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Patent Trials and Appeals Board

Aug 25, 2021

2021000539 (P.T.A.B. Aug. 25, 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.
14/360,503 05/23/2014 Steven Bloembergen PAT 92237W-2 1386
42534 7590 08/25/2021
BORDEN LADNER GERVAIS LLP
1300-100 QUEEN ST
OTTAWA, ONTARIO K1P 1J9
CANADA
EXAMINER
BROWE, DAVID
ART UNIT PAPER NUMBER
1617
NOTIFICATION DATE DELIVERY MODE
08/25/2021 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):
ipinfo@blg.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte STEVEN BLOEMBERGEN, IAN J. MCLENNAN,
NATHAN JONES, AREET KRSNA GANESH SHERMON,
ABDEL ELSAYED, and JUEWEN LIU
____________

Appeal 2021-000539
Application 14/360,503
Technology Center 1600
____________

Before DONALD E. ADAMS, ULRIKE W. JENKS, and
TIMOTHY G. MAJORS, 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 1, 3, 6–9, and 34–37 (Appeal Br. 1; see also Reply
Br.2 2). We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as “GreenMark
Biomedical Inc.” (Appellant’s September 13, 2019, Appeal Brief (Appeal
Br.) 3).
2 Appellant’s February 20, 2020, Reply Brief.
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STATEMENT OF THE CASE
Appellant’s disclosure relates to “relates to a delivery device for drugs
or other agents, to methods of making and using the delivery device, and to
the treatment of cancer” (Spec. ¶ 2). Appellant’s only independent claim,
claim 1, is reproduced below:
1. A delivery system comprising
nanoparticles comprising a mass of crosslinked and
functionalized starch biopolymers, wherein the starch
biopolymers comprise glucose repeating units and carboxyl
groups; and,
amine modified aptamer targeting molecules directly
linked to the carboxyl groups of the nanoparticles,
wherein the aptamer targeting molecules are attached to
the nanoparticles in an amount sufficient to provide a molar
ratio of the glucose repeating units to the targeting molecules
within a range from about 100:1 to less than 1000:1.
(Appeal Br. 13.)

Claims 1, 3, 6–9, and 34–37 stand rejected under 35 U.S.C. § 103(a)
as unpatentable over the combination of Giezen,3 Xiao,4 Fishman,5 and
Aravind.6

3 Giezen et al., US 6,677,386 B1, issued Jan. 13, 2004.
4 Xiao et al., Preparation of folate-conjugated starch nanoparticles and its
application to tumor-targeted drug delivery vector, 51 CHINESE SCIENCE
BULLETIN 1693–97 (2006).
5 Marshall L. Fishman et al., Molar Masses and Sizes of Starches by High-
Performance Size-Exclusion Chromatography with On-Line Multi-Angle
Laser Light Scattering Detection, 44 J. AGRIC. FOOD CHEM. 3182–3188
(1996).
6 Athulya Aravind et al., Aptamer-labeled PLGA nanoparticles for targeting
cancer cells, 3 CANCER NANO 1–12 (2012).
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ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Giezen “relates to a process for producing nanoparticles, i.e. particles
essentially consisting of a biopolymer such as starch” and “to nanoparticles
obtainable by such a process” (Giezen 1:5–8; see Final Act.7 4; see also
Final Act. 6 (Examiner finds that starch “is a polymer of repeating glucose
units”)).
FF 2. Giezen discloses “that [its] biopolymers such as starch . . . may be
previously modified, e.g. with[, inter alia,] carboxy-methyl groups” (Giezen
1:13–19; see Final Act. 4; see also Appeal Br. 7 (Appellant concedes that “a
carboxymethyl group could be considered a type of carboxyl group”)).
FF 3. Giezen discloses that its nanoparticles can be used as “carriers e.g. in
medicines, where they may be complexed or covalently coupled to active
substances” (Giezen 3:8–11; see Final Act. 4).
FF 4. Examiner finds that Giezen does not disclose that its “starch
nanoparticles are conjugated to . . . [an] aptamer at a ratio of glucose units to
aptamer of about 100:1 to about 500:1” (Final Act. 5).
FF 5. Xiao discloses the conjugation of PEG modified folate (FA-PEG) to
the surface of starch nanoparticles (StNP) “to obtain . . . folate-conjugated
starch nanoparticles . . . a potentially useful system [for] . . . the targeted
delivery of anticancer drug DOX” (Xiao, Abstr.; see also id. at 1693 (Xiao
discloses that “[f]olate displays extremely high affinity to its receptor, which

7 Examiner’s August 16, 2018, Final Office Action.
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enables them to rapidly bind to the FR and become internalized via an
endocytic process”); Final Act. 4).
FF 6. Xiao discloses the “[p]reparation of FA-PEG/StNP,” wherein
1 mg of StNP was suspended in 1 mL of distilled water, and 0.1
mg of FA-PEG-NH2 was added to the StNP solution, shaking
for 3 h under room temperature. The solution was centrifuged
and washed twice with PBS (pH 7.4), and the precipitate was
lyophilized. 1 mg of the lyophilized product was suspended in
1 mL of distilled water, and then treated with a-amylase for 2 h
in 37°C with shaking to digest starch. The concentration of FA
in digested solution was detected by UV spectrophotometer at
363 nm, while there is no absorbance of other materials in
solution under this wavelength. Serially distilled water-diluted
folate was used to construct a calibration curve.
(Xiao § 1.2(iii); see also id. § 2.3 (Xiao discloses that “[t]he FA modified
concentration in FA-PEG/StNP was 0.8 μg/mg detected by UV
spectrophotometer at 363 nm. This indicated that activated folate was
coupled to StNP successfully.”).)
FF 7. Examiner relies on Fishman to “disclose that ‘starch’ has an average
molecular weight on the order of about 106 g/mol, for example about 2 X 106
g/mol for presolubilized potato starch” (Final Act. 4 (citing Fishman, Table
6)).
FF 8. Aravind discloses “[a]ptamer-labeled [poly(lactic-co-glycolic acid
(PLGA)] nanoparticles for targeting cancer cells” (Aravind, Title; see also
id., Abstr.; id. at 3 (Aravind discloses that “[a]mine-modified AS1411
aptamer was conjugated on the carboxyl group carrying nanoparticles using
the common conjugation strategy of carbodiimide chemistry (cross-linking
of the carboxylic acid group on the nanoparticle surface and the amine group
of the aptamer to form an amide linkage)”); see generally Final Act. 4).
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FF 9. Aravind discloses that conjugation of the AS1411, tumor cell
targeting, aptamer onto PLGA nanoparticles loaded with the anti-cancer
drug paclitaxel (PTX) enhanced the anti-tumor efficacy of the PTX-PLGA
nanoparticle compared to non-targeted PTX-PLGA nanoparticles (Aravind
2; see generally Final Act. 4).
ANALYSIS
The combination of Giezen, Xiao, Fishman, and Aravind establishes
that, prior to Appellant’s effective filing date, those of ordinary skill in this
art recognized that starch and PLGA were both useful in producing
nanoparticle drug delivery vehicles or carriers (see FF 1–9). This prior art
further establishes that, prior to Appellant’s effective filing date, those of
ordinary skill in this art recognized that the foregoing nanoparticles can
comprise targeting molecules, such as folate and aptamer, i.e. AS1411, to
effectively target a nanoparticle to a desired location (id.). The prior art
relied upon by Examiner also directs those of ordinary skill in this art to
functionalize the nanoparticle with, for example, carboxy-methyl groups,
which Appellant concedes is a type of “carboxyl group” (see FF 2) and
attach the targeting molecule, i.e. amine-modified AS1411 aptamer, to the
carboxyl group on the nanoparticle (see, e.g., FF 8).
Thus, we find no error in Examiner’s conclusion that the combination
of Giezen, Xiao, Fishman, and Aravind, makes obvious a delivery system
comprising nanoparticles comprising a mass of crosslinked and
functionalized starch biopolymers, wherein the starch biopolymers comprise
glucose repeating units and carboxyl groups; and, amine modified aptamer
targeting molecules directly linked to the carboxyl groups of the
nanoparticles (see FF 1–9; see also Final Act. 8 (“Examiner concludes that
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the subject matter defined by the instant claims would have been obvious
within the meaning of . . . [35 U.S.C. §] 103(a), especially in the absence of
evidence to the contrary”)).
Appellant’s independent claim 1, however, further requires that “the
aptamer targeting molecules are attached to the nanoparticles in an amount
sufficient to provide a molar ratio of the glucose repeating units to the
targeting molecules within a range from about 100:1 to less than 1000:1”
(Appeal Br. 13). Recognizing this requirement of Appellant’s claimed
invention, Examiner reasons that because Fishman
disclose[s] that the average molecular weight of presolubilized
starch is on the order of about 2 X 106 g/mol, and . . . [because]
one of ordinary skill in the art would know that the molecular
weight of a single glucose unit is about 180 g/mol, it follows
that there are on average about 2 X 106/180, or about 11,000,
glucose repeating units per starch molecule.
(Final Act. 6.) Examiner further reasons that Xiao
disclose[s] targeting molecule conjugated crosslinked starch
nanoparticles in which 1 mg of starch is combined with 0.1 mg
of targeting molecule, e.g. FA-PEG-NH2, and that the PEG-bis
(amino) they employ has a molecular weight of 3350 g/mol . . .,
making the molecular weight of FAPEG-NH2 about 3800 g/mol
from the sum of the molecular weight of folate, which one of
ordinary skill in the art would know is about 442 g/mol, and the
molecular weight of PEG-bis (amino).
(Id. (citing Xiao § 1.1).) Examiner then explains that when formulating a
starch nanoparticle to comprise a targeting molecule, e.g., folate, those of
ordinary skill in this art would understand “that there are about 6.022 X 1023
(Avogadro’s number) starch molecules per mole and likewise about 6.022 X

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1023 FA-PEG-NH2 molecules per mole” (id. at 6–7). Thus, Examiner
concludes that
factoring in the 11,000 glucose repeating units per starch
molecule . . ., one of ordinary skill in the art would reasonably
expect that Xiao’s folate conjugated starch nanoparticles will
have a ratio of glucose repeating units to the targeting ligand of
about 212 glucose repeating units per targeting ligand; i.e. a
ratio of 212:1, well within [Appellant’s] claimed range of about
100:1 to about 500:1.
(Id. at 7.)
Although the forgoing analysis based on Xiao relates to a folate
targeting molecule rather than an aptamer, as is required by Appellant’s
claimed invention, Examiner appears to take the position that there is no
reason to expect that a different targeting molecule would require a different
molar ratio of glucose repeating units to targeting molecules, or that such an
effective molar ratio could not be obtained through routine optimization
using Xiao’s ratio as a starting point (see generally Ans.8 8–9). We are not
persuaded.
As Appellant explains, “the folate to glucose ratio calculated in the
Office Action is improperly based on a combination of 1 mg of starch and
0.1 mg of FA-PEG-NH2,” which are the “amounts introduced at the start of
the reaction” to produce nanoparticles, rather than the amounts present in the
final nanoparticle produced in the reacted reagents (see Appeal Br. 9–10;
Reply Br. 8 (“Applicant submits that the Examiner’s calculation is based on
amounts of folate and starch added to a reactor but with no evidence that
they reacted in those same amounts.”); see also FF 6). As Xiao makes clear,
the FA concentration in its final nanoparticle preparation was 0.8 μg/mg

8 Examiner’s December 20, 2019, Answer.
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(FF 6). Thus, using the amount of folate conjugated to the final
nanoparticle, “the molar ratio of glucose repeating units to folate attached to
the nanoparticles in [Xiao’s final nanoparticle preparation] is about 3000:1,”
which “is . . . numerically far outside of the claimed range of about 100:1 to
less than 1000:1” (Appeal Br. 9–10; see generally id. at 10–11).
In view of the foregoing, we are not persuaded by Examiner’s
assertion that Xiao’s starting amounts of folate and starch should be used to
calculate the molar ratio required by Appellant’s claimed invention rather
than the amounts present in the final product (see Ans. 9–11). To the
contrary, we find that Examiner failed to establish an evidentiary basis on
this record to support a conclusion that the combination of Giezen, Xiao,
Fishman, and Aravind makes obvious the subject matter of Appellant’s
claimed invention.
CONCLUSION
The preponderance of evidence relied upon by Examiner does not
support a conclusion of obviousness. The rejection of claims 1, 3, 6–9, and
34–37 under 35 U.S.C. § 103(a) as unpatentable over the combination of
Giezen, Xiao, Fishman, and Aravind is reversed.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 3, 6–9,
34–37
103(a) Giezen, Xiao,
Fishman, Aravind
1, 3, 6–9,
34–37

REVERSED