Tillman, Bryan et al.

Patent Trials and Appeals Board

Feb 19, 2020

12356982 - (D) (P.T.A.B. Feb. 19, 2020)

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.
12/356,982 01/21/2009 Bryan Tillman 140155.03101 9854
959 7590 02/19/2020
NELSON MULLINS RILEY & SCARBOROUGH LLP
FLOOR 30, SUITE 3000
ONE POST OFFICE SQUARE
BOSTON, MA 02109
EXAMINER
CHEN, SHIN LIN
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
02/19/2020 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
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte BRYAN TILLMAN, ANTHONY ATALA, and JAMES YOO
__________

Appeal 2019-000913
Application 12/356,982
Technology Center 1600
__________

Before FRANCISCO C. PRATS, JEFFREY N. FREDMAN, and
TAWEN CHANG, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL

Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 13–21, 23, 25, 27, and 28. We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant states that “Wake Forest University Health
Sciences is the real party in interest.” Appeal Br. 1.
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STATEMENT OF THE CASE
The following rejections are before us for review:
(1) Claims 13–17, 19–21, 25, 27, and 28, under 35 U.S.C. § 103(a) as
being unpatentable over Flameng,2 Xu,3 and Shamblott4 (Ans. 3–9);
(2) Claims 13, 17, and 18, under 35 U.S.C. § 103(a) as being
unpatentable over Flameng, Xu, Shamblott, and Alarcon5 (Ans. 9–14); and
(3) Claims 13, 17, and 23, under 35 U.S.C. § 103(a) as being
unpatentable over Flameng, Xu, Shamblott, and Hsieh6 (Ans. 14–16).
Claim 13, the sole independent claim on appeal, is representative and
reads as follows:
13. A self-seeding, implantable vascular scaffold for in vivo
seeding and development of target cells comprising:
a three-dimensional, biomatrix scaffold having a
supportive framework that allows the target cells to attach and
grow, wherein the biomatrix scaffold comprises a decellularized
matrix having an intact acellular infrastructure comprising a
collagen network with interstitial distances suitable for cell-cell
interactions; and
an affinity moiety with substantial affinity for a target
stem cell population comprising endothelial progenitor cells
expressing a CD133 marker, wherein the affinity moiety
comprises a CD133 antibody incorporated into and covalently
coupled to the decellularized matrix and is capable of attracting
and binding to said CD133+ endothelial progenitor cells in
vivo, following implantation.
Appeal Br. 27.

2 US 2007/0264306 A1 (published Nov. 15, 2007).
3 US 2007/0042341 A1 (published Feb. 22, 2007).
4 US 2008/0233087 A1 (published Sept. 25, 2008).
5 US 2005/0239155 A1 (published Oct. 27, 2005).
6 US 2006/0149392 A1 (published July 6, 2006).
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OBVIOUSNESS
The Examiner’s Prima Facie Case
The Examiner cited Flameng as disclosing implantable biocompatible
matrices useful as vascular or arterial grafts, the implantable matrices having
“homing factors” bound to the surface of the matrices. Ans. 4. The
Examiner noted that the “homing factor is a ligand of [a] receptor or a
peptide that binds to the receptor expressed on stem cells or progenitor
cells.” Id. (citing Flameng ¶ 20). The Examiner further noted that Flameng
listed CD133 among “5 markers predominantly expressed by
stem/progenitor cells.” Id. at 5.
The Examiner found that Flameng’s implantable matrices differed
from the implantable scaffold recited in Appellant’s representative claim 13
in that Flameng did not use a CD133 antibody as the homing factor on the
surface of its implantable matrices, and that Flameng did not expressly state
that its matrices were composed of a collagen network with interstitial
distances suitable for cell-cell interactions. See Ans. 6.
The Examiner determined that the scaffold of Appellant’s claim 13
would have been obvious despite the differences between Flameng’s
matrices and claim 13’s scaffold. Specifically, the Examiner cited Xu as
evidence that it was known in the art to covalently link an antibody to a
collagen substrate, thereby allowing the collagen-bound antibody to select
cells from a population. Ans. 6.
In addition, the Examiner cited Shamblott as evidence that it was
known in the art to use matrix-bound antibodies to CD133, as recited in
Appellant’s representative claim 13, to identify and select pancreatic
endocrine progenitor cells from a mixed population of cells. Ans. 6–7.
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Based on the references’ combined teachings, the Examiner reasoned
that a skilled artisan would have considered it obvious to use a “collagen
network with interstitial distances suitable for cell-cell interactions because
Flameng teaches preparation of scaffolds comprising a structural matrix
coated with one or more homing factors that is a ligand of receptor or a
peptide binding to stem cells or progenitor cells and the scaffold is
composed of collagen.” Ans. 7.
The Examiner reasoned that a skilled artisan would have considered it
obvious to use a CD133-binding antibody as the homing factor on
Flameng’s scaffolds “because Flameng teaches preparation of scaffolds
comprising a structural matrix coated with one or more homing factors that
binds to stem cells or progenitor cells having cell marker CD 133 . . . .”
Ans. 7. In particular, the Examiner reasoned:
Since both Flameng and Shamblott teach using CD 133
antibody for selecting CD 133 expressing cells and Shamblott
also teaches using CD 133 antibody bound to or conjugated to
matrix for isolating or enriching CD 133 expressing cells, it
would be obvious for of ordinary skill in the art at the time of
the invention to bind or conjugate the CD 133 antibody onto the
scaffolds comprising a structural matrix such as collagen as
taught by Flameng in order to isolate or enrich cells expressing
CD 133 from a mixed population of cells with reasonable
expectation of success.
Id. at 8.
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
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record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
Having carefully considered the evidence and arguments advanced by
Appellant and the Examiner, Appellant does not persuade us that the
preponderance of the evidence fails to support the Examiner’s conclusion of
obviousness as to representative claim 13 over Flameng, Xu, and Shamblott.
In particular, Appellant does not persuade us that the Examiner erred in
determining that a skilled artisan would have been motivated to use
antibodies to CD133 as the homing factors in Flameng’s matrices. See
Appeal Br. 13–18; Reply Br 3–5.
Flameng discloses “the use of matrices in cell recruitment and . . .
modified matrices comprising homing factors for in vivo recellularisation of
implantable medical devices such as cardiac valves and vascular grafts.”
Flameng, abstract.
In one embodiment, Flameng describes affixing its homing factors to
“scaffolds for use in the cardiovascular system, lymphatic system or other
vessels, such as but not limited to, urethra.” Flameng ¶ 18. Flameng
discloses in particular that “the homing factors of the present invention are
factors capable of binding to stem cells or progenitor cells.” Id.
In one embodiment, Flameng discloses implanting its homing
factor-bearing scaffold into a human or animal body, allowing the cells to
seed themselves onto the scaffold, and then removing the implanted
cellularized scaffold from the body to recover desired cell populations,
among them stem cells. See Flameng ¶ 43 (“Typically, for the isolation of
stem cells and/or precursor cells from the peritoneal cavity the scaffold is
maintained in the body for 2 or 3 days, whereafter it is retrieved for isolation
of the cells.”).
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Flameng discloses that cells bearing the CD133 surface antigen are
among the desirable types of stem cells that may be obtained using its
scaffolds, and that CD133 cells may be isolated from the scaffold-retrieved
cells using an antibody to the CD133 marker. Flameng ¶ 46 (“Examples of
suitable antibodies for selecting precursor and/or progenitor cells include but
are not limited to CD133 (primitive stem cells, subset of the CD34+ stem
and progenitor cells, endothelial precursor cells) . . . .”).
Flameng differs from Appellant’s representative claim 13 in that
Flameng does not list antibodies to the CD133 marker among its preferred
homing factors. See Flameng ¶¶ 57–66.
Flameng, however, broadly defines its homing factors as molecules
that interact only with specific cell types:
Homing proteins or homing factors are defined as docking
molecules which interact with one or more specific cell types
and thus, when attached to a matrix, allow the enrichment of
those cells types on the matrix. A docking molecule ensures
the interaction between the matrix and a molecule at the surface
of the cell, such as another protein, or a carbohydrate structure,
also referred to herein as the cellular target molecule.
According to a particular embodiment of the invention, the
homing factor is a molecule which ensures a specific interaction
between the matrix and one or more specific cell types; this can
be ensured by the binding of the homing factor to a molecule
which occurs essentially only on the surface of one or more
specific cell types or by adjusting the homing factor so as to
bind only to the cellular target molecule on the one or more
specific cell types.
Flameng ¶ 50.
Thus, to summarize, Flameng teaches that its homing factor should be
a protein that ensures specific interaction between its matrix and one or more
specific cell types, in particular stem/progenitor cells. See Flameng ¶¶ 43–
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46, 50. Flameng teaches that the specific interaction between the desired
cells and the matrix “can be ensured by the binding of the homing factor to a
molecule which occurs essentially only on the surface of one or more
specific cell types or by adjusting the homing factor so as to bind only to the
cellular target molecule on the one or more specific cell types.” Id. ¶ 50.
And, Flameng teaches that cells bearing the CD133 surface antigen are
among the desirable types of stem cells that may obtained using its scaffolds,
and that CD133 cells may be isolated from the scaffold-retrieved cells using
an antibody to the CD133 marker. Id. ¶ 46.
Accordingly, given Flameng’s teaching that its homing factors should
provide cell type-specific binding to its matrices/scaffolds, and given
Flameng’s teaching that CD133 cells, isolatable using anti-CD133
antibodies, are among the types of stem cells that are desirable to bind to its
matrices/scaffolds, Appellant does not persuade us that the Examiner erred
in determining that a skilled artisan had a good reason for, and a reasonable
expectation of success in, using an anti-CD133 antibody as the homing
factor attached to Flameng’s matrices/scaffolds. To the contrary, given the
undisputed teachings in Xu and Shamblott that it was known in the art to
attach anti-CD133 antibodies to substrates for the purpose of binding
CD133-specific cells to the substrates, we agree with the Examiner that the
anti-CD133 antibody-bearing scaffold recited in Appellant’s representative
claim 13 would have been prima facie obvious to a skilled artisan in view of
the combined teachings of Flameng, Xu, and Shamblott.
Appellant does not persuade us that the results in Flameng’s examples
would have caused a skilled artisan to ignore Flameng’s teachings, discussed
above, suggesting the use of a CD133 antibody as a homing factor on the
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surface of Flameng’s matrices/scaffolds, or would have dissuaded a skilled
artisan from following those teachings. Specifically, in Example 7, Flameng
discloses that implanting a scaffold coated with a combination of fibronectin
(FN) and stromal derived factor 1 (SDF-1) as homing factors “results in a
more natural composition of the cell populations with respect to a native
heart valve.” Flameng ¶ 160; see also id. at ¶ 147 (in Example 4
combination of FN and SDF-1 as homing factors “significantly increased”
CD117-positive stem cells adhering to scaffold).
That a CD133 antibody was not among an exemplified combination of
homing factors providing positive results does not persuade us that a skilled
artisan would have ignored the other teachings in Flameng, discussed above,
suggesting the use of a CD133 antibody as a homing factor on the surface of
Flameng’s matrices/scaffolds. It is well settled that “[a]ll the disclosures in a
reference must be evaluated, including nonpreferred embodiments, and a
reference is not limited to the disclosure of specific working examples.” In
re Mills, 470 F.2d 649, 651 (CCPA 1972) (citations omitted).
In sum, for the reasons discussed, Appellant does not persuade us that
the Examiner erred in determining that the anti-CD133 antibody-bearing
scaffold recited in Appellant’s representative claim 13 would have been
prima facie obvious to a skilled artisan in view of the combined teachings of
Flameng, Xu, and Shamblott. Appellant also does not persuade us that it has
advanced evidence of unexpected results sufficient to outweigh the evidence
of prima facie obviousness advanced by the Examiner.
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We acknowledge the disclosure in the Jordan publication7 identified
by Appellant that, after three months’ in vivo implantation in sheep, cells
seeded significantly better onto a scaffold with CD133 antibodies on its
surface, as compared to scaffolds that were pre-seeded with cells, and
compared to a scaffold with no cell-specific binding moieties on its surface.
See Jordan 204 (Fig. 2). We acknowledge that both the Williams8
publication and Vossler publication9 describe similar results. See Williams
411 (abstract), 415–16; see also Vossler 1 (abstract) and 6.
It is well settled, however, that “any superior property must be
unexpected to be considered as evidence of non-obviousness.” Pfizer, Inc. v.
Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007). It is also well settled
that, by themselves, assertions in briefing by counsel as to the
unexpectedness of experimental results are of little probative value toward
nonobviousness, absent some evidence, beyond the assertions in the briefs,
that a skilled artisan actually would have considered the results unexpected.
See In re Geisler, 116 F.3d 1465, 1470–71 (Fed. Cir. 1997) (finding
arguments of unexpected results unpersuasive “naked attorney argument”
because applicant “did not offer evidence of unexpected results in the form
of a statement to that effect from the inventors or any third party, or any
objective evidence from a respected source” nor did applicant make any

7 J. E. Jordan, Ph.D. et al., Bioengineered self-seeding heart valves, 143 THE
JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2018–208 (2012)
8 J. Koudy Williams et al., Characterization of CD133 Antibody-Directed
Recellularized Heart Valves, 8 J. OF CARDIOVASC. TRANS. RES. 411–420
(2015).
9 J. D. Vossler et al., CD133 antibody conjugation to decellularized human
heart valves intended for circulating cell capture, 10 BIOMED. MATER. 1–19
(2015).
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statements of unexpectedness in its specification or in an affidavit under 37
C.F.R. § 1.132).
In the present case, other than the assertions in its briefs, Appellant
does not identify, nor do we discern, any statements in the Specification, or
elsewhere in the record, suggesting that the experimental results shown in
the Jordan, Williams, and Vossler publications actually would have been
unexpected by a skilled artisan. Appellant’s assertions of unexpectedness
are, therefore, of little probative value. Indeed, given the evidence of record
that substrate-immobilized CD133 antibodies allow CD133-bearing cells to
adhere to the substrate, we agree with the Examiner that the results advanced
by Appellant, on this record, would have been expected.
We acknowledge that in its Example 4, Flameng discloses that
“[o]verall no difference in quantitative cell adhesion was found (Table 5)”
after 24 hours of implantation of scaffolds with different homing factors.
Flameng ¶ 145. As noted above, however, in Example 4 Flameng also
discloses that the combination of FN and SDF-1 as homing factors provided
a positive result by “significantly increas[ing]” CD117-positive stem cells
adhering to scaffold. Id. ¶ 160.
We acknowledge that Table 6 of Flameng (Example 6) shows that
after 3 days of implantation, CD133 cells were a relatively small percentage
of cells that adhered to an implanted scaffold which lacked specific homing
factors. See Flameng ¶ 153.
Given the differences in implantation times and homing factors used
in Flameng’s Examples 4 and 6, as compared to the Jordan, Williams, and
Vossler publications, we are not persuaded Flameng’s Examples 4 and 6
provide an adequate basis for a comparison sufficient to show
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unexpectedness. To the contrary, given Flameng’s disclosure that CD133
cells adhered to its decellularized scaffolds even in the absence of
CD133-specific homing factors, and further given Flameng’s disclosure that
it was desirable to obtain CD133 cells, we agree with the Examiner that a
skilled artisan would have been motivated to use CD133 antibodies as
Flameng’s homing factor, to ensure the adherence of CD133 cells to the
implanted scaffolds.
In sum, for the reasons discussed, Appellant does not persuade us that
the Examiner erred in finding that the scaffold recited in Appellant’s
representative claim 13 would have been prima facie obvious to a skilled
artisan in view of the combined teachings of Flameng, Xu, and Shamblott.
For the reasons discussed, Appellant also does not persuade us that it has
advanced evidence of unexpected results sufficient to outweigh the evidence
of prima facie obviousness advanced by the Examiner. We, therefore,
affirm the Examiner’s rejection of Appellant’s representative claim 13 over
Flameng, Xu, and Shamblott. Because Appellant did not argue claims 14–
17, 19-21, 25, 27, and 28 separately, claims 14–17, 19-21, 25, 27, and 28 fall
with claim 13.
The Examiner also rejected claims 13, 17, and 18 for obviousness
over Flameng, Xu, Shamblott, and Alarcon. See Ans. 9–14. In traversing
this rejection, Appellant argues only that the Alarcon reference fails to
remedy the deficiencies, discussed above, of the combination of Flameng,
Xu, and Shamblott in relation to claim 13. See Appeal Br. 19–20. As
discussed above, however, we are not persuaded that the combined teachings
of Flameng, Xu, and Shamblott fail to establish the obviousness of the
scaffold recited in claim 13. We, therefore, also affirm the Examiner’s
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rejection of claims 13, 17, and 18 for obviousness over Flameng, Xu,
Shamblott, and Alarcon.
The Examiner also rejected claims 13, 17, and 23 for obviousness
over Flameng, Xu, Shamblott, and Hsieh. See Ans. 14–16. In traversing
this rejection, Appellant argues only that the Hsieh reference fails to remedy
the deficiencies, discussed above, of the combination of Flameng, Xu, and
Shamblott in relation to claim 13. See Appeal Br. 20–21. As discussed
above, however, we are not persuaded that the combined teachings of
Flameng, Xu, and Shamblott fail to establish the obviousness of the scaffold
recited in claim 13. We therefore also affirm the Examiner’s rejection of
claims 13, 17, and 23 for obviousness over Flameng, Xu, Shamblott, and
Hsieh.
CONCLUSION

In summary:
Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed
13–17, 19–21, 25,
27, 28
103(a) Flameng, Xu,
Shamblott
13–17, 19–21,
25, 27, 28

13, 17, 18 103(a) Flameng, Xu,
Shamblott, Alarcon
13, 17, 18
13, 17, 23 103(a) Flameng, Xu,
Shamblott, Hsieh
13, 17, 23
Overall Outcome 13–21, 23, 25,
27, 28

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

AFFIRMED