James Ankrum et al.

Patent Trials and Appeals Board

May 12, 2021

2020002994 (P.T.A.B. May. 12, 2021)

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.
14/986,904 01/04/2016 James Ankrum 8150BSC0320 1045
121974 7590 05/12/2021
Kacvinsky Daisak Bluni PLLC (8150)
2601 Weston Parkway, Suite 103
Cary, NC 27513
EXAMINER
THAKOR, DEVANG K
ART UNIT PAPER NUMBER
1619
NOTIFICATION DATE DELIVERY MODE
05/12/2021 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):
docketing@kdbfirm.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
_________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
_________________

Ex parte JAMES ANKRUM, JAMES D. CEZO, and STEVEN L. KANGAS

_________________

Appeal 2020-002994
Application 14/986,904
Technology Center 1600
_________________

Before DEBORAH KATZ, JON M. JURGOVAN, and
JOHN E. SCHNEIDER, Administrative Patent Judges.

KATZ, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 seeks our review2, under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 1–12 and 18–21. We have jurisdiction
under 35 U.S.C. § 6(b). We AFFIRM.

1 We use the word “Appellant” as defined in 37 C.F.R. § 1.42. Appellant
identifies the real parties-in-interest as University of Minnesota and Boston
Scientific Scimed, Inc. (Appeal Br. 2.)
2 We consider the Final Office Action issued March 7, 2019 (“Final Act.”),
the Appeal Brief filed August 8, 2019 (“Appeal Br.”), the Examiner’s
Answer issued on January 13, 2020 (“Ans.”), the Reply Brief filed March
13, 2020 (“Reply Br.”).
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Appellant’s specification is directed to tissue bulking compositions
that can be used to support and augment tissues in cardiology, orthopedics,
urology, gastroenterology, and in cosmetic and reconstructive surgery.
(Spec. ¶ 2.)
The Examiner made the following rejections of the claims, each for
obviousness under 35 U.S.C. § 103:
Claims References Citation in Final
Office Action
1–11, 18, 21 Moura,3 Gan,4 Sawhney, 5
Shi,6 Le Renard7
3–68
19 Moura, Gan, Sawhney, Shi,
Le Renard, Singelyn9
10

3 Moura et al., “In Situ Forming Chitosan Hydrogels Prepared via
Ionic/Covalent Co-Cross-Linking,” BIOMACROMOLECULES 12:3275-84
(2011).
4 Gan, et al., “In Situ Gelation of P(NIPAM-HEMA) Microgel Dispersion
and Its Applications as Injectable 3D Cell Scaffold,” BIOMACROMOLECULES
10:1410-15 (2009).
5 Sawhney and Edelman, U.S. Patent 6,703,047 B2, issued March 9, 2004.
6 Shi et al., “Therapeutic Potential of Chitosan and its Derivatives
in Regenerative Medicine,” JOURNAL OF SURGICAL RESEARCH, 133:185-92
(2006).
7 Le Renard, et al., “The in vivo performance of magnetic particle-loaded
injectable, in situ gelling, carriers for the delivery of local hyperthermia,”
BIOMATERIALS 31:691-705 (2010).
8 The Examiner does not indicate that Sawhney is cited for the rejection of
claims 1–11, 18, and 21 under 35 U.S.C. § 103, but refers to this reference in
the discussion of the rejection. (See, e.g., Final Act. 3–5.) Accordingly, we
understand the recitation of the rejection on pages 3–4 to have erroneously
failed to include Sawhney.
9 Singelyn et al., “Catheter-Deliverable Hydrogel Derived from
Decellularized Ventricular Extracellular Matrix Increases Endogenous
Cardiomyocytes and Preserves Cardiac Function Post-Myocardial
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20 Moura, Gan, Sawhney, Shi,
Le Renard, Vedrine10
11
1, 2, 12, and 21 Leor,11 Gan, Sawhney,
Naryani,12 Clark13
12–14

Appellant’s claim 1 recites:
A tissue bulking composition comprising:
(a) liquid dispersion of solid particles comprising a pH-
sensitive polymer that has a pH-dependent solubility such that
the solid particles dissolve upon an increase or decrease in pH,
(b) a crosslinking agent for the pH-sensitive polymer and
(c) a pH modifying agent that generates acid or base in
vivo,
wherein when the tissue bulking composition comprises
solid particles that dissolve upon a decrease in pH, the pH
modifying agent generates acid in vivo and
wherein when the tissue bulking composition comprises
solid particles that dissolve upon an increase in pH, the pH
modifying agent generates base in vivo.

(Appeal Br. 16 (indentations added).) Appellant’s dependent claim 7 limits
the pH-sensitive polymer to chitosan. (See Appeal Br. 16.) Appellant’s
dependent claim 11 limits the cross-linking age to genipin. (See Appeal Br.

Infarction,” JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 59:751–
63 (2012).
10 Verdine et al., U.S. Patent 8,262,641 B2, issued Sept. 11, 2012.
11 Leor et al., “Intracoronary injection of in Situ forming Alginate Hydrogel
Reverses left Ventricular Remodeling After Myocardial infarction in
Swine,” JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 54:1014-23
(2009).
12 Narayani and Rao, “pH-Responsive Gelatin Microspheres for Oral
Delivery of Anticancer Drug Methotrexate,” JOURNAL OF APPLIED POLYMER
SCIENCE 58:1761-69 (1995).
13 Clark and Leung, U.S. Patent 6,143,352, issued Nov. 7, 2000.
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17.) Thus, an embodiment of Appellant’s independent claim 1 has three
components: (a) a liquid dispersion of solid particles that comprises
chitosan, (b) genipin, and (c) a pH modifying agent that generates acid or
base in vivo. (See Appeal Br. 8–9.)
Rejection under 35 U.S.C. § 103 over Moura, Gan, Sawhney, Shi, and
Le Renard
The Examiner rejects claims 1–11, 18, and 21 under 35 U.S.C. § 103
over Moura, Gan, Sawhney, Shi, and Le Renard. (See Final Act. 3–6.)
Moura teaches compositions comprising chitosan, which cross-links to form
hydrogels in situ. (See Moura abstract; see Final Act. 4.) Moura teaches
further that chitosan is a pH-sensitive polymer with a pH-dependent
solubility that dissolves with an increase or decrease in pH. (See Moura
abstract; see Final Act 4.) Moura provides genipin as a chemical cross-
linker for chitosan hydrogels. (See Moura abstract; see Final Act. 4.) In the
method of Moura chitosan is a dissolved polymer that gels into a hydrogel
when administered in situ. (See Final Act. 4; see Moura 3276.)
Moura does not teach including a pH modifying agent that generates
acid or base in vivo to regulate dissolution of a composition. (See Final Act.
4.)
Gan teaches using thermosensitive microgel particles or microspheres
for construction of the macroscopic hydrogel scaffolds. (See Gan Abstract.)
Gan teaches that such particles or microspheres have advantages over linear,
branched, or grafted macromolecules when constructing a hydrogel scaffold
because the particles reduce viscosity and exhibit better mechanical
properties. (See Gan Abstract, 1410; see Final Act. 4.)
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Gan reports on a polymer, P(NIPAM-HEMA), which is different from
chitosan, as a “proof of concept” for microgel dispersion undergoing thermal
gelation in situ. (See Gan 1410.) Gan teaches further that chitosan “holds
great promise for the use as injectable scaffolds.” (Gan 1410.) The
Examiner finds that Gan demonstrates it was known in the art to use the
chitosan of Moura as insoluble, small gelled particles that would accumulate
and form a full hydrogel at the site of interest, instead of using chitosan in a
non-gelled, soluble state. (See Ans. 5–6.)
Sawhney teaches compositions and methods for forming tissue-
adherent hydrogels using dry precursors. (See Sawhney Abstract.) The
Examiner cites to Sawhney for its teaching that particles can be dissolved in
situ and then crosslinked in situ to form a hydrogel. (See Sawhney 3:2–10,
Examples 3 and 5; see Final Act. 5.)
The Examiner cites to Shi for its teaching that chitosan is insoluble in
neutral or basic conditions, but is soluble in acidic conditions. (See Shi 186;
see Final Act. 5.) And the Examiner cites to Le Renard for its teaching of an
injectable composition using in situ acidification to locally dissolve a
substance that is only soluble in acidic conditions. (See Le Renard 186; see
Final Act. 5.) Specifically, Le Renard demonstrates that δ-gluconolactone
was known to provide delayed acidification to locally dissolve a substance
used for in situ implantation of anti-cancer agents. (See Le Renard 692; see
Final Act. 5.) Although Le Renard teaches that chitosan was found to be
inadequate for incorporating the specific nanoparticles used to treat cancer
(likely because of the silica included in those nanoparticles), Le Renard
refers to other uses of in situ implants, such as vascular lesion filling. (See
Le Renard 691.)
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The Examiner determines that it would have been obvious to one of
ordinary skill in the art at the time of invention to include δ-gluconolactone
in the composition of Moura, Gan, and Sawhney to provide delayed
acidification of the composition, thus dissolving the chitosan particles in
situ, as described by Sawhney, and allowing it to form a bulk hydrogel in
situ upon crosslinking by the genipin, as described by Moura. (Final Act. 5.)
We note that Appellant’s Specification reflects this technique by
providing injectable compositions of pH sensitive chitosan, genipin, and
glucono-delta-lactone (GDL), wherein
[j]ust prior to injection, an aqueous fluid such as water, saline or PBS
may be added to a container containing the three components. The
genipin and GDL dissolve, and the chitosan, being insoluble at neutral
pH is dispersed in particulate form (i.e., it exists in the form of a
dispersion). The dispersed chitosan particles add little to the solution
viscosity. The dispersion is then injected into the tissue. Without
being bound by theory, it is believed that within a few minutes the
GDL begins to hydrolyze to gluconic acid, thereby reducing the pH
and causing the chitosan to swell and dissolve, which increases the
viscosity. As the chitosan dissolves; the genipin begins to crosslink
the chitosan resulting in a crosslinked hydrogel. In addition, the
genipin is also capable of crosslinking surrounding collagen to itself
and to the chitosan1 thereby forming a chitosan-collagen composite.

(Spec. ¶ 57.) The prior art cited by the Examiner shows that these elements
of the claimed invention were known to those of ordinary skill. Specifically,
chitosan was a known pH sensitive polymer (Moura) that could be
administered as insoluble particles (Gan), that genipin was a known cross-
linking agent (Moura), and δ-gluconolactone was a known latent acid
generator that could be used to dissolve chitosan by reducing the pH (Shi)
and allowing it to be cross-linked in situ (Le Renard). Sawhney
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demonstrates that it was known to dissolve hydrogel particles in situ and
cross-link them in the same location.
Appellant argues that one of ordinary skill in the art would not have
combined the teachings of Moura and Gan because Moura teaches using
dissolved particles, whereas Gan teaches insoluble microgel particles. (See
Appeal Br. 9–10; see Reply Br. 8.) Appellant argues that contrary to the
Examiner’s determination, one of ordinary skill in the art would not have
considered it obvious to inject the chitosan of Moura as insoluble
particulates rather than as a dissolved polymer because the dissolved
particles of Moura and the insoluble particles of Gan are mutually exclusive.
(See Appeal Br. 9–10.) According to Appellant, an ordinarily skilled artisan
would not have replaced one for the other. (See id.) Appellant argues that
there would not have been a reason to make such a substitution. (See id.)
We are not persuaded by Appellant’s argument because Gan includes
chitosan as a polymer that holds great promise for use as an injectable
scaffold and, thus, as a polymer that would be more beneficial if injected as
an insoluble microparticle rather than a dissolved, non-gelled hydrogel. (See
Gan 1410.) Even though Gan reports results of a different hydrogel,
Appellant fails to direct us to evidence that one of ordinary skill would not
have considered these results to also occur with chitosan, given Gan’s
discussion of chitosan as having promise. (See Reply Br. 9, 12.) We do not
agree with Appellant that the dissolved polymers of Moura would have been
considered to be mutually exclusive to the insoluble particles of Gan because
Gan teaches that chitosan is among the type of polymer that can gelate by
heating to form an injectable scaffold. (See Ans. 5–7.) As The Examiner
notes, both Moura and Gan are directed to the same goal – creating hydrogel
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scaffolds at a desired location in the body after injection and both provide
chitosan as a polymer to achieve that goal. (See id.) Therefore, we are not
persuaded that the teachings of Moura and Gan are as distinct as Appellant
argues.
Appellant argues further that the Examiner’s reliance on Sawhney
does not provide a reason for why one would have substituted the dissolved
particles of Moura for the insoluble particles of Gan. (See Appeal Br. 10.)
Appellant asserts that combining the teaching in Sawhney to dissolve
particles in situ before cross-linking to form a final hydrogel merely to
provide a reason to use the dissolved particles of Moura instead of the
insoluble particles of Gan is merely an attempt to “piece the combination
together” to arrive at the claimed composition. (Appeal Br. 10; Reply Br. 9.)
Appellant argues that the Examiner’s rejection does not address how
dissolving dehydrated particles, as taught in Sawhney, would work with
insoluble particles, as taught in Gan. (See Ans. 11.)
We are not persuaded by Appellant’s arguments because the
Examiner’s rejection is not based on the substitution of the dissolved
particles of Moura for the insoluble particles of Gan, per se, but rather on the
use of chitosan, as taught in both Moura and Gan, as pre-gelled particles
taught in Gan, instead of as dissolved in a liquid taught in Moura. (See Ans.
9.) Sawhney was cited for its teaching of bulk gelation of chitosan particles,
because neither Moura nor Gan teaches how to achieve bulk gelation. (See
Ans. 9.) Sawhney demonstrates that it was known that such bulk gelation
can be achieved by dissolving hydrogel precursor particles in situ using
naturally-occurring body fluids, followed by in situ cross-linking to form a
final hydrogel. (See Ans. 9–10; see Final Act. 5.) Thus, we agree with the
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Examiner that it would have been considered obvious by one of ordinary
skill in the art to use the system of Sawhney with a hydrogel as taught in
Moura and Gan. (Contra Reply Br. 10–11.)
The Examiner explains that use of the process taught in Sawhney to
achieve the claimed composition is further supported by Shi and Le Renard.
(See Ans. 10, see Final Act. 5; contra Reply Br. 11.) Specifically, Shi
teaches that chitosan is soluble at acidic pH and Le Renard teaches that
injectable compositions can be locally dissolved in acidic conditions by
including δ-gluconolactone to provide delayed acidification through slow
lactone hydrolysis. (See Shi, 186; see Le Renard, 692.) Thus, we agree with
the Examiner that Sawhney, as well as Shi and Le Renard, render the
claimed composition obvious because their teachings demonstrate using
delayed acidification of a composition to dissolve chitosan particles in situ
before forming a cross-linked bulk hydrogel in situ was a known technique.
(See Ans. 10.)
“[I]f a technique has been used to improve one device, and a person of
ordinary skill in the art would recognize that it would improve similar
devices in the same way, using the technique is obvious unless its actual
application is beyond his or her skill.” KSR Int'l Co. v. Teleflex Inc., 550
U.S. 398, 417 (2007). In light of the teachings in the cited prior art, we are
not persuaded that the Examiner erred in rejecting claim 1. Appellant does
not raise separate arguments against the other claims rejected as being
obvious over Moura, Gan, Sawhney, Shi, and Le Renard. Accordingly, we
are not persuaded that the Examiner erred in the rejection.
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Rejection under 35 U.S.C. § 103 over Moura, Gan, Sawhney, Shi, Le
Renard and Singelyn or Vedrine
The Examiner rejects claims 19 and 20 over Moura, Gan, Sawhney,
Shi, Le Renard and Singelyn or Vedrine, citing Singelyn and Vedrine for
teaching needle injection catheter and a needle-penetration septum,
respectively. (See Final Act. 10–11.) Appellant argues only that neither
Singelyn nor Verdine cures the deficiencies of Moura, Gan, Sawhney, Shi,
and Le Renard. (See Final Act. 12; see Reply Br. 13.) As explained above,
we are not persuaded the rejection of claim 1 over these references is
deficient. Accordingly, Appellant does not persuade us that the Examiner
erred in rejecting claims 19 and 20.
Rejection under 35 U.S.C. § 103 over Leor, Gan, Sawhney, Naravani,
and Clark
The Examiner rejects claims 1, 2, 12, and 21 as being rendered
obvious by the teachings of Leor, Gan, Sawhney, Naravani, and Clark. (See
Final Act. 12–14.) Leor teaches tissue bulking with alginate by
intracoronary injection into the myocardium to form a hydrogel and prevent
some effects of myocardial infarction. (See Leor abstract.) The Examiner
finds that alginate is a pH-sensitive polymer that has pH-dependent
solubility. (See Final Act. 12.) Leor teaches that a calcium cross-linked
alginate solution is prepared by combining a sodium alginate solution with a
calcium D-gluconate solution. (See Leor 1015.)
The Examiner finds that Leor does not teach that sodium alginate is
present in solid particles, teaching instead to use alginate as a dissolved
polymer. (See Final Act. 13.) The Examiner cites to Gan for the teaching,
as discussed above, to use in situ gelling injectable hydrogel materials as
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insoluble microgel particles rather than as dissolved polymers. (See Final
Act. 13, citing Gan 1410.) Thus, the Examiner finds that it would have been
obvious to one of ordinary skill in the art to use the sodium alginate of Leor
in insoluble particulate form. (See Final Act. 13.)
The Examiner finds that neither Leor nor Gan teaches forming bulk
hydrogel formations in situ, but cites Sawhney as discussed above in regard
to the rejection based on Moura and Gan. (See Final Act. 13.) As in that
rejection, the Examiner cites Sawhney for its teaching of dissolving in situ
and then cross-linking to form a final hydrogel. (See Final Act. 13, citing
Sawhney 3:2–10, Examples 3 and 5.) In addition, the Examiner cites
Narayani for its teaching that alignate is highly soluble in alkaline pH, but
insoluble in acidic pH. (See Final Act. 14, citing Narayani 1767.)
The Examiner determines that it would have been obvious to include
sodium carbonate in the composition of Lear, Gan, Sawhney, and Naryani,
providing alkalinization of the composition and dissolving the alginate
particles in situ as described by Sawhney, thus allowing the alginate to be
cross-linked by the calcium D-gluconate as described by Leor. (See Final
Act. 14.)
Appellant raises similar arguments against the rejection based on Leor
as raised against the rejection based on Moura. Specifically, Appellant
argues that the soluble state of the alginate hydrogels of Leor and the
insoluble micro gel particles of Gan are mutually exclusive and that
replacing the former with the latter would be a complete transformation from
one state to another. (See Appeal Br. 12; see Reply Br. 14–15.) According
to Appellant, Gan teaches away from the combination of insoluble particles
with soluble alginate hydrogels as taught in Leor. Appellant cites to the
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teaching in Leor that alginate hydrogel implants provide only temporary
physical support for damaged cardiac tissue and then gradually disappear.
(See Appeal Br. 12.)
We are not persuaded by Appellant’s argument because the
Examiner’s rejection is not based on a combination of soluble and insoluble
particles. Instead, the rejection is based on the teaching in Gan of injecting
insoluble microgel particles rather than injecting dissolved polymer. (See
Final Act. 15, citing Gan 1410.)
Appellant also argues that it is unreasonable to determine that one of
skill in the art would have look to “swap out” the soluble particles of Leor
with the insoluble microgel particles of Gan and further to dissolve those
insoluble microgel particles in order to “piece this combination together.”
(Appeal Br. 13.) We are not persuaded by these arguments because, as
explained above, the rejection is not based on a substitution of compounds,
but instead on the preference for hydrogels in one form (insoluble) over
another (soluble).
Appellant argues further that there would have been no reason for one
of ordinary skill to have looked to the teachings of Narayani and Clark and
that these references do not explain how dissolving the dehydrated particles
of Sawhney would work with the insoluble particles of Gan. (See Appeal
Br. 14.) We are not persuaded by these arguments because Sawhney was
cited to demonstrate that it was known that bulk gelation can be achieved by
dissolving hydrogel precursor particles in situ using naturally-occurring
body fluids, followed by in situ cross-linking to form a final hydrogel. (See
Ans. 9–10; see Final Act. 5.) Thus, the rejection is based on the use of
insoluble particles, solubilized in situ and then cross-linked.
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As explained above, Appellant’s Specification provides for the same scheme
to achieve the claimed composition. (See Spec. ¶ 57.)
None of Appellant’s arguments persuade us that the Examiner erred in
rejecting claim 1 as being obvious over Leor, Gan, Sawhney, Naravani, and
Clark. Appellant does not raise separate arguments against the rejection of
claims 2, 12, or 21 over these references. Accordingly, we are not persuaded
that the Examiner erred.
Conclusion
Upon consideration of the record and for the reasons given, we affirm
the Examiner’s rejection.
In summary:
Claims
Rejected
35 U.S.C. § Basis/Reference(s) Affirmed Reversed
1–11, 18, 21

103 Moura, Gan,
Sawhney, Shi, Le
Renard
1–11, 18,
21

19

103 Moura, Gan,
Sawhney, Shi, Le
Renard, and
Singelyn
19

20 103 Moura, Gan,
Sawhney, Shi, Le
Renard, Vedrine

20
1, 2, 12, 21 103 Leor, Gan,
Sawhney, Naryani,
Clark
1, 2, 12, 21
Overall
Outcome
1–12, 18–
21

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No time period for taking any subsequent action in connection with
this appeal may be extended. See 37 C.F.R. § 1.136(a)(1)(iv).

AFFIRMED