STICHTING KATHOLIEKE UNIVERSITEIT

Patent Trials and Appeals Board

Jul 9, 2021

2020004378 (P.T.A.B. Jul. 9, 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.
14/428,350 03/13/2015 Carl Gustav Figdor IPEC-YY-PCT-US 7236
28862 7590 07/09/2021
Hudak, Shunk & Farine Co. LPA
30B Northwest Avenue, Suite 210
Tallmadge, OH 44278
EXAMINER
PERREIRA, MELISSA JEAN
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
07/09/2021 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):
dhudakjr@hsf-iplaw.com
dperkins@hsf-iplaw.com
lbelinsky@hsf-iplaw.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte CARL GUSTAV FIGDOR,
INGRID JOLANDA MONIQUE DE VRIES, MANGALA SRINIVAS,
LUIS JAVIER CRUZ RICONDO, and
CHRISTOFFEL LEENDERT DE KORTE
____________

Appeal 2020-004378
Application 14/428,350
Technology Center 1600
____________

Before DONALD E. ADAMS, DEVON ZASTROW NEWMAN, and
JAMIE T. WISZ, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s
decision to reject claims 8, 18–20, and 28–39 (Final Act.2 1). We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM-IN-PART.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as “STICHTING
KATHOLIEKE UNIVERSITEIT” (Appellant’s January 14, 2020, Appeal
Brief (Appeal Br.) 1).
2 Examiner’s July 31, 2019, Final Office Action.
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STATEMENT OF THE CASE
Appellant’s disclosure “relates to contrast agent enhanced medical
imaging. In particular, the contrast agents provided are useful for cell
imaging, cell therapy and in vivo targeting and drug delivery applications”
(Spec.3 1:4–6). Appellant’s independent claims 8 and 37 are reproduced
below:
8. A method of ultrasound imaging a subject, wherein the
imaging consists of amplitude-based ultrasound imaging, the
method comprising:
providing to the subject a poly(lactic-co-glycolic) acid
(PLGA) particle comprising a liquid perfluoro crown ether
selected from the group consisting of perfluoro-15-crown-5-
ether, perfluoro-12-crown-4-ether, and perfluoro-18-crown-6-
ether; and gadoteridol, wherein the PLGA of the particle is
present in the form of a matrix, wherein the gadoteridol and
liquid perfluoro crown ether are distributed in the matrix, and
imaging the particle using the amplitude-based
ultrasound, wherein the particle provides enhanced contrast
during imaging as compared to imaging performed without the
particle comprising the gadoteridol, wherein the liquid
perfluoro crown ether remains in liquid form during the
imaging.
(Appeal Br. 16.)
37. A method of ultrasound imaging a tissue, wherein the
imaging consists of amplitude-based ultrasound imaging, the
method comprising:
imaging the tissue using the amplitude-based ultrasound
to detect a particle provided to the tissue, and
wherein the particle comprises a poly(lactic-co-glycolic)
acid particle comprising a liquid perfluoro crown ether selected
from the group consisting of perfluoro-15-crown-5-ether,
perfluoro-12-crown-4-ether, and perfluoro-18-crown-6-ether;

3 Appellant’s March 13, 2015, Specification.
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and gadoteridol, wherein the particle provides enhanced
contrast during imaging as compared to imaging performed
without the particle comprising the gadoteridol, wherein the
liquid perfluoro crown ether remains in liquid form during
imaging, wherein the PLGA of the particle is present in the
form of a matrix, wherein the gadoteridol and liquid perfluoro
crown ether are distributed in the matrix.
(Id. at 18.)

Claims 8, 18–20, and 28–39 stand rejected under 35 U.S.C. § 103(a)
as unpatentable over the combination of Kreuter,4 Pisani,5 Rapoport,6
Dieck,7 Neubauer,8 Morawski,9 Acharya,10 and Qin.11

4 Kreuter et al., WO 2012/113733 A1, published Feb. 17, 2012. Examiner
relied upon a “translation pasted at the end of the reference” (Examiner’s
April 1, 2020, Answer (Ans.) 3). The Kreuter translation is not paginated.
Therefore, all reference to Kreuter, herein, refers to the Kreuter translation
as if it were paginated consecutively beginning with the first page of the
translation.
5 Pisani et al., Polymeric Nano/Microcapsules of Liquid Perfluorocarbons
for Ultrasonic Imaging: Physical Characterization, 22 Langmuir 4397–
4402 (2006).
6 Rapoport et al., US 2011/0177005 A1, published July 21, 2011.
7 Dieck et al., US 2003/0004533 A1, published Jan. 2, 2003.
8 Neubauer et al., Gadolinium-Modulated 19F Signals From Perfluorocarbon
Nanoparticles as a New Strategy for Molecular Imaging, 60 Magnetic
Resonance in Medicine 1066–1072 (2008).
9 Morawski et al., Quantitative “Magnetic Resonance
Immunohistochemistry” with Ligand-Targeted 19F Nanoparticles, 52
Magnetic Resonance in Medicine 1255–1262 (2004).
10 Acharya et al., PLGA nanoparticles containing various anticancer agents
and tumour delivery by EPR effect, 63 Advanced Drug Delivery Reviews
170–183 (2011).
11 Ruogu Qin, Intraoperative Imaging Platform, (Masters Thesis), The Ohio
State University, 1–118 (2011).
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ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Kreuter discloses:
[M]agnetic resonance tomography (MRT) is an imaging
method, in medical diagnostics for the representation of the
structure and function of the tissues and organs in the body.
The magnetic resonance tomography is based on very strong
magnetic fields as well as electromagnetic alternating fields in
the radio frequency range, with which certain atomic nuclei
(mostly the water nuclei/protons) are resonantly excited in the
body which then induce electrical signals in the receiver circuit.
Contrast agents are used to improve the representation of
structures and functions of tissues/organs in MRT. In magnetic
resonance tomography gadolinium chelates are primarily used
as contrast agents . . . to reduce the relaxation times in the
vicinity of the contrast agent.
(Kreuter 1; see Ans. 3–4.)
FF 2. Kreuter “relates to nanoparticles, comprising a gadolinium
compound and/or incorporated perfluorooctyl bromide, for use as contrast
media in . . . (MRT)-assisted diagnosis of liver diseases, more particularly of
hepatocellular carcinoma” (Kreuter 1; see Ans. 3–4).
FF 3. Kreuter discloses that “[b]iodegradation and biocompatibility are
essential properties of human-compatible nanoparticles” and
“[n]anoparticles from the polymeric human serum albumin (HSA) or poly(d,
l-lactic-co-glycolic) acid (PLGA) are well tolerated” (Kreuter 1).
FF 4. Kreuter discloses that PLGA nanoparticles mixed with a gadolinium
compound (gd-DTPA) can be successfully used for improved contrasting in
MRT of hepatocellular carcinoma (see Kreuter 1; see Ans. 3–4).
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FF 5. Kreuter discloses PLGA nanoparticles in the size range of 100–300
nm (see Kreuter 6; see Ans. 3).
FF 6. Pisani discloses:
Ultrasonic imaging is a widely available, noninvasive,
and cost-effective diagnostic modality, but vessels smaller than
200 μm in diameter are impossible to visualize. Commercial
ultrasound contrast agents (UCAs), consisting of encapsulated
gas micro bubbles injected intravenously, enable only a
qualitative visualization of the microvascularization for a short
period of time since they are rather unstable. In a strategy to
develop more stable UCAs, we designed a process to obtain
nano/microcapsules with a single core of liquid
perfluorocarbons within a biodegradable polymeric shell of
homogeneous thickness. The polymer shell should improve the
stability of the capsules as compared to UCAs stabilized by a
monomolecular layer, while the acoustic impedance of the
perfluorocarbons should ensure their echogenicity. These
capsules have been optimized to encapsulate several liquid
perfluorocarbons; perfluorohexane, perfluorodecalin, and
perfluorooctyl bromide. The system is rather versatile: the
mean size of the capsules can be adjusted between 70 nm and
25 μm.
(Pisani, Abstract; id. at 4399–4400 (Pisani discloses that the
perfluorocarbons had “diverse boiling points ranging from 36 ºC for
perfluoropentane to 140 ºC for perfluorooctyl bromide.”); see Ans. 4.)
FF 7. Pisani discloses contrast agents having an “organic phase [that] is a
mixture of PLGA, methylene chloride (a low-boiling good solvent for
PLGA) and liquid perfluorocarbon (a high boiling very poor solvent for
PLGA)” (Pisani 4399; see Ans. 4).
FF 8. Examiner finds that the combination of Kreuter “does not disclose
liquid perfluoro crown ethers of [Appellant’s] . . . claims or ultrasound of an
organism, sample from an organism or cells” (Ans. 4).
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FF 9. Rapoport discloses “methods for using . . . nanoemulsions to
treat tumors and cancers as well as using them as imaging agents” and
that its “nanoemulsions are stable and are excellent drug delivery
devices for ultrasound-mediated, image guided drug delivery”
(Rapoport, Abstract; see Ans. 4).
FF 10. Rapoport discloses that its “nanoemulsions . . . can include a
(1) block copolymer wherein the block copolymer is polyethylene
glycol poly(l)lactic acid block copolymer or a polyethylene glycol
poly(d,l)lactic acid block, (2) a perfluoro crown ether, such as
perfluoro 15-crown-5 ether, and (3) a therapeutic agent” (Rapoport
¶ 55; see also id. ¶ 57 (Rapoport discloses that “the therapeutic agent
includes paclitaxel, doxorubicin, or any combinations thereof.”); see
Ans. 4).
FF 11. Rapoport discloses that its nanoemulsions
possess a number of advantageous properties. For example,
due to large differences in acoustic impedance between the
fluoro ether and water, the nanoemulsions generate relatively
strong ultrasound contrast. . . . The nanoemulsions readily form
microbubbles under therapeutic ultrasound. Despite the
presence of the high boiling fluoro ether, the nanoemulsions
can be readily converted to microbubbles . . ., which makes the
nanoemulsions effective as a drug delivery device and imaging
agent. . . . The microbubbles oscillate and cavitate under the
action of tumor-directed low energy therapeutic ultrasound.
(Rapoport ¶ 63; see Ans. 4.)
FF 12. Rapoport’s
nanoemulsions . . . exhibit high thermal stability, which is
important for prolonging their shelf life and facilitate handling.
The nanoemulsions also remain stable even during prolonged
heating. For example, the nanodroplets can remain stable for 3
to 14 days at temperatures ranging from about 30° C. to about
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50° C. Despite thermal stability, the nanoemulsions are
sensitive to ultrasound; for example, when perfluoro 15-crown-
5 ether having a boiling point of 146° C. was used, the
nanoemulsions converted into microbubbles under the action of
therapeutic ultrasound.
(Rapoport ¶ 64; see Ans. 4.)
FF 13. Rapoport discloses that when its
[n]anoemulsion contains perfluoro 15-crown-5-ether, 19F MRI
can be used to image the presence of the nanoemulsion in the
subject after administration . . . to monitor nanoemulsion
distribution within a tumor and normal tissue. . . . [In addition,]
imaging of the tissue contacted with these nanoemulsions can
be conducted by using ultrasound imaging because of a
mismatch in acoustic impedances of the nanoemulsions and
endogenous water within a tissue. These impedances generate
ultrasound contrast capable of being imaged. In some aspects,
ultrasound imaging includes harmonic imaging, doppler
imaging such as color doppler, power doppler, and spectral
doppler. Thus, the nanoemulsions described . . . [in Rapoport]
provide two-modal imaging (i.e., using 19F MRI and ultrasound
imaging).
The imaging of the tumor with the nanoemulsions
described . . . [in Rapoport] also aids in the application of the
ultrasound to the tumor. By identifying the precise location of
the nanoemulsion in the tumor, it is possible to apply a focused
beam of ultrasound energy to the tumor in order to convert the
nanoemulsion into microbubbles and subsequently release the
therapeutic agent in the tumor. For example, using 19F MRI can
pinpoint the location of the nanoemulsions. This approach
ultimately results in a much more efficient and effective way to
deliver therapeutic agents to tumors.
For example, the methods described . . . [in Rapoport]
include treating a tumor by the following steps: (a) contacting
the tumor with a therapeutic agent encapsulated in a first
nanoemulsion, wherein the first nanoemulsion comprises at
least a fluoro containing ether; and (b) exposing the tumor to a
first ultrasonic radiation (e.g., in an amount from about 30 kHz
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to about 20 MHz). In some aspects, a second nanoemulsion can
be directly injected into the tumor (i.e., via intratumoral
injection) after step (a) but before step (b). . . .
The nanoemulsions may be used to treat tumor growth,
prevent tumor growth, or kill tumors because these
nanoemulsions can accumulate and/or extravasate in tumors
via, for example, the enhanced permeability and retention
(EPR) effect. The nanoemulsions can be subsequently
converted into microbubbles in situ with ultrasonic radiation,
and if a therapeutic agent is present within the nanoemulsion,
the therapeutic agent can be released from the nanoemulsion via
ultrasound-triggered drug release. The conversion from a
nanoemulsion, which includes nanodroplets, to microbubbles is
known as acoustic droplet vaporization (ADV); however, other
mechanisms of droplet-to-bubble transitions are also possible.
(Rapoport ¶¶ 70–73; see Ans. 4.)
FF 14. Examiner finds that Kreuter “does not disclose Gadoteridol or that
the particle provides enhanced contrast during imaging as compared to
imaging performed without the particle containing the gadoteridol” (Ans. 5).
FF 15. Dieck “relates to vaso-occlusive devices and methods of treating
conditions manifesting abnormal blood flow employing the vaso-occlusive
devices” (Dieck ¶ 2; see Ans. 5).
FF 16. Dieck discloses a device comprising a polymer (such as PLGA), a
bioactive agent (such as a drug, receptor ligand, or antibody), and a radio
pacifier (such as “a gadolinium-based MRI contrast agent,” which includes,
but is not limited to, “Gd DTPA” and “Gadoteridol”) (Dieck, Abstract; id.
¶¶ 8–10, 15, 16, 18, 62, 68; see Ans. 5–6).
FF 17. Neubauer discloses:
Recent advances in the design of fluorinated nanoparticles for
molecular magnetic resonance imaging (MRI) have enabled
specific detection of 19F nuclei, providing unique and
quantifiable spectral signatures. However, a pressing need for
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signal enhancement exists because the total 19F in imaging
voxels is often limited. By directly incorporating a relaxation
agent, gadolinium (Gd), into the lipid monolayer that surrounds
the perfluorocarbon (PFC), a marked augmentation of the 19F
signal from 200-nm nanoparticles was achieved. . . . By
varying the surface concentration of Gd, the relaxation effect
can be quantitatively modulated to tailor particle properties.
This novel strategy dramatically improves the sensitivity and
range of 19F MRI/MRS and forms the basis for designing
contrast agents capable of sensing their surface chemistry.
(Neubauer, Abstract; see also Ans. 6 (Examiner finds that Neubauer
discloses, inter alia, “nanoparticles compris[ing] perfluoro-15-crown-5 ether
and Gd-DTPA-BOA”.12)
FF 18. Morawski discloses “that fibrin-targeted, liquid perfluorocarbon
nanoparticles, which carry a high payload of gadolinium, have a high
sensitivity and specificity for detecting fibrin with clinical 1H MRI” and “the
potential use of these particles for uniquely identifying unstable
atherosclerotic lesions in vivo” (Morawski, Abstract; see Ans. 6–7; see also
Ans. 7 (Examiner finds that Morawski discloses 200–300 nm “nanoparticles
compris[ing] perfluour-15-crown-5 and Gd-DTPA-BOA”)).
FF 19. Examiner finds that Kreuter “does not disclose a fluorescent dye”
and relies on Acharya to disclose a fluorescent probe encapsulated within
“~100 nm” PLGA nanoparticles (Ans. 8 (citing Acharya Abstract, 171–173);
see generally Acharya 173:§ 2 (Acharya discloses “[m]any studies
demonstrated rapid and efficient cellular uptake of PLGA NPs, based on

12 Neubauer discloses that “bis-oleate (BOA) diethylene-triamine-
pentaacetic acid (DTPA) derivatives are employed as chelates for . . . GD
ions” (Neubauer 1067).
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microscopic observation of PLGA NPs encapsulating a fluorescent probe
and/or measurement of the intracellular level of the probe”)).
FF 20. Examiner finds that Kreuter “does not disclose in vitro imaging [of]
a sample from [a] subject [, wherein the sample is] taken after the particle
has been provided to the subject” and relies on Qin to disclose a “method of
imaging [that] involves injection of . . . [fluorescent microbubbles into] a
patient, intraoperative imaging, specimen retrieval, specimen analysis, etc.”
(Ans. 9 (citing Qin 3, 6–7, 23, 28)).
ANALYSIS
The combination of Kreuter, Pisani, Rapoport, Dieck, Neubauer,
Morawski, Acharya, and Qin establishes that nanoparticles comprising
PLGA were known to be useful in both MRI and ultrasound imaging13 (see
FF 2–6, 9–13, 17–19; cf. Reply Br.14 1 (Appellant contends that Kreuter
alone “does not disclose a method of ultrasound imaging [of] any particle
provided to a subject, much less the highly specific amplitude-based
ultrasound imaging.”)). Appellant failed to establish an evidentiary basis on
this record to support a conclusion that those of ordinary skill in this art
would have expected that a nanoparticle comprising PLGA, as recited in
Appellant’s claim 8, exhibits a structure, i.e. matrix, that differs from the
prior art nanoparticles, which comprise PLGA. Therefore, we are not
persuaded by Appellant’s contention that the prior art fails to make obvious
“the claimed structure of the particle, namely wherein the PLGA of the

13 Amplitude mode, or amplitude-based, ultrasound “is a standard ultrasound
characterization technique” (see Spec. 15:13). Therefore, we find that
“amplitude-based ultrasound” is encompassed by the generic use of the term
“ultrasound imaging.”
14 Appellant’s May 26, 2020, Reply Brief.
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particle is present in the form of a matrix” (Appeal Br. 7; see also Reply Br.
1 (Appellant contends that Kreuter alone “does not disclose the claimed
structure of the particle, namely wherein the PLGA of the particle is present
in the form of a matrix and the gadoteridol and liquid perfluoro crown ether
are distributed in the matrix”)).
Kreuter discloses that “[c]ontrast agents are used to improve the
representation of structures and functions of tissues/organs in MRT” and that
“gadolinium chelates are primarily used as contrast agents . . . to reduce the
relaxation times in the vicinity of the contrast agent” (FF 1; see also FF 4
(Kreuter discloses that PLGA nanoparticles mixed with a gadolinium
compound (gd-DTPA) can be successfully used for improved contrast in
MRT)). Neubauer and Morawski similarly disclose the benefits of utilizing
nanoparticles comprising a gadolinium (Gd) relaxation agent (see FF 17–
18). Dieck discloses that a number of “gadolinium-based MRI contrast
agent[s] are known in the art, including, not only the “Gd DTPA” disclosed
by Kreuter, but also “Gadoteridol,” as required by Appellant’s claimed
invention (FF 16; cf. Reply Br. 1 (Appellant contends that “Kreuter does not
disclose gadoteridol”)). Thus, we find no error in Examiner’s conclusion
that, at the time Appellant’s invention was made, it would have been prima
facie obvious to substitute Dieck’s gadoteridol for Kreuter’s gadolinium
compound, Gd-DTPA, because Dieck discloses that Gd-DTPA and
gadoteridol are both useful gadolinium-based MRI contrast agents, which
“can be incorporated into a PLGA matrix” (see Ans. 7; id. at 7–8 (Examiner
also relies on Neubauer and Morawski to disclose the benefit of using
fluorinated nanoparticles containing gadolinium compounds in MRI
procedures); see also FF 1–5, 15–18)).
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In addition to a gadolinium compound, as discussed above, Kreuter
discloses that its nanoparticle MRT contrast agent, comprises perfluorooctyl
bromide (see FF 2). Pisani discloses that perflourocarbons, such as
Kreuter’s perfluorooctyl bromide, are also useful as a component of stable
ultrasound contrast agents, wherein “a single core of liquid
perfluorocarbons” are contained “within a biodegradable polymeric shell,”
such as PLGA (see FF 6–7). Similar to Pisani, Rapoport discloses methods
of using stable PLGA-based nanoemulsions comprising “a perfluoro crown
ether, such as perfluoro 15-crown-5 ether,” as ultrasound imaging agents (FF
9, 13; cf. Reply Br. 1 (Appellant contends that Kreuter alone “does not
disclose the presence of . . . liquid perfluoro crown ethers”)).15 Rapoport
discloses that “imaging of the tissue contacted with . . . [its] nanoemulsions
can be conducted by using ultrasound imaging because of a mismatch in
acoustic impedances of the nanoemulsions and endogenous water within a
tissue. These impedances generate ultrasound contrast capable of being
imaged” (FF 13; see Ans. 5 (Examiner emphasizes that Rapoport’s
disclosure distinguishes between the use of ultrasound for imaging purposes
and the use of therapeutic ultrasound to facilitate ultrasound-triggered
release of a therapeutic agent from Rapoport’s nanoemulsion, wherein
“nanoemulsions can be . . . converted into microbubbles in situ with
ultrasonic radiation, and if a therapeutic agent is present within the
nanoemulsion, the therapeutic agent can be released from the

15 Rapoport also discloses that its stable PLGA-based nanoemulsions may
serve as vehicles for delivery of therapeutic agents via ultrasound-triggered
drug release (FF 9–13).
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nanoemulsion”)).16 As Examiner explains, the evidence of record
establishes that perfluorooctyl bromide and perfluour-15-crown-5 are useful
components of ultrasound contrast agents and share a similar boiling point
(see Ans. 4–5). Thus, we find no error in Examiner’s conclusion that, at the
time Appellant’s invention was made, it would have been prima facie
obvious to substitute Rapoport’s liquid perfluour-15-crown-5 ether for
Kreuter’s liquid perfluorocarbon, perfluorooctyl bromide (Ans. 4–5).
Rapoport further discloses that “19F MRI can be used to image the
presence of . . . [its] nanoemulsion in the subject after administration . . . to
monitor nanoemulsion distribution within a tumor and normal tissue” (FF
13). “Thus, the nanoemulsions described . . . [in Rapoport] provide two-
modal imaging (i.e., using 19F MRI and ultrasound imaging)” (id.; see Ans.
5; cf. Reply Br. 4 (Appellant contends that “Neubauer and Morawski . . .
only teach[] that liquid [perfluoro crown ether (PFCE)] can be used for
MRI” and “do not teach or suggest that PFCE remains in liquid form if
diagnostic ultrasound is used”)). Because the nanoparticle made obvious by
the combination of Kreuter, Pisani, Rapoport, Dieck, Neubauer, Morawski,
Acharya, and Qin can be used for both MRI and ultrasound imaging, we find
no error in Examiner’s conclusion that the combination of Kreuter, Pisani,
Rapoport, Dieck, Neubauer, Morawski, Acharya, and Qin makes obvious a
method of amplitude-based ultrasound imaging comprising a PLGA
nanoparticle comprising liquid perfluoro-15-crown-5-ether and gadoteridol

16 Rapoport discloses that the “nanoemulsions readily form microbubbles
under therapeutic ultrasound” and, thereby, release a therapeutic agent
encapsulated in “the nanoemulsion via ultrasound-triggered drug release”
(FF 11, 13).
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(see Ans. 3–9; cf. Reply Br. 2 (Appellant contends that “a critical flow in the
obviousness analysis relates to the inventive step jumping from MRI in
Kreuter to the amplitude-based ultrasound imaging specifically required in
[Appellant’s] claim 8)).
Acharya discloses PLGA-based nanoparticles encapsulating a
fluorescent probe for microscopic detection of nanoparticles in cells (see FF
19).17 Examiner relies on Qin to disclose a “method of imaging [that]
involves injection of . . . [fluorescent microbubbles into] a patient,
intraoperative imaging, specimen retrieval, specimen analysis, etc.” (FF 20).
Thus, we find no error in Examiner’s conclusion that, at the time Appellant’s
invention was made, it would have been prima facie obvious to (a)
incorporate a fluorescent dye, as disclosed by Acharya, into the nanoparticle
made obvious by the combination of Kreuter, Pisani, Rapoport, Dieck,
Neubauer, Morawski, Acharya, and Qin and (b) perform in vitro imaging of
a sample from a subject that was obtained after the particle has been
provided to the subject, as suggested by Qin and Acharya (see generally
Ans. 8–9; see also FF 1–20).
Appellant provides separate arguments for the following groups of
claims: (a) claim 8; (b) claims 18–20; (c) claim 28; (d) claim 29; (e) claim
30; (f) claim 37; and (g) claims 38–39 (see Appeal Br. 5–15). Appellant’s
contentions with respect to representative claims 8, 18, 28, 29, 30, 37, and
38 are addressed below:

17 We also note that Pisani discloses the use of a fluorescent marker to study
the structure of its nanocapsule ultrasound contrast agents (see Pisani 4399).
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Claim 8:
Appellant’s independent claim 8 is reproduced above.
The prior art relied upon by Examiner discloses nanoparticles
comprising PLGA (see, e.g., FF 3–5, 7, 10). Appellant failed to establish an
evidentiary basis on this record to establish that a nanoparticle comprising
PLGA, as recited in Appellant’s claim 8, exhibits a structure, i.e. matrix, that
differs from the prior art nanoparticles, which comprise PLGA. Therefore,
we are not persuaded by Appellant’s contention that the prior art fails to
make obvious “the claimed structure of the particle, namely wherein the
PLGA of the particle is present in the form of a matrix” (Appeal Br. 7; see
also id. at 8 (Appellant contends “[t]he highly specified structural
arrangement of the particles claimed unexpectedly and surprisingly shows
enhanced contrast in the specifically defined special mode of ultrasound,
amplitude-based ultrasound”)).
Appellant contends that Kreuter does not disclose ultrasound imaging,
liquid perfluoro crown ethers, or gadoteridol (Appeal Br. 6–7). Appellant’s
contention, however, fails to address Kreuter in combination with Pisani,
Rapoport, Dieck, Neubauer, Morawski, Acharya, and Qin and is, therefore,
not persuasive. See In re Keller, 642 F.2d 413, 425 (CCPA 1981) (“[T]he
test [for obviousness] is what the combined teachings of the references
would have suggested to those of ordinary skill in the art.”); In re Merck &
Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (“Non-obviousness cannot
be established by attacking references individually where the rejection is
based upon the teachings of a combination of references. . . . [The
reference] must be read, not in isolation, but for what it fairly teaches in
combination with the prior art as a whole.”).
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As discussed above, based on the combination of Kreuter, Pisani,
Rapoport, Dieck, Neubauer, Morawski, Acharya, and Qin, we find no error
in Examiner’s conclusion that, at the time of Appellant’s claimed invention,
it would have been prima facie obvious to substitute liquid perfluor-15-
crown-5 for Kreuter’s liquid perfluorocarbon, perfluorooctyl bromide. Thus,
we are not persuaded by Appellant’s contention that “there is no . . . hint in
[the combination of references relied upon by Examiner] . . . that the
claimed perfluoro crown ether would work in Kreuter’s MRT process, much
less in amplitude-based ultrasound imaging as claimed,” by Appellant
(Appeal Br. 8).
As discussed above, Rapoport discloses methods of using stable
PLGA-based nanoemulsions comprising “a perfluoro crown ether, such as
perfluoro 15-crown-5 ether,” as ultrasound imaging agents ultra-sound
imaging (see FF 9, 13). As further discussed above, Rapoport’s disclosure
distinguishes between the use of ultrasound for imaging purposes and the
use of therapeutic ultrasound to facilitate ultrasound-triggered release of a
therapeutic agent from Rapoport’s nanoemulsion. Thus, we are not
persuaded by Appellant’s contention that “one of ordinary skill in the art
would not look to Rapoport and substitute the liquid perfluoro crown ethers
thereof into Kreuter, absent hindsight,” because Rapoport’s disclosure of
therapeutic ultrasound “deals with acoustic droplet vaporization, (i.e. liquid-
to-gas phase change), which the [Appellant] has extensively shown does not
occur in the particles,” used according to Appellant’s claimed method
(Appeal Br. 8; see also id. at 11 (Appellant contends Examiner’s rejection is
based on improper hindsight); Reply Br. 1 (Appellant contends that Kreuter
alone “does not . . . suggest[] the claimed requirement of the liquid perfluoro
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crown ether remaining in liquid for during the imaging”); Reply Br. 2–3
(Appellant contends that Rapoport’s “ultrasonic imaging involv[es] [a]
phase change from liquid to gas”); Reply Br. 4 (Appellant contends that
“Rapoport explicitly teaches that the focused beam of ultrasound would lead
to phase change” and “[i]n Rapoport, ultrasound imaging is performed so
that the PFCE changes from liquid to gas”); Reply Br. 6 (Appellant contends
that a “liquid to gas phase change of the PFCE is the whole purpose for
performing ultrasonic imaging in Rapoport”)). Stated differently, we are not
persuaded by Appellant’s contention that Examiner relied upon improper
hindsight simply because Appellant’s claimed invention does not require the
use of therapeutic ultrasound, which Rapoport discloses as a second, distinct,
aspect of its disclosed ultrasound methodology (see, e.g., FF 9 (Rapoport
discloses “methods for using . . . nanoemulsions . . . as imaging agents” and
“for ultrasound-mediated, image guided drug delivery”)).
For the foregoing reasons, we are not persuaded by Appellant’s
contention that “[t]here is no reasonable expectation of success to combine
the liquid perfluoro crown ether of Rapoport into Kreuter[’s]” particle
(Appeal Br. 8).
As discussed above, the combination of Kreuter, Pisani, Rapoport,
Dieck, Neubauer, Morawski, Acharya, and Qin makes obvious the use of a
particle comprising perfluoro 15-crown-5 ether and gadoteridol incorporated
into a PLGA matrix for use in an ultrasound or MRI imaging method.
“[T]he law does not require that the references be combined for the reasons
contemplated by the inventor.” In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir.
1992). Therefore, we are not persuaded by Appellant’s contention that
Dieck relates to MRI, wherein Gd compounds are commonly used,” “does
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not relate to ultrasound,” and provides “no reasonable expectation of success
to incorporate the gadoteridol into Kreuter to obtain any improvement in
amplitude-based ultrasound as specifically claimed” (Appeal Br. 9). Using
the particle made obvious by the combination of Kreuter, Pisani, Rapoport,
Dieck, Neubauer, Morawski, Acharya, and Qin in ultrasound imaging, as
disclosed by Rapoport, would necessarily result in enhanced contrast as
compared to imaging performed without a particle comprising gadoteridol
(cf. Reply Br. 1 (Appellant contends that Kreuter alone “does not . . .
suggest[] . . . the particle provides enhanced contrast during imaging as
compared to imaging performed without the particle comprising
gadoteridol”)). See Ex parte Obiaya, 227 USPQ 58, 59 (BPAI 1985) (“The
fact that appellant has recognized another advantage which would flow
naturally from following the suggestion of the prior art cannot be the basis
for patentability when the differences would otherwise be obvious.”).
For the foregoing reasons, we are not persuaded by Appellant’s
contention that
an agent that works for one type of imaging (such as
gadolinium in MRI) cannot reasonably be expected to generate
contrast in a different imaging modality (such as ultrasound),
when the imaging modalities function on completely distinct
physical principles (magnetic resonance and acoustics). The
results of any combination would be unpredictable to one of
ordinary skill in the art.
(Appeal Br. 10.)
For the foregoing reasons, we are not persuaded by Appellant’s
contention that, although, Morawski discloses “the combination of a
perfluoro-15-crown-5-ether with a gadolinium agent in a nanoparticle,”
because Marowaski “deals exclusively with MRI,” it alone provides no
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“reasonable expectation of success to take particles . . . apply them
to . . . ultrasound” (Appeal Br. 9). For the same reasons, we are not
persuaded by Appellant’s contention that because neither Neubauer nor Qin
disclose amplitude-based ultrasound they fail to provide the requisite
“reasonable expectation of success” on this record (id.).

Claim 18:
The method of Appellant’s claim 18 depends from and further limits
Appellant’s claim 8 to require that “the particle is comprised in a particulate
matter wherein the mean particle diameter is of a value of between 100 and
300 nanometers” (Appeal Br. 16).
Appellant does not dispute Examiner’s finding that Kreuter discloses
nanoparticles that fall within the scope of Appellant’s claimed invention (see
Appeal Br. 12–13; cf. FF 5).
Appellant contends, however, that because Kreuter’s nanoparticles do
not comprise perfluoro-15-crown-5-ether or gadoteridol, “Kreuter does not
describe and enable the PLGA particle of the specific sizes defined in”
Appellant’s claim 18 (Appeal Br. 13). We are not persuaded. Appellant
failed to establish an evidentiary basis on this record to support a conclusion
that the particle made obvious by the combination of Kreuter, Pisani,
Rapoport, Dieck, Neubauer, Morawski, Acharya, and Qin would not have a
mean particle diameter between 100 and 300 nanometers. See In re
Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a
brief cannot take the place of evidence.”).

Claim 28:
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The method of Appellant’s claim 18 depends from and further limits
Appellant’s claim 8 to require that “the particle comprises a detecting agent,
such as a dye, such as a fluorescent dye or a radionuclide” (Appeal Br. 17).
For the reasons set forth above, we are not persuaded by Appellant’s
contention that Kreuter’s “particles . . . are compositionally distinguished
from the particle specifically defined in [Appellant’s] claim 8,” “Acharya
does not supply any of the deficiencies missing that would lead one of
ordinary skill in the art to the specifically defined particle of [Appellant’s]
claim 8 further comprising a detecting agent,” and “the prior art does not
describe and enable the claimed invention with sufficient clarity and detail to
establish that the subject matter of claim 28 already existed in the prior art as
required for obviousness” (Appeal Br. 13).

Claim 29:
The method of Appellant’s claim 29 depends from and further limits
Appellant’s claim 8 to require that “the particle comprises a therapeutic
agent, such as a drug, a receptor ligand, or an antibody” (Appeal Br. 17).
For the reasons set forth above, we are not persuaded by Appellant’s
contention that Kreuter’s “particles . . . are compositionally distinguished
from the particle specifically defined in [Appellant’s] claim 8,” Kreuter’s
“particles . . . are specifically utilized for diagnosis, monitoring and/or early
recognition of HCC using magnetic resonance tomography,” and “[o]ne of
ordinary skill in the art would not be led to include a therapeutic agent in a
method that uses a particle for diagnosis, monitoring and/or early
recognition of a liver disease, absent impermissible hindsight” (Appeal Br.
13–14).
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Claim 30:
The method of Appellant’s claim 30 depends from and further limits
Appellant’s claim 8 to require that “the particle is essentially surfactant free
or surfactant free” (Appeal Br. 17).
Appellant contends that Examiner failed to address “the limitation of
claim 30 or cite[] any prior art with respect to this feature” (Appeal Br. 14).
We agree. We also note that Examiner failed to respond to Appellant’s
contention with respect to Appellant’s claim 30.

Claim 37:
Appellant’s independent claim 37 is reproduced above.
Appellant contends that “[t]he particle [set forth in Appellant’s claim
37] requires the same structural and compositional limitations as set forth in
[its] claim 8 and the arguments regarding the same are incorporated herein
by reference for brevity” (Appeal Br. 14). We are not persuaded for the
reasons set forth above with respect to Appellant’s claim 8.

Claim 38:
The method of Appellant’s claim 38 depends from and further limits
Appellant’s claim 37 to require that “the perfluoro crown ether is perfluoro-
15-crown-5-ether” (Appeal Br. 18).
Appellant contends:
[T]here would be no reasonable expectation of success to
combine the liquid perfluoro crown ether of Rapoport into
Kreuter in view of the explicit scope and content of each
reference. As mentioned above, Rapoport deals with acoustic
droplet vaporization whereas it is specifically claimed that the
liquid perfluoro crown ether of the claimed invention remains
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in liquid form during imaging. Rapoport specifically teaches
away from this limitation.
The cited references do not describe and enable the
claimed invention with sufficient clarity and detail to establish
that the subject matter of claim[] 38 . . . would be recognized by
one of ordinary skill in the art.
(Appeal Br. 14–15.) We are not persuaded, for the reasons set forth above,
particularly with respect to Appellant’s claim 8.

CONCLUSION
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness with respect to Appellant’s claims 8, 18, 28, 29,
37, and 38. The rejection of claim 8, 18–20, and 28–39 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Kreuter, Pisani, Rapoport,
Dieck, Neubauer, Morawski, Acharya, and Qin is affirmed.
The preponderance of evidence relied upon by Examiner fails to
support a conclusion of obviousness with respect to Appellant’s claim 30.
The rejection of claim 30 under 35 U.S.C. § 103(a) as unpatentable over the
combination of Kreuter, Pisani, Rapoport, Dieck, Neubauer, Morawski,
Acharya, and Qin is reversed.

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
8, 18–20,
28–39
103(a) Kreuter, Pisani,
Rapoport, Dieck,
Neubauer,
Morawski,
Acharya, Qin
8, 18–20,
28, 29,
31–39
30

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TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv) (2019).

AFFIRMED-IN-PART