Capricor, Inc.

Patent Trials and Appeals Board

Jun 23, 2020

2020000277 (P.T.A.B. Jun. 23, 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.
15/531,254 05/26/2017 Michelle Kreke Cap15.1-PCT-US 1041
137994 7590 06/23/2020
Capricor Therapeutics, Inc.
8840 Wilshire Blvd FL2
Beverly Hills, CA 90211
EXAMINER
POPA, ILEANA
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
06/23/2020 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):
tuhm@capricor.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte MICHELLE KREKE, RACHEL SMITH, PETER HANSCOME,
KIEL PECK, and AHMED IBRAHIM
____________

Appeal 2020-000277
Application 15/531,254
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
JOHN G. NEW, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134(a) involving claims to
stable lyophilized formulations of cardiosphere-derived cell exosomes. The
examiner rejected the claims as obvious, on the ground of obviousness-type
double patenting, and as reciting non-statutory subject matter. 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(a). Appellant identifies the real party in interest as Capricor, Inc.
(Appeal Br. 3).
2 We have considered the Specification of May 26, 2017 (“Spec.”); Final
Office action of Sept. 6, 2018 (“Final Act.”); Appeal Brief of Mar. 6, 2019
(“Appeal Br.”); Examiner’s Answer of Aug. 15, 2019 (“Ans.”); and Reply
Brief of Oct. 15, 2019 (“Reply Br.”).
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Statement of the Case
Background
“The leading cause of death in the US remains heart disease . . . [with]
an increasing number of heart attack survivors and disability years due to
nonfatal ischemic heart disease” (Spec. 1:15–20). “Cardiosphere-derived
cells (CDCs) are in clinical testing. CDCs administered after a myocardial
infarction (Ml) . . . have been shown to be safe and effective in reducing scar
size and increasing viable myocardium” (id. at 1:25–28).
“CDC-derived exosomes have been shown to recapitulate the effects
of CDCs now in numerous preclinical models” (Spec. 2:1–2). Exosomes are
membrane-bound vesicles . . . generated by inward budding of endosomal
multivesicular bodies” (id. at 1:3–6). “CDCs secrete exosomes containing
particular miRNAs that stimulate cardiomyocyte proliferation, spur
angiogenesis, and improve functional recovery in Ml models” (id. at 2:4–6).
“It was found that miR-201 and miR-146a were up-regulated in CDC
exosomes in comparison to NHDF (normal human dermal fibroblast)
exosomes” (id. at 3:6–8).
The Specification states “[t]here is a need in the art for better exosome
formulations, particularly for clinical use, and that are stable” (Spec. 3:24–
25).
The Claims
Claims 1–15 are on appeal. Because Appellant does not argue the
claims separately, we focus our analysis on claim 1, and claims 2–15 stand
or fall with that claim. 37 C.F.R. § 41.37 (c)(1)(iv). Claim 1 reads as
follows:
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1. A stable dry lyophilized exosome formulation suitable
for administration to a human comprising at least 106 exosomes,
wherein, upon rehydration, the lyophilized exosomes maintain
at least 90% of the levels of miR-210 and miR-146a of the
exosome formulation pre-lyophilization, and wherein the
exosome formulation is generated from cardiosphere-derived
cells (CDCs).

The Issues
A. The Examiner rejected claims 1–15 as unpatentable under 35 U.S.C.
§ 101 as directed to non-statutory subject matter (Final Act. 6–8).
B. The Examiner rejected claims 1–15 as unpatentable under 35 U.S.C.
§ 103 as obvious over Ibrahim,3 Mitsialis,4 Vrijsen,5 and Chang6 (Final Act.
10–11).
C. The Examiner rejected claims 1–15 as unpatentable on the ground of
obviousness-type double patenting over claims 1–3 and 9–17 of U.S. Patent
9,828,603 in view of Chen, Mitsialis, and Chang7 (Final Act. 3–4).
D. The Examiner rejected claims 1–15 as unpatentable on the ground of
obviousness-type double patenting over claims 12–17 of copending
application 15/790,962 (now US 10,457,942, issued Oct. 29, 2019) in view

3 Ibrahim, et al, MicroRNA-Containing Exosomes from Cardiosphere-
Derived Cells Stimulate Cardiomyocyte Proliferation and Angiogenesis in
vitro, and Improve Functional Recovery after Myocardial Infarction in
Mice, 126 Circulation Res. Suppl. 21, Abstract 14697 (2012).
4 Mitsialis et al., US 2014/0065240 A1, published Mar. 6, 2014.
5 Vrijsen et al, Cardiomyocyte Progenitor Cell-Derived Exosomes Stimulate
Migration of Endothelial Cells, 14(5) J. Cell. Mol. Med. 1064–70 (2010).
6 Chang et al, U.S. 2005/0002998 A1, published Jan. 6, 2005.
7 Chen, et al, Cardiac Progenitor-Derived Exosomes Protect Ischemic
Myocardium from Acute Ischemia/Reperfusion Injury, 431 Biochem.
Biophys. Res. Comm. 566–71 (2013).
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of Chen, Mitsialis, and Chang (Final Act. 5–6).

A. 35 U.S.C. § 101
The Examiner finds that claim 1 is “directed to a preparation of
exosomes obtained from CDCs, wherein the exosomes comprise miR-210
and miR-146a” (Final Act. 7).
The Examiner cites references to establish that the human heart
comprises resident CDCs8 (Final Act. 7). The Examiner finds
no evidence of record demonstrating that the claimed exosomes
are any different from naturally occurring exosomes derived
from the resident CDCs nor is there any evidence of record
demonstrating that lyophilization (process routinely used in the
prior art) results in a composition which is markedly different
from the naturally occurring counterparts.
(id.).
Appellant contends “cardiospheres and CDCs are in vitro products
without a natural counterpart, and exosomes generated therefrom also must
be recognized as an in vitro product without a natural counterpart” (Appeal
Br. 8).
The Alice Test
The Supreme Court has long interpreted 35 U.S.C. § 101 to include
implicit exceptions: “[l]aws of nature, natural phenomena, and abstract

8 Liang, et al, Migration of Resident Cardiac Stem Cells in Myocardial
Infarction, 296 Anatom. Rec. 184–91 (2013); Li, et al, Cardiospheres
Recapitulate a Niche-Like Microenvironment Rich in Stemness and Cell-
Matrix Interactions, Rationalizing Their Enhanced Functional Potency for
Myocardial Repair, 28 Stem Cells 2088–98 (2010); Koudstaal, et al,
Concise Review: Heart Regeneration and the Role of Cardiac Stem Cells, 2
Stem Cells Transl. Med. 434–43 (2013).
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ideas” are not patentable. See, e.g., Alice Corp. v. CLS Bank Int’l, 573 U.S.
208, 216 (2014).
In determining whether a claim falls within an excluded category, we
are guided by the Supreme Court’s two-step framework, described in Mayo
and Alice. Id. at 217–18 (citing Mayo Collaborative Servs. v. Prometheus
Labs., Inc., 566 U.S. 66, 75–77 (2012)). In accordance with that framework,
we first determine if there is a judicial exception. Although composition of
matter claims are generally eligible subject matter, claims that are directed
only to laws of nature and/or natural phenomena are directed to patent
ineligible concepts. Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d
1371, 1376 (Fed. Cir. 2015).
If the claim is “directed to” a judicial exception, we turn to the second
step of the Alice and Mayo framework, where “we must examine the
elements of the claim to determine whether it contains an ‘inventive
concept’ sufficient to ‘transform’ the claimed abstract idea into a patent
eligible application.” Alice, 573 U.S. at 221 (quotation marks omitted).
2019 Guidance
The United States Patent and Trademark Office published guidance
on the application of 35 U.S.C. § 101. USPTO’s 2019 Revised Patent
Subject Matter Eligibility Guidance (“Guidance”).9 Under the Guidance, in
determining what concept the claim is “directed to,” we first look to whether
the claim recites:
(1) any judicial exceptions, including “[l]aws of nature,
natural phenomena, and abstract ideas,” (quoting Alice, 573
U.S. at 216) and/or including certain groupings of abstract ideas

9 2019 Revised Patent Subject Matter Eligibility Guidance, 84 Fed. Reg.
50 (January 7, 2019).
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(i.e., mathematical concepts, certain methods of organizing
human activity such as a fundamental economic practice, or
mental processes) (Guidance Step 2A, Prong 1); and
(2) additional elements that integrate the judicial
exception into a practical application (see MPEP § 2106.05(a)–
(c), (e)–(h)) (Guidance Step 2A, Prong 2).

Only if a claim (1) recites a judicial exception and (2) does not
integrate that exception into a practical application, do we then look to
whether the claim contains an “‘inventive concept’ sufficient to ‘transform’”
the claimed judicial exception into a patent-eligible application of the
judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82).
In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial
exception that are not “well-understood, routine and
conventional in the field” (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional
activities previously known to the industry, specified at a high level of
generality, to the judicial exception.

(Guidance Step 2B). See Guidance, 84 Fed. Reg. at 54–56.
Analysis
Appellant’s claims recite patent-eligible subject matter. Because the
same issues are present in each of the claims, we focus our consideration on
representative claim 1. The same analysis applied below to claim 1 also
applies to the other rejected claims.
A. Guidance Step 1
We first consider whether the claimed subject matter falls within the
four statutory categories set forth in § 101, namely “[p]rocess, machine,
manufacture, or composition of matter.” Guidance, 84 Fed. Reg. at 53–54;
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see 35 U.S.C. § 101. Claim 1 recites a “formulation” and, thus, falls
squarely within the “composition of matter” category. Consequently, we
proceed to the next steps of the analysis.
B. Guidance Step 2A, Prong 1
The Revised Guidance instructs us first to determine whether any
judicial exception to patent eligibility is recited in the claim. The Revised
Guidance identifies products of nature as having been identified by the
courts as judicial exceptions. 84 Fed. Reg. at 54. We therefore first look to
see if the claim recites any judicial exceptions.
The Examiner, as noted above, finds that CDC-derived exosomes are
products of nature, specifically the result of a series of steps giving rise to a
preferential enrichment of a particular naturally-occurring cell type. (Final
Act. 7–8; Ans. 12). Appellant, however, contends that the evidence does not
support a finding that the claimed exosomes are naturally occurring (Appeal
Br. 8–9). Appellant contends
cardiosphere-derived cells (CDCs) and exosomes generated
therefrom are produced by a series of in vitro manipulations
that begin with processing a donor cardiac tissue specimen
(e.g., biopsy) into a plurality of tissue explants, which are then
cultured until cells migrate from the explant, collecting the cells
that migrate from the explant, thereby generating explant-
derived cells (EDCs).
(Appeal Br. 5; cf. Spec. 17:25 to 18:24).
“[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting a prima facie case of unpatentability.” In
re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). The initial burden of
demonstrating that exosomes obtained from CDCs are naturally occurring
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therefore rests upon the Examiner, and only if that burden is met, does
Appellant then have the burden of rebutting the Examiner’s position.
Examiner’s cited art
The Examiner finds “[i]t is well-known that human heart comprises a
heterogeneous population of resident CDCs capable of forming
cardiospheres in culture” (Ans. 6; citing Liang,10 Li,11 Koudstaal12). The
Examiner also finds that “[i]t is also well-known in the art that exosomes are
naturally secreted by cells in vivo where they are involved in intercellular
communication between different cell types” (Ans. 7, citing Vrijsen).
We are not persuaded that the cited references support the Examiner’s
position that cardiospheres are not markedly different from naturally
occurring cells in the human heart. Liang teaches that:
Several different types of CSCs have so far been isolated and
expanded by several groups . . . There is partial overlap in
marker expression but the origins and exact lineage
relationships among these various CSC populations are still not
clear. It remains to be determined whether some or all of these
cells originate from a common stem cell population and are
simply at different stages of development in the heart, or
whether they are independent cell lineages derived from distinct
stem/progenitor cell populations.
(Liang 186, col. 1). Thus, Liang does not clearly demonstrate that CSC
populations are identical to naturally occurring cells.

10 Liang et al., Migration of Resident Cardiac Stem Cells in Myocardial
Infarction, 296 The Anatomical Record 184–91 (2013).
11 Li et al., Cardiospheres Recapitulate a Niche-Like Microenvironment Rich
in Stemness and Cell-Matrix Interactions, Rationalizing Their Enhanced
Functional Potency for Myocardial Repair, 28 Stem Cells 2088–98 (2010).
12 Koudstaal et al., Concise Review: Heart Regeneration and the Role of
Cardiac Stem Cells, 2 Stem Cells Translational Medicine 434–43 (2013).
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Li teaches “expression profile of ECM and adhesion molecule genes
was analyzed using pathway-focused PCR arrays . . . Twelve of these
mRNAs were increased more than fourfold after 3 days of 3D cardiosphere
culture” (Li 2092, col. 1–2). Li teaches “enhanced expression levels of
integrin-α2 and laminin-β1 in cardiospheres disappear in the dissociated
cells, falling to levels comparable with those in monolayer-cultured cells” Li
2095, col. 1). Thus, Li provides evidence that cardiospheres express
different genes during culture, differ from dissociated cells, and therefore
suggests that cardiospheres markedly differ from naturally occurring cells.
Table 1 of Koudstaal is reproduced below:

Table 1 depicts a “schematic overview of resident stem/progenitor cells in
the mammalian heart” (Koudstaal 436, 438). Table 1 of Koudstaal teaches
that cardiosphere-derived cells (CDC) lack any isolation marker and differ
from known types of cardiac stem cells which have particular isolation
markers and which are not CD34 positive and MDR-1 negative (see
Koudstaal 438). Thus, the evidence in Koudstaal does not demonstrate that
cardiosphere-derived cells are naturally occurring.
Vrijsen does not directly address the status of cardiosphere-derived
cells, rather focusing on cardiomyotcyte progenitor cells, and do not discuss
the impact of culture on such cells (see Vrijsen 1065, col. 1).
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Ibrahim Declaration13
The Specification teaches the process by which exosomes were
prepared:
Immediately upon receipt, hearts were grossly dissected and cut
into biopsy-sized pieces . . . referred to as explants . . . In order
to generate allogeneic CDCs, explants were plated on
CELLBIND® CellSTACK® vessels (Corning Life Sciences).
After 1-2 weeks, cellular outgrowth emerging from the explants
became confluent. These explant derived cells (EDCs) were
harvested using IX TrypLE™ (lnvitrogen). EDCs were either
cryopreserved as the master cell bank (MCB), and then cultured
as cardiospheres (CSps), or placed immediately into CSp
culture conditions. . . . Allogeneic CDCs were grown by
seeding CSps on fibronectin-coated Nunc* TripleFlasks
(Thermo Scientific), and passaging when confluent. CDCs at
varying passage number were seeded on to fibronectin-coated
Cell Bind cellstacks and allowed to become confluent for
exosome production. . . . Exosomes were filtered using a 0.45
μm to remove cellular debris and then isolated by ultrafiltration.
(Spec. 17:27 to 18:20).
The Ibrahim Declaration “performed experiments to measure
exosome microRNA contents, including miR-146a, and compared exosomes
derived from explant cells, EDCs and CDCs, with each of the
aforementioned explant cells, EDCs and CDCs being derived from the same
donor” (Ibrahim Decl. 3). The Ibrahim Declaration compared “exosome
microRNA contents across explant cell-, EDC- and CDC-derived exosomes”
(Ibrahim Decl. ¶ 4). Figures 1 and 2 of the Ibrahim Declaration are
reproduced below:

13 Declaration of Dr. Ahmed Ibrahim, dated Feb. 24, 2017 in US Application
14/421,355.
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Figures 1 and 2 of the Ibrahim Declaration show comparisons “of miR-146a
levels in exosomes isolated from the conditions media of explants, Explant-
derived Cells (EDCs), and cardiosphere-derived cells (CDCs)” harvested at
24 hours and 15 days of conditioning, respectively (Ibrahim Decl. 4–5).
Based on this data, Dr. Ibrahim concludes “CDCs-derived exosomes are
different from explant cell-, EDC-derived exosomes” (Ibrahim Decl. ¶ 8).
The Examiner responds that “the observed increase in the miR-146a
and miR-22 levels from explant to EDCs and from EDCs to CDCs reflects
an enrichment in cells (i.e., CDCs) secreting exosomes naturally comprising
higher miR-146a and miR-22 levels as opposed to exosomes secreted from
the other cell types” (Ans. 12). The Examiner contends the final cell
population with higher miR-146a levels is due to enrichment “and not
changes in the phenotype following isolation and cultivation for 15 days”
(Ans. 14).
However, the Examiner provides no rebuttal evidence, as opposed to
argument, demonstrating that the increased miR-146a levels result solely
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from enrichment of naturally occurring cells, and not changes that occur
during in vitro isolation and culture of the cells for several weeks.
Appellant’s cited art
Appellant cites White14 and Davis15 to support the position
“cardiospheres and CDCs are in vitro products without a natural counterpart,
and exosomes generated therefrom also must be recognized as an in vitro
product without a natural counterpart” (Appeal Br. 8).
The Examiner responds “White et al. and Davis et al. teach that EDCs
are heterogeneous and include a subpopulation of cardiosphere forming cells
from which CDCs are derived” (Ans. 19).
Figure 1 of White is reproduced below:

14 White et al., Intrinsic Cardiac Origin of Human Cardiosphere-Derived
Cells, 34 European Heart Journal 68–75 (2013).
15 Davis et al., Validation of the Cardiosphere Method to Culture Cardiac
Progenitor Cells from Myocardial Tissue, 4(9) PLoS ONE, 2009 e7195 1–8
(2009).
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Figure 1 Representative cell morphology during each stage of
the cardiosphere-derived cell protocol. (A) A cardiac biopsy
explant (Ex.), with outgrowth of a monolayer of cells on
fibronectin coated plastic. (B) The monolayer is harvested and
placed into poly-D-lysine-coated plastic wells, resulting in the
formation of floating clusters of cells known as cardiospheres.
(C) The cardiospheres are plated back onto fibronectin-coated
plastic, whereupon they adhere, flatten and spread once again as
a monolayer (cardiosphere-derived cells). Black arrow
indicates one cardiosphere. (D) Sheets of cardiosphere-derived
cells become confluent. They are then harvested and passaged.
(White 71).
Davis teaches, with respect to cardiospheres, that “core cells have a
cardiac progenitor immunophenotype dominated by the expression of stem
cell and cardiomyocyte-related antigens. Peripheral cells represent
spontaneous differentiation of precursor cells into endothelial,
mesenchymal, or cardiomyogenic lineages, and/or the encapsulation of core
progenitors by a subset of supportive cardiac mesenchymal cells” (Davis 5,
col. 1–2; emphasis added). Davis further explains that “when CPCs are
cultured directly from myocardial tissue by carefully-established methods,
further sub-culture permits the formation of self-organizing cardiospheres
that create a complex, niche-like environment” (Davis 5, col. 2). Thus,
Davis explains that the explant cells undergo changes in expression and
differentiation from cells naturally found in the heart (see id.).
White teaches that the morphology of cardiospheres differs from that
of naturally occurring heart cells, supporting the position that the cells have
altered in culture (see White 71). Davis expressly states that the cells are
differentiated and therefore differ from naturally occurring heart cells, and
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form cardiospheres that show different morphology than naturally occurring
heart cells (see Davis 5).
Therefore, a preponderance of the evidence supports Appellant’s
position that the cells recited in claim 1 are not naturally occurring and
markedly different than naturally occurring heart cells. None of the
Examiner’s cited prior art demonstrates that the CPCs are naturally
occurring as discussed above. The Ibrahim Declaration demonstrates a
marked difference in the expression of each of miR-146a and miR-22 in
exosomes obtained from CDCs compared to each of explant and explant-
derived cell exosomes (cf. Appeal Br. 8–9). Appellant’s cited art suggests
that cardiospheres are composed of cells that have undergone changes from
naturally occurring cells and thereby are markedly different from naturally
occurring cells.
In the instant case, the evidence discussed above does not establish
that the claimed exosome formulation of cardiosphere-derived cells is itself
necessarily naturally occurring, or that the cells themselves are necessarily
naturally occurring.
Accordingly, under Guidance Step 2A, Prong 1, we conclude that the
composition of claim 1 has not been shown to be a product of nature, and
thus is not directed to a patent ineligible judicial exception. Consequently,
our analysis ends here.
Conclusion of Law
A preponderance of the evidence of record supports the conclusion
that claims 1–15 are directed to patent eligible subject matter.

B. 35 U.S.C. § 103 over Ibrahim, Mitsialis, Vrijsen, and Chang.
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The Examiner finds Ibrahim teaches “a liquid exosome preparation
generated from human CDCs, wherein the exosomes comprise high amounts
of miR-210 and miR-146a” (Final Act. 11). The Examiner acknowledges
that Ibrahim does “not specifically teach at least 106 or at least 108
exosomes” but finds it “obvious to vary the amount of exosomes in the
preparation to optimize the preparation for therapeutic purposes” (id.).
The Examiner also acknowledges that Ibrahim does “not teach
stabilizing and preserving activity via lyophilization” (Final Act. 12). The
Examiner finds Mitsialis teaches “exosomes can be lyophilized” (id.).
The Examiner finds Vrijsen teaches that, like liposomes, “exosomes
are lipid bilayer vesicles . . . comprising proteins and nucleic acids” (Final
Act. 12). The Examiner finds that Chang evidences that “lyophilizing
liposomes comprising proteins, and nucleic acids results in stable
compositions which maintain at least 90% of biological activity upon
reconstitution” (id.) The Examiner finds it would have been obvious to
combine the teachings of Ibrahim, Mitsialis, Vrijsen, and Chang “to achieve
the predictable result of obtaining a stable [exosome] composition suitable
for prolonged storage and maintaining at least 90% of its biological activity
upon rehydration” (id.).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that the combination of Ibrahim,
Mitsialis, Vrijsen, and Chang renders the claims obvious?
Principle 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.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
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Findings of Fact
1. Ibrahim teaches “[e]xosomes are rich in microRNAs (mirs)
which may function in a paracrine fashion. Cardiosphere-derived cells
(CDCs) have been shown to regenerate heart after myocardial infarction
(MI) in animal models and in the CADUCEUS clinical trial” (Ibrahim,
abstract).
2. Ibrahim teaches “mice injected with exosomes from CDCs
during acute MI showed higher LVEF at two weeks . . . and four weeks . . .
as well as increased regeneration of the infarcted myocardium” (Ibrahim,
abstract).
3. Ibrahim teaches: “Mir microarray analysis identified mir-146a,
mir 22, mir 24, and mir 210 among the most highly-upregulated mirs in
CDC-exosomes compared to NHDF” (Ibrahim, abstract). Ibrahim
concludes: “Mir-containing exosomes secreted by CDCs exhibit multiple
beneficial effects on injured myocardium, suggesting that exosomes may
mediate some of the therapeutic effects of CDCs” (Ibrahim, abstract).
4. Mitsialis teaches “exosomes may be used (e.g., administered) in
pharmaceutically acceptable preparations” and teaches:
The preparations of the invention are administered in effective
amounts. An effective amount is that amount of an agent that
alone stimulates the desired outcome. The absolute amount
will depend upon a variety of factors, including the material
selected for administration, whether the administration is in
single or multiple doses, and individual patient parameters
including age, physical condition, size, weight, and the stage of
the disease. These factors are well known to those of ordinary
skill in the art and can be addressed with no more than routine
experimentation.
(Mitsialis ¶¶ 85, 93).
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5. Mitsialis teaches “the exosomes may be in lyophilized or other
powder or solid form for constitution with a suitable vehicle, e.g., sterile
pyrogen-free water, before use” (Mitsialis ¶ 97).
6. Vrijsen teaches: “Exosomes are small membrane vesicles with a
lipid bilayer” (Vrijsen 1066, col. 1).
7. Chang teaches “a method of preparing a stable complex
comprising a ligand and a cationic liposome encapsulating a therapeutic or
diagnostic agent” (Chang ¶ 2).
8. Chang teaches a “method for preparing a stable complex
comprising a ligand and a cationic liposome . . . [by] combining a complex
comprising a ligand and a cationic liposome . . . and lyophilizing the
resultant solution of complex and sucrose to obtain a lyophilized
preparation” (Chang ¶¶ 11–13).
9. Chang teaches “the preparation retains at least about 85% of its
pre-lyophilization activity, and more preferably, at least about 90% of its
prelyophilization activity” (Chang ¶ 15).
10. Chang teaches the “lyophilized preparation is stable within a
range of from about 2-8° C. to about -80° C. for a period of at least 6 months
without losing significant activity” (Chang ¶ 27). Chang further explains
“[t]hese studies indicate that lyophilization of the complete complex is
feasible and that previous difficulties with stability and shelf life . . . can be
overcome” (Chang ¶ 78).
Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Final Act. 10–13; FF 1–10) and agree that
the claims are obvious over Ibrahim, Mitsialis, Vrijsen, and Chang. We
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address Appellant’s arguments below.
Appellant contends that because “there is no indication in Mitsialis et
al. that lyophilization of exosomes was ever performed or that it could result
in a stable dry lyophilized exosome formulation . . . Mitsialis et al. cannot
provide any expectation of success in achieving the claimed invention”
(Appeal Br. 10–11). Appellant further contends that “Mitsialis et al. only
pertains to compositions comprising mesenchymal stem cell (MSC) derived
exosomes, whereas the claimed invention pertains to exosomes derived from
CDCs” and argues the “impropriety of such an overbroad approach” (id. at
11).
We find these arguments unpersuasive. The Examiner reasonably
asserts that lyophilization of one type of exosome, as taught by Mitsialis,
would have had a reasonable expectation of success when applied to a
different type of exosome (FF 5). Mitsialis is a published US patent
application and as such, “is presumptively enabling barring any showing to
the contrary by a patent applicant.” In re Antor Media Corp., 689 F.3d
1282, 1288 (Fed. Cir. 2012). No such showing has been made by Appellant.
Moreover, “[o]bviousness does not require absolute predictability of
success . . . all that is required is a reasonable expectation of success.” In re
Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009). While Mitsialis alone
provides a reasonable expectation of success, that expectation is enhanced
by the express disclosure of Chang. Chang teaches that liposomes,
composed of a lipid bilayer containing nucleic acids and studded with
proteins, can be successfully lyophilized with retention of 90% activity (FF
7–10). Because the exosomes of Ibrahim are also composed of lipid bilayers
containing nucleic acids and studded with proteins, the ordinary artisan
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would have found it reasonable to expect that substituting Ibrahim’s
exosomes for liposomes in the lyophilization method of Chang (FF 1–3, 7–
10), as suggested by Mitsialis for exosomes (FF 5), would have had a
reasonable expectation of success. Appellant provides no evidence to the
contrary.
As to the issue of an “overbroad” approach, “[w]hen a patent simply
arranges old elements with each performing the same function it had been
known to perform and yields no more than one would expect from such an
arrangement, the combination is obvious.” KSR, 550 U.S. at 417. Appellant
provides no persuasive reasoning or evidence explaining why using well-
known storage methods like lyophilization for Ibrahim’s exosomes would
not have obtained the expected result shown by Chang (FF 1–3, 7–10).
Appellant contends “Vrijsen et al. does not teach lyophilizing
exosomes, and Chang et al. pertains to liposomes, not exosomes. Further,
Vrijsen et al. teaches using foetal heart tissue and using mouse anti-Sea-I
coated magnetic beads to isolate and/or purify cardiomyocyte progenitor
cells” (Appeal Br. 12). Appellant contends “CDCs, unlike the cells of
Vrijsen et al., are an unsorted mixed population of cells, and CDCs comprise
a mixed population of cells having fixed collective properties, as evidenced
by White et al. and Davis et al.” (id. at 14).
We find Appellant’s argument unpersuasive because it fails to
recognize that the rejection is based on the combination of references, not
any single reference alone. In re Keller, 642 F.2d 413, 425 (CCPA 1981)
(“The test for obviousness is not whether the features of a secondary
reference may be bodily incorporated into the structure of the primary
reference; nor is it that the claimed invention must be expressly suggested in
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any one or all of the references. Rather, the test is what the combined
teachings of the references would have suggested to those of ordinary skill
in the art.”). Here, Ibrahim teaches the exosome composition of interest for
treatment of patients with myocardial infarction (FF 1–3), but does not teach
storage of these exosomes. Mitsialis and Chang teach that lyophilization
may be used to store exosomes and liposomes, respectively, where
exosomes are a naturally occurring type of liposome16 (FF 4, 5, 7–10) as
demonstrated by Vrijsen (FF 6).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that the
combination of Ibrahim, Mitsialis, Vrijsen, and Chang renders the claims
obvious.

C. & D. Double Patenting
Appellant advances the same argument concerning the double
patenting rejections made by the Examiner over each of the claims of the
9,828,603 patent, and the claims of 15/790,962 application (now US
10,457,942), both in view of Chen, Mitsialis, and Chang. Because the same
issue is dispositive for both rejections, they will be addressed together.
Appellant argues “for the same reasons as presented above with
respect to the rejections under 35 U.S.C. §§ 101 and 103, the cited claims
and references provide no reasonable expectation of success.” (Appeal Br.
14; cf. id. at 16).

16 See, e.g., https://medical-dictionary.thefreedictionary.com/liposome,
which defines “liposome” as “a microscopic spherical particle formed by a
lipid bilayer enclosing an aqueous compartment.” (Accessed June 16, 2020).
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Because we do not find Appellant’s arguments persuasive with regard
to the obviousness rejection over Ibrahim, Mitsialis, Vrijsen, and Chang as
discussed above, we similarly are not persuaded by Appellant’s arguments
regarding the double patenting rejection, which relies on substantially the
same art. We adopt the reasoning and arguments of the Examiner (see Final
Act. 3–6) and affirm these two rejections.
CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1–15 101 1–15
1–15 103 Ibrahim, Mitsialis,
Vrijsen, Chang
1–15
1–15 Obviousness-
type Double
Patenting
US 9,828,603,
Chen, Mitsialis,
Chang
1–15
1–15 Obviousness-
type Double
Patenting
US 14/958,784,
Chen, Mitsialis,
Chang
1–15
Overall
Outcome
1–15

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