MegaPro Biomedical Co., Ltd.

Patent Trials and Appeals Board

Jan 22, 2021

2020003541 (P.T.A.B. Jan. 22, 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.
14/796,539 07/10/2015 Chih-Lung Chen 218379-0002U 2406
24267 7590 01/22/2021
CESARI AND MCKENNA, LLP
ONE LIBERTY SQUARE
SUITE 310
BOSTON, MA 02109
EXAMINER
LAMBERSKI, JENNIFER A
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
01/22/2021 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):
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte CHIH-LUNG CHEN, WEN-YUAN HSIEH, CHEN-HSUAN LIN
and SHIAN-JY WANG

____________

Appeal 2020-003541
Application 14/796,539
Technology Center 1600
____________

Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and
MICHAEL A. VALEK, Administrative Patent Judges.

VALEK, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 submits this appeal under 35 U.S.C. § 134(a) involving
claims to methods of tracking immune cells that have been rejected as
obvious. 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 MegaPro Biomedical Co., Ltd. as
the real party in interest. Appeal Br. 2. Herein, we refer to the Final Action
mailed June 27, 2019 (“Final Act.”); Appellant’s Appeal Brief filed
November 26, 2019 (“Appeal Br.”); and Examiner’s Answer mailed
December 30, 2019 (“Ans.”).
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STATEMENT OF THE CASE
The Specification purports to disclose “a simple and non-invasive
method for tracking immune cells with biocompatible magnetic
nanoparticles using magnetic resonance imaging (‘MRI’) scans” that
“provides unexpectedly high sensitivity.” Spec. 2.
Claims 1–5 and 7–24 are on appeal and can be found in the Claims
Appendix of the Appeal Brief. Claim 1 is representative of the claims on
appeal and reads as follows:
1. A method of tracking immune cells, the method comprising:
identifying a patient having a disease associated with an
organ;
providing an aqueous suspension containing
biocompatible magnetic nanoparticles, the aqueous suspension
being free of particles having a size greater than 1000 nm, the
biocompatible magnetic nanoparticles each containing a
superparamagnetic core that is covered by one or more
biocompatible polymers, each of which has a polyethylene
glycol group, a silane group, and a linker linking, via a covalent
bond, the polyethylene glycol group and the silane group;
administering the aqueous suspension into the blood
stream of the patient; and
after the administration step, obtaining a magnetic
resonance image of the organ, wherein the organ is kidney or
lymph node, the biocompatible magnetic nanoparticles each
have an r2 relaxivity of 120 to 250 (mM·S)-1, and the presence of
hyperintense or hypointense spots in the magnetic resonance
image indicates immune response in the patient.
Appeal Br. 8.
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Appellant seeks review of the following rejections:
I. Claims 1–3, 5, 7–19, and 21–24 under 35 U.S.C. § 103 as obvious
over Hudgins,2 Chang,3 and Tong;4 and
II. Claims 1–4 and 7–24 under 35 U.S.C. § 103 as obvious over Zhang,5
Chang, and Tong.
See Appeal Br. 3–7.
Findings of Fact
FF1. Hudgins describes a study involving the administration of “[d]extran-
coated ultrasmall superparamagnetic iron oxide ferumoxtran-10 (Combidex)”
to image lymph nodes in patients using MRI. Hudgins, Abstr. Hudgins
teaches that the Ferumoxtran-10 (Combidex) particles were administered
intraveneously in an aqueous suspension. See Id. at 650 (subsection
“Ferumoxtran-10”). After administration, magnetic resonance images
showing the patient’s lymph nodes were obtained. See Id. at 653 (Fig. 3);
656 (“the specificity of ferumoxtran-10 in the detection of normal lymph
nodes was consistently high with T2-weighted and T2*-weighted [magnetic
resonance] images obtained 24 and 36 hours after the administration of 2.6
and 3.4 mg Fe/kg doses”).

2 Patricia A. Hudgins et al., Ferumoxtran-10, A Superparamagnetic Iron
Oxide as a Magnetic Resonance Enhancement Agent for Imaging Lymph
Nodes: A Phase 2 Dose Study, 23 Am. J. Neuroradiol 649–656 (2002)
(“Hudgins”).
3 US 2011/0171715 A1, published July 14, 2011 (“Chang”).
4 Sheng Tong et al., Coating Optimizations of Superparamagnetic Iron
Oxide Nanoparticles for High T2 Relaxivity, 10 Nano Lett. 4607–4613
(2010) (“Tong”).
5 Yuqing Zhang et al., Magnetic Resonance Imaging Detection of Rat Renal
Transplant Rejection By Monitoring Macrophage Infiltration, 58 Kidney
Int’l 1300–1310 (2000) (“Zhang”).
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FF2. While Hudgins’ study was conducted on healthy patents, Hudgins
teaches that “[p]reclinical studies have demonstrated the potential use of
ferumoxtran-10-enhanced MR imaging to differentiate normal and reactive
lymph nodes from metastatic lymph nodes.” Hudgins, 655. According to
Hudgins, “[t]h results of this open-label, single-center, dose-ranging, phase 2
study” on healthy patients “will help in determining the optimal dose and
postdose timing of imaging in patients with suspected metastatic nodal
disease.” Id. at 656.
FF3. Chang teaches “a biocompatible polymer for covalently modifying
magnetic nanoparticles” and a “magnetic nanoparticle with biocompatibilities
comprising the biocompatible polymer.” Chang, Abstr. Chang teaches the
biocompatible polymer corresponds to the structures shown in Formulas I
and II. Id. ¶¶ 18–19, 21. Formulas I and II of Chang depict a chemical
structure having a silane group covalently bound via a linker to a variable
length polyethylene glycol (PEG) group. Id.
FF4. Chang teaches that this biocompatible polymer can be used to
“chemically modify the surface of the iron oxide nanoparticle to increase
biocompatibility” and to “provide greater contrast enhancement when being
used as an MRI contrast agent.” Chang ¶¶ 20, 23.
FF5. Chang teaches that a targeting agent, e.g., an antibody or protein, is
coupled to the biocompatible polymer via covalent bonds and that the
“magnetic nanoparticle may have a diameter of about 3-500 nm after
coupling with the targeting agent.” Chang ¶ 24.
FF6. In Example 7, Chang describes a “Relaxivity Test” showing that the
“r2 relaxivity of the modified iron oxide nanoparticles of the invention” was
higher than that of certain prior art particles. Chang ¶¶ 41–43. According to
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the results in Example 7, the modified iron oxide nanoparticle tested there
had a r2 relaxivity of “321.8 ± 2.3” (mM·S)-1 as compared to values ranging
from 160–229 (mM·S)-1 for the prior art particles. Id. ¶ 43 (Table 1).
FF7. Tong teaches that T2 relaxivity6 of superparamagetic iron oxide
nanoparticles (SPIOs) having a PEG coating may be optimized by varying the
size of the iron oxide core and/or the PEG chain length. See Tong, Abstr. In
particular, Tong teaches that T2 relaxivity increased with the core size and
decreased when a higher molecular weight PEG (i.e., a longer PEG chain
length) was used to coat the particle. Id. at 4608, 4610 (Fig. 2a showing T2
relaxivity values, ranging from approximately 380 to 40 (mM·S)-1, for
particles of different core size and PEG chain length).
FF8. According to Tong, the SPIOs in its tests have a “relatively short”
blood circulation half-life. Tong, 4612. Tong teaches that “[a]lthough a
quick removal of SPIOs from the circulation may be beneficial for
minimizing the background signal from unbound SPIOs, longer-circulating
SPIOs may increase the chance of binding to the target molecules, thus an
enhanced contrast.” Id. Tong further teaches that “circulation half-life of the
SPIOs increases with the PEG chain length.” Id.
FF9. Zhang describes a study in a “rat renal transplantation model” using
“magnetic resonance imaging (MRI) with an infusion of ultrasmall
superparamagnetic iron oxide (USPIO) particles to test whether the
accumulation of immune cells such as macrophages, could be detected in
vivo while the kidney transplant was being rejected.” Zhang, 1300. In

6 Examiner finds, and Appellant does not dispute, that the “T2 relaxivity”
referred to in Tong (see, e.g., Tong, Abstr.) is “equivalent to” the “r2
relaxivity” in Appellant’s claims (Ans. 10).
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Zhang’s study, a “stock suspension of dextran-coated USPIO particles” was
infused into rats that had undergone renal transplantation, some of which
were undergoing immunosuppressant treatment to prevent rejection and some
of which were not. Id. at 1302. Magnetic resonance images of the
transplanted kidneys were then taken, “showing the effect of USPIO
infusion.” Id. at 1304 (Fig. 2).
FF10. Zhang explains that the magnetic resonance images obtained from rats
“without the immunosuppressant treatment (I) shows a decrease of the MR
signal intensity within the transplant at one day after USPIO infusion.”
Zhang, 1304 (Fig. 2). Zhang teaches that “[t]his decrease in MR signal
intensity is believed to be due to an accumulation of macrophages containing
USPIO particles in the rejecting transplanted kidney.” Id. According to
Zhang, these
results show that an intravenous administration of USPIO
particles into a transplanted animal appears to be a valuable tool
for detecting the accumulation of macrophages at the site of graft
rejection. The presence of the USPIO particles decreases the
signal intensity of MR images at the site of allografts and thus
provides a possible new, noninvasive means of detecting graft
rejection not only in kidney, but also in other organs.
Id. at 1309.
Analysis
I. 103 Rejection: Hudgins, Chang, and Tong
Appellant does not argue any claim separately from independent
claim 1 for this rejection. See Appeal Br. 17–18. We select claim 1 as
representative for our analysis and the other rejected claims stand or fall
with that claim. See 37 C.F.R. § 41.37(c)(iv). The issue for this rejection is:
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Does the preponderance of evidence of record support Examiner’s
conclusion that claim 1 is obvious over the cited references?
Examiner finds that Hudgins teaches a method comprising “providing
an aqueous suspension of Ferumoxtran-10 (Combidex; dextran iron oxide)
nanoparticles; intravenously administering the Ferumoxtran-10 nanoparticles
to the patient . . . and obtaining T2- and T2*-weighted magnetic resonance
(MR) images of the neck to differentiate normal and reactive lymph nodes
from metastatic lymph nodes.” Ans. 3. Examiner acknowledges that “the
studies of Hudgins are proof-of-principle studies on healthy volunteers,” but
finds that Hudgins reasonably suggests this method “for use on diseased
patients.” Id.
Examiner finds that Chang teaches biocompatible magnetic particles
comprising “a polyethylene glycol group, a silane group, and a linker
link[ing], via a covalent bond, the polyethylene glycol group to the silane
group” as claimed. Ans. 4. Examiner determines “it would have been
obvious . . . to use the biocompatible magnetic nanoparticles of Chang
instead of the Ferumoxtran-10 (Combidex; dextran iron oxide) nanoparticles
[in] the method of Hudgins” because Chang teaches that its particles
“provide greater contrast enhancement when used as an MRI contrast
agent.” Id. at 5.
Regarding the recited range of “r2 relaxivity” values, Examiner finds
that Tong teaches “SPIOs having r2 values between 130 – 385 (s-1mM-1)
may be achieved by fine-tuning core size and PEG coating chain length,
wherein increasing core size increases r2 values but increasing PEG coating
chain length decreases r2 values but increases circulation half-life, which
increases the chance of binding to the target molecule.” Ans. 6. Examiner
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concludes “it would have been obvious . . . to optimize the transverse
magnetic relaxivity rate (r2 value) by optimizing the core size and PEG
coating length of the biocompatible magnetic nanoparticles of Chang”
because Tong evidences that the r2 value of such particles is a “results
effective parameter.” Id.
We agree with, and adopt Examiner’s findings and reasoning in
support of the obviousness rejection based on Hudgins, Chang, and Tong.
See FF1–FF8; Ans. 3–6. We are not persuaded by Appellant’s arguments to
the contrary.
Appellant argues that Examiner has failed to establish a prima facie
case because Hudgins does not teach the “use of nanoparticles covered by
PEG-silane, each nanoparticle having an r2 value required by claim 1, i.e.,
120 to 250 (mM·S)-1” and Chang and Tong “do not remedy this deficiency.”
Appeal Br. 3 (citing Ex. C, 8–9, 11). We disagree. Examiner’s rejection is
premised on using the PEG-silane covered nanoparticle taught in Chang,
modified according to Tong, in the method of tracking immune cells taught
in Hudgins. Ans. 5. Examiner has articulated a sufficient and persuasive
rationale for that combination, i.e., to achieve “greater contrast
enhancement,” (id.) and the record supports that finding (FF4).
As for the r2 relaxivity range, Examiner has provided sufficient
evidence to support the finding that the recited r2 values would have been
the obvious result of optimizing a result effective variable. Tong teaches
that the r2 value of a PEG-coated iron oxide nanoparticle, similar to the
particles taught in Chang, can be adjusted to values within the recited range
by varying the core diameter or PEG chain length of the coating. FF7. In
addition, Tong teaches that it may be advantageous to increase the PEG
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chain length, even though doing so would decrease the r2 value, in order to
increase the blood circulation half-life of the particles. FF8. Thus, not only
does Tong support Examiner’s finding that the r2 relaxivity of the particles
at issue is a result effective variable, it provides a motivation for a skilled
artisan to increase the PEG chain length (thereby lowering the r2 value) in
order to obtain a more favorable circulation half-life. This evidence is
sufficient to support a prima facie case of obviousness. See In re Aller, 220
F.2d 454, 456 (CCPA 1955) (“[W]here the general conditions of a claim are
disclosed in the prior art, it is not inventive to discover the optimum or
workable ranges by routine experimentation.”); In re Boesch, 617 F.2d 272,
276 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective
variable . . . is ordinarily within the skill of the art.”).
Appellant’s argument that Chang “would have led away” from an r2
value within the recited range because the embodiment in Chang Example 7
exhibited a somewhat higher r2 value is not persuasive. See Appeal Br. 3
(citing Ex. C, 8–9). First, Chang does not teach away from the claimed
particles because it does not “criticize, discredit, or otherwise discredit” the
use of particles with a lower r2 value than that exemplified in Example 7.
Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013)
(quotations omitted). Second, Tong teaches that the PEG coating of such
particles can be optimized to achieve a balance between high r2 and longer
circulation half-life. FF8. Thus, Tong provides a motivation for the skilled
artisan to increase circulation half-life by increasing the PEG chain length,
which would in turn lower the slightly higher r2 relaxivity of the particles in
Chang Example 7 toward the range recited in claim 1. For all these reasons,
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we determine that Examiner has met the burden to present a prima facie
showing for the rejection.
In an effort to rebut Examiner’s prima facie showing, Appellant offers
a declaration from Dr. Chih-Lung Chen dated June 13, 2019 (“Chen
Declaration”). Appellant argues that the Chen Declaration provides
“comparative data that shows three unexpected advantages of biocompatible
nanoparticles required by claim 1.” Appeal Br. 4. Specifically, the Chen
Declaration compares:
ex vivo macrophage uptake, in vivo lymph node imaging, and in
vivo effect on plasma fibroblast growth factor (FGF23) levels of
biocompatible magnetic iron oxide nanoparticles covered by a
biocompatible polymer containing a polyethylene glycol group
linked to a silane group (IOP) with those of commercially
available dextran-coated iron oxide particles (Feraheme and
Feridex) similar to the dextran-coated particles described in
Hudgins and Zhang.
Chen Decl. ¶ 3. According to Appellant, each of the three comparisons in
the Chen Declaration shows an “unexpected advantage[]” that is “sufficient
to successfully rebut the prima facie case of obviousness allegedly
established by the Examiner.” Appeal Br. 7.
We are not persuaded by the evidence in the Chen Declaration
because that evidence is not reasonably commensurate with the scope of
claim 1. Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 965 (Fed. Cir. 2014)
(“It is the established rule that objective evidence of non-obviousness must
be commensurate in scope with the claims which the evidence is offered to
support.”) (quotations omitted). Claim 1 broadly recites the use of a
nanoparticle “covered by one or more biocompatible polymers, each of
which has a polyethylene glycol group, a silane group, and a linker linking,
via a covalent bond, the polyethylene glycol group and the silane group.”
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Thus, claim 1 encompasses the use of any biocompatible polymer having
three features: (1) a PEG group (of any length), (2) a silane group, and (3) a
linker, which given its broadest reasonable interpretation can be essentially
any chemical structure that joins the PEG and silane groups via a covalent
bond. In contrast to the breadth of claim 1, the Chen Declaration purports to
test iron oxide particles coated with only one such polymer, which the
declaration identifies with the acronym “IOP.”7 Appellant has “not provided
an adequate basis to support the conclusion that other embodiments falling
within the claim,” e.g., particles coated with other polymers within the scope
of claim 1, “will behave in the same manner.” South Alabama Medical
Science Foundation v. Gnosis S.P.A., 808 F.3d 823, 827 (Fed. Cir. 2015)
(citing In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011). Thus,
even if we accept that the Chen Declaration evidences that the tested IOP
exhibited unexpected results relative to the prior art particles, Appellant has
not shown that those results are “reasonably commensurate” with the
substantially broader scope of particles encompassed by the method of claim
1.8 Id.

7 The Chen Declaration states that IOP is “covered by a biocompatible
polymer containing a polyethylene glycol group linked to a silane group,”
but does not identify the particular chemical structure of that coating. Chen
Decl. ¶ 3.
8 In addition to the biocompatible polymer limitation, Claim 1 recites
nanoparticles having a range of r2 relaxivity values. The Chen Declaration
does not identify the r2 value of the IOP used in its tests, but presumably
IOP has a r2 value within the claimed range. Even so, Appellant has not
provided an adequate basis to conclude that the results achieved for IOP
would be expected across the full range of r2 relaxivity values recited in
claim 1, or otherwise shown that range to be critical.
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For these reasons, we determine that the preponderance of the
evidence supports Examiner’s rejection of claim 1 as obvious over the
articulated combination of Hudgins, Chang, and Tong. We affirm
Examiner’s rejection of claims 2, 3, 5, 7–19, and 21–24 for the same reasons
we affirm the rejection of claim 1.
II. 103 Rejection: Zhang, Chang, and Tong
Appellant does not argue any claim separately from independent
claim 1 for this rejection. See Appeal Br. 18–20. We again select claim 1 as
representative for our analysis. The issue for this rejection is: Does the
preponderance of evidence of record support Examiner’s conclusion that
claim 1 is obvious over the cited references?
Examiner finds that Zhang teaches a method of tracking immune cells
involving the intravenous administration of an aqueous suspension of
“dextran-coated ultrasmall superparamagnetic iron oxide (USPIO) particles”
and MRI in a rat kidney transplantation model “to observe accumulation of
immune cells and rejection of the transplanted kidney.” Ans. 7. As with the
rejection involving Hudgins, Examiner relies on the teachings in Chang and
Tong, noted above, for the limitations relating to the biocompatible polymer
coating on the nanoparticle and the r2 relaxivity range. Id. As with the
other rejection, Examiner concludes it would have been obvious to use
Chang’s particles, modified according to Tong, in Zhang’s method to
“provide greater contrast enhancement” and that it would have been obvious
to optimize the r2 relaxivity range because Tong evidences that r2 relaxivity
is a “results oriented parameter.” See Id. at 7–8.
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We agree with, and adopt Examiner’s findings and reasoning in
support of the obviousness rejection based on Zhang, Chang, and Tong as
set forth in the Answer. See FF3–FF10; Ans. 7–8.
Appellant does not argue this rejection separately from Examiner’s
other obviousness rejection and presents the same arguments to contest the
rejection based on Zhang, Chang, and Tong. See generally Appeal Br. 3–7.
Appellant’s arguments are not persuasive for the same reasons discussed
above.
Accordingly, we likewise determine that the preponderance of the
evidence supports Examiner’s rejection of claim 1 as obvious over the
articulated combination of Zhang, Chang, and Tong. We affirm Examiner’s
rejection of claims 2–4 and 7–24 for the same reasons we affirm the
rejection of claim 1.
CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1–3, 5, 7–
19, 21–24
103 Hudgins, Chang,
Tong
1–3, 5, 7–
19, 21–24

1–4, 7–24 103 Zhang, Chang,
Tong
1–4, 7–24
Overall
Outcome
11–5, 7–24

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

AFFIRMED