Preethi H. Gunaratne et al.

Patent Trials and Appeals Board

Oct 22, 2019

14059027 - (D) (P.T.A.B. Oct. 22, 2019)

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.
14/059,027 10/21/2013 Preethi H Gunaratne D6993CIP 5443
27851 7590 10/22/2019
BENJAMIN A. ADLER
8011 CANDLE LANE
HOUSTON, TX 77071
EXAMINER
POPA, ILEANA
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
10/22/2019 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):
Ben@adlerandassociates.com
Colleen@adlerandassociates.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte PREETHI H. GUNARATNE, LALITHYA C. SINGH,
and MATTHEW L. ANDERSON

__________

Appeal 2018-000647
Application 14/059,027
Technology Center 1600
__________

Before DONALD E. ADAMS, TIMOTHY G. MAJORS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

MAJORS, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 submits this appeal under 35 U.S.C. § 134 involving
claims to a polyelectrolyte complex comprising, inter alia, unmodified
microRNAs. The Examiner rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 Appellant identifies the Real Party in Interest as the named inventors,
Preethi H. Gunaratne, Lalithya C. Singh, and Matthew L. Anderson. Appeal
Br. 3.
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STATEMENT OF THE CASE
“The present invention relates to the fields of nanoparticles, dendrons
and cancer treatments.” Spec. 1:19–20. More specifically, according to the
Specification, the invention relates to the design and use of “gold
nanoparticles and their applications in delivery of therapeutic agents to
various cancer and tumor cells.” Id. at 1:20–22. The Specification explains
that, based on ability to silence patterns of gene expression underlying
specific disease conditions, microRNAs (or miRNAs) have been “earmarked
. . . as promising therapeutic agents in the context of personalized medicine,”
and alternatives to high dose chemotherapy. Id. at 4:3–8. According to the
Specification, however, there are obstacles in the clinical application of such
microRNAs, including how to best identify and deliver such agents with
maximal therapeutic impact. Id. at 4:8–10.

Claims 1, 2, 10–14, and 17–20 are on appeal. Independent claim 1 is
representative of the claims on appeal and reads:
1. A polyelectrolyte complex, comprising:
aminothiol functionalized cationic gold nanoparticles;
unmodified microRNAs; and
thiolated polyethylene glycol; said complex having a
diameter about 66 nm to less than 100 nm and an optimized
gold nanoparticle to unmodified micro RNA to thiolated
polyethylene glycol weight ratio of 10 to 1 to 0.5.

Appeal Br. 11 (Claims App’x).
Claim 10 recites a method of delivering the microRNA into the cells
of a subject, which includes the step of administering the complex of claim 1
to the subject. Id. Claims 11 and 12 depend directly or indirectly from
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claim 10 and recite that the cells are tumor cells, and that such tumor cells
are, for example, neuroblastoma, osteosarcoma, ovarian, or prostate cells.
Id. Claim 14 recites a “formulation” for delivering the complex/microRNA
to a subject.2 Id. at 12.
The claims stand rejected3 under 35 U.S.C. § 103(a) as obvious over
Niitome,4 Lieberman,5 Niidome,6 and Wang.7 Final Act. 3–7; Ans. 2–13.
DISCUSSION
The issue on appeal is whether a preponderance of the evidence cited
by the Examiner supports the Examiner’s conclusion of obviousness.
Appellant argues the claims are nonobvious over the combined art.
Appeal Br. 7–8. Appellant does not, however, provide separate argument as
to any of the claims on appeal. Id. Our analysis focuses on claim 1.

2 Claim 14 recites “cysteamine functionalized cationic gold nanoparticles,”
which the Examiner finds are a variant of the functionalized aminothiol in
claim 1. Ans. 3 (“cysteamine-functionalized gold nanoparticles (i.e.,
cationic gold nanoparticles comprising 2-aminoethanethiol, an aminothiol
wherein ‘n’ is 2)”).
3 A rejection of certain claims under 35 U.S.C. § 112(d), or § 112, fourth
paragraph (pre-AIA), was withdrawn as those claims were canceled. See
Adv. Act. (Dec. 14, 2016) 2; Supp. Amend. (Dec. 22, 2016) 2 (cancelling
claims 3–9); Adv. Act. (Jan. 27, 2017), 2.
4 Niitome et al., JPO2005287507 (English translation of record).
5 Lieberman et al., US 2010/0310583 A1, publ. Dec. 9, 2010.
6 Takuro Niidome et al., Preparation of primary amine-modified gold
nanoparticles and their transfection ability into cultivated cells, CHEM.
COMMUN. 1978–79 (2004).
7 Chang-Hai Wang et al., Optimizing the size and surface properties of
polyethylene glycol (PEG)-gold nanoparticles by intense x-ray irradiation,
41 J. PHYS. D: APPLIED PHYS. 1–8 (2008).
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Claim 1
The Examiner finds that Niitome teaches a polyelectrolyte complex
comprising aminothiol functionalized cationic gold nanoparticles (including
2-aminoethanethiol), unmodified plasmid DNA, and thiolated PEG having a
molecular weight of 5000 Da (PEG5000). Ans. 3 (citing Niitome ¶¶ 10–11,
37–39). According to the Examiner, Niitome teaches that the complex may
be obtained in diverse sizes, and that a complex with a size of, for example,
89 nm is suitable for in vivo delivery of nucleic acids. Ans. 3 (citing
Niitome ¶¶ 21, 23–25, 27, and 43). The Examiner further finds that,
although Niitome suggests the complexes may be used for the delivery of
nucleic acids generally, Niitome’s examples use plasmid DNA, and thus
Niitome “do[es] not specifically teach microRNA” as claimed. Ans. 3, 12.
So, the Examiner turns to Lieberman. Id. at 3–4.
The Examiner finds that Lieberman teaches delivering complexes
comprising microRNAs to cells in order to treat cancers, such as prostate
cancer. Id. (citing, e.g., Lieberman Abst., ¶¶ 3, 7, 184, and 226). Also, the
Examiner finds, Lieberman teaches that such microRNAs may be delivered
in polycationic carrier complexes. Id. (citing, e.g., Lieberman ¶¶ 214–215).
The Examiner reasons it would have been obvious to use the functionalized
gold nanoparticle/PEG complex of Niitome to deliver the microRNAs of
Lieberman in order to form compositions suitable for the treatment of certain
cancers. Ans. 4.
Finding Niitome and Lieberman “do not specifically teach a ratio of
10:1:05” for the gold nanoparticle/microRNA/PEG as in claim 1, the
Examiner cites Niidome and Wang. Ans. 4–5. According to the Examiner,
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Niidome teaches the gold nanoparticle to nucleic acid ratio was a known,
result-effective variable that is optimizable to modify transfection efficiency.
Id. at 4 (citing, e.g., Niidome, para. bridging 1978–1979 (“Gold
nanoparticle/DNA complexes at various w/w ratios were added to HeLa
cells. Significant gene expression was observed and its level increased by
increasing the charge ratio. At a w/w ratio of 17, the expression was 100-
fold”), Figs. 3–4).8 The Examiner finds that the ratio of gold nanoparticles
to PEG was also recognized as a result-effective variable affecting the size
and stability of the complex, as evidenced by Wang. Ans. 5 (citing, e.g.,
Wang 4 (“Both such parameters [PEG/Au] affect the particle size and
distribution of our colloidal”), Table 2). As the Examiner explains, Wang
“tested PEG having molecular weights of 1500, 6000, and 20,000 Da and
concluded that PEG having a molecular weight around 6000 D is optimal
for size control and gold particle stability.” Ans. 5.
From the above teachings, the Examiner concludes that the subject
matter of claim 1 would have been obvious. And, the Examiner reasons the
skilled artisan would have arrived at the claimed ratio by “routine
optimization and vary[ing] the amounts of aminothiol-functionalized gold

8 Niidome discloses: “In this study, we developed an easy method for the
preparation of cationic gold nanoparticles modified with 2-aminoethanethiol
. . . and examined the DNA-binding ability and transfection efficiency of
these nanoparticles into cultivated cells.” Niidome, 1978 (first col.).
Niidome further teaches “[t]he amount of DNA uptake into cells
corresponded to the expression levels. As the addition of excess cationic
gold nanoparticles produces cationic complexes, the cationic surface of the
complex would be advantageous for adsorption onto the negatively charged
cell surfaces.” Niidome, 1979, (first col.).
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nanoparticles, microRNA, and PEG5000 with the intent of optimizing the
polyelectrolyte complex for microRNA delivery.” Ans. 5.
We agree with, and adopt, the Examiner’s findings of fact and
reasoning in support of the rejection of claim 1 for obviousness. Final Act.
4–7; see also Ans. 3–12. We explain further below.
Niitome teaches the aminothiol functionalized cationic gold/PEG
complex that is claimed with two exceptions. First, Niitome does not
expressly disclose using its complex to deliver microRNA. Importantly,
however, Niitome discloses that, with its complexes,
[t]here are no particular limitations, what can be delivered
nucleic acid into a cell, or is administered to an individual
animal, preferably those capable of delivering a nucleic acid
into the tissue, as the nucleic acid is single-stranded or double-
stranded DNA, RNA, oligonucleotides, viral DNA, viral RNA,
it may be mentioned plasmid DNA, etc., among these nucleic
acid for gene therapy is useful as a drug delivery system, and
from this point plasmid DNA and viral DNA for use in gene
therapy is preferred.

Niitome ¶ 24 (emphases added). In other words, Niitome’s complexes are
not limited to delivery of plasmid DNA. The complexes may alternatively
deliver, for example, single-stranded RNA and oligonucleotides. Id.
Lieberman teaches the use of microRNAs as a therapeutic agent, and the
Examiner has provided reasons (i.e., development of IV cancer treatments)
for the skilled artisan to have used Niitome’s complexes to facilitate delivery
of Lieberman’s microRNAs to certain cells. Ans. 3–4; see also Niitome
¶ 21 (disclosing that the complexes are also intended to inhibit
biodegradation of the therapeutic nucleic acid).
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Second, the combination of Niitome and Lieberman does not
expressly disclose the gold nanoparticle/miRNA/PEG ratio of 10:1:0.5 as
recited in claim 1. Ans. 4; Final Act. 6–7. As the Examiner notes, however,
Niitome teaches “PEG efficiently forms complexes with gold nanoparticles
at gold nanoparticles to nucleic acid ratios of . . . 8.4 and 16.8 ([0039]).”
Final Act. 6.9 And, the Examiner provides reasoning, backed by Niidome
and Wang, which reasoning we find persuasive on this record, to support the
determination that the ratio of gold nanoparticle to nucleic acid to PEG in
the complex is a result-effective variable that would have been optimized as
a matter of routine for the particular type of nucleic acid being delivered to
the cell to arrive at the claimed ratio. Id. at 6–7; Ans. 4–5, 7–9; In re Aller,
220 F.2d 454, 456 (CCPA 1955) (holding that where “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.”).
Appellant argues the cited prior art does not disclose the weight ratio
of 10:1:0.5 to achieve optimal gene expression or silencing. Appeal Br. 8.
Appellant, thus, urges that “a suggestion for using the beneficial, claimed

9 The Examiner explains that these ratios are further evidenced by “Kawano
. . . , which represents the published results of Niitome . . . . In fact, Fig. 1 in
Kawano . . . demonstrates more efficient DNA complexation at PEGylated
gold nanoparticles to nucleic acid ratios of more than 5.6.” Final Act. 6–7
(citing Takahito Kawano et al., Stabilizing of plasmid DNA in vivo by PEG-
modified cationic gold nanoparticles and the gene expression assisted with
electrical pulses, 111 JOURNAL OF CONTROLLED RELEASE 382–89 (2006)).
Appellant concedes that Niitome teaches that a gold nanoparticle to nucleic
acid ratio of 5.6 or higher, with or without PEG, forms stable complexes.
Appeal Br. 7.
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ratio of 10:1:0.5 can only be obtained by taking recourse to the disclosure of
the instant Application.” Id. (citing Spec. Figs. 9B–9E).
We are unpersuaded. As discussed above, the Examiner
acknowledges that the prior art does not expressly disclose claim 1’s ratio,
but the Examiner reasons that the ratio is merely the product of routine
optimization, and specifically determines that Niitome’s complex would
predictably require optimization for the particular nucleic acid agent being
delivered to the cell—microRNA, rather than the plasmid DNA used in
Niitome’s examples. Ans. 6–8. Niidome and Wang also support the
Examiner’s finding that the proportion of gold nanoparticles, nucleic acid,
and PEG in the complex are known, result-effective variables that would
have been optimized for transfection efficiency, and complex stability. Ans.
4–5, 7–9.
Insofar as Appellant alleges the claimed ratio provided “the most
efficient transfection and silencing,” Appellant’s argument and evidence,
when considered together with the evidence of obviousness is not sufficient
to establish that claim 1 is nonobviousness. Importantly, the testing cited by
Appellant is not commensurate with the breadth of claim 1. In re Lindner,
457 F.2d 506, 508 (CCPA 1972) (“It is well established that the objective
evidence of nonobviousness must be commensurate in scope with the
claims.”). For example, the Examiner observes that “claim 1 generally
recites thiolated PEG and thus encompasses PEG of any molecular weight,”
but “the instant specification only provides results for polyelectrolyte
complexes obtained with PEG5000.” Ans. 11 (“The instant specification
does not provide results demonstrating that the same optimal ratio
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extrapolates to polyelectrolyte complexes obtained with PEG of other
molecular weights.”). Appellant provides no persuasive response to the
Examiner on this point.10 Also, the cited testing was conducted on two
human neuroblastoma cell lines, but claim 1 is not limited to any particular
cell type. (Spec. 17:8–11 (describing the NGP and CHLA-255-MYCN
lines); Figs. 9B–E). For at least those reasons, Appellant’s argument does
not overcome the Examiner’s prima facie case and the evidence of
obviousness.
Appellant contends that Niitome does not teach the ratios that result in
maximal transfection. Appeal Br. 9. According to Appellant, at best, the
skilled person “could only consider the suggestion from Niidome’s
disclosure that a AuNP to plasmid DNA weight ratio of 17:1 yields the most
efficient transfection.” Id. To the extent there was any optimization,
Appellant urges that “the suggestion would be to at least keep a AuNP to
unmodified microRNA ratio of 17:1 as taught by Niidome . . . and vary the
thiolated PEG by routine experimentation.” Id. But, because a 17:1 ratio of
gold nanoparticle to microRNA is not what is claimed, Appellant contends
claim 1 is nonobvious. Id.
We remain unpersuaded. The Examiner explains that Niidome’s 17:1
complex is optimized for plasmid DNA and not microRNA. Ans. 7–8.
According to the Examiner, the skilled artisan “would have known that
ratios optimized for long nucleic acids such as plasmid DNA would not
extrapolate to short nucleic acids such as microRNAs.” Id. at 7. And, the

10 Appellant did not submit a reply brief here.
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Examiner reasons, the skilled artisan “would have readily recognized that
the amount of aminothiol-functionalized gold nanoparticles necessary to
condense large nucleic acids would be different from the amount needed to
condense short nucleic acids,” like microRNAs. Id. at 7–8. Based on this
reasoning, we agree with the Examiner that the skilled person would not
simply maintain the 17:1 ratio of Niidome as Appellant suggests, but would
instead modify the ratio downward through routine optimization for
transfection with smaller microRNAs. The amount of PEG in the complex
would also be optimized for complex stability as suggested in Wang. On
these points, Appellant provides insufficient persuasive argument or
evidence to the contrary.
For the above reasons, we conclude that the preponderance of the
evidence supports the Examiner’s conclusion that claim 1 would have been
obvious over Niitome, Lieberman, Niidome, and Wang.
Other Claims
We also adopt the Examiner’s findings and reasoning in support of the
rejection of claims 2, 10–14, and 17–20. Final Act. 4–7; see also Ans. 3–12.
Appellant did not provide separate argument on claims 2, 10–14, and 17–20,
therefore those claims fall with claim 1.
SUMMARY
We affirm the rejection for obviousness on appeal.
Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 2, 10–14,
17–20
103 Niitome,
Lieberman,
Niidome, Wang
1, 2, 10–14,
17–20

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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).

AFFIRMED