Document ID: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-ca13-15-01881/USCOURTS-ca13-15-01881-0/pdf.json

Parties Involved:
Children's Medical Center Corporation
Appellee
Massachusetts Institute of Technology
Appellee
Shire Pharmaceuticals, Inc.
Appellant
Shire Regenerative Medicine, Inc.
Appellant

Document Text:

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. 

______________________ 

Case: 15-1881 Document: 56-2 Page: 1 Filed: 10/13/2016
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 Regenerative Medicine, Inc. (collectively, “Shire”) for infringement of U.S. Patent Nos. 5,770,193 and 5,759,830. 

The ’193 and ’830 patents are directed to threedimensional scaffolding for growing cells in vitro to produce 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 determination 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 vitro1 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. 

 

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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, scientists created organ tissue with scaffolds made of either 

“permanent” synthetic polymers or biodegradable, nonsynthetic 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 absorption 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 diffusion 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 implantation. 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 invention can support the growth of organs with varying thickCase: 15-1881 Document: 56-2 Page: 3 Filed: 10/13/2016
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, including 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 sufficient 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 diffusion of nutrients and gases must occur through 

a mass of cells attached to the fibers is between 

100 and 300 microns; and

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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 synthetic, 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 polyglactin 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, biodegradable 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 disclaimer 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 patents began with their parent application, U.S. Application Serial No. 06/933,018, filed in 1986 and abandoned in 

1989. The ’193 patent, a continuation of the parent, and 

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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 application 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 being configured to allow adequate diffusion of nutrients 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 application’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 substitutes. In particular, MIT described the prior art as “limited 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 structures for implantation have been made in the past, the 

pores have not allowed adequate diffusion through the 

matrix material between the environment and the attached 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 geometric configuration to uniformly support cell growth in a 

nutrient solution.” J.A. 22231–32.

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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 “limited 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 matrix configured to provide points of attachment for 

a cell suspension, said matrix being configured to 

uniformly support cell growth in a nutrient solution, having sufficient area to allow adequate diffusion 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 dimensional cell-matrix structure. 

J.A. 8142–43. 

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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 polymeric 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 nonskin 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 constituted 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 description or teachings of enablement in the present 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 applicants, 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 continued to prosecute the applications that ultimately 

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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 animal 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 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. 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. 

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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 supplementing tissue function, specifically pancreatic, 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 structures 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 prevent 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 vascularized organs, and structures that are thicker than skin.” 

J.A. 9125. MIT further described Yannas as “suitable for 

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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 limited the term to certain types of cells, namely parenchymal 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 “threedimensional 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 apCase: 15-1881 Document: 56-2 Page: 11 Filed: 10/13/2016
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 “threedimensional 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 

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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. ComplementSoft, 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 unmistakable’ 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). 

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14 MIT v. SHIRE PHARMACEUTICALS, INC. 

B.

On the first term, “vascularized organ tissue,” the district court determined that there was no clear and unmistakable 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 functionally 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 

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MIT v. SHIRE PHARMACEUTICALS, INC. 15

single sentence from the 1988 interview summary prepared 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 preparing skin substitutes, which could not be used to create 

organ equivalents.” J.A. 22234. These statements, however, 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 particularly emphasized that “a crucial aspect of applicants’ invention” is that the scaffold’s structure allows “adequate 

diffusion through the matrix material between the environment 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 invention’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 distinguish the claims from the prior art on the ground that 

organs do not include skin. Rather, Dr. Vacanti contrasted the prior art from the then-claimed invention on the 

ground that the prior art matrices cannot support “cells 

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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 limitations requiring a matrix of a minimum thickness. No 

such limitation is present in the issued claims. In determining 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 thenpending claims. See Ecolab, Inc. v. FMC Corp., 569 F.3d 

1335, 1342 (Fed. Cir. 2009) (“Even if an isolated statement 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 conclusion 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 

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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 isolated statements by MIT during the course of the prosecution 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 conclude 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 describes the design of matrices for use as skin replacements, 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 misplaced. 

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 pasCase: 15-1881 Document: 56-2 Page: 17 Filed: 10/13/2016
18 MIT v. SHIRE PHARMACEUTICALS, INC. 

sage indicates that MIT was merely showing the examiner 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 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 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 prior 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 formation of thick organ structures that is the primary goal 

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MIT v. SHIRE PHARMACEUTICALS, INC. 19

of the invention.” Id. (emphasis added). As such, MIT’s 

statement cannot be read as limiting the ordinary meaning 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 history, the statements that Shire pulls out as alleged disclaimers, regarding claim limitations not present in the 

issued claims, do not alter or disclaim the ordinary meaning of “vascularized organ tissue” as used in the specification. 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 acknowledges 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. 

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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 possessing the ‘necessary’ or ‘desired’ function.” Appellant 

Br. 44. But Shire has not shown that these descriptions 

are synonymous, such that the invention should be limited to only parenchymal cells, especially in the face of the 

broad ordinary meaning of “cells derived from a vascularized 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 prosecution 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 response 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 

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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 rejection, 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 parenchymal cells, as limiting the term “cells derived from a vascularized tissue” to parenchymal cells. 

Shire also points to a statement made during prosecution 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 dictionaries 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 disclosure 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 intestine and kidney cells, which would include both parenchymal and non-parenchymal cells. MIT later shifted its 

prosecution strategy and removed the limitation of parenchymal 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 

Case: 15-1881 Document: 56-2 Page: 21 Filed: 10/13/2016
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 determination 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 indefiniteness if its language, when read in light of the specification 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 Instruments, Inc., 134 S. Ct. 2120, 2124 (2014). Patents are 

2 Because the ’193 and ’830 patents were filed before 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). 

 

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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 scaffold” is indefinite because the intrinsic record provides “no 

guidance” as to the meaning of “three-dimensional.” 

Appellant Br. 64. The district court rejected this argument and construed the term “three dimensional” according to its accepted, ordinary meaning, as confirmed by 

dictionary definitions. Shire complains that the dictionaries 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 contemporaneous 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 “twodimensional” and “three-dimensional” in the context of growing cells . . . . At that time a POSA 

would have understood the term “threedimensional” 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 dimensions was an attempt to contrast this system 

(i.e., growing on and within) with the more traditional and widely-practiced “two-dimensional” 

conditions in which cells are grown in a single 

layer, usually on a flat, hard glass or plastic surface.

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 

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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 “threedimensional scaffold.” We affirm its determination that 

the term “three-dimensional scaffold” is not indefinite. 

Accordingly, we affirm the district court’s judgment. 

AFFIRMED. 

Case: 15-1881 Document: 56-2 Page: 24 Filed: 10/13/2016
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.

______________________ 

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 “threedimensional 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.

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2 MIT v. SHIRE PHARMACEUTICALS, INC. 

DISCUSSION

The appellants assert that jurisdiction is proper because “[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 pending 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 willfulness 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 willfulness determinations are sufficiently ‘ministerial’ to constitute 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 

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MIT v. SHIRE PHARMACEUTICALS, INC. 3

properly characterized as interlocutory and are, therefore, 

improper.

It is well established that “[t]he finality requirement . . . 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 undecided multiplies judicial proceedings by endorsing piecemeal 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 piecemeal 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 practice 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 efficient administration of justice.

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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. Desktop 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.

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