Eduardo Marban

Patent Trials and Appeals Board

Jun 8, 2020

2019005766 (P.T.A.B. Jun. 8, 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.
13/412,051 03/05/2012 Eduardo Marban 44807-0101001 6835
147364 7590 06/08/2020
FISH & RICHARDSON P.C. (JOHNS HOPKINS)
P.O. BOX 1022
MINNEAPOLIS, MN 55440-1022
EXAMINER
SCHUBERG, LAURA J
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
06/08/2020 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
following e-mail address(es):
PATDOCTC@fr.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte EDUARDO MARBAN
__________

Appeal 2019-005766
Application 13/412,051
Technology Center 1600
__________

Before ERIC B. GRIMES, FRANCISCO C. PRATS, 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 39 and 58–74. We have jurisdiction
under 35 U.S.C. § 6(b).
We REVERSE.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant states that “[t]he real patties in interest are The
Johns Hopkins University, a Maryland corporation, the assignee of this
application; and Capricor Therapeutics, Inc., a Delaware corporation, an
exclusive licensee of this application from The Johns Hopkins University.”
Appeal Br. 4.
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STATEMENT OF THE CASE
The following rejections are before us for review:
(1) Claims 73 and 74, under pre-AIA 35 U.S.C. § 102(a) as being
anticipated by Messina2 (Final Act. 4–5 (entered January 25, 2018))
(2) Claims 39, 58–63, and 70–74, under pre-AIA 35 U.S.C. § 103(a)
as being unpatentable over Messina,3 Heng,4 and Harvey5 (Final Act. 5–10);
(3) Claims 64–66, under pre-AIA 35 U.S.C. § 103(a) as being
unpatentable over Messina, Heng, Harvey, Beltrami,6 and Piper7 (Final Act.
11–12); and
(4) Claims 64–69, under pre-AIA 35 U.S.C. § 103(a) as being
unpatentable over Messina, Heng, Harvey, Piper, and Beltrami (Final Act.
13–14).
Claims 39, 73, and 74, the independent claims on appeal, read as
follows:

2 Elisa Messina et al., Isolation and Expansion of Adult Cardiac Stem Cells
From Human and Murine Heart, 95 CIRCULATION RESEARCH 911–921
(2004).
3 WO 2009/087087 A1 (published July 16, 2009).
4 Boon Chin Heng et al., Strategies for directing the differentiation of stem
cells into the cardiomyogenic lineage in vitro, 62 CARDIOVASCULAR
RESEARCH 34–42 (2004).
5 Richard P. Harvey, Molecular Determinants of Cardiac Development and
Congenital Disease (Chapter 16), MOUSE DEVELOPMENT 331–370 (2002).
6 Antonio P. Beltrami et al., Adult Cardiac Stem Cells Are Multipotent and
Support Myocardial Regeneration, 114 CELL 763–776 (2003).
7 H. Michael Piper et al., Determinants of Cardiomyocyte Development in
Long-term Primary Culture, 20 J. MOL. CELL. CARDIOL. 825–835 (1988).
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39. A method of treating a subject having diseased or
damaged cardiac tissue, the method comprising administering
to the subject a therapeutically effective amount of
cardiosphere-derived cells (CDCs),
wherein said CDCs are a population of cells
obtained by plating and expanding cardiospheres (CSps)
as an adherent monolayer culture on a solid surface of a
culture vessel; and
wherein said CDCs are not further manipulated to
form secondary cardiospheres (IICSps).

73. A method of treating a subject having diseased or
damaged cardiac tissue, the method comprising administering
to the subject a therapeutically effective amount of
cardiosphere-derived cells (CDCs), wherein said CDCs are a
population of cells obtained by:
collecting cardiospheres (CSps);
plating said CSps onto a culture vessel; and
expanding said CSps as an adherent monolayer
culture on a solid surface of said culture vessel to form
said therapeutically effective amount of said CDCs.

74. A method of treating a subject having diseased or
damaged cardiac tissue, the method comprising administering
to the subject a therapeutically effective amount of
cardiosphere-derived cells (CDCs), wherein said CDCs are a
population of cells obtained by plating and expanding
cardiospheres (CSps) as an adherent monolayer culture on a
solid surface of a culture vessel.
Appeal Br. 27–29.

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ANTICIPATION
It is well settled that a reference can only anticipate a claim if it
discloses all the claimed limitations “arranged or combined in the same way
as in the claim.” Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683
F.3d 1356, 1361 (Fed. Cir. 2012) (quoting Net MoneyIN, Inc. v. VeriSign,
Inc., 545 F.3d 1359, 1370 (Fed. Cir. 2008)).
In the present case, we agree with Appellant that Messina does not
anticipate claims 73 and 74. In particular, we agree with Appellant that
Messina does not disclose administering the same product as recited in
Appellant’s claims 73 and 74.
Claim 73 recites administering, to a subject with diseased or damaged
cardiac tissue, “cardiosphere-derived cells (CDCs).” Appeal Br. 28. Claim
73 requires the CDCs to be “a population of cells obtained by: collecting
cardiospheres (CSps); plating said CSps onto a culture vessel; and
expanding said CSps as an adherent monolayer culture on a solid surface of
said culture vessel.” Id.
Similarly, claim 74 recites administering CDCs, “wherein said CDCs
are a population of cells obtained by plating and expanding cardiospheres
(CSps) as an adherent monolayer culture on a solid surface of a culture
vessel.” Appeal Br. 29.
Appellant’s Specification explains that cardiospheres, from which the
CDCs of claims 73 and 74 are derived, are clusters of cells that
spontaneously generate when processed cardiac tissue is cultured in a
specific fashion. See Spec. ¶¶ 145, 222. Once removed from the initial
culture, the cardiospheres may be maintained in poly-D-lysine-coated
dishes. See id. ¶ 222.
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To obtain the CDCs recited in claims 73 and 74, the cardiosphere
clusters are disaggregated and then cultured in fibronectin-coated vessels,
which results in formation of an adherent monolayer of cells on the vessels’
fibronectin-coated surface. See Spec. ¶ 145 (“In several embodiments,
growth on the surface is monolayer growth. These cells are cardiosphere-
derived cells (CDCs).”) (emphasis added).
Appellant’s Specification, thus, distinguishes between cardiospheres,
which are populations of cells that have a clustered structure, and
cardiosphere-derived cells (i.e. CDCs as recited in claims 73 and 74), which
are populations of cells that have been induced to form an adherent
monolayer, a structure distinct from a clustered structure.
Rather than administering CDCs as recited in claims 73 and 74,
Messina discloses administering cardiospheres to mice having
experimentally induced myocardial infarctions. See Messina 916–917
(“[T]hawed (cryopreserved) adult human CSs [cardiospheres] from three
atrial (one male and two female) and one ventricular (one female) biopsy
specimens were injected into the viable myocardium bordering a freshly
produced infarct.”).
As Appellant contends, and the Examiner does not dispute, Messina’s
cardiospheres are made by substantially the same process as the process
described in Appellant’s Specification, and have the same clustered structure
as the cardiospheres described in Appellant’s Specification. See Appeal Br.
13–14; see also Messina 192 (describing Messina’s cardiospheres as
“clusters of small, round, phase-bright cells”).
Thus, when Messina describes administering cardiospheres to
infarcted mice, Messina describes administering a population of cells that
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has a clustered structure. As discussed above, however, and explained in
Appellant’s Specification, the CDCs of claims 73 and 74 do not have
cardiospheres’ clustered structure. We are not persuaded, therefore, that in
administering cardiospheres to infarcted mice, Messina describes
administering same product (CDCs) as recited in claims 73 and 74.
As Appellant contends, moreover, CDCs have a distinct expression
profile of growth factors as compared to cardiospheres. See Appellant’s Fig.
18A–C; see also Spec. 283 (“FIG. 18 shows two representative blots (18A)
from cardiospheres and CDCs derived from the same patient sample,
together with the corresponding densitogram (l8B and 18C), showing the
cardiosphere/CDC optical density ratios for each [growth] factor.”). And, as
Appellant also contends, the level of β-catenin expression in CDCs is
significantly different than in cardiospheres. See Ibrahim Decl. ¶ 4.8
Thus, to summarize, Appellant’s Specification distinguishes between
cardiospheres, which are populations of cells that have a clustered structure,
and cardiosphere-derived cells (i.e. CDCs as recited in claims 73 and 74),
which are populations of cells that have been induced to form an adherent
monolayer, a structure distinct from a clustered structure. And, evidence of
record shows that cardiospheres and CDCs have different protein expression
profiles. We therefore agree with Appellant that the cardiospheres
administered by Messina to mice are not the same product as the CDCs
administered to subjects in Appellant’s claims 73 and 74. We also agree
with Appellant, therefore, that Messina does not anticipate claims 73 and 74.

8 Declaration of Ahmed Ibrahim, Ph.D., under 37 C.F.R. § 1.132 (signed
October 28, 2016).
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We recognize, as the Examiner contends, that the CDCs recited in
claims 73 and 74 are recited using product-by-process language, which
encompasses any identical prior art product, regardless of whether the prior
art product is made by the process recited in the claims. See In re Thorpe,
777 F.2d 695, 697 (Fed. Cir. 1985). The Examiner, however, points to no
persuasive evidence suggesting that the cardiospheres administered by
Messina are identical to the population of cells, CDCs, administered in the
processes of claims 73 and 74. Indeed, as discussed above, the evidence of
record supports Appellant’s contention that cardiospheres and CDCs are
distinct populations of cells with distinct properties.
In sum, for the reasons discussed, we agree with Appellant that
Messina does not disclose administering the same populations of cells as
recited in Appellant’s claims 73 and 74. We therefore reverse the
Examiner’s rejection of claims 73 and 74 as anticipated by Messina.
OBVIOUSNESS
In rejecting claims 39, 58–63, and 70–74 over Messina, Heng, and
Harvey, the Examiner again cited Messina as describing a process of
administering CDCs to treat damaged cardiac tissue. Final Act. 7.
The Examiner conceded that Messina differs from the rejected claims
in two respects: (1) “Messina et al do not expressly teach wherein the
administered CDCs had not been further manipulated to form secondary
cardiospheres” and (2) “Messina et al do not expressly teach wherein the
cardiospheres were disaggregated before plating and expanding as an
adherent monolayer culture on a solid surface.” Final Act. 8.
The Examiner cited Heng and Harvey as evidence that it would have
been desirable to culture Messina’s cardiospheres in the presence of
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fibronectin, which the Examiner asserts, based on Appellant’s Specification,
would inherently yield the adherent monolayer of cells recited in the rejected
claims. Final Act. 8–10.
We reverse this rejection as well. Consistent with the Examiner’s
contention, and as noted above, Appellant’s Specification discloses that an
adherent monolayer of CDCs results when cardiospheres are cultured in a
vessel in which the surface is coated with fibronectin. See Spec. ¶ 145.
As the Examiner also found, Heng discloses that, when using stem
cells to treat infarcted animals, it is advantageous for the cells to have at
least some limited degree of differentiation:
There is a strong possibility that some degree of
cardiomyogenic differentiation of stem cells in vitro prior to
transplantation would result in higher engraftment efficiency, as
well as enhanced myocardial regeneration and recovery of heart
function. Additionally, this may also alleviate the probability
of spontaneous differentiation of stem cells into undesired
lineages and reduces the risk of teratoma formation, in the case
of embryonic stem cells.
Heng 34 (abstract).
As the Examiner found, Heng discloses that fibronectin is among a
number of extracellular matrix (ECM) proteins that may induce
differentiation of cardiac stem cells:
[T]he introduction of appropriate extracellular matrix molecules
within in vitro culture would certainly enhance the directed
differentiation of stem cells into the cardiomyogenic lineage.
With commonly used ECM supplements in cell culture, such as
collagen, laminin and fibronectin, there was reported to be
enhanced myofibrillogenesis, spontaneous contractile activity
and differentiated morphology of neonatal cardiomyocytes
cultured in vitro. It is likely that such supplemented ECM
molecules would also be beneficial for the cardiomyogenic
differentiation of stem cells, although there are as yet no
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reported studies. Other ECM molecules that were shown to
play an important role in cardiomyogenic differentiation in
histological studies include Syndecan-4[,] Tenascin C [,] and
hyaluronic acid. However, the effects of these molecules on the
in vitro culture of primary cardiomyocytes, as well as the
cardiomyogenic differentiation of stem cells remain to be
investigated.
Heng 37 (citations omitted).
As noted above, however, to induce formation of an adherent
monolayer of CDCs, Appellant’s Specification discloses that the fibronectin
must be coated onto the surface of the culture vessel. See Spec. ¶ 145.
Thus, although we acknowledge Heng’s disclosure that including
fibronectin in stem cell culture medium can aid in differentiation, the
Examiner does not identify any teaching in Heng specifically suggesting that
the fibronectin should be coated onto the surface of the culture vessel.
Absent impermissible hindsight, therefore, we are not persuaded that Heng
would have suggested culturing Messina’s cardiospheres in a fibronectin-
coated vessel, so as to produce an adherent monolayer of CDCs, as recited in
the rejected claims.
We acknowledge Harvey’s disclosure, identified by the Examiner,
that during embryonic cardiac development “[t]he timing and direction of
movement of cardiac progenitors toward the midline depends on the graded
distribution of fibronectin in extracellular matrix, deposited at the
mesodermal/endodermal interface.” Harvey 340 (citation omitted). We are
not persuaded, however, that Harvey’s disclosure regarding cell movement
in a developing embryo would have suggested culturing Messina’s
cardiospheres in a fibronectin-coated vessel, even when viewed in
combination with Heng.
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In sum, for the reasons discussed, the Examiner does not persuade us
that the combined teachings of Messina, Heng, and Harvey, would have
suggested culturing Messina’s cardiospheres in a fibronectin-coated vessel,
so as to produce an adherent monolayer of CDCs, as recited in claims 39,
58–63, and 70–74. We therefore reverse the Examiner’s rejection of claims
39, 58–63, and 70–74 over Messina, Heng, and Harvey.
In rejecting claims 64–69 over Messina, Heng, Harvey, Piper, and
Beltrami, the Examiner cited Piper and Beltrami as evidence that additional
features recited in claims 64–69 would have been obvious variations of the
process suggested by the combination of Messina, Heng, and Harvey. See
Final Act. 11–14. Because Piper and Beltrami do not remedy the
deficiencies discussed above in the combination of Messina, Heng, and
Harvey, we also reverse the Examiner’s rejections of claims 64–69.
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CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/
Basis
Affirmed Reversed
73, 74 102(a) Messina 73, 74
39, 58–63,
70–74
103(a) Messina,
Heng, Harvey
39, 58–63, 70–74
64–66 103(a) Messina,
Heng, Harvey,
Beltrami,
Piper
64–66
64–69 103(a) Messina,
Heng, Harvey,
Piper,
Beltrami
64–69
Overall
Outcome
39, 58–74

REVERSED