Ex Parte Klann et al

Patent Trial and Appeal Board

Jan 19, 2017

12274765 (P.T.A.B. Jan. 19, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O.Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/274,765 11/20/2008 Richard C. Klann P63782 1030.1 (0016.2) 1876
26158 7590 01/23/2017
WOMBLE CARLYLE SANDRIDGE & RICE, LLP
ATTN: IP DOCKETING
P.O. BOX 7037
ATLANTA, GA 30357-0037
EXAMINER
PYLA, PAUL D
ART UNIT PAPER NUMBER
1653
NOTIFICATION DATE DELIVERY MODE
01/23/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
IPDocketing@WCSR.COM
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte RICHARD C. KLANN, FRANCIS V. LAMBERTI, and
RONALD S. HILL1
Appeal 2015-007751
Application 12/274,765
Technology Center 1600
Before ULRIKE W. JENKS, RICHARD J. SMITH, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
NEWMAN, Administrative Patent Judge.
DECISION ON APPEAL
This decision on appeal under 35 U.S.C. § 134 involves claims to
methods of cryopreservation using hydrogels. The Examiner entered final
rejections for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
1 Appellants identify the Real Party in Interest as RTI SURGICAL, INC.
Br. 1.
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STATEMENT OF THE CASE
Background
The Specification teaches cryopreservation using a hydrogel matrix,
explaining that the hydrogel matrix:
provides a scaffold for cell attachment before, during, and after
cryopreservation and that can be directly used in vitro or in vivo
to deliver the previously cryopreserved cells to a site of interest
or need. The bioactive hydrogel matrix can thus function as a
growth substrate for cells, as a carrier for long-term storage
during cryopreservation, and as a delivery device after
resuscitation of cryopreserved cells. Moreover, the bioactive
hydrogel matrix can actually provide therapeutic benefits in
association with the cell delivery, including modulation of
localized wound healing and tissue integration. The cells may
be at least partially retained on an exposed surface on the
hydrogel matrix particles. In further embodiments, the cells
may be at least partially retained within one or more pores
present in the hydrogel matrix particles.
The hydrogel may be comprised completely of natural
components, may be comprised completely of synthetic
components, or may comprise a combination of natural and
synthetic components. Examples of natural components
include, but are not limited to, naturally occurring proteins and
polypeptides and naturally occurring polyglycans, such as
polysaccharides. Specific examples of synthetic hydrogels that
may be used according to the invention include hydrogels
comprising polyethylene glycol (PEG), acrylates, methacrylates
(e.g., 2-hydroxyethyl methacrylate or pHEMA), and polyvinyl
alcohol.
Spec. 3.
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The Claims
Claims 1—6, 8—19, 21—25, 27—30, 32-41, 43, and 44 are on appeal.2
Independent claims 1, 30, and 44 are illustrative and read as follows:
1. A method of cryopreserving cells comprising subjecting
particles of a cross-linked bioactive hydrogel matrix to
cryopreservation conditions, wherein said hydrogel matrix
particles and the cells for cryopreservation are combined such
that the cells are attached to an exposed surface of the hydrogel
matrix particles when the combination of the cells and the
particles is subjected to the cryopreservation conditions.
30. A cell-seeded composition comprising the combination of
particles of a cross-linked bioactive hydrogel matrix and cells,
the cells being attached to the hydrogel matrix particles, the
composition being in a cryopreserved form.
44. A cell-seeded composition comprising particles of a
crosslinked bioactive hydrogel matrix, cells that are attached to
the hydrogel matrix particles, and a cryoprotectant.
Br. (Claims App’x.) 23, 27, and 30.
The Issues
The following rejections are before us to review (Ans. 2):
Claims 1, 2, 8-13, 17-19, 21-25, 27, 28, 30, 32-35, and 37-41 are
rejected under 35 U.S.C. § 103(a) as obvious over Frondoza.3
2 Although Appellants state “all of claims 1—6, 8—30, and 32-44 are
appealed herein,” claims 20, 26, and 42 are withdrawn and are therefore not
addressed herein. Br. 2.
3 U.S. Publication No. 2004/0117033 Al, published June 17, 2004, to
Frondoza et al. (hereinafter “Frondoza”).
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Claims 14—16 and 36 are rejected under 35 U.S.C. § 103(a) as obvious
over Frondoza and Qian.4
Claim 29 is rejected under 35 U.S.C. § 103(a) as obvious over Frondoza
and Hill.5
Claims 3—6, 43, and 44 are rejected under 35 U.S.C. § 103(a) as obvious
over Frondoza and Usala.6
The Examiner finds that Frondoza teaches “a microcarrier cell culture
method that facilitated maintenance of a specific phenotype while enhancing
proliferation, where cells (e.g., articular chondrocytes) were grown on
dextran or crosslinked collagen microcarrier beads under controlled pH,
oxygen levels, nutrient supply[,] and mechanical agitation conditions” and
“a method of culturing cells within this microcarrier system.” Ans. 5. The
Examiner finds that Frondoza teaches “cells that are attached to a surface of
the microcarrier beads may be cryopreserved by standard methods in order
to maintain cell viability.” Id. at 6.
The Examiner finds that although Frondoza teaches “the microcarrier
particle can be a cross-linked collagen or can comprise of organic materials
such as gelatin, dextran, hydrogels, etc. . . . Frondoza does not explicitly
indicate that the microcarrier particle is a cross-linked gelatin-dextran
hydrogel.” Id. at 7. The Examiner finds that because “Frondoza indicates
4 U.S. Publication No. 2007/0248685 Al, published Oct. 25, 2007, to Qian
et al. (hereinafter “Qian”).
5 U.S. Publication No. 2005/0118230 Al, published June 2, 2005, to Hill et
al. (hereinafter “Hill”).
6 U.S. Patent No. 6,730,315 B2, issued May 4, 2004, to Usala et al.
(hereinafter “Usala”).
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that the microcarrier may be organic resorbable materials which might
include biopolymers (e.g. collagen, gelatin, dextran, etc.) or chemically
modified derivatives of these materials (e.g., cross-linked derivatives) as
well as hydrogels or any other synthetic polymers that can be produced in
appropriate bead form”, the combination of two compositions disclosed in
Frondoza for the specific purposes would be obvious. Id. at 7.
The Examiner concludes that, based on the teachings of Frondoza, it
would have been obvious “to combine organic resorbable materials (such as
dextran and gelatin) to produce a crosslinked hydrogel in appropriate bead
(i.e., particle) form, since each organic material is taught to be useful as a
microcarrier particle used for cell attachment, and that once attached, the
cell-microcarrier particle can be cryopreserved.” Id. at 8. The Examiner
concludes that because Frondoza discloses
all of the limitations . . . expressly suggested as suitable for
inclusion within Frondoza’s microcarrier particles ... a person
of ordinary skill at the time the invention was made would have
been motivated to combine the recited components as described
above (i.e., crosslinked gelatin-dextran hydrogel microcarrier,
cells that are attached on an exposed surface of the microcarrier
particle, and then the combined particle-cell is cryopreserved
under standard methods), with a reasonable expectation of
success since Frondoza teaches that these are desirable
components within its cell-based composite.
Id.
The Examiner finds the claims obvious because Frondoza teaches “a
cross-linked hydrogel matrix [which is] the final product,” that “the starting
material can be cross-linked collagen, and that other starting materials such
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as collagen, gelatin, or chemically derived modifications of dextran, agarose,
or calcium alginate can be used.” Id. at 21.
The Examiner relies on Usala to teach “cryoprotectant (e.g., sulfated
dextran) may be added that allows a matrix to be stored at lower
temperatures without cellular damage.” Ans. 13. The Examiner concludes
that it would have been obvious to a person of ordinary skill in the art “to
combine Frondoza and Usala since cryopreservation temperatures in
standard cryopreservation methods are routinely used and are well known in
the art, and the addition of a cryoprotectant allows a matrix to be stored at
lower temperatures without cellular damage” and that the combination
would have had “a reasonable expectation of success . . . since both are
involved in tissue engineering and cell preservation.” Id. at 14.
The Examiner relies on Qian to teach “a cross-linked gelatin dextran
hydrogel powder having a particle size in the range from 150 pm to 750 pm;
Qian also teaches that particle sizes outside of this range may find use in
many circumstances.” Id. In light of these teachings, the Examiner finds it
would have been obvious “to grind (mill) the cross-linked bioactive
hydrogel matrix to a particular particle size range.” Id. at 11.
The Examiner relies on Hill to teach dehydration of a hydrogel matrix,
including by lyophilization. Ans. 11. The Examiner concluded it would
have been “obvious ... to dry and mill the cross-linked bioactive hydrogel
matrix based on the teachings in Hill so as to provide a cross-linked
bioactive hydrogel matrix that is easy to store, preserves the shelf life of the
material, as well as provides a customized particle size.” Id. at 12.
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The issue with respect to these rejections is whether a preponderance
of the evidence of record supports the Examiner’s conclusion that the claims
are obvious over the cited art.
Findings of Fact
1. The Specification teaches “a stabilized cross-linked bioactive
hydrogel matrix that provides a scaffold for cell attachment before, during,
and after cryopreservation and that can be directly used in vitro or in vivo to
deliver the previously cryopreserved cells to a site of interest or need.”
Spec. 3:4—7.
2. The Specification teaches
[t]he hydrogel may be comprised completely of natural
components, may be comprised completely of synthetic
components, or may comprise a combination of natural and
synthetic components. Examples of natural components
include, but are not limited to, naturally occurring proteins
and polypeptides and naturally occurring polyglycans, such
as polysaccharides. Specific examples of synthetic
hydrogels that may be used according to the invention
include hydrogels comprising polyethylene glycol (PEG),
acrylates, methacrylates (e.g., 2-hydroxyethyl methacrylate
or pHEMA), and polyvinyl alcohol.
Spec. 3:16-23.
3. The Specification teaches:
In certain embodiments, the hydrogel matrices of the
invention may comprise a first high molecular weight
component and a second high molecular weight component
covalently cross-linked to the first high molecular weight
component. The first high molecular weight component
and the second high molecular weight component
particularly can be selected from the group consisting of
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polyglycans and polypeptides. The polyglycan can
particularly be a polysaccharide or a derivatized
polysaccharide (e.g., sulfates, acetates, phosphates, and
ammonium salts of polysaccharides) and can include
polysaccharides such as commonly found in biofilms or
extracellular matrices. The polyglycans, for example, and
can be selected from the group consisting of dextran,
heparan, heparin, hyaluronic acid, alginate, agarose,
carageenan, amylopectin, amylose, glycogen, starch,
cellulose, chitin, chitosan, heparan sulfate, chondroitin
sulfate, dextran sulfate, dermatan sulfate, and keratan
sulfate. The polypeptide can be selected from the group
consisting of collagens, gelatins, keratin, decorin, aggrecan,
glycoproteins, laminin, nidogen, fibulin, and fibrillin. In
one embodiment, the polyglycan can be dextran and the
polypeptide can be gelatin.
Spec. 3:24-4:7.
4. The Specification teaches “[t]he bioactive hydrogel matrix can
be in particulate form when combined with the cells for cryopreservation.”
Spec. 4:15-16.
5. Frondoza teaches:
a microcarrier spinner culture system that facilitated
maintenance of chondrocytic phenotype while enhancing
proliferation. Articular chondrocytes were grown on
dextran or crosslinked collagen microcarrier beads under
controlled pH, oxygen levels, nutrient supply and
mechanical agitation conditions. This represents a great
advantage over the traditional static monolayer culture
system, which facilitates proliferation but leads to a
fibroblastic shift in phenotype. Likewise, it offers an
alternative to the battery of three-dimensional gel or
scaffold systems, which include agarose or collagen gels,
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calcium alginate gel, mixed fibrin-alginate gels, three-
dimensional meshes of resorbable polymers such as
polylactides or polyglycolides, and encapsulation in
alginate beads. These latter culture techniques facilitate
the maintenance of a chondrocytic phenotype, but are
limited in maximizing proliferation.
Frondoza 1 3.
6. Frondoza teaches:
a method of preparing cells for implantation comprising
allowing cells (e.g., chondrocytes) to grow on microcarrier
particles for an extended period of time and to secrete
extracellular matrix components, thereby producing a cell-
microcarrier aggregate useful for transplantation to a
patient. The cell-microcarrier aggregates can be implanted
directly or further cultured inside a mold that has been
shaped to configure the geometry of the area of the body
receiving the cells for transplantation. When further
cultured in a mold, cell microcarrier aggregates are
consolidated into an implantable structure for repair or
replacement of missing or diseased tissue. The
microcarrier used to prepare the aggregate is a
biocompatible, biodegradable material. This method also
anticipates that cell-microcarrier aggregates, or
consolidated implants prepared therefrom by further
culturing in a mold, may be cryopreserved by standard
methods in order to maintain cell viability and aggregate
structure for future implantation or analysis.
Frondoza 14.
7. Frondoza teaches “the implantation of a combination of (1)
cell-microcarrier aggregates or cell-scaffold or cell-free biomaterial
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formulations in a solid implantable format; and (2) cells or cell-microcarrier
aggregates in an injectable format. Frondoza 115.
8. Frondoza teaches:
The microcarrier may be inorganic or organic resorbable
materials suitable for maintaining seeded cells in culture.
Inorganic materials include, for example: calcium
phosphates, calcium carbonates, calcium sulfates or
combinations of these materials. Organic materials might
include, for example: biopolymers such as collagen, gelatin,
hyaluronic acid or chemically derived modifications of
hyaluronic acid, chitin, chitosan or chitosan derivatives,
fibrin, dextran, agarose, or calcium alginate, particles of
tissue such as bone or demineralized bone, cartilage, tendon,
ligament, fascia, intestinal mucosa or other connective
tissues, or chemically modified derivatives of these
materials. Organic materials might also include synthetic
polymeric materials, including, for example: polylactic acid,
polyglycolic acid or copolymers or combinations of the two,
polyurethanes, polycarbonates, poly-caprolactones,
hydrogels such as polyacrylates, polyvinyl alcohols,
polyethylene glycols, or polyethyleneimines, or any other
synthetic polymers that can be produced in appropriate bead
form.
Frondoza^ 17.
9. Frondoza teaches:
a material capable of polymerizing or gelling after
implantation may be mixed with the aggregate suspension
prior to implantation in order to improve the fixation and
localization of the aggregates after implantation, to stimulate
more rapid consolidation of the aggregates in vivo, or to
promote more rapid integration of the aggregates into the
surrounding tissue. Examples of such binding materials are .
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. . collagen, combinations of fibrin glues and collagen,
transglutaminase-catalyzed binding systems, hydrogels such
as polyacrylates, polyvinyl alcohols, polyethylene glycols,
or polyethyleneimines, or similar materials with suitable
gelling compositions. In situ gelling of these materials may
be initiated by thermal, enzymatic or chemical catalysts, pH
or ionic strength changes or photo-initiation procedures.
Frondoza ]f 18.
10. Frondoza teaches that a “solid formulation may [be] formed by
the extended culturing of chondrocytes or stem cells, for example, on
porous, biocompatible solid scaffolds suitable for implantation into the
body.” Frondoza 133.
11. Frondoza teaches that a composition “for producing an injectable cell-
microcarrier aggregate suspension containing a gel-forming system” can
include “collagen, combinations of fibrin/collagen, transglutaminase-
catalyzed binding systems, hyaluronic acid, calcium alginate gels, chitosan
derivatives capable of gelling at body temperature, hydrogels such as
polyacrylates, polyvinyl alcohols, polyethylene glycols, or
polyethyleneimines, or similar materials with suitable gelling compositions.”
Frondoza teaches that “[i]n situ gelling of these materials may be initiated by
thermal, enzymatic or chemical catalysts, pH or ionic strength changes or
photo-initiation procedures.” Frondoza 137.
12. Frondoza teaches a “solid implant [that] is made by culturing
cells on a porous biodegradable scaffold.” Frondoza 6, claim 13.
13. Usala discloses “[a] method of maintaining cell viability and
functioning during storage is provided wherein the cells are imbedded in the
hydrogel matrix of the present invention.” The matrix protects cells during
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storage, including frozen storage, which is disclosed as “at least -20- C.”
Usala 2:62-65; 11:40-43.
14. Usala teaches a hydrogel matrix for long-term storage and
proliferation of cellular tissue. One hydrogel matrix composition is a
mixture of:
gelatin;
dextran or sulfated dextran;
at least one polar amino acid; and
about 1 to about 8 mM of a divalent chelator, the divalent
chelator comprising EDTA.
Another hydrogel matrix composition is a mixture of:
denatured collagen;
dextran or sulfated dextran;
an L-arginine analogue; and
at least one polar amino acid selected from the group
consisting of arginine, lysine, histidine, glutamic acid,
aspartic acid, and mixtures thereof.
Usala 18:1—16, claims 23 and 24.
15. Usala discloses:
For long term storage, an effective amount of
cryoprotectant may be added that allows the matrix to be stored
at lower temperatures without cellular damage. Preferably, the
cryoprotectant is metabolically stable and capable of creating an
inert cushion to prevent thermal expansion and contraction of
cells. A preferred cryoprotectant is sulfated dextran.
Usala 11:53-55.
16. Qian teaches “[t]he compositions comprise a dry cross-linked
gelatin powder which has been prepared to re-hydrate rapidly . . .
A preferred particle size [of gelatin] will be the range from 150 pm
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to 750 pm, but particle sizes outside of this preferred range may
find use in many circumstances.” Qian 110.
17. Qian teaches:
After cross-linking, at least 50% (w/w) of the re­
hydration aid will be removed from the resulting hydrogel.
Usually, the re-hydration aid is removed by filtration of the
hydro gel followed by washing of the resulting filter cake
After filtration, the gelatin is dried, typically by drying
the final filter cake which was produced. The dried filter cake
may then be broken up or ground to produce the cross-linked
powder having a particle size in the desired ranges set forth
above.
Qian 1117-18.
18. Qian teaches that the cross-linked “powder has a mean particle
size in the range from 150 pm to 750 pm.” Qian 7:3—4, claim 41.
19. Hill teaches:
In addition to being in its usual, hydrated form ... the
bioactive hydro gel matrix . . . can further be in a dehydrated
form . . . Any method generally known in the art for
dehydrating materials normally in a hydrated state would be
useful according to the present invention, so long as it is not
detrimental to the connective tissue regenerative properties of
the hydrogel matrix as described herein. For example, one
preferred method of dehydrating the bioactive hydrogel matrix
is freeze drying.
Freeze drying generally comprises the removal of water
or other solvent from a frozen product through sublimation,
which is the direct transition of a material (e.g., water) from a
solid state to a gaseous state without passing through the liquid
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phase. Freeze drying allows for the preparation of a stable
product being readily re-hydratable, easy to use, and aesthetic
in appearance. The freeze drying process consists of three
stages: 1) pre-freezing, 2) primary drying, and 3) secondary
drying.
Hill 11 87-88.
20. Hill teaches “[t]he dehydrated hydrogel matrix could also be
ground to a particulate form.” 194.
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of
ordinary skill can implement a predictable variation, § 103 likely bars its
patentability.” Id. at 417.
Wrigley found a “strong case of obviousness based on the prior art
references of record. [The claim] recites a combination of elements that
were all known in the prior art, and all that was required to obtain that
combination was to substitute one well-known . . . agent for another.” Wm.
Wrigley Jr. Co. v. Cadbury Adams USALLC, 683 F.3d 1356, 1364 (Fed.
Cir. 2012).
DISCUSSION
The Examiner provides sound based reasoning for rejecting claims 1,
2, 8—13, 17—19, 21—25, 27, 28, 30, 32—35, and 37—41 as obvious over
Frondoza, Usala, Qian, and Hill. We adopt and incorporate by reference the
Examiner’s findings and conclusions as presented in the Final Action mailed
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August 8, 2014, and Answer. We adopt the fact finding and analysis of the
Examiner as our own as Findings of Fact 1—20. As noted by the Examiner,
Appellants responded to all rejections “as a compilation of arguments based
on the rejection under 35 U.S.C. § 102(a) to Frondoza.” Ans. 16. We
address Appellants’ arguments in a similar manner below, with analysis
directed to the secondary references addressed by Appellants within
Appellants’ combined arguments.
We begin with claim interpretation because it is at the heart of patent
examination as a claim cannot be compared to the prior art before its scope
is properly ascertained. Cf. In re Abbott Diabetes Care Inc., 696 F.3d 1142,
1146 (Fed. Cir. 2012)). “[Djuring examination proceedings, claims are
given their broadest reasonable interpretation consistent with the
specification.” In re Hyatt, 211 F.3d 1367, 1372 (Fed. Cir. 2000). We first
turn to the Specification to interpret the term “cross-linked bioactive
hydrogel matrix.”
The Specification provides: “a stabilized cross-linked bioactive
hydrogel matrix that provides a scaffold for cell attachment before, during,
and after cryopreservation and that can be directly used in vitro or in vivo to
deliver the previously cryopreserved cells to a site of interest or need.”
Spec. 3:4—7. The Specification provides various suitable components for
cross-linked bioactive hydrogel matrices and states “[t]he bioactive hydrogel
matrix can be in particulate form when combined with the cells for
cryopreservation.” FF1—3. We agree with the Examiner that the
Specification does not provide a definition for “cross-linked bioactive
hydrogel matrix” and merely describes suitable components and
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embodiments. Ans. 4. The requirement that the hydrogel provide a scaffold
for cell attachment before, during, and after cryopreservation and that it can
be directly used in vitro or in vivo to deliver the previously cryopreserved
cells also does not impart further structural limitations. FF1. The broadest
reasonable interpretation of “cross-linked bioactive hydrogel matrix” in light
of the Specification is a generic cross-linked bioactive hydrogel matrix.
Ans. 4.
Turning to Appellants’ arguments, the Appellants contend that the
Examiner’s finding that “Frondoza teaches that crosslinked collagen
microcarrier beads equate to a cross-linked hydrogel matrix particle as
presently claimed” is incorrect because “a person of skill in the art would not
view Frondoza as teaching a cross-linked hydrogel matrix particle"
Appellants argue
“[a] person of ordinary skill in the art would recognize
crosslinked collagen beads as being a very specific material that
is formed by highly crosslinking collagen upon itself, typically
with glutaraldehyde crosslinking. Crosslinked collagen beads
are not particles of a hydrogel matrix and a person of skill in the
art would not only recognize the difference but would recognize
that paragraph [0003] of Frondoza expressly distinguishes
between the materials.
Br. 8—9. Further, Appellants argue Frondoza “teaches that crosslinked
collagen beads ‘offer[] an alternative to the battery of three-dimensional gel
or scaffold systems, which include agarose or collagen gels,”’ which is
necessary because, as Frondoza discloses, “three-dimensional gel or scaffold
systems do not provide desired cell proliferation.” Appellants argue the
skilled artisan would “recognize that Frondoza teaches away from three-
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dimensional gel or scaffold systems, and such person would limit any
extension of Frondoza to beads and not hydrogels” and “would not seek to
prepare such a hydro gel and use it in a cryopreservation method.” Id. at 9—
10. These arguments are not persuasive.
Frondoza teaches a method of culturing cells within a microcarrier
system, by growing cells on dextran or cross-linked collagen microcarrier
beads (i.e., a cross-linked hydrogel matrix particle) under controlled
conditions. FF5—12. Frondoza teaches allowing cells to grow on
microcarrier particles in which the microcarrier used to prepare the
aggregate is a porous biocompatible, biodegradable material and that the
cells that are attached to a surface of the microcarrier beads may be
cryopreserved by standard methods in order to maintain cell viability. FF8.
While Frondoza recognizes that use of “three-dimensional gel or
scaffold systems” may limit maximizing cell proliferation, Frondoza
discloses and claims scaffolding systems as embodiments of the invention.
Frondoza states “[contemplated in this invention is the implantation of a
combination of (1) cell-microcarrier aggregates or cell-scaffold or cell-free
biomaterial formulations in a solid implantable format; and (2) cells or cell-
microcarrier aggregates in an injectable format.” FF7. Further, Frondoza
specifies that hydrogels may be used for “polymerizing or gelling after
implantation may be mixed with the aggregate suspension prior to
implantation in order to improve the fixation and localization of the
aggregates after implantation.” FF9.
“Under the proper legal standard, a reference will teach away when it
suggests that the developments flowing from its disclosures are unlikely to
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produce the objective of the applicant’s invention. A statement that a
particular combination is not a preferred embodiment does not teach away
absent clear discouragement of that combination.” Syntex (U.S.A.) LLC v.
Apotex, Inc., 407 F.3d 1371, 1380 (Fed. Cir. 2005) (citations omitted).
Because Frondoza encourages rather than discourages scaffolding systems,
Frondoza does not teach away from their use.
Appellants offer no support for their statement that ‘Tclrosslinked
collagen beads are not particles of a hydrogel matrix.” Br. 9. The
Specification states that hydrogel matrix embodiments “may include a first
high molecular weight component and a second high molecular weight
component covalently cross-linked to the first high molecular weight
component” and that those components “can be selected from the group
consisting of polyglycans and polypeptides.” FF3. Dextran is listed as an
example polyglycan and collagen as an example polypeptide. Id. The
Specification further states “[t]he bioactive cross-linked hydrogel matrix
utilized in each of the embodiments described herein may be comprised
solely of the two high molecular weight components cross-linked to one
another.” 27:11—13. The Specification does not define “components.”
Therefore, the dextran and cross-linked collagen microcarrier beads
disclosed by Frondoza (FF5) fall within the Specification’s disclosed
embodiments for a generic cross-linked bioactive hydrogel matrix.
Appellants next argue that “[njothing in Frondoza discloses or
suggests that a ‘chemically modified derivative’ means crosslinked” and that
because Frondoza “suggests a ‘chemically modified derivative’ of bone,
demineralized bone, cartilage, tendon, ligament, fascia, or intestinal mucosa,
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one of skill in the art clearly would not interpret this phrase to mean
crosslinking.” Br. 10. These arguments are not persuasive.
Frondoza discloses that a material capable of polymerizing or gelling
may be used to stimulate rapid integration of aggregates into surrounding
tissue and lists examples of binding materials. FF9, 11. Frondoza teaches
these materials may be gelled in situ by thermal, enzymatic or chemical
catalysts, pH or ionic strength changes or photo-initiation procedures. FF11.
We agree with the Examiner that “[s]uch materials and techniques (e.g.,
enzymatic, chemical catalysts, photo-initiation procedures) are well known
techniques that involve crosslinking and chemical crosslinking in the tissue
engineering arts.” Ans. 22; see also Qian 110. Moreover, Frondoza
discloses growth of articular chondrocyte cells on crosslinked collagen
microcarrier beads. FF5.
Appellants next argue
The examiner has not pointed to any teaching in Frondoza that
would lead a person of skill in the art to take any of the
materials disclosed therein, form a hydro gel, cross-link the
hydrogel, particularize the hydrogel, attach cells to the particles
of the cross-linked hydro gel, and subject the combination of
cells and particles to cryopreservation conditions. Such level of
teaching is necessary for a person of skill in the art to make the
leap from Frondoza to the presently claimed subject matter.
Br. 11. Similarly, Appellants argue “[ajthough . . . Frondoza teaches that the
prior art cell-microcarrier aggregates may be cryopreserved, Frondoza still
does not teach particles of a cross-linked hydro gel matrix that have [cjells
attached thereto and that is in a cryopreserved condition.” Id. Appellants
also argue “Frondoza does not teach forming a hydrogel, cross-linking a
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hydrogel, and particularizing the cross-linked hydrogel.” Br. 13. Appellants
also argue “the presently recited particles of a cross-linked hydrogel matrix
are nowhere suggested by Frondoza because the document does not teach
that particles of hydrogels may be used as a cell attachment scaffold for
cryopreservation of cells.” Br. 14—15. According to Appellants, “the
present claims do not recite the combination of two compositions that are
each expressly taught to be useful for the same purpose.” Id. at 15.
Appellants further argue “nothing in Frondoza suggests cross-linking
together two specific materials, particularly a polyglycan and a polypeptide.”
Br. 19.
These arguments are not persuasive because the Examiner’s rejection
is based on obviousness, not anticipation. Further,
[a] claim can be obvious even where all of the claimed features
are not found in specific prior art references, where ‘there is a
showing of a suggestion or motivation to modify the
teachings of [the prior art] to the claimed invention. ’ SIBIA
Neurosciences, Inc. v. Cadus Pharm. Corp., 225 F.3d 1349,
1356 (Fed. Cir. 2000) (concluding that patent would have been
obvious in light of teachings in prior art which provided
motivation and suggestion to modify existing techniques to
arrive at method in question).
Ormco Corp. v. Align Technology Inc., 463 F.3d 1299, 1307 (Fed. Cir.
2006). Moreover, “interrelated teachings of multiple patents; the effects of
demands known to the design community or present in the marketplace; and
the background knowledge possessed by a person having ordinary skill in
the art, all [can provide] an apparent reason to combine the known elements
in the fashion claimed.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418
(2007).
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Here, the Examiner has combined the components disclosed in
Frondoza as the skilled artisan would have been motivated to do so based on
the teachings in the reference to show that each element of claims 1,2, 8—13,
17—19, 21—25, 27, 28, 30, 32—35, and 37-41 would have been obvious or
inherent based on the physical and chemical properties of the components
and the ways in which Frondoza has taught they may be used and combined.
Appellants have presented insufficient persuasive evidence, and provided
only attorney argument, that the skilled artisan would not have been so
motivated to create the combination. As discussed above with respect to
“components,” Frondoza teaches components used in the same manner as
those claimed by Appellants.
With regard to Appellants’ contention that “the examiner has not
shown that a person of ordinary skill in the art, without knowledge of the
present claims, could select specific components from Frondoza, make
modifications thereto, and arrive at the [claimed] methods and
compositions,” (Br. 8), we note that our reviewing court has stated that
“picking and choosing may be entirely proper in the making of a 103,
obviousness rejection. . . but it has no place in the making of a 102,
anticipation rejection.” In reArkley, 455 F.2d 586, 587 (CCPA 1972)
(emphasis removed). The instant rejection is for obviousness. Both
Frondoza and the Specification disclose various components for the purpose
of creating cell-binding systems (e.g., microcarriers such as hydrogels) that
may be cryopreserved. See e.g., FF 2, 3, 5, 8 and 9. We agree with the
Examiner that the skilled artisan would find it obvious to combine the
disclosed components as claimed.
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Appellants next argue the Examiner has failed to “point[] to any
portion of Frondoza providing predictability in relation to using particles of
a cross-linked hydrogel matrix as an attachment scaffold for cells and
cryopreserving such combination of the cells and the particles of a cross-
linked hydro gel matrix.” This argument is not persuasive. “Obviousness
does not require absolute predictability of success. . . . For obviousness
under § 103, all that is required is a reasonable expectation of success.” In
re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988). Appellants have
presented insufficient persuasive evidence, and provide only attorney
argument, that the skilled artisan would not be successful in using particles
of a cross-linked hydrogel matrix as an attachment scaffold for cells and
cryopreserving the matrix as disclosed by Frondoza. Appellants’ arguments
without more do not meet this requirement. See In re Geisler, 116 F.3d
1465, 1470 (Fed. Cir. 1997) (“[Attorney argument [is] not the kind of
factual evidence that is required to rebut a prima facie case of obviousness”).
Appellants argue claims 43 and 44 are not obvious because Frondoza
does not “suggest[] a cell-seeded composition wherein particles of a cross-
linked hydrogel matrix with cells attached thereto are in combination with a
cryoprotectanf ’ and because a skilled artisan “viewing Frondoza would not
predict that such combination is useful or even possible.” Br. 11.
Appellants argue the skilled artisan would read Usala to teach “that cells
may be frozen when they are encapsulated in a hydrogel matrix” and “would
not predict that Usala’s materials would be useful when cells are not
encapsulated and would not predict that cryopreservation temperatures as
presently recited may be utilized when cells are not encapsulated.” Id.
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Appellants also argue claims 4—6 are not obvious because “Frondoza
is silent as to any aspect of cryopreservation” and “Usala does not cure this
deficiency because Usala only teaches cryopreservation of encapsulated
cells and not cells that are attached to particles.” Br. 16—17.
These arguments are unpersuasive because the Examiner’s rejection is
based on the combined teachings of Frondoza and Usala. See Ans. 12—16.
We agree with the Examiner that nonobviousness cannot be established by
attacking the references individually when the rejection is predicated upon a
combination of prior art disclosures. In re Merck & Co. Inc., 800 F.2d 1091,
1097 (Fed. Cir. 1986); see also In re Keller, 642 F.2d 413, 426 (CCPA
1981) (finding “one cannot show nonobviousness by attacking references
individually where, as here, the rejections are based on combinations of
references” (citations omitted)). Thus, whether Frondoza or Usala
individually fails to teach a cell-seeded composition wherein particles of a
cross-linked hydrogel matrix with cells attached thereto are in combination
with a cryoprotectant is not dispositive to the sufficiency of the rationale
underlying the rejection. As stated by the Examiner, Frondoza teaches
compositions for cell-microcarriers, including hydrogels that comprise
multiple components as disclosed by the Specification and that can be
cryopreserved. FF6 and 8. The Examiner has also established that Usala
discloses a method of maintaining cell viability and functioning during
storage where a matrix protects cells during frozen storage and that storage
temperatures can be -20°C. FF13. The disclosed method includes addition
of a cryoprotectant to the matrix. FF15. The Examiner sufficiently
establishes that an ordinary artisan reading Frondoza and Usala in
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combination would have reasonably expected that the methods for
cryopreservation and the cryoprotectants disclosed in Usala would likewise
useful in cryopreserving the cell-microcarriers of Frondoza. Ans. 12—16.
Appellants next argue that dependent claims 8—13, 17, 18, and 32—35
are not obvious because “the examiner has not shown how a person of skill
in the art may arrive at a composition based upon the disclosure of Frondoza
that would inherently exhibit the properties recited.” Br. 17. This argument
is not persuasive.
We have addressed the obviousness of the teachings of Frondoza and
Usala above. With regard to Appellants’ argument that the Examiner did not
establish that the elements of the dependent claims were inherent,
‘“it is elementary that the mere recitation of a newly discovered
function or property, inherently possessed by things in the prior
art, does not cause a claim drawn to those things to distinguish
over the prior art. Additionally, where the Patent Office has
reason to believe that a functional limitation asserted to be
critical for establishing novelty in the claimed subject matter
may, in fact, be an inherent characteristic of the prior art, it
possesses the authority to require the applicant to prove that the
subject matter shown to be in the prior art does not possess the
characteristic relied on.’” In re Best, 562 F.2d 1252, 1254—55,
(CCPA 1977) (quoting In re Swinehart, 439 F.2d 210, 212—13
(CCPA 1971)).
The Examiner finds that “the microcarrier particle [that can be produced
from the Frondoza teachings such as] (cross-linked gelatin-dextran hydrogel;
the scaffold — microcarrier particles can be porous)” would inherently
possess the properties recited claims 8—13, 17, 18, and 32—35. Ans. 8.
Appellants have presented no evidence to prove that the elements of the
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dependent claims are not present. Without evidence, Appellants’ attorney
argument fails to rebut the prima face case.
Appellants next argue that claims 8—13 and 32—35 are not obvious
because the Examiner has “pointed to nothing in Frondoza teaching the use
of porous particles . . . The only porous materials discussed in Frondoza are
porous scaffolds that may have the pores filled to form a tissue-like matrix.
This, however, does not teach porous particles of a hydrogel matrix and
certainly does not teach particles having specifically defined porosities.” Br.
18. Similarly, Appellants argue claims 17—18 are not obvious because “the
examiner has pointed to nothing in Frondoza teaching attachment of a
defined number of cells to a particle.” Id. These arguments are not
persuasive.
As discussed above, Appellants claim a generic cross-linked bioactive
hydrogel matrix. Frondoza discloses the use of hydrogels as cell-
microcarriers as well as the use of a “porous biodegradable scaffold.” FF8
and 12. Absent evidence to the contrary, we agree with the Examiner that it
is obvious to combine these two components, “each of which is taught by
the prior art to be useful for the same purpose, in order to form a third
composition which is to be used for the very same purpose. . . . [T]he idea of
combining them flows logically from their having been individually taught
in the prior art.” In re Kerkhoven, 626 at 846, 850 (CCPA 1980). We
further agree with the Examiner that “[a] person of ordinary skill in the art
would adjust the pores, the porosity or the particle size of the scaffold based
on tissue characteristics needed for cell growth.” The Supreme Court has
found “[a] person of ordinary skill in the art is also a person of ordinary
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creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 82
USPQ2d at 1397. Appellants have provided insufficient evidence that the
claimed number of cells is impossible to reach within the disclosures of
Frondoza. “[W]here the general conditions of a claim are disclosed in the
prior art, it is not inventive to discover the optimum or workable ranges by
routine experimentation.” In re Alien, 220 F.2d 454, 456 (CCPA 1955).
Absent evidence to the contrary, the disclosures in Frondoza are sufficient to
render obvious the elements of claims 8—13, 17, 18, and 32—35.
Appellants next argue that “cross-linked hydrogels can provide
properties that would not be expected based on knowledge of the properties
of the separate materials alone.” Br. 19. Appellants argue Figure 4,
reproduced below, shows that
in relation to a hydrogel formed from cross-linking gelatin with
dextran . . . fibroblast cells exhibit only about 40% aggregation
when left untreated. When fibroblasts were treated with
collagen monomer alone or dextran alone . . . only about 20 to
25% of the cells were aggregated . . . when treated with the
hydrogel formed from dextran and gelatin, at least 80% of the
cells present were in an aggregated state.
Br. 19.
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Aggregation of Multiple Cell Types in Hydrogel Matrix
FIG, 4
Figure 4 depicts a bar chart showing the percent of aggregation of
multiple cell types in a hydrogel matrix.
Appellants claim the skilled artisan “with knowledge of Frondoza
would not expect that the use of a polymer alone would reduce cell
aggregation while a hydrogel formed from a combination thereof would
dramatically increase cell aggregation.” Id. at 19—20.
We are not persuaded. Appellants have not presented persuasive
evidence that the use of their cross-linked hydrogels is not obvious. “[B]y
definition, any superior property must be unexpected to be considered
evidence of non-obviousness.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348,
1371 (Fed. Cir. 2007). Appellants’ arguments point to data in Figure 4 of
the Specification, but this data is not sufficient for our analysis. Data for a
single “control monomer” is shown, but without identification of the cell
type, which may not match the tested cell types. In addition, this data does
not compare against the hydrogel taught by Frondoza, the closest prior art.
“To be particularly probative, evidence of unexpected results must establish
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that there is a difference between the results obtained and those of the closest
prior art, and that the difference would not have been expected by one of
ordinary skill in the art at the time of the invention.” Bristol-Myers Squibb
Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014). We find
no error in the Examiner’s understanding of claims 8—13, 17, 18, and 32—35
or analysis of the prior art.
Appellants next argue that claims 14—16 and 36 are not obvious
because “[njothing in Qian suggests that the hemostatic sealants discussed
therein would be suitable as cell-seeded microcarriers . . . The examiner
[has] not shown that a person of skill in the art would predict that a ground
hydrogel as taught by Qian would be a suitable cell-seeded microcarrier.”
Br. 20.
We are not persuaded. The Specification teaches “[t]he bioactive
hydrogel matrix can be in particulate form when combined with the cells for
cryopreservation.” FF4. Qian teaches a dry cross-linked gelatin powder that
can be cross-linked, dehydrated, and ground. FF16—17. The particle sizes
disclosed range from 150 pm to 750 pm, and Qian suggests “particle sizes
outside of this preferred range may find use in many circumstances.” FF18.
Given this teaching and the express suggestion to use other particle sizes as
desired, we agree with the Examiner that the invention disclosed by claims
14—16 and 36 is obvious, absent any evidence to the contrary from
Appellants.
Similarly, with regard to claim 29, Appellants argue “the examiner
has pointed to nothing in Hill that cures the various failures of Frondoza
discussed above ... a person of skill in the art viewing Frondoza would have
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no reason to attempt to modify the disclosure of Frondoza utilizing teaching
from Hill.” Br. 20. Appellants further argue the Examiner did not make a
showing that the combination is predictable. Id. at 21.
These arguments are not persuasive because they are merely attorney
argument without evidence. Hill teaches that a hydrogel may be dehydrated
by “[a]ny method known in the art,” including freeze drying, and then
ground to particulate form. FF19—20. We agree with the Examiner that
Appellants’ claim 29 is obvious in light of Hill and Frondoza, and that the
Examiner has established that the skilled artisan would have a reasonable
predictability of success making the invention of claim 29. In re O ’Farrell,
853 F.2d at 903—04. We find no error in the Examiner’s rejection of claim
29.
Conclusion of Law
In summary, we find a preponderance of the evidence supports the
Examiner’s conclusion that claims 1—6, 8—19, 21—25, 27—30, 32-41, 43, and
44 are obvious over the cited art.
SUMMARY
We affirm the rejection of claims 1, 2, 8—13, 17—19, 21—25, 27, 28,
30, 32—35, and 37-41 under 35 U.S.C. § 103(a) as obvious over Frondoza.
We affirm the rejection of claims 14—16 and 36 under 35 U.S.C.
§ 103(a) as obvious over Frondoza and Qian.
We affirm the rejection of claim 29 under 35 U.S.C. § 103(a) as
obvious over Frondoza and Hill.
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We affirm the rejection of claims 3—6, 43, and 44 under 35 U.S.C.
§ 103(a) as obvious over Frondoza and Usala.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
30