The Children's Medical Center Corporation

Patent Trials and Appeals Board

Nov 10, 2021

2021002940 (P.T.A.B. Nov. 10, 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.
15/767,116 04/09/2018 Alina Y. Rwei CMCC 2928 371 5955
23579 7590 11/10/2021
PABST PATENT GROUP LLP
1355 PEACHTREE STREET NE
SUITE 800
ATLANTA, GA 30309
EXAMINER
WESTERBERG, NISSA M
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
11/10/2021 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):
docketing@pabstpatent.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ALINA Y. RWEI, CHANGYOU ZHAN,
KATHLEEN J. CULLION, and DANIEL S. KOHANE
Appeal 2021-002940
Application 15/767,116
Technology Center 1600
Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims to a pharmaceutical liposome
composition encapsulating at least one site I sodium channel blocker, where
the liposome includes a sonosensitizer as being obvious and for non-
statutory double patenting. 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 Children’s Medical
Center Corporation. (Appeal Br. 6.) All references to Appeal Brief refer to
the Substitute Appeal Brief filed December 2, 2020.
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Application 15/767,116

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STATEMENT OF THE CASE
Appellant’s Specification teaches that “injectable sustained drug
release systems that provide prolonged duration local anesthesia lasting days
to weeks from one or more injections” have been reported in the prior art.
(Spec. 2.) “However, these formulations have the limitation that once
initiated, nerve blockade proceeds relatively monotonically until the drug
content is depleted.” (Id.) Appellant’s invention is directed to
“compositions for on-demand nerve blockade with local anesthetics.” (Id. ¶
1.)
Claims 1–5, 13–17, 20, 21, and 252 are on appeal. Claim 1,
reproduced below, is illustrative of the claimed subject matter:
1. A pharmaceutical composition comprising
triggerable liposomes, particles or microbubbles
encapsulating at least one site I sodium channel blocker,
wherein the site I sodium channel blocker is repeatably
released upon exposure to a triggering agent in an amount
effective to produce anesthesia,
wherein the triggerable liposomes, particles or
microbubbles comprise one or more triggerable elements
selected from the group consisting of gold nanorods, gold
nanoshells, gold nanostars, gold nanocages, photosensitizers,
and sonosensitizers.
(Appeal Br. 28.) In response to a restriction requirement and species
election requirement, Appellant elected liposomes as the triggerable
component, and sonosensitizers as the triggerable element. (Non-Final
Rejection June 17, 2019 2.) We limit discussion and consideration to the
elected species, and take no position respecting the patentability of the

2 Claims 6–12, 22, 23, and 27–43 are pending but are withdrawn from
consideration as drawn to non-elected inventions and/or species.
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broader generic claims, including the remaining, non-elected species. See
Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (BPAI 1987).

The prior art relied upon by the Examiner is:
Name Reference Date
Kohane US 2005/0202093 A1 Sept. 15, 2005
Bettinger US 2013/0156706 A1 June 20, 2013
Ana S. Abreu et al. Nanoliposomes for
encapsulation and
delivery of the
potential antitumoral
methyl 6-methoxy-3-(4-
methoxyphenyl)-1H-
indole-2-carboxylate, 6
Nanoscale Res. Letters,
482
2011
Hirotomo Shibaguchi
et al.
Sonodynamic Cancer
Therapy: A Non-
invasive and
Repeatable Approach
Using Low-intensity
Ultrasound with a
Sonosensitizer, 31
Anticancer Res. 2425-
2430
2011
Barbara Kneidl et al. Thermosensitive
liposomal drug
delivery systems: state
of the art review, 9
Int’l J of
Nanomedicine, 4387–
98
2014

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The following grounds of rejection by the Examiner are before us on
review:
Claims 1–5, 13, 14, 20, 21, and 25 under 35 U.S.C. § 103 as
unpatentable over Kohane and Shibaguchi.
Claim 15 under 35 U.S.C. § 103 as unpatentable over Kohane,
Shibaguchi, and Kneidl.
Claims 16 and 17 under 35 U.S.C. § 103 as unpatentable over
Kohane, Shibaguchi, Kneidl, Abreu, and Bettinger.
Claims 1–5, 13–17, 20, 21, and 25 on the ground of non-statutory
double patenting as being unpatentable over claims 1–14 of U.S. Patent No.
10,010,709 in view of Kohane and optionally further in view of Shibaguchi,
Kneidl, Abreu, and Bettinger.
Claims 1–5, 13–17, 20, 21, and 25 on the ground of non-statutory
double patenting as being unpatentable over claims 1–23 of U.S. Patent No.
9,408,846 in view of Kohane and optionally further in view of Shibaguchi,
Kneidl, Abreu, and Bettinger.
Claims 1–5, 13–17, 20, 21, and 25 on the ground of non-statutory
double patenting as being unpatentable over claims 1–30 of U.S. Patent No.
8,609,733 in view of Kohane and optionally further in view of Shibaguchi,
Kneidl, Abreu, and Bettinger.
Claims 1–5, 13–17, 20, 21, and 25 on the ground of non-statutory
double patenting as being unpatentable over claims 1–23 of U.S. Patent No.
8,658,699 in view of Kohane and optionally further in view of Shibaguchi,
Kneidl, Abreu, and Bettinger.
Claims 1–5, 13–17, 20, 21, and 25 on the ground of non-statutory
double patenting as being unpatentable over claims 1–17 of U.S. Patent No.
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10,314,833 in view of Kohane and optionally further in view of Shibaguchi,
Kneidl, Abreu, and Bettinger.
Claims 1–5, 13–17, 20, 21, and 25 on the ground of non-statutory
double patenting as being unpatentable over the of U.S. Patent No.
10,881,6473 in view of Kohane and optionally further in view of Shibaguchi,
Kneidl, Abreu, and Bettinger.
DISCUSSION
Obviousness Rejections
The Examiner found that Kohane discloses a pharmaceutical
composition to “treat disease states characterized by aberrant electrical
activity in excitable tissue” where the composition comprises a microparticle
that includes a site I sodium channel blocker and the composition provides
for controlled release of the site I sodium channel blocker which “can be
triggered by various triggering agents including “magnetism or the presence
of a particular triggering agent (claim 17).” (Ans. 3 (emphasis added).)
The Examiner recognized that “inclusion of a sonosensitizer in the
composition is not disclosed.” (Id. at 4.) The Examiner relied on
Shibaguchi in concluding that modification of Kohane to include such a
sonosensitizer would have been obvious. (Id. at 4–5.)
In particular, the Examiner found that Shibaguchi describes using
sonodynamic therapy (SDT) “which uses low-intensity ultrasound together
with a sonosensitizer[, such as the porphyrin, protoporphyrin IX (PPIX),] for
cancer treatment” in place of photodynamic therapy (PDT). (Id. at 4.) The

3 The rejection in the Final Office Action from which the Appeal was taken
was provisional over the then pending application, which issued as a patent
on January 5, 2021. (Ans. 16.)
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Examiner noted that Shibaguchi teaches that the ultrasound used in SDT
“and subsequent cavitation collapse can have similar effects in producing
free radicals by facilitating porphyrin derivatives, such as the effect of light
on PDT.” (Id.) The Examiner further noted that Shibaguchi teaches that
SDT would be more advantageous than PDT because “[u]ltrasound can
penetrate into tissue better than light, and mediates both thermal and non-
thermal effects in biological tissue with bioeffects that are generally
intensity- and frequency dependent (p 2426, col 1, ¶ 3).” (Id.) The
Examiner found that one of skill in the art would have found it obvious “to
“incorporate a sonosensitizer such as PPIX into the liposomes of Kohane”
which “discloses that controlled release of the type I sodium channel
blocker, alone or in combination with other therapeutic agents such as local
anesthetics, can be triggered by variolous [sic] stimuli such as light to
release the drug” because Shibaguchi “discloses that ultrasound has better
tissue penetration than light and the use of sonosens[i]tizers such as PPIX
with ultrasound can trigger the release of therapeutic agent but in more
locations due to the better tissue penetration of ultrasound.” (Id. at 4–5
(emphasis added).) The Examiner further found that because the bioeffects
of ultrasound energy are known to be intensity and frequency dependent
“not all of the liposomes will be triggered” when ultrasound energy is
delivered, and thus, “the composition of Kohane et al. and Shibaguchi et al.
is capable of repeatedly releasing the cargo.” (Id. at 5.)
Appellant argues that the rejection is in error because Shibaguchi
“describes using ultrasound to activate a sonosensitizer to lyse tumor cells
(not release agent from delivery vehicles).” (Appeal Br. 13.) Appellant
explains that in Shibaguchi, the sonosensitizer is a porphyrin, however, the
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porphyrin is accumulated in tumor cells, then ultrasound is applied thereby
preferentially lysing the tumor cells. (Id.) “The ultrasound is not applied to
particles to cause release of agent.” (Id.)
We conclude that the Examiner’s rejection is not adequately
supported by the prior art cited. It is true that Shibaguchi teaches ultrasound
used with a sonosensitizer such as PPIX as an alternative to using light with
a photosensitizer in PDT, but it does so in the context of the ultrasound
causing the production of free radicals and reactive oxygen species (ROS)
from the porphyrin derivative, just as it does in PDT, which act to destroy
tumor. (Shibaguchi 2425, 2427.) In particular, Shibaguchi explains that in
PDT singlet oxygen and free radicals are generated with a sensitizing agent
and light energy, which mediate cellular toxicity. (Shibaguchi 2425.)
Shibaguchi explains that the ROS can cause apoptosis or photodynamic
distress to the cell which can trigger a signaling cascade that causes a cell
death response. (Id. 2425–26.) Shibaguchi explains that with respect to
PDT
there are at least two notable shortcomings that need to be
overcome: limited penetration of light into deep tumor tissue,
which is required to activate the photosensitizer, and certain
potentially serious side-effects, such as long-lasting skin
sensitivity due to the retention of the photosensitizer in
cutaneous tissues.
(Id. at 2426.) Shibaguchi explains:
Exposure to ultrasound and subsequent cavitation collapse can
have similar effects in producing free radicals by facilitating
porphyrin derivatives, such as the effect of light on PDT (35,
36). Thereafter, SDT together with a sonosensitizer was
developed for cancer therapy (37).
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(Id. at 2427.) Given the foregoing teachings, we agree with Appellant that
Shibaguchi teaches activation of a sonosensitizer with ultrasound so as to
produce free radicals and/or single oxygen that can lyse tumor cells, not that
a sonosensitizer would or could release from a delivery vehicle, a
therapeutic agents that is part of or inside that delivery vehicle. Thus,
although it may be true to some extent that Shibaguchi discloses “the use of
sonosens[i]tizers such as PPIX with ultrasound can trigger the release of
therapeutic agent but in more locations due to the better tissue penetration of
ultrasound” (Ans. at 4–5), the therapeutic agent released is ROS or free
radicals from the PPIX. There is nothing that the Examiner points to in
Shibaguchi to suggest that the ROS generated from a sonosensitizer
stimulated by ultrasound can be used to permeabilize a membrane to release
a therapeutic or that the sonosensitizer itself could otherwise be triggered to
permeabilize a membrane to release a therapeutic. Without such teachings,
we do not find support for the Examiner’s position that a person of ordinary
skill in the art considering Kohane’s teachings of a controlled release
microparticle that can be triggered to release an agent encapsulated thereby
with radio-frequency or electrical activity or the presence of a particular
triggering agent would have sought to include a sonosensitizer, like
porphyrin derivatives taught by Shibaguchi, in the microparticle of Kohane.
The Examiner’s conclusion is driven by impermissible hindsight. “The
Patent Office has the initial duty of supplying the factual basis for its
rejection. It may not . . . resort to speculation, unfounded assumptions or
hindsight reconstruction to supply deficiencies” in the cited references. In re
Warner, 379 F.2d 1011, 1017 (CCPA 1967).
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For this reason, we reverse the Examiner’s rejection of claims 1–5, 13,
14, 20, 21, and 25 under 35 U.S.C. § 103 as unpatentable over Kohane and
Shibaguchi. Furthermore, the remaining references that the Examiner relies
on to reject claims 15–17 do not cure the defect noted. Thus, we also
reverse the Examiner’s rejection of claim 15 under 35 U.S.C. § 103 as
unpatentable over Kohane, Shibaguchi, and Kneidl, and claims 16 and 17
under 35 U.S.C. § 103 as unpatentable over Kohane, Shibaguchi, Kneidl,
Abreu, and Bettinger.

Non-Statutory Double Patenting
Among the many differences between the claims of the cited patents
and the claimed invention is that the cited patent claims do not teach the use
of a liposome that includes a sonosensitizer. At least for the reasons
discussed above, i.e., the Examiner’s failure to support with sufficient
evidence a reason to include a sonosensitizer in the controlled release
liposome formulation taught by Kohane, we reverse all of the Examiner’s
non-statutory double patenting rejections.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–5, 13, 14,
20, 21, 25
103 Kohane,
Shibaguchi
1–5, 13, 14,
20, 21, 25
15 103 Kohane,
Shibaguchi, Kneidl
15
16, 17 103 Kohane,
Shibaguchi,
16, 17
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Kneidl, Abreu,
Bettinger
1–5, 13–17,
20, 21, 25
Non-statutory
Double Patenting:
10,010,709,
Kohane,
Shibaguchi,
Kneidl, Abreu,
Bettinger
1–5, 13–17,
20, 21, 25
1–5, 13–17,
20, 21, 25
Non-statutory
Double Patenting:
9,408,846,
Kohane,
Shibaguchi,
Kneidl, Abreu,
Bettinger
1–5, 13–17,
20, 21, 25
1–5, 13–17,
20, 21, 25
Non-statutory
Double Patenting:
8,609,733,
Kohane,
Shibaguchi,
Kneidl, Abreu,
Bettinger
1–5, 13–17,
20, 21, 25
1–5, 13–17,
20, 21, 25
Non-statutory
Double Patenting:
8,658,699,
Kohane,
Shibaguchi,
Kneidl, Abreu,
Bettinger
1–5, 13–17,
20, 21, 25
1–5, 13–17,
20, 21, 25
Non-statutory
Double Patenting:
10,314,833,
Kohane,
Shibaguchi,
Kneidl, Abreu,
Bettinger
1–5, 13–17,
20, 21, 25
1–5, 13–17,
20, 21, 25
Non-statutory
Double Patenting:
1–5, 13–17,
20, 21, 25
Appeal 2021-002940
Application 15/767,116

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10,881,647
Kohane,
Shibaguchi,
Kneidl, Abreu,
Bettinger
Overall
Outcome
1–5, 13–17,
20, 21, 25

REVERSED