaimer in the specifi-
cation.
     13 The district court relied on our decision in Ad-
vanced Display Systems to find that Doyle was not part of
the intrinsic record because it was not incorporated with
“detailed particularity.” J.A. 22. SkinMedica argues that
was error. Appellant’s Br. 27-30.
    It is unnecessary for us to decide whether Doyle was
incorporated into the specification with adequate particu-
larity to become part of the intrinsic record. We conclude
that the inventors’ reference to Doyle does not avoid a
clear disclaimer of beads because it was not relied on by
the inventors for an explicit or implicit definition of “cul-
turing in three-dimensions” that included beads. The
SKINMEDICA INC   v. HISTOGEN INC                          37
    Therefore, because Doyle does not define culturing
with beads as “three-dimensional” and the inventors did
not refer to Doyle for the purpose of defining what they
meant by three-dimensional culturing, it does not inform
our analysis in this case.
                          c. Seldon
    SkinMedica argues that Seldon, an international pa-
tent application listed on the face of only the ’746 patent,
“expressly acknowledges that three-dimensional culturing
with beads provides the same inherent advantages—i.e.,
mimicking an in vivo environment—as other three-
dimensional culturing.”      Reply Br. 30.      Specifically,
SkinMedica asserts Seldon teaches that:
    Cells cultured in three dimensions using beads
    (i.e., cells that “formed attachments to both the
    bead surface and other cells” and “grew as bridges
    between . . . beads”)—as opposed to “cells attached
    as monolayers” on “the bead’s surface”—“were
    more reminiscent of that expected in vivo.”
Reply Br. 30 (quoting Seldon).
    At oral argument though, Histogen contended that
SkinMedica’s reliance on Seldon was improper because
SkinMedica raised Seldon for the first time in its reply
brief on appeal.        Oral Argument available at
http://www.cafc.uscourts.gov/oral-argument-
recordings/2012-1560/all 26:36-50. We agree.

Advanced Display Systems detailed particularity re-
quirement may, however, be a helpful framework for
determining whether a patentee has clearly intended to
rely on a portion of an incorporated document to effect or
avoid a disclaimer. Cf. Helmsderfer, 527 F.3d at 1381.
(discussing how patentees must “clearly express an in-
tent” to disclaim the ordinary meaning of the words they
use in a claim).
38                          SKINMEDICA INC   v. HISTOGEN INC
    Clearly, Seldon is not part of the intrinsic record we
consider for claim construction. It was listed on the face
of the ’746 patent as a reference cited during prosecution.
But Seldon is not in evidence. It is not in the record on
appeal and played no part in the proceedings below.
Indeed, when referring to Seldon in its reply brief,
SkinMedica could only cite to a publically available copy
of the reference, not the record. See Reply Br. 30. Thus,
Seldon is, at best, extrinsic evidence belatedly cited by
SkinMedica in its reply brief.
    Even as extrinsic evidence, though, we decline to con-
sider Seldon. Seldon is a technically-dense patent appli-
cation. It has a fifty-one page written description and
twenty-four claims directed at “hepatocytes in three
dimensional support systems.” Seldon at 1. SkinMedica
crafts a nuanced theory about cell culturing with beads by
simply quoting a few short disjointed phrases from the
lengthy reference. Yet it has provided no context for those
quotes or any reasoning for its conclusions past the quotes
themselves. And because it waited until its reply brief on
appeal to first mention Seldon, neither the district court
nor Histogen have had an opportunity to fully discuss the
importance of the disclosures in the reference.
“[E]xtrinsic evidence can shed useful light on the relevant
art” during claim construction. Phillips, 415 F.3d 1317.
However, SkinMedica’s tardiness has so shaded what
light Seldon may have shed on the relevant art here that
we cannot fairly consider it. We simply cannot decipher
the import of the reference without adequate context.
SkinMedica has waived its ability to rely on the reference
for claim construction purposes on appeal. See Conoco
Inc. v. Energy & Envtl. Int’l, L.C., 460 F.3d 1349, 1358-59
(Fed. Cir. 2006) (“[A] party may not introduce new claim
construction arguments on appeal or alter the scope of the
claim construction positions it took below.”); Harris Corp.
v. Ericsson Inc., 417 F.3d 1241, 1251 (Fed. Cir. 2005) (“An
SKINMEDICA INC   v. HISTOGEN INC                           39
appellate court retains case-by-case discretion over
whether to apply waiver.”).
                 d. Dr. Salomon’s Testimony
    The district court afforded Dr. Salomon’s testimony
“no weight” after finding that it was “inconsistent with
the intrinsic patent record.” J.A. 23 n.5. SkinMedica,
however, believes that Dr. Salomon’s testimony is rele-
vant because of two points to which he testified “without
contradiction”: (1) “skilled practitioners understood that
three-dimensional culturing could be performed using
beads” and (2) “culturing using beads in three-dimensions
produces the same benefits over two-dimensional cultur-
ing that the patents describe—i.e., ‘exhibit[ing] cell-to-cell
and cell-matrix interaction characteristic of whole tissue
in vivo.’” Appellant’s Br. 33 (quoting J.A. 101615); see
also Reply Br. 31. We agree with the district court.
    The first point from Dr. Salomon’s testimony high-
lighted by SkinMedica—that culturing with beads in
three-dimensions was known in the art—simply confirms
an assumption we already made during our analysis of
the intrinsic record. When we determined that the inven-
tors disclaimed culturing with beads, we assumed that
culturing with beads in three-dimensions was known in
the art. Dr. Salomon’s validation of our assumption is
irrelevant.
    Dr. Salomon’s discussion of the benefits of culturing
with beads is equally unhelpful here because it is conclu-
sory and incomplete. SkinMedica asserts that Dr. Salo-
mon testified that three-dimensional bead cultures can
produce the same benefits of three-dimensional culturing
described by the patents. To support that assertion, it
points us to a single passage from Dr. Salomon’s testimo-
ny. Appellant’s Br. 33–34 (arguing that Dr. Salomon’s
testimony is extrinsic evidence to show that “ordinary
meaning applies”); see also Reply Br. 31.
40                           SKINMEDICA INC   v. HISTOGEN INC
     Q. In your opinion, Dr. Salomon, do fibroblasts
     that are cultured in three-dimensions on micro-
     carriers or beads, do they exhibit cell-to-cell and
     cell-matrix interactions characteristic of whole
     tissue in vivo.
     A. Yes.
     Q. And have you seen that?
     ...
     A. Yes.
     Q. And is that—is your opinion about that func-
     tional definition applied to three-dimensional use
     of beads consistent with what we saw in the Doyle
     reference . . . ?
     A. Yes.
J.A. 101614–15 (emphasis added).
    While it does appear from that passage that Dr. Sa-
lomon agreed that bead cultures can provide benefits
similar to three-dimensional cultures, Dr. Salomon’s
testimony consists exclusively of three conclusory affirma-
tions elicited by leading questions posed by SkinMedica’s
counsel. His testimony lacks any convincing detail ex-
plaining why or how cells in bead cultures exhibit the
characteristics of whole tissue in vivo he claims they
possess. Indeed, the patentees explained at length how
the three-dimensional cultures used in their inventions
have specific and valuable characteristics of tissue in vivo.
For example, they described how their three-dimensional
cultures can provide for: sustained long-term proliferation
of cells; stimulation of cell growth and proliferation;
provision of a greater surface area for protein attachment;
regulation of cell differentiation; adequate spatial distri-
bution of cellular elements; establishment of localized
microenvironments; and greater potential for movement
of migratory cells. See ’494 patent col. 1 ll. 37–40; col. 11
SKINMEDICA INC   v. HISTOGEN INC                        41
ll. 20–53; col. 14 ll. 20–36; J.A. 101245. But Dr. Salomon
does not explain how culturing with beads provides for
any of those important characteristics. He even fails to
explain how culturing with beads provides for the sus-
tained long-term proliferation of cells, the key character-
istic of three-dimensional cultures that the patentees
identified as distinguishing their invention from prior
art—in both the specification and prosecution history.
See discussion supra, Section I(A). Dr. Salomon’s one-
word confirmations of directed conclusions in leading
questions simply lack any helpful or informative detail
regarding the benefits of culturing with beads.
     Moreover, while SkinMedica believes Dr. Salomon’s
statements are “perfectly consistent with the intrinsic
record,” Appellant’s Br. 34, they are not. The patentees
plainly stated in the written description that: “Cell lines
grown as a monolayer or on beads, as opposed to cells
grown in three-dimensions, lack the cell-cell and cell-
matrix interactions characteristic of whole tissue in
vivo.” ’494 patent col. 1 ll. 37–40 (emphases added). Dr.
Salomon, though, testified that “fibroblasts culture[ed] in
three-dimensions on microcarriers or beads, . . . exhibit
cell-to-cell and cell-matrix interactions characteristic of
whole tissue in vivo.” J.A. 101614–15 (emphasis added).
As the district court found, Dr. Salomon’s testimony is
“inconsistent with the intrinsic patent record.” J.A. 23
n.5.
    In whole, Dr. Salomon’s opinions are unhelpful to our
analysis here. They are conclusory and incomplete; they
lack any substantive explanation tied to the intrinsic
record; and they appear to conflict with the plain lan-
guage of the written description. Without a more detailed
explanation of how Dr. Salomon formed his conclusions
and why they conflict with the plain language of the
specification, we must agree with the district court that
42                            SKINMEDICA INC   v. HISTOGEN INC
Dr. Salomon’s testimony deserves no weight. 14 See Phil-
lips, 415 F.3d at 1318 (discussing how expert testimony
“can suffer from bias that is not present in intrinsic
evidence,” is “not useful” if based on “conclusory, unsup-
ported assertions,” and should be “discount[ed]” if “clearly
at odds with . . . the written record of the patent”); see also
Bell Atl. Network Servs., 262 F.3d at 1269 (“[Extrinsic
evidence] may not be used to vary, contradict, expand, or
limit the claim language from how it is defined, even by
implication, in the specification or file history.”); Vitron-
ics, 90 F.3d at 1584 (“[W]here the patent documents are
unambiguous, expert testimony regarding the meaning of
a claim is entitled to no weight.”).
                      III. CONCLUSION
    Based on the clear language of the specification and
the statements made by the patentees during prosecution,

     14  Dr. Salomon also discussed his view of the inven-
tors’ statements differentiating culturing with beads from
three-dimensional cultures. He appears to have conclud-
ed that they were simply instructions to culture with
beads in three-, not two-, dimensions. See J.A. 101613
(Dr. Salomon testifying that the inventors referenced
beads to merely teach that if “you should grow [cells]
using beads[,] . . . you needed to set up your conditions in
the bead cultures to favor the formation of . . . three-
dimensional cultures. If you didn’t, you were actually
going to end up growing in 2-D.”). But that conclusion
suffers the same problem as the points Dr. Salomon
makes in the parts of his testimony relied upon by
SkinMedica: he never fully explained why and how he
arrived at his opinion. Nor did he explain how his conclu-
sions accounted for the fact that the written description
was originally drafted to support the use of both two- and
three- dimensional cultures to condition the medium used
in the patentees’ inventions.
SKINMEDICA INC   v. HISTOGEN INC                           43
we hold that the inventors of the ’494 and ’796 patents
disclaimed beads as a method to culture the cells that
condition the medium used in their claimed inventions.
We accordingly affirm the district court’s construction of
the term “culturing . . . cells in three-dimensions,” com-
mon to all the assert claims, as “growing . . . cells in three
dimensions (excluding growing in monolayers or on mi-
crocarrier beads).” Because the construction of that
phrase is the only issue raised by SkinMedica on appeal,
we affirm the district court’s grant of summary judgment
of noninfringement to Histogen.
                        AFFIRMED
  United States Court of Appeals
      for the Federal Circuit
                 ______________________

                 SKINMEDICA, INC.,
                  Plaintiff-Appellant,

                            v.

 HISTOGEN INC., HISTOGEN AESTHETICS LLC,
         AND GAIL K. NAUGHTON,
             Defendants-Appellees.
            ______________________

                       2012-1560
                 ______________________

   Appeal from the United States District Court for the
Southern District of California in No. 09-CV-0122, Judge
Janis L. Sammartino.
                ______________________

RADER, Chief Judge, dissenting.
    There is a “heavy presumption” in favor of the ordi-
nary meaning of claim language. Bell Atl. Network Servs.,
Inc. v. Covad Commc’ns Grp., Inc., 262 F.3d 1258, 1268
(Fed. Cir. 2001). To overcome this presumption, the
patentee must “clearly set forth” and “clearly redefine” a
claim term away from its ordinary meaning. Id. The
disavowal must be “unmistakable” and “unambiguous.”
Dealertrack, Inc. v. Huber, 674 F.3d 1315, 1322 (Fed. Cir.
2013). This standard is “exacting.” Thorner v. Sony
Computer Entm’t Am. LLC, 669 F.3d 1362, 1366 (Fed. Cir.
2012). In my judgment, the patentees did not disavow the
ordinary meaning of “culturing . . . cells in three-
2                           SKINMEDICA INC   v. HISTOGEN INC

dimensions” to exclude the use of beads.       Therefore, I
respectfully dissent.
                             I.
    Cells can be cultured on microcarrier beads in two-
dimensions or in three-dimensions. Appellee’s Br. 7–8.
When cultured on beads in two-dimensions, the cells grow
on the surface of each bead as single layer—or monolay-
er—of cells. J.A. 100972.

Appellant’s Br. 7.
    When cultured on beads in three-dimensions, the cells
growing on the surface of one bead are allowed to connect
with cells growing on the surface of another bead. This
forms an interconnected structure having “cellular bridg-
es” comprised of multiple layers of cells. J.A. 100974.

Appellant’s Br. 7.
   The district court found, and the parties do not dis-
pute, that the ordinary meaning of “culturing . . . cells in
SKINMEDICA INC   v. HISTOGEN INC                          3

three-dimensions” includes the use of beads. J.A. 21. The
district court held, however, that the patentees disavowed
the ordinary meaning to exclude the use of beads, based
on four references to beads in the patent specification. As
described below, these references do not amount to an
unmistakable and unambiguous disavowal.
                             II.
    The first reference to beads appears in the “Back-
ground of the Invention” section of the specification:
   Conditioned medium contains many of the origi-
   nal components of the medium, as well as a varie-
   ty of cellular metabolites and secreted proteins,
   including, for example, biologically active growth
   factors, inflammatory mediators and other extra-
   cellular proteins. Cell lines grown as a monolayer
   or on beads, as opposed to cells grown in three-
   dimensions, lack the cell-cell and cell-matrix in-
   teractions characteristic of whole tissue in vivo.
’494 patent col. 1 ll. 33–44 (emphasis added). In my view,
the patentees used the disjunctive phrase “as opposed to”
to distinguish “cells grown in three-dimensions” from cells
grown “on beads” in two-dimensions.
    The phrase “[c]ell lines grown as a monolayer or on
beads” can reasonably be interpreted to mean cells cul-
tured as a monolayer, or, as a monolayer on beads as
described at the outset of this opinion. The parties do not
dispute that cells cultured as a monolayer are inherently
two-dimensional. See ’494 patent col. 1 ll. 5–8.
    Furthermore, the specification teaches that cells cul-
tured “as a monolayer or on beads” are inferior to cells
cultured in three-dimensions because they “lack the cell-
cell and cell-matrix interactions characteristic of whole
tissue in vivo.” ’494 patent col. 1 ll. 39–40. Uncontrovert-
ed extrinsic evidence shows that cells cultured in three-
dimensions with beads have the same beneficial cell-cell
4                           SKINMEDICA INC   v. HISTOGEN INC

and cell-matrix interactions as cells cultured in three-
dimensions without beads:
    Q. In your opinion, Dr. Salomon, do fibroblasts
    that are cultured in three-dimensions on micro-
    carriers or beads, do they exhibit cell-to-cell and
    cell-matrix interactions characteristic of whole
    tissue in vivo.
    A. Yes.
    Q. And have you seen that?
    ...
    A. Yes.
    Q. And is that—is your opinion about that func-
    tional definition applied to three-dimensional use
    of beads consistent with what we saw in the Doyle
    reference, the . . . Qiu reference and the other ar-
    ticle?
    A. Yes.
J.A. 101614–15.
    Dr. Salomon’s testimony seems to confirm that the pa-
tentees’ reference to cells grown “on beads” is in the
context of two-dimensional cultures. Otherwise, it would
not have made sense for the patentees to distinguish cells
grown “on beads” from “cells grown in three-dimensions”
because they have the same cell-cell and cell-matrix
interactions characteristic of whole tissue in vivo.
    The court recognizes this, but refuses to give Dr. Sa-
lomon’s testimony any weight because it “consists exclu-
sively of three conclusory affirmations elicited by leading
questions posed by SkinMedica’s counsel. His testimony
lacks any convincing detail explaining why or how cells in
bead cultures exhibit the characteristics of whole tissue in
vivo he claims they possess.” Majority Op. at 39–40. To
my eyes, Dr. Salomon’s testimony, when viewed as a
whole, deserves great weight and respect.
SKINMEDICA INC   v. HISTOGEN INC                               5

    Dr. Salomon testified extensively as to the nature of
cells cultured on beads in both two-dimensions and three-
dimensions. He discussed growth factors, cell prolifera-
tion, adhesion molecules, extracellular matrices, and gene
expression, and “show[ed] you how you can do the same
things with beads but now get three-dimensional growth.”
J.A. 101546–55. Dr. Salomon’s testimony also included a
detailed animated presentation and references to “a very
well-known text-book to [persons of skill] in the field.”
J.A. 101553–55.
     Much of Dr. Salomon’s testimony does not appear in
the parties’ joint appendix because the extent of Dr.
Salmon’s testimony was not an issue in front of the dis-
trict court.    Dr. Salomon’s testimony—including his
assertion that cells cultured in three-dimensions with
beads have the same beneficial cell-cell and cell-matrix
interactions as cells cultured in three-dimensions without
beads—was unrefuted. Histogen even conceded at oral
argument that cells cultured in three-dimensions with
beads have superior cell-cell and cell-matrix interactions
compared to cells cultured in two-dimensions with beads.
Oral Argument at 23:53, available at http://www.cafc.
uscourts.gov/oral-argument-recordings/2012-1560/all.
    The reason the district court refused to consider Dr.
Salomon’s testimony was because it “is inconsistent with
the intrinsic patent record . . . .” J.A. 23 n. 5. This court
agrees and states:
    The patentees plainly stated in the written de-
    scription that: “Cell lines grown as a monolayer or
    on beads, as opposed to cells grown in three-
    dimensions, lack the cell-cell and cell-matrix in-
    teractions characteristic of whole tissue in vivo.”
    Dr. Salomon, though, testified that “fibroblasts
    culture[ed] in three-dimensions on microcarriers
    or beads, . . . exhibit cell-to-cell and cell-matrix in-
    teractions characteristic of whole tissue in vivo.”
    As the district court found, Dr. Salomon’s testi-
6                           SKINMEDICA INC   v. HISTOGEN INC

    mony is “inconsistent with the intrinsic patent
    record.”
Majority Op. at 41 (emphases original) (citations omitted).
However, this conclusion only highlights the issue:
whether or not the patentees’ reference to “on beads” is in
the context of two-dimensional cultures. If so, then Dr.
Salomon’s testimony is entirely consistent with the in-
trinsic patent record.
    As to the leading nature of the questions posed by
SkinMedica’s counsel, Histogen did not object. Any defect
as to the form of those questions has been waived. Fed. R.
Civ. P. 32(d)(3)(B).
    In sum, this reference to “on beads” is not a clear dis-
avowal of “culturing . . . cells in three-dimensions.” At a
minimum, even absent Dr. Salomon’s probative testimo-
ny, the specification is ambiguous. This court’s precedent
requires more.
                            III.
     The second reference to beads immediately follows the
first and is part of the same discussion:
    Cell lines grown as a monolayer or on beads, as
    opposed to cells grown in three-dimensions, lack
    the cell-cell and cell-matrix interactions charac-
    teristic of whole tissue in vivo. Consequently,
    such cells secrete a variety of cellular metabolites
    although they do not necessarily secrete these me-
    tabolites and secreted proteins at levels that ap-
    proach      physiological   levels.    Conventional
    conditioned cell culture medium, medium cultured
    by cell-lines grown as a monolayer or on beads, is
    usually discarded or occasionally used in culture
    manipulations such as reducing cell densities.
’494 patent col. 1 ll. 33–44 (emphasis added). This refer-
ence to beads is not a clear disavowal for the same rea-
sons noted above.
SKINMEDICA INC   v. HISTOGEN INC                           7

    This reference merely states that the medium result-
ing from cells grown “as a monolayer or on beads” do not
secrete cellular metabolites and proteins at levels that
approach physiological levels. However, as mentioned
above, cells cultured in three-dimensions using beads
have the same beneficial cell-cell and cell-matrix interac-
tions as cells cultured in three-dimensions without beads.
Thus, the resulting mediums would contain the same
levels of metabolites and proteins. It would not make
sense for the patentees to distinguish the medium result-
ing from cells cultured “on beads” from that of cells cul-
tured in three-dimensions unless “on beads” is in the
context of two-dimensional culturing.
                             IV.
    The third reference to beads is in the section titled
“Detailed Description of the Invention”:
    The present invention relates to novel composi-
    tions comprising any conditioned defined or unde-
    fined medium, cultured using any eukaryotic cell
    type or three-dimensional tissue construct and
    methods for using the compositions. The cells are
    cultured in monolayer, beads (i.e., two-dimensions)
    or, preferably, in three-dimensions.
’494 patent col. 7 ll. 24–29 (emphasis added). This refer-
ence to beads is not an unmistakable and unambiguous
disavowal.
     The abbreviation “i.e.” is commonly used as a qualifi-
er, meaning “that is to say” or “in other words.” That is
consistent with how the patentees used “i.e.” in other
parts of the specification. Contra Majority Op. at 22; see,
e.g., ’494 patent col. 15 ll. 15–19. It is reasonable to view
the “i.e.” in this case as merely clarifying that the refer-
ence to beads is in the context of two-dimensions. The
ambiguity is readily apparent. Nonetheless this court,
without well-grounded reasoning, concludes that the
patentees used “i.e.” to redefine beads as something other
8                            SKINMEDICA INC   v. HISTOGEN INC

than the plain and ordinary meaning as understood by
those skilled in the art. Majority Op. at 20–26.
                             V.
    The fourth reference to beads also occurs in the sec-
tion titled “Detailed Description of the Invention”:
    The cells may be cultured in any manner known
    in the art including in monolayer, beads or in
    three-dimensions and by any means . . . . Meth-
    ods of cell and tissue culturing are well known in
    the art . . . .”
’494 patent col. 9 ll. 66–col. 10 l. 3. Again, because cultur-
ing cells using beads in both two-dimensions and three-
dimensions was well-known in the art, I do not find a
clear and unmistakable disavowal merely because the
patentees used “the disjunctive ‘or’ to differentiate be-
tween cells cultured using beads and those cultured in
three-dimensions.” Majority Op. at 26.
                             VI.
    In sum, to my eyes, the four references to beads relied
on by this court are ambiguous. They do not meet the
exacting standard imposed by this court’s precedent.
Because I would find that the patentees did not unmis-
takably and unambiguously disavow the ordinary mean-
ing of “culturing . . . cells in three-dimensions” to exclude
the use of beads, I would reverse the district court’s grant
of summary judgment.