Mit v. Shire Pharmaceuticals, Inc. , 839 F.3d 1111 ( 2016 )

United States Court of Appeals
for the Federal Circuit
______________________
MASSACHUSETTS INSTITUTE OF TECHNOLOGY,
CHILDREN’S MEDICAL CENTER CORPORATION,
Plaintiffs-Appellees
v.
SHIRE PHARMACEUTICALS, INC., NKA SHIRE
PHARMACEUTICALS LLC, SHIRE
REGENERATIVE MEDICINE, INC.,
Defendants-Appellants
______________________
2015-1881
______________________
Appeal from the United States District Court for the
District of Massachusetts in No. 1:13-cv-10020-MLW,
Chief Judge Mark L. Wolf.
______________________
Decided: October 13, 2016
______________________
DARYL L. WIESEN, Goodwin Procter LLP, Boston, MA,
argued for plaintiffs-appellees. Also represented by KEVIN
PAUL MARTIN.
SANDRA KUZMICH, Frommer Lawrence & Haug LLP,
New York, NY, argued for defendants-appellants. Also
represented by EDGAR HAUG, LAURA ANN FANELLI,
RUSSELL ALAN GARMAN, JONATHAN HERSTOFF.
______________________
2 MIT v. SHIRE PHARMACEUTICALS, INC.
Before O’MALLEY, CHEN, and STOLL, Circuit Judges.
Opinion for the court filed by Circuit Judge STOLL.
Concurring opinion filed by Circuit Judge O’MALLEY.
STOLL, Circuit Judge.
Massachusetts Institute of Technology and Children’s
Medical Center Corporation (collectively, “MIT”) brought
suit against Shire Pharmaceuticals, Inc. and Shire Re-
generative Medicine, Inc. (collectively, “Shire”) for in-
fringement of U.S. Patent Nos. 5,770,193 and 5,759,830.
The ’193 and ’830 patents are directed to three-
dimensional scaffolding for growing cells in vitro to pro-
duce organ tissue in vivo. Following the district court’s
construction of the terms “vascularized organ tissue” and
“cells derived from a vascularized tissue” and its determi-
nation that the term “three-dimensional scaffold” was not
indefinite, the parties stipulated to a final judgment of
validity and infringement. For the reasons below, we
affirm.
BACKGROUND
I.
In the field of organ transplantation, surgeons face
the challenge of donor scarcity in addition to the technical
complexity of transplanting whole or segmented organs
into organ recipients. Given the limited availability of
implantable organs, scientists have developed methods of
growing artificial organ tissue in vitro 1 by seeding cells
onto support structures, known as scaffolds or matrices.
These scaffolds are engineered to allow cells to attach and
1 In vitro refers to an artificial environment outside
of a living organism, such as a test tube or culture. In
vivo means within a living body.
MIT v. SHIRE PHARMACEUTICALS, INC. 3
grow, while enabling the diffusion of vital cell nutrients to
the cells to contribute to the growth of new functional
tissue.
Before the inventions of the asserted patents, scien-
tists created organ tissue with scaffolds made of either
“permanent” synthetic polymers or biodegradable, non-
synthetic materials like collagen. Preferably, these
scaffolds eventually would be absorbed by the body,
leaving behind the newly formed tissue. With the former
method, however, the “permanent” synthetic matrix could
not be absorbed by the body. Drawbacks of the latter
collagen-based matrix included the inability to control the
collagen structure’s configuration and the variable ab-
sorption of the collagen matrix by the surrounding tissue.
It was also generally understood that in engineering
thick organs, like a liver or pancreas, the cells at the
center of the artificial structure tended to die as the cell
density increased. This was due to the decreased diffu-
sion rate of oxygen and nutrients to the inner cells at the
center of the growing structure. These prior art methods
of tissue engineering, therefore, were primarily used to
make thinner organs such as artificial skin.
In the face of these challenges, the inventors of the
’193 and ’830 patents, Drs. Vacanti and Langer, developed
biodegradable, synthetic matrices that provide support for
cell growth and enhance the formation of blood vessels
(i.e., vascularization) of the growing cell mass after im-
plantation. The specifications of the ’193 and ’830 patents
state that “[t]he design and construction of the scaffolding
is of primary importance,” and that the scaffolding must
be “shaped to maximize surface area to allow adequate
diffusion of nutrients and growth factors to the cells.”
’193 patent col. 6 ll. 25–27; ’830 patent col. 10 ll. 12–15.
While the prior art methods were generally used to grow
only artificial skin, the scaffolding of the claimed inven-
tion can support the growth of organs with varying thick-
4 MIT v. SHIRE PHARMACEUTICALS, INC.
nesses. Indeed, the specifications describe that an object
of the invention is to “provid[e] a variety of organs, includ-
ing skin, liver, kidneys, blood vessels, nerves, and muscles
which functionally resemble the naturally occurring
organ.” ’193 patent col. 3 ll. 9–13.
II.
The ’193 and ’830 patents claim three-dimensional,
synthetic, biodegradable structures for growing tissue for
vascularized organs as well as methods for creating those
structures. MIT brought suit against Shire in the United
States District Court for the District of Massachusetts,
alleging that Shire’s sale of its Dermagraft® scaffold
infringes claims 1–4, 6–9, and 15–16 of the ’193 patent
and claims 1–4, 6, and 8 of the ’830 patent. Claim 1 of the
’830 patent is illustrative and recites the following, with
emphasis given to the disputed terms:
1. A cell-scaffold composition prepared in vitro for
growing cells to produce functional vascularized
organ tissue in vivo, comprising:
a fibrous three-dimensional scaffold composed of
fibers of a biocompatible, biodegradable, synthetic
polymer; and
cells derived from a vascularized tissue attached
in vitro to the surface of the fibers of the scaffold
uniformly throughout the scaffold;
wherein the fibers of the scaffold provide suffi-
cient surface area to permit attachment in vitro of
an amount of the cells effective to produce the
functional vascularized organ tissue in vivo;
wherein the fibers of the scaffold are spaced apart
such that the maximum distance over which dif-
fusion of nutrients and gases must occur through
a mass of cells attached to the fibers is between
100 and 300 microns; and
MIT v. SHIRE PHARMACEUTICALS, INC. 5
wherein the diffusion provides free exchange of
nutrients, gases and waste to and from the cells
uniformly attached to the fibers of the scaffold and
proliferating throughout the scaffold in an amount
effective to maintain cell viability throughout the
scaffold in the absence of vascularization.
’830 patent col. 24 ll. 23–46 (emphases added).
Shire’s accused Dermagraft® scaffold uses a synthet-
ic, bioabsorbable scaffold seeded with connective tissue
cells called fibroblasts to grow the dermis (or inner) layer
of skin for “the treatment of full-thickness diabetic foot
ulcers.” J.A. 1004. Product literature for Dermagraft®
describes that “[d]uring the manufacturing process, the
human fibroblasts are seeded onto a bioabsorbable poly-
glactin mesh scaffold.” Id. After seeding onto the
Dermagraft® scaffold, “[t]he fibroblasts proliferate to fill
the interstices of this scaffold and secrete human dermal
collagen, matrix proteins, growth factors and cytokines, to
create a three-dimensional human dermal substitute
containing metabolically active, living cells.” Id. The
fibroblasts attach to the top, bottom, and sides of the
fibers of the mesh scaffolding that, after implantation, is
gradually absorbed by the surrounding tissue. According
to MIT, Shire uses a three-dimensional, synthetic, biode-
gradable scaffold to grow vascularized organ tissue and
thus infringes the asserted claims of the ’193 and ’830
patents.
III.
The parties dispute whether prosecution history dis-
claimer applies to the asserted claims. In particular,
Shire argues that prosecution disclaimers apply to the
terms “vascularized organ tissue” and “cells derived from
a vascularized tissue.” Prosecution of the asserted pa-
tents began with their parent application, U.S. Applica-
tion Serial No. 06/933,018, filed in 1986 and abandoned in
1989. The ’193 patent, a continuation of the parent, and
6 MIT v. SHIRE PHARMACEUTICALS, INC.
the ’830 patent, a continuation-in-part of the parent, both
issued in 1998. During the intervening years, MIT’s
strategy shifted in response to the examiners’ prior art
rejections, and the claim language evolved over the course
of prosecution.
As originally filed, the pending claims in the ’018 ap-
plication were directed to:
[P]roviding a matrix formed of a biocompatible
material, wherein said matrix is used to support
cell growth in a nutrient solution, said matrix be-
ing configured to allow adequate diffusion of nu-
trients from the nutrient solution to all of the cells
so as to maintain cell growth and proliferation to
form a three dimensional cell-matrix structure.
J.A. 22231–32. An examiner rejected the ’018 applica-
tion’s claims based on prior art that, according to the
examiner, “shows a tissue culture method on a carrier as
claimed.” J.A. 22212. In 1988, during an examiner
interview in response to the prior art rejection, MIT
explained that the prior art was directed to skin substi-
tutes. In particular, MIT described the prior art as “lim-
ited to extremely thin pieces of collagen matrix for use in
preparing skin substitutes, which could not be used to
create organ equivalents.” J.A. 22234. This interview
summary further explained that “although porous struc-
tures for implantation have been made in the past, the
pores have not allowed adequate diffusion through the
matrix material between the environment and the at-
tached cells to support the growth and proliferation of
cells on the interior of the matrix material unless the
dimensions of the matrix were very small.” J.A. 22238.
At the same time, MIT sought to amend the claims to
recite a “matrix having adequate surface area to provide
surfaces of attachment for a cell suspension and a geo-
metric configuration to uniformly support cell growth in a
nutrient solution.” J.A. 22231–32.
MIT v. SHIRE PHARMACEUTICALS, INC. 7
Dr. Vacanti, a co-inventor on the asserted patents,
submitted a declaration in 1989 in support of allowance of
the ’018 application, explaining that the prior art methods
relied on by the examiner to reject the claims were “lim-
ited to a very thin layer of cells, principally serving as
skin substitutes.” J.A. 22268. He described the “key
difference” between the claims and prior art as “the
design of a polymer scaffold which provides adequate sites
for attachment and growth of enough cells to survive and
function in vivo yet does not limit survival and growth of
cells adjacent to the matrix surface as cells increase in
number in vitro.” Id. Dr. Vacanti further emphasized the
“general applicability” of the invention, which may be
“use[d] with different cell types.” Id.
In response, the examiner maintained his rejections of
the ’018 application’s claims over prior art disclosing skin
substitutes, dismissing MIT’s argument that “the claimed
method is not a method for making very thin structures.”
J.A. 22313. The examiner explained that the “claims
herein are not exclusive to methods involving only thick
structures.” Id. At that time, the claims did not include a
thickness limitation and were directed to:
An artificial matrix for controlled cell growth in a
nutrient solution comprising: a biocompatible ma-
trix configured to provide points of attachment for
a cell suspension, said matrix being configured to
uniformly support cell growth in a nutrient solu-
tion, having sufficient area to allow adequate dif-
fusion of nutrients, elimination of waste, and
adequate gas exchange from the nutrient solution
to all of the cells such that, in the absence of a
vascular network, sufficient cellular growth and
differentiation can occur to form a three dimen-
sional cell-matrix structure.
J.A. 8142–43.
8 MIT v. SHIRE PHARMACEUTICALS, INC.
In 1989, in response to these continued rejections,
MIT amended the claims of the ’018 application to limit
the claims to scaffolds for growing “non-skin organ cells.”
J.A. 8142–43. Likewise, MIT amended the claims in the
applications that ultimately issued as the ’830 and ’193
patents to claim, respectively, “[a] biodegradable polymer-
ic support matrix for culturing non-skin organ cells” and
“[a] method for preparing a biodegradable polymeric
matrix that serves as a cell culture scaffolding for non-
skin organ cells.” J.A. 1866, 3735. The examiner rejected
all the new claims in each application under 35 U.S.C.
§ 112, reasoning that the “non-skin” limitations constitut-
ed new matter that was not supported by the original
patent application. For example, the examiner of the ’193
patent application stated:
Claim 1, newly amended, recites an invention that
includes “non-skin” organ cells. There is no de-
scription or teachings of enablement in the pre-
sent specification of “non-skin” organ cells, per se.
Consequently, the present specification as filed
fails to meet the requirements of 35 USC 112, first
paragraph with respect to “non-skin” organ cells.
The term “non-skin” in claim 1 is deemed to be
new matter.
J.A. 3768 (’193 patent); see also J.A. 8166 (same rejection
for ’830 patent).
MIT then withdrew the “non-skin” amendments for
the asserted patents. J.A. 2272–73, 3774–75, 8173–74.
In doing so, MIT emphasized that “no one, prior to appli-
cants, recognized that the free diffusion of nutrients and
gases, as opposed to cells, in combination with structure
and sufficient attachment sites for the number of cells
required to replace lost function, was essential to the
formation of an organ replacement.” J.A. 3789.
MIT abandoned the ’018 parent application and con-
tinued to prosecute the applications that ultimately
MIT v. SHIRE PHARMACEUTICALS, INC. 9
issued as the ’193 and ’830 patents. At the time, MIT’s
claims included a limitation directed to the thickness of
the claimed cell mass. For example, claim 1 of the ’193
patent recited “[a] method for preparing cell-matrix
structures comprising: determining the thickness through
which nutrients and oxygen can diffuse through an ani-
mal cell mass for attachment and survival of the cells
throughout the cell mass, wherein the dimensions of the
cell mass are greater than 300 microns.” J.A. 1638. The
examiner rejected the claims under 35 U.S.C. § 112, first
paragraph, asserting that “[t]he original specification fails
[to] contain adequate support for steps a) and b) of claim
1, and for dimensions of a cell mass of greater than 300
microns.” J.A. 4795. MIT responded by pointing to
support in the specification, stating:
Skin is differentiated from organs at page 6 of the
application [i.e., ’193 patent col. 2 l. 64 – col. 3
l. 17], where it is noted that it is considered to be
such a thin structure that one does not have the
limitations as to free diffusion into the center of
the tissue.
. . . It is clear from the foregoing excerpts
from the patent application that construction of
matrices for implantation of cells forming organs
(as opposed to skin) are intended; it is described
that this is only a problem when the diffusion dis-
tance to the middle is greater than 200 to 300 mi-
crons; and that volumes of greater than two to
three mm3 are intended to be implanted.
J.A. 1645. In that same office action response, MIT
distinguished prior art “directed to formation of a skin
substitute” on the ground that the prior art structure “has
only been used to make relatively thin pieces of skin, not
organ structures.” J.A. 1653.
10 MIT v. SHIRE PHARMACEUTICALS, INC.
Later during prosecution, again in response to § 112
rejections of claims with the “greater than 300 microns”
limitation, MIT stated:
The specification identifies the problem to be
solved as the need for structures replacing or sup-
plementing tissue function, specifically pancreat-
ic, liver, intestine, heart and skeletal or smooth
muscle function (pages 2-5). The failure of the
prior art to meet this need is reviewed at pages 5-
6, noting that the prior art only exemplified skin
replacement, not replacement of organs. . . . The
objects of the invention recited at page 7 make
clear that it is the formation of thick organ struc-
tures that is the primary goal of the invention.
J.A. 1709. Similarly, in the same office action response,
Applicants discussed the prior art reference Yannas,
which is directed to skin substitutes: “[B]ecause Yannas,
et al. never makes a thick structure, they do not recognize
the inherent limitation of their collagen gels which pre-
vent making thick structures, which are essential for
making organs but not for making skin replacements.”
J.A. 1716.
In 1997, when the examiners continued to reject the
claims directed to a cell mass greater than 300 microns,
MIT removed these thickness limitations from the claims
and again shifted its prosecution strategy. Specifically,
MIT cancelled the pending independent claims and added
claims in both the ’193 and ’830 patents to require that
the scaffold be used “to produce functional vascularized
organ tissue in vivo.” J.A. 4972, 9116. In an examiner
interview summary, MIT explained that, “although the
[prior art Yannas] lattice is uniquely suited for treating
skin, it would be unsuitable for carrying out the goal of
the claimed invention, especially when applied to vascu-
larized organs, and structures that are thicker than skin.”
J.A. 9125. MIT further described Yannas as “suitable for
MIT v. SHIRE PHARMACEUTICALS, INC. 11
skin repair, or for regenerating nonvascular tissues.” J.A.
9126. MIT asserted that Yannas could not, “without
serious modification, be applied to the purposes of the
presently claimed invention for producing vascularized
tissues and organs.” J.A. 9126–27. MIT also cited a
report by Yannas himself, which stated that his matrix
“supported regeneration of the epidermis (i.e., the outer
avascular layer of skin) on top of the grafted lattices” but
that it “induced only partial regeneration of the dermis—
i.e., the vascularized component of skin.” J.A. 9127.
Following minor amendments, the ’193 and ’830 patents
issued in 1998, claiming structures for growing cells to
produce functional vascularized organ tissue and methods
for creating those structures.
IV.
During claim construction proceedings in the district
court, Shire argued that the term “vascularized organ
tissue” should be construed to exclude skin as an organ
based on various statements made during the prosecution
of the asserted patents, discussed above. Shire made
similar arguments regarding construction of the term
“cells derived from a vascularized tissue,” arguing that
MIT had made statements during prosecution that lim-
ited the term to certain types of cells, namely parenchy-
mal cells and bone forming cells. Shire further argued
that the term “three-dimensional scaffold” was indefinite
under 35 U.S.C. § 112. The district court, however,
determined that prosecution history disclaimer did not
apply and additionally held that the term “three-
dimensional scaffold” was not indefinite.
Following the district court’s claim construction and
indefiniteness determinations, Shire stipulated to validity
and infringement of the patents-in-suit and dismissed its
declaratory judgment counterclaims of invalidity and
noninfringement. The district court accordingly entered
judgment of validity and infringement, and Shire ap-
12 MIT v. SHIRE PHARMACEUTICALS, INC.
pealed. We have jurisdiction pursuant to 28 U.S.C.
§ 1295(a)(1).
DISCUSSION
Shire argues on appeal that the district court erred in
construing the term “vascularized organ tissue” simply as
“vascularized tissue from an organ” and in determining
that the term “cells derived from a vascularized tissue”
encompasses “at least some cells derived from skin.”
See J.A. 3–4. Shire also challenges the district court’s
determination that the term “three-dimensional” is not
indefinite, as well as its construction of the term “three-
dimensional scaffold” to mean “a supporting structure
that allows cells to attach along its width, length, and
height.” J.A. 4. We address each claim limitation in turn
below.
I.
The “ultimate interpretation” of a claim term, as well
as interpretations of “evidence intrinsic to the patent (the
patent claims and specifications, along with the patent’s
prosecution history),” are legal conclusions, reviewed by
this court de novo. Teva Pharm. USA, Inc. v. Sandoz,
Inc., 135 S. Ct. 831, 841 (2015). “Subsidiary factual
determinations based on extrinsic evidence are reviewed
for clear error.” Info–Hold, Inc. v. Applied Media Techs.
Corp., 783 F.3d 1262, 1265 (Fed. Cir. 2015) (citing Teva,
135 S. Ct. at 841).
The purpose of claim construction is to give claim
terms the meaning understood by a person of ordinary
skill in the art at the time of invention. Phillips v. AWH
Corp., 415 F.3d 1303, 1312–14 (Fed. Cir. 2005) (en banc).
“There is a heavy presumption that claim terms are to be
given their ordinary and customary meaning.” Aventis
Pharm. Inc. v. Amino Chems. Ltd., 715 F.3d 1363, 1373
(Fed. Cir. 2013). “Properly viewed, the ‘ordinary meaning’
of a claim term is its meaning to the ordinary artisan
MIT v. SHIRE PHARMACEUTICALS, INC. 13
after reading the entire patent.” Phillips, 415 F.3d at
1321. A patent’s prosecution history, though “‘less useful
for claim construction purposes’ than the claim language
and written description, plays various roles in resolving
uncertainties about claim scope.” SAS Inst., Inc. v. Com-
plementSoft, LLC, 825 F.3d 1341, 1349 (Fed. Cir. 2016)
(quoting Phillips, 415 F.3d at 1317). We recognize that
“the prosecution history can often inform the meaning of
the claim language by demonstrating how the inventor
understood the invention.” Phillips, 415 F.3d at 1317.
A.
“The doctrine of prosecution disclaimer . . . preclud[es]
patentees from recapturing through claim interpretation
specific meanings disclaimed during prosecution.” Omega
Eng’g, Inc. v. Raytek Corp., 334 F.3d 1314, 1323 (Fed. Cir.
2003). “[I]n order for prosecution disclaimer to attach, the
disavowal must be both clear and unmistakable.” 3M
Innovative Props. Co. v. Tredegar Corp., 725 F.3d 1315,
1325 (Fed. Cir. 2013). This case therefore requires that
we analyze whether statements MIT made during the
prosecution of the asserted patents amount to a clear and
unmistakable disclaimer limiting the meaning of the
claim terms. “Where the alleged disavowal is ambiguous,
or even ‘amenable to multiple reasonable interpretations,’
we have declined to find prosecution disclaimer.” Avid
Tech., Inc. v. Harmonic, Inc., 812 F.3d 1040, 1045 (Fed.
Cir. 2016) (quoting Cordis Corp. v. Medtronic AVE, Inc.,
339 F.3d 1352, 1359 (Fed. Cir. 2003) and citing Omega
Eng’g, 334 F.3d at 1325 (“[W]e have thus consistently
rejected prosecution statements too vague or ambiguous
to qualify as a disavowal of claim scope.”)). “The party
seeking to invoke prosecution history disclaimer bears the
burden of proving the existence of a ‘clear and unmistak-
able’ disclaimer that would have been evident to one
skilled in the art.” Trivascular, Inc. v. Samuels, 812 F.3d
1056, 1063–64 (Fed. Cir. 2016).
14 MIT v. SHIRE PHARMACEUTICALS, INC.
B.
On the first term, “vascularized organ tissue,” the dis-
trict court determined that there was no clear and unmis-
takable disclaimer that would exclude skin from the
term’s ordinary meaning. The court therefore construed
the term “vascularized organ tissue” according to its
ordinary meaning as “vascularized tissue from an organ,”
reasoning that because “the dermal layer of skin contains
blood vessels, this term encompasses skin.” J.A. 3. We
agree with the district court.
Shire does not dispute that the ordinary meaning of
“organ” includes skin. Similarly, the ordinary meaning of
“vascularized organ tissue” includes skin because skin
contains vascularized layers, such as the dermis (or inner)
layer. As MIT points out, the parties’ Joint Technology
Tutorial, provided to the district court as background
during claim construction, expressly categorizes skin as
an “organ,” J.A. 3379, 3381, that is “vascularized,”
J.A. 3383–84.
The patents’ respective specifications also support the
district court’s determination that the term “organ”
includes skin. The specifications explicitly state that
“[s]kin is an organ subject to damage by disease or injury”
and that skin is “considered an ‘organ’ of the body.” ’193
patent col. 2 ll. 31, 64; see also ’830 patent col. 4 ll. 8–9,
59. Moreover, the specifications state that “an object of
the present invention” is “to provide a method and means
for providing a variety of organs, including skin, liver,
kidneys, blood vessels, nerves, and muscles which func-
tionally resemble the naturally occurring organ.” ’193
patent col. 3 ll. 9–13 (emphasis added); see also ’830
patent col. 5 ll. 10–14.
Shire nonetheless argues that skin should be excluded
from the construction of “vascularized organ tissue” based
on certain statements made by MIT during prosecution of
the asserted patents’ family. First, Shire pulls out a
MIT v. SHIRE PHARMACEUTICALS, INC. 15
single sentence from the 1988 interview summary pre-
pared during prosecution of the parent ’018 application,
which stated that the asserted prior art “was limited to
extremely thin pieces of collagen matrix for use in prepar-
ing skin substitutes, which could not be used to create
organ equivalents.” J.A. 22234. These statements, how-
ever, were made in the context of different claims that did
not include the terms “vascularized organ tissue” or even
“organ tissue.” Rather, the claims were directed to
“providing a matrix formed of a biocompatible material.”
J.A. 22231. Moreover, the interview summary particular-
ly emphasized that “a crucial aspect of applicants’ inven-
tion” is that the scaffold’s structure allows “adequate
diffusion through the matrix material between the envi-
ronment and the attached cells to support the growth and
proliferation of cells on the interior of the matrix.”
J.A. 22238. Reading the selected sentence in the context
of the entire summary and the claim terms then at issue
reveals that MIT emphasized the structure of the inven-
tion’s scaffold, not the type of organ it can be used to
grow.
Shire also points to Dr. Vacanti’s 1989 declaration
submitted during prosecution of the ’018 application when
the claims had been amended to require “determining the
distance over which adequate nutrients and oxygen can
diffuse through a cell mass having dimensions of greater
than 200 microns to maintain viability of the cells on the
interior of the cell mass.” J.A. 2043. In particular, Shire
relies on Dr. Vacanti’s statement that, “[w]hile making
skin equivalents does not require the use of thick layers of
cells, making functional organs in vivo does.” J.A. 22268.
Review of the then-pending claims and Dr. Vacanti’s
declaration in full, however, reveals that he did not dis-
tinguish the claims from the prior art on the ground that
organs do not include skin. Rather, Dr. Vacanti contrast-
ed the prior art from the then-claimed invention on the
ground that the prior art matrices cannot support “cells
16 MIT v. SHIRE PHARMACEUTICALS, INC.
[that] are grown to a thickness greater than the thickness
which allows adequate diffusion of oxygen and nutrients
to [the] inner cells.” Id. Dr. Vacanti further explained
that the claimed polymer matrices can be used “with
different cell types,” id., and that, while his research
focused on growing artificial livers, “a great strength of
our approach is the generic application of knowledge to
other organ systems.” J.A. 22286. A skilled artisan
would not read these statements in context as limiting the
invention to any particular organ or as excluding skin.
Shire also points to Dr. Vacanti’s statement that the
prior art methods were “limited to a very thin layer of
cells,” whereas “the claimed method is not a method for
making very thin structures.” J.A. 22268, 2048. The
declaration, however, was filed in support of claim limita-
tions requiring a matrix of a minimum thickness. No
such limitation is present in the issued claims. In deter-
mining whether a clear and unambiguous disclaimer
attaches to particular claim language, it is important to
consider the statements made by the applicant both in the
context of the entire prosecution history and the then-
pending claims. See Ecolab, Inc. v. FMC Corp., 569 F.3d
1335, 1342 (Fed. Cir. 2009) (“Even if an isolated state-
ment appears to disclaim subject matter, the prosecution
history as a whole may demonstrate that the patentee
committed no clear and unmistakable disclaimer.”). In
the context of the overall prosecution history, the isolated
statements plucked from Dr. Vacanti’s declaration do not
meet the high standard for prosecution disclaimer to
attach.
MIT’s attempt to add the “non-skin” limitation during
prosecution of the asserted patents reinforces our conclu-
sion that the asserted claims as issued include skin
within their scope. MIT tried to narrow the application
claims early in prosecution to exclude skin organ cells, but
the examiner rejected the “non-skin” limitation under
§ 112 as new matter. MIT never again sought to limit the
MIT v. SHIRE PHARMACEUTICALS, INC. 17
claims to exclude skin organ cells. Had the examiner
actually agreed with MIT’s arguments and allowed the
proposed amendments, the claims could well have a
different claim scope. But the examiner did not, and MIT
took a different approach. Since claims to “vascularized
organ tissue” were ultimately allowed over the prior art
without the proposed “non-skin” amendment, it is difficult
to infer that a skilled artisan would interpret other isolat-
ed statements by MIT during the course of the prosecu-
tion history as a clear and unmistakable disclaimer of
claim scope. Rather, we determine that a skilled artisan,
reading the prosecution history as a whole, would con-
clude that MIT’s invention does in fact cover vascularized
skin.
Shire also points to a statement made by MIT during
prosecution of a related but ultimately abandoned patent
application. MIT stated there that “[t]he prior art de-
scribes the design of matrices for use as skin replace-
ments, having different requirements than those of thick
matrices required for organ function.” J.A. 1913. The
pending claims, however, required that the “dimensions of
the cell mass are greater than 300 microns.” J.A. 1972.
Moreover, MIT described the pending claims as directed
to “a method for the design and preparation of a matrix
for the creation of thick organ equivalents.” J.A. 1912. In
context, Shire’s reliance on MIT’s statements is mis-
placed.
Shire similarly identifies statements made in 1995
during prosecution of the ’193 patent to the effect that
“construction of matrices for implantation of cells forming
organs (as opposed to skin) are intended.” J.A. 1645.
Again, the pending claim language at that time included a
thickness limitation, requiring that the “dimensions of the
cell mass are greater than 300 microns.” J.A. 1638. And
these remarks were made in response to § 112 rejections
in which the examiner stated that the original application
lacks support for the thickness limitation. The full pas-
18 MIT v. SHIRE PHARMACEUTICALS, INC.
sage indicates that MIT was merely showing the examin-
er where the specification provided support for the claim
limitation “greater than 300 microns”:
Adequate support means that one of ordinary skill
in the art would be able to make and use the
claimed invention. It is clear from the foregoing
excerpts from the patent application that con-
struction of matrices for implantation of cells
forming organs (as opposed to skin) are intended;
it is described that this is only a problem when
the diffusion distance to the middle is greater
than 200 to 300 microns; and that volumes of
greater than two to three mm3 are intended to be
implanted.
J.A. 1645. MIT thus directed the examiner to written
description support in the specification, which describes
that “[a]lthough skin is considered to be an ‘organ’ of the
body, these methods for making artificial skin have not
been used to make other types of organs such as a liver or
pancreas.” ’193 patent col. 2 ll. 64–66. MIT’s remarks
were made in the context of a thickness limitation not
present in the issued claims and supported the notion
that while the prior art was limited to creating artificial
skin, the invention is capable of creating skin and also
has a broader application. Moreover, several paragraphs
later, the specification expressly states that an object of
the invention is “to provide a method and means for
providing a variety of organs, including skin.” Id. col. 3 ll.
9–11 (emphasis added).
Finally, Shire points to MIT’s statement that “the pri-
or art only exemplified skin replacement, not replacement
of organs.” J.A. 1709. Again, this statement must be read
in context. It was made when the claims included a
thickness minimum, and MIT attempted to distinguish
the claims on that basis, asserting that “it is the for-
mation of thick organ structures that is the primary goal
MIT v. SHIRE PHARMACEUTICALS, INC. 19
of the invention.” Id. (emphasis added). As such, MIT’s
statement cannot be read as limiting the ordinary mean-
ing of “vascularized organ tissue” in the issued claims,
which do not recite a thickness minimum.
We agree with the district court that Shire failed to
meet its burden of demonstrating the existence of a “clear
and unmistakable” disclaimer that would have been
evident to one skilled in the art. See Elbex Video, Ltd. v.
Sensormatic Elecs. Corp., 508 F.3d 1366, 1371–72 (Fed.
Cir. 2007). In the context of the entire prosecution histo-
ry, the statements that Shire pulls out as alleged dis-
claimers, regarding claim limitations not present in the
issued claims, do not alter or disclaim the ordinary mean-
ing of “vascularized organ tissue” as used in the specifica-
tion. We conclude that the district court properly
determined that “vascularized organ tissue” includes skin
as an organ.
C.
We also agree with the district court’s construction of
“cells derived from a vascularized tissue” to include both
parenchymal and non-parenchymal (e.g., bone-forming)
cells.
The claims themselves do not distinguish between
parenchymal and non-parenchymal cells. Shire acknowl-
edges that bone-forming cells, a type of non-parenchymal
cell, fall within the claims’ scope. Similarly, Shire’s
expert agrees that the ordinary meaning of “cells derived
from a vascularized tissue” would “encompass both the
parenchymal and non-parenchymal cells.” J.A. 1320. In
addition, several dependent claims expressly include
organs with parenchymal and non-parenchymal cells. For
example, claim 11 of the ’193 patent lists smooth muscle
cells, which are non-parenchymal stromal cells, not
parenchymal cells.
20 MIT v. SHIRE PHARMACEUTICALS, INC.
Moreover, the respective specifications do not limit
the term “cells derived from a vascularized tissue” to
parenchymal cells, but instead use the term to also refer
to several types of non-parenchymal stromal cells, namely
cells forming smooth muscle and blood vessel endothelial
cells. E.g., ’193 patent col. 4 ll. 6–16, col. 7 ll. 39–42;
’830 patent col. 6 ll. 27–34, col. 7 ll. 51–56. Shire points
out that the specifications “repeatedly refer to the cells of
the invention as ‘parenchymal,’ ‘functional,’ or cells pos-
sessing the ‘necessary’ or ‘desired’ function.” Appellant
Br. 44. But Shire has not shown that these descriptions
are synonymous, such that the invention should be lim-
ited to only parenchymal cells, especially in the face of the
broad ordinary meaning of “cells derived from a vascular-
ized tissue.” And the specifications’ reference to “an
advantage of the present method” being “a means for
selective transplantation of parenchymal cells” does not
amount to a clear and unmistakable disclaimer restricting
the claims to only parenchymal cells. ’193 patent col. 5
ll. 56–58; see also ’830 patent col. 9 ll. 14–18.
Finally, Shire pulls out statements from the prosecu-
tion of the ’193 patent and a related patent that it argues
disclaim non-parenchymal cells. The pending claims in
these patent applications at the time of the statements,
however, did not include the limitation in dispute—“cells
derived from a vascularized tissue”—and do not clearly
and unmistakably show that MIT intended to limit the
claims at issue to only parenchymal cells.
For example, Shire quotes MIT’s remarks made in re-
sponse to a double patenting rejection during prosecution
of the ’193 patent. Specifically, MIT stated that “there
are two major differences between what appellants are
claiming and the claims” in Application No. 07/509,952
relating to cartilage, including “the requirement for
chondrocytes rather than parenchymal cells.” J.A. 1695–
96. At the time of the double patenting rejection, the
claims pending in the application that ultimately issued
MIT v. SHIRE PHARMACEUTICALS, INC. 21
as the ’193 patent did not require the use of “cells derived
from a vascularized tissue,” and dependent claim 14
specifically recited cells forming cartilage (chondrocytes).
J.A. 4672–74. In response to the double patenting rejec-
tion, MIT amended the ’193 application claims to require
the formation of “vascularized tissue” and removed claim
14’s recitation of cartilage. The statements to which Shire
points, therefore, simply distinguished the co-pending
’952 application claims as being limited to cartilage,
which is an avascular tissue. A skilled artisan would not
read MIT’s statements, which distinguish avascular
cartilage from vascularized tissue made with parenchy-
mal cells, as limiting the term “cells derived from a vascu-
larized tissue” to parenchymal cells.
Shire also points to a statement made during prosecu-
tion of another related patent in the family, U.S. Patent
No. 5,770,417, where MIT stated that “the types of cells
described in the application are defined in Medical dic-
tionaries and textbook[s] as ‘parenchymal’ cells.”
J.A. 1579. At that time, the application that ultimately
issued as the ’417 patent had claims directed to “cells
selected from the group consisting of parenchymal cells
from vascularized tissue and cells forming bone.”
J.A. 1598. This remark was made in response to an
indefiniteness rejection, in which the examiner directed
MIT to identify support in the specification for the disclo-
sure of “parenchymal cells from vascularized tissue.” MIT
referenced the specification’s list of types of cells, which
included parenchymal cells as well as non-parenchymal
stromal cells, in addition to general categories like intes-
tine and kidney cells, which would include both paren-
chymal and non-parenchymal cells. MIT later shifted its
prosecution strategy and removed the limitation of paren-
chymal cells in the claims, electing instead to require that
the cells come from a vascularized tissue.
After reading the full prosecution history in light of
the then-pending claim language, we conclude that a
22 MIT v. SHIRE PHARMACEUTICALS, INC.
skilled artisan would not read MIT’s statement made
during prosecution of the ’417 patent—and directed to
very different claim language—as limiting the term “cells
derived from a vascularized tissue” to parenchymal cells.
We, like the district court, determine that the ordinary
meaning applies because Shire has not shown that a clear
and unmistakable disclaimer attaches to limit the claim
scope.
II.
Finally, Shire appeals the district court’s determina-
tion that the term “three-dimensional scaffold” is not
indefinite, as well as the court’s ultimate construction of
the term as “a supporting structure that allows cells to
attach along its width, length, and height.” J.A. 4. We
affirm the district court’s validity determination and
adopt its claim construction.
“We review a district court’s ultimate determination
that a claim is invalid as indefinite under 35 U.S.C. § 112¶ 2 de novo, although, as with claim construction, any
factual findings by the district court based on extrinsic
evidence are reviewed for clear error.” UltimatePointer,
L.L.C. v. Nintendo Co., 816 F.3d 816, 826 (Fed. Cir. 2016)
(internal footnote omitted). 2 A claim is invalid for indefi-
niteness if its language, when read in light of the specifi-
cation and the prosecution history, “fail[s] to inform, with
reasonable certainty, those skilled in the art about the
scope of the invention.” Nautilus, Inc. v. Biosig Instru-
ments, Inc., 134 S. Ct. 2120, 2124 (2014). Patents are
2 Because the ’193 and ’830 patents were filed be-
fore the adoption of the Leahy–Smith America Invents
Act, Pub. L. No. 112–29, § 4(e), 125 Stat. 284, 296-97
(2011), the previous version of § 112 governs. See AbbVie
Deutschland GmbH & Co. KG v. Janssen Biotech, Inc.,
759 F.3d 1285, 1290 n.3 (Fed. Cir. 2014).
MIT v. SHIRE PHARMACEUTICALS, INC. 23
presumed valid, and the challenger bears the burden of
establishing invalidity. See 35 U.S.C. § 282; Nautilus,
134 S. Ct. at 2130 n.10.
Shire asserts that the term “three-dimensional scaf-
fold” is indefinite because the intrinsic record provides “no
guidance” as to the meaning of “three-dimensional.”
Appellant Br. 64. The district court rejected this argu-
ment and construed the term “three dimensional” accord-
ing to its accepted, ordinary meaning, as confirmed by
dictionary definitions. Shire complains that the dictionar-
ies cited by the district court are from the present day and
are not technical in nature. Yet Shire does not explain
how technical dictionaries or dictionaries contemporane-
ous to the patents’ filing date would define the term any
differently. Moreover, the district court’s construction is
consistent with Shire’s own expert’s opinion regarding the
term’s ordinary meaning at the time of the invention:
[A]t the time of the invention, . . . a POSA would
have had some familiarity with the phrases “two-
dimensional” and “three-dimensional” in the con-
text of growing cells . . . . At that time a POSA
would have understood the term “three-
dimensional” as it relates to cell culture to refer to
growing cells on and within a structure . . . . It is
my understanding that a reference to three di-
mensions was an attempt to contrast this system
(i.e., growing on and within) with the more tradi-
tional and widely-practiced “two-dimensional”
conditions in which cells are grown in a single
layer, usually on a flat, hard glass or plastic sur-
face.
J.A. 1356.
Given the ordinary meaning of “three-dimensional”
and Shire’s own expert’s description of “three-dimensional
scaffold,” we agree that the claim language is sufficiently
definite under Nautilus. We likewise discern no error in
24 MIT v. SHIRE PHARMACEUTICALS, INC.
the district court’s construction of “three-dimensional
scaffold” to mean “a supporting structure that allows cells
to attach along its width, length, and height.” J.A. 4.
CONCLUSION
For the above reasons, we find no error in the district
court’s claim constructions of “vascularized organ tissue,”
“cells derived from a vascularized tissue,” and “three-
dimensional scaffold.” We affirm its determination that
the term “three-dimensional scaffold” is not indefinite.
Accordingly, we affirm the district court’s judgment.
AFFIRMED.
United States Court of Appeals
for the Federal Circuit
______________________
MASSACHUSETTS INSTITUTE OF TECHNOLOGY,
CHILDREN'S MEDICAL CENTER CORPORATION,
Plaintiffs-Appellees
v.
SHIRE PHARMACEUTICALS, INC., NKA SHIRE
PHARMACEUTICALS LLC, SHIRE
REGENERATIVE MEDICINE, INC.,
Defendants-Appellants
______________________
2015-1881
______________________
Appeal from the United States District Court for the
District of Massachusetts in No. 1:13-cv-10020-MLW,
Chief Judge Mark L. Wolf.
______________________
O’MALLEY, Circuit Judge, concurring.
I agree with the majority that the district court did
not err either in its construction of the disputed claim
terms or in its conclusion that the term “three-
dimensional scaffold” was not indefinite. Indeed, I believe
the district court thoroughly and correctly analyzed all
arguments and issues presented. I write separately,
however, because I continue to believe that a judgment
that is final except for a determination of damages and
willfulness is not a final judgment at all.
2 MIT v. SHIRE PHARMACEUTICALS, INC.
DISCUSSION
The appellants assert that jurisdiction is proper be-
cause “[t]he judgment is ‘final except for an accounting.’”
Appellants’ Br. 1 (quoting 28 U.S.C. § 1292(c)(2)). This is
apparently so “because aside from MIT’s request for (i)
damages and (ii) a finding of willful infringement, the
judgment disposes of all claims and counterclaims pend-
ing in the present case.” Id.In Robert Bosch, LLC v. Pylon Manufacturing Corp.,
719 F.3d 1305 (Fed. Cir. 2013) (en banc), we created a
broad jurisdictional rule that excepts this court from the
rules of finality followed by every other Article III court of
appeals. We held that 28 U.S.C. § 1292(c)(2) “confers
jurisdiction on this court to entertain appeals from patent
infringement liability determinations when a trial on
damages has not yet occurred” or “when willfulness issues
are outstanding and remain undecided.” Id. at 1317,
1319. And while I fully understand that § 1292(c)(2) is an
exception to the final judgment rule that applies only to
patent cases, I do not believe we should have strayed so
far from the wise judgment of our sister courts. See id. at
1331 (O’Malley, J., dissenting) (collecting cases from other
circuits holding that the finality requirement applies to
outstanding damages determinations).
In declaring this broad, new rule in Bosch, we framed
the question as “whether a trial on damages and willful-
ness is an accounting for the purposes of § 1292(c)(2)” and,
therefore, an “exception[] to the final judgment rule.” Id.
at 1308. We answered that question by “conclud[ing]
(albeit incorrectly in my view) that damages and willful-
ness determinations are sufficiently ‘ministerial’ to consti-
tute no more than an ‘accounting.’” ePlus, Inc. v. Lawson
Software, Inc., 789 F.3d 1349, 1371 (Fed. Cir. 2015)
(O’Malley, J., dissenting). In so doing, we hammered a
square peg into a round hole—these appeals are more
MIT v. SHIRE PHARMACEUTICALS, INC. 3
properly characterized as interlocutory and are, therefore,
improper.
It is well established that “[t]he finality require-
ment . . . embodies a strong congressional policy against
piecemeal reviews, and against obstructing or impeding
an ongoing judicial proceeding by interlocutory appeals.”
United States v. Nixon, 418 U.S. 683, 690 (1974). Yet this
court’s continuing practice of allowing parties to appeal
judgments where damages and willfulness remain unde-
cided multiplies judicial proceedings by endorsing piece-
meal review. See Dow Chem. Co. v. Nova Chems. Corp.
(Canada), 809 F.3d 1223, 1229 (Fed. Cir. 2015) (“[Bosch]
authorized, nay encouraged, parties to engage in piece-
meal appeals in patent cases and encouraged district
judges to authorize the same.”) (O’Malley, J., dissenting
from denial of petition for rehearing en banc). This prac-
tice further incentivizes the disruption of district court
proceedings by encouraging “district courts to bifurcate
liability determinations from damages and willfulness
trials—and all other remedial determinations,” which will
“drag out the litigation” in many cases, “causing multiple
appeals and probably multiple remands.” Fresenius USA,
Inc. v. Baxter Int’l, Inc., 733 F.3d 1369, 1381 (Fed. Cir.
2013) (O’Malley, J., dissenting from denial of petition for
rehearing en banc).
The final judgment rule is invaluable to ensuring the
efficient and just resolution of patent disputes.
The final judgment rule serves several important
interests. It helps preserve the respect due trial
judges by minimizing appellate-court interference
with the numerous decisions they must make in
the pre-judgment stages of litigation. It reduces
the ability of litigants to harass opponents and to
clog the courts through a succession of costly and
time-consuming appeals. It is crucial to the effi-
cient administration of justice.
4 MIT v. SHIRE PHARMACEUTICALS, INC.
Flanagan v. United States, 465 U.S. 259, 263–64 (1984).
Exceptions to that rule are rare and disfavored. The
Supreme Court has “repeatedly stressed,” in the context
of the collateral order doctrine, that a “‘narrow’ exception
should stay that way and never be allowed to swallow the
general rule that a party is entitled to a single appeal, to
be deferred until final judgment has been entered, in
which claims of district court error at any stage of the
litigation may be ventilated.” Dig. Equip. Corp. v. Desk-
top Direct, Inc., 511 U.S. 863, 868 (1994). The increasing
regularity of appeals taken under § 1292(c)(2), with
damages and willfulness yet to be decided, demonstrates
that the exception is indeed swallowing the general rule.
CONCLUSION
For these reasons, while I understand I am bound by
it, I continue to believe that our decision in Bosch was in
error. I concur in the result reached by the majority on
the merits, but do not believe this court should continue
its practice of exercising jurisdiction in cases where, as
here, the district court has yet to determine damages
and/or willfulness.