Chang, Esther H. et al.

Patent Trials and Appeals Board

Oct 21, 2019

12216715 - (D) (P.T.A.B. Oct. 21, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
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Alexandria, Virginia 22313-1450
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/216,715 07/09/2008 Esther H. Chang 2474-0012US1 9616
56719 7590 10/21/2019
MEDLER FERRO WOODHOUSE & MILLS PLLC
8201 Greensboro Drive, Suite 1060
McLean, VA 22102
EXAMINER
EPPS -SMITH, JANET L
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
10/21/2019 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):
aferro@medlerferro.com
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte ESTHER H. CHANG and KATHLEEN F. PIROLLO
____________

Appeal 2018-008905
Application 12/216,715
Technology Center 1600
____________

Before ERIC B. GRIMES, ULRIKE W. JENKS, 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 treating a viral disease. We have jurisdiction under
35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
According to the Specification, ligand-targeted liposomes are “useful

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42(a). Appellant identifies Synergene Therapeutics and
Georgetown University as the real parties in interest. App. Br. 3. Herein,
we refer to the Final Action mailed April 21, 2017 (“Final Act.”);
Appellant’s Appeal Brief filed May 9, 2018 (“App. Br.”); Examiner’s
Answer mailed August 7, 2018 (“Ans.”); and Appellant’s Reply Brief filed
September 14, 2018 (“Reply”).
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for the delivery of molecules to induce immune responses against viral
antigens or to treat or prevent viral diseases.” Spec. ¶ 2. “The specificity of
the delivery system is derived from the targeting ligands” complexed with
the liposome. Id.
Claims 19–27, 214, and 216–2192 are on appeal and can be found in
the Claims Appendix of the Appeal Brief. Claim 19 is independent and
representative of the claims on appeal. It reads as follows:
19. A method of treating or preventing a viral disease
in a mammal comprising:
1) administering to the mammal a ligand-targeted
cationic liposome complex having a size of about 50–400 nm,
wherein the ligand-targeted cationic liposome complex
comprises:
(a) a cationic liposome;
(b) a ligand directly complexed with, but not
chemically conjugated to, the external surface of the cationic
liposome, wherein the ligand does not comprise a lipid tag;
(c) one or more nucleic acid molecules encoding
one or more viral proteins associated with the cationic
liposome; and
(d) one or more nucleic acid molecules encoding
one or more interleukins associated with the cationic liposome,
wherein the nucleic acid molecules are present at a molar ratio
of about 0.1 moles of one or more nucleic acid molecules
encoding one or more viral proteins to about 10 moles of one or
more nucleic acid molecules encoding one or more interleukins,
to about 10 moles of one or more nucleic acid molecules
encoding one or more viral proteins to about 0.1 moles of one
or more nucleic acid molecules encoding one or more
interleukins;

2 Appellant’s briefing also refers to claim 215, but that claim was cancelled
by amendment and is not before us now. Advisory Action mailed May 4,
2018 (entering Amendment filed April 19, 2018).
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2) targeting the ligand-targeted cationic liposome
complex to one or more antigen presenting cells via the ligand;
and
3) delivering the nucleic acid molecules encoding the
viral proteins and the interleukins to the one or more antigen
presenting cells via the ligand-targeted cationic liposome
complex to increase T cells, cytokines and peripheral T-cell
responses to the viral disease.
App. Br. 17–18. Claims 218 and 219 depend from claim 19 and further limit
the “molar ratio” limitation in element 1)(d) as follows:
218. The method of claim 19, wherein the nucleic acid
molecules are present at a molar ratio of about 0.5 moles of one
or more nucleic acid molecules encoding one or more viral
proteins to about 1 moles of one or more nucleic acid molecules
encoding one or more interleukins, to about 2 moles of one or
more nucleic acid molecules encoding one or more viral
proteins to about 1 moles of one or more nucleic acid molecules
encoding one or more interleukins.

219. The method of claim 19, wherein the nucleic acid
molecules are present at about a molar ratio of about 1 moles of
one or more nucleic acid molecules encoding one or more viral
proteins to about 1 moles of one or more nucleic acid molecules
encoding one or more interleukins.

Id. at 20.
Appellant seeks review of Examiner’s rejection of claims 19–27, 214,
and 216–219 under 35 U.S.C. § 103 as unpatentable over Chang13 and
Chang24 in view of Bot.5 App. Br. 6. In addition to the arguments
Appellant presents regarding claim 19, Appellant urges that the narrower

3 Chang et al., US 2003/0044407 A1; published Mar. 6, 2003 (“Chang1”).
4 Chang et al., US 2007/0065499 A1; published Mar. 22, 2007 (“Chang2”).
5 Bot et al., US 2002/0103165 A1; published Aug. 1, 2002 (“Bot”).
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molar ratio limitations in claims 218 and 219 further distinguish those claims
over the cited prior art. See App. Br. 14–16. Appellant does not argue
claims 20–27, 214, and 216– 217 separately from claim 19 so those claims
stand or fall with claim 19. 37 C.F.R. § 41.37 (c)(1)(iv).
The issue is: Does the preponderance of evidence of record support
Examiner’s conclusion that the cited prior art renders the claimed methods
obvious?
Findings of Fact
FF1. Chang1 teaches “antibody- or antibody fragment-targeted
immunoliposomes . . . made via a simple and efficient non-chemical
conjugation method.” Chang1 ¶ 20. According to Chang1, “[t]he resultant
complexes are as effective as, or more effective than, similar complexes in
which the antibody or antibody fragment is chemically conjugated to the
liposome.” Id. ¶ 38. Chang1 further teaches “[t]he size of the liposome
complex is typically within the range of about 50-400 nm.” Id. ¶ 45.
FF2. Chang1 teaches that these targeted liposome complexes “can be used
to target non-tumor cells,” such as dendritic cells, “for delivery of a
therapeutic molecule.” Chang1 ¶ 51. Chang1 teaches that a variety of
therapeutic molecules can be delivered via these targeted liposome
complexes, including “nucleic acids, viral particles,” and
“immunomodulating agents.” Id. ¶ 44.
FF3. Chang1 further teaches that these “complexes can be optimized for
target cell type through the choice and ratio of lipids, the ratio of antibody or
antibody fragment to liposome, the ratio of antibody or antibody fragment
and liposome to the therapeutic or diagnostic agent.” Chang1 ¶ 49.
Moreover, Chang1 describes the preparation of liposome complexes at
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different lipid to DNA agent ratios to optimize binding ability of the complex
to the target cells in an exemplary application. Id. ¶¶ 60–65 (Ex. 2).
FF4. Bot teaches “Spray-Dried Lipid Microparticles (SDLM) that are
comprised of lipid, a ligand and agent. The ligand is specific for a cell
surface receptor, thereby enabling targeting of the agent to cells bearing
receptors specific for the targeting ligand.” Bot Abstr.
FF5. Bot teaches that the delivery of “one or more therapeutic or
biologically active agent[s]” can be targeted to particular cells to induce an
immune response. Bot ¶¶ 6–7. Bot teaches that such agents include “a
nucleic acid encoding an antigen” (id. ¶ 8) as well as “immunomodulatory
agents” such as interleukins (id. ¶ 36) that may be “administered by using a
DNA encoding” the polypeptide agent (id. ¶ 48).
FF6. Bot teaches that the amount of agent delivered should be “effective to
induce or enhance a detectable immune response” and that “this amount will
vary depending on the nature of the agent (e.g., antigen), the relative state of
the subject’s immune system, the age, weight and size of the subject, and the
like.” Bot ¶ 43. According to Bot, in vitro assays to determine whether or
not a particular antigen induces an immune response are well known in the
art. Id.
Analysis
Examiner finds that Chang16 teaches ligand-targeted cationic
liposome complexes that can be used to deliver a nucleic acid agent to
dendritic cells, as recited in claim 19. See Ans. 4–6. Examiner relies on Bot

6 The application in Chang2 is a continuation-in-part of Chang1. It contains
the same disclosure cited in FF1–FF3 above. For ease of reference, we refer
to and cite only to Chang1 in our analysis herein.
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for its teaching that “ligand targeted lipid based particles” can be used to
deliver “one or more therapeutic agents to antigen presenting cells,”
including nucleic acids encoding “viral proteins (antigens) and interleukins.”
Id. at 6–9. Examiner determines “[i]t would have been obvious to the
ordinary skilled artisan at the time of the instant invention to have used the
ligand targeted liposomes of Chang#1 and Chang#2 to deliver a biological
response modifier and an immunomodulatory agent,” in the form of nucleic
acid molecules encoding a viral protein and interleukin, as taught by Bot.
Id. at 10–11. According to Examiner, a skilled artisan “would have been
motivated to make this combination” because the cited references all
disclose targeted lipid based particles of “similar structure” that are
described as “useful for the same purpose, specifically for the targeted
delivery of therapeutic agents to antigen presenting cells for the purpose of
enhancing an immune response in a subject.” Id.
Appellant argues that Examiner’s rejection should be reversed for
three reasons. First, Appellant contends “there is no disclosure in either
Chang1 or Chang2 of the co-delivery of two or more nucleic acid molecules
to target cells.” App. Br. 7. Second, Appellant argues that “Bot cannot be
combined with Chang1 or Chang2, as the complexes are significantly
different, operate under significantly different circumstances, and overall,
are not combinable.” Id. at 9. Third, Appellant urges that even if Bot is
combinable “there is no disclosure of any ratios, methods of co-delivery,
mixing conditions, and specifically no disclosure of nucleic acid molecules
that would encode such proteins, so as to enable the co-delivery required in
the methods of the presently claimed invention.” Id. at 12.
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We are not persuaded by Appellant’s arguments and agree with
Examiner’s statement of the rejection and responses to Appellant’s
arguments in the Answer and Final Action, which we adopt and incorporate
by reference. We further address Appellant’s arguments below.
We are not persuaded by Appellant’s argument that the rejection
should be reversed because Chang1 fails to disclose the co-delivery of two
nucleic acid molecules. See App. Br. 7–8. Examiner relies on Chang1 for
its teaching of the claimed ligand-targeted liposome complex and Bot for its
teaching of delivering more than one agent comprising the recited nucleic
acid molecules. Thus, as Examiner has articulated the rejection, Chang1
teaches the delivery vehicle, i.e., the ligand-targeted liposome, explaining
that this vehicle can be used to deliver a variety of agents, including nucleic
acids, viral particles and immunomodulating agents, to dendritic cells. FF1–
FF2. And Bot teaches the contents of that vehicle, i.e., two nucleic acid
agents––one encoding an antigen and a second encoding an interleukin.
Thus, it is the combination of the references that teaches co-delivery of both
agents. Appellant cannot overcome that combination by arguing that the
references individually fail to teach the recited claim elements. Soft Gel
Techs., Inc. v. Jarrow Formulas, Inc., 864 F.3d 1334, 1341 (Fed. Cir. 2017)
(“[N]on-obviousness cannot be established by attacking references
individually where the rejection is based upon the teachings of a
combination of references.”) (quoting In re Merck & Co., 800 F.2d 1091,
1097 (Fed. Cir. 1986)).
Appellant’s argument that the references are not combinable is
likewise unpersuasive. See App. Br. 9–12. Examiner found that a skilled
artisan would combine the agents taught in Bot with the ligand-targeted
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liposome complex in Chang1 because: (1) Bot teaches “targeted lipid based
particles . . . of similar structure,” and (2) both references teach that their
targeted delivery vehicles are “useful for the same purpose, specifically for
the delivery of therapeutic agents to antigen presenting cells for the purpose
of enhancing an immune response.” Ans. 10–11. We agree with Examiner
that this is a sufficient rationale for the stated combination.
Appellant argues that because the structure of Bot’s particles is
different from that recited in claim 19, Bot is not “combinable” with the
liposome complexes taught in Chang1 and Chang2. See App. Br. 8–12. We
disagree. As explained above, the rejection relies on the ligand-targeted
liposome complex, i.e., the delivery vehicle taught in Chang1––not the
vehicle taught in Bot. Thus, the fact that both references teach the use of
their respective vehicles for same purpose is itself a sufficient rationale for
using Chang1’s ligand-targeted liposome complexes to deliver the agents
taught in Bot. This is particularly so because Chang1 teaches that its
liposome complexes are useful for delivering the same types of agents (e.g.,
nucleic acids, viral proteins, and immunomodulatory agents) taught in Bot.
FF2, FF5.
We are also unpersuaded by Appellant’s argument that the cited
references fail to provide sufficient detail to enable the co-delivery recited in
Appellant’s claims. See App. Br. 12–14; Reply 4–6. Chang1 describes
procedures for making ligand-targeted liposome complexes comprising a
nucleic acid agent. See, e.g., Chang1 ¶¶ 60–65. Indeed, Appellant’s
Specification incorporates Chang1 by reference to describe “[e]xemplary
methods and compositions in which the complexes in accordance with
embodiments of [the present] invention are made.” Spec. ¶ 37. Moreover,
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Chang1 teaches that the ratio of the agent to other components in the
liposome can be varied to optimize the complex for the particular application
and exemplifies that process in a detailed example.7 FF3. What Appellant
contends is not taught by the cited prior art is the “molar ratio” between the
nucleic acid molecules encoding the antigen and the nucleic acid molecules
encoding the interleukin. App. Br. 12. That much is true because Chang1
describes only a single nucleic acid agent and, while Bot teaches “one or
more” agents, it does not disclose a specific ratio or relative concentration of
those agents to each other. See FF6. However, it is well-settled that the
identification of an optimal range or concentration of a combination of
ingredients disclosed in the prior art is generally insufficient to distinguish
an obviousness rejection. See MPEP § 2144.05.II(A) (“Generally,
differences in concentration . . . will not support the patentability of subject
matter encompassed by the prior art unless there is evidence indicating such
concentration . . . is critical.”) (citing cases). This is particularly so here
because claim 19 recites a very broad range that includes equal amounts of
the two types of recited nucleic acid molecules (i.e., a one-to-one ratio) and
extends out to “about” a 100-to-one ratio of either molecule type to the
other. Based on these facts, Examiner found, and we agree the record

7 Appellant argues that the information in Tables I and II of Example 2 are
“not related to delivery to antigen presenting cells” and that the “disclosed
ratios relate to the amount of DNA to total lipid, not the ratios of multiple
nucleic acid molecules to each other” because in that example only one type
of nucleic acid agent was added to the liposome. Reply 5. While that is
true, the description in Example 2 is relevant because it exemplifies
experiments for optimizing ratios of the components in Chang1’s liposome
complexes and therefore further supports Examiner’s finding that identifying
an optimal or workable range would be a matter of routine optimization.
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supports, that “it would be obvious for the ordinary skilled artisan to identify
optimal or workable ranges through routine experimentation,” including the
claimed one-to-one ratio and broadly recited range. Final Act. 4.
Appellant argues this finding is erroneous because “‘the general
conditions’” of claim 19 “are not disclosed in the cited art.” App. Br. 13
(quoting In re Aller, 220 F.2d 454, 456 (CCPA 1955)). We disagree.
Chang1 teaches the recited ligand-targeted cationic liposome and Bot
teaches the delivery of the two recited nucleic acid agents. FF1–FF2, FF5.
Thus, the “general conditions” are disclosed in the prior art. See Aller, 220
F.2d at 456. As Aller instructs, in such instances it is “[n]ormally . . .
expected that a change . . . in concentration . . . would be an unpatentable
modification.” Id. Indeed, our reviewing court has specifically applied this
principle to claims reciting a ratio of one active ingredient to another, just as
Appellant’s claims do here. See Merck & Co., Inc. v. Biocraft Labs., Inc.,
874 F.2d 804, 806–09 (Fed. Cir. 1989) (rejecting patent owner’s argument
that the recitation of a ratio of “about 1:1 to 1:10 by weight” and “1 to 10 by
weight” of one active ingredient to another in claims 1 and 2 distinguished
prior art disclosing the combination of both agents, but not the relative
amounts of those agents).
While “[p]atentability may be imparted . . . if the results achieved at
the designated concentrations are ‘unexpectedly good,’” no such showing
has been made here. See id. at 809 (quoting In re Antonie, 559 F.2d 618,
620 (CCPA 1977)). Appellant argues that the Declaration of Esther H.
Chang dated February 21, 2017 (“Chang Decl.”) evidences that “[t]he
increase in T cells, cytokines and peripheral T-cell responses to viral disease,
achieved by the presently claimed invention is only achieved when the
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nucleic acid molecules are present” at a ratio within the claimed range. App.
Br. 12–13 (citing Chang Decl. ¶ 18) (emphasis added). But there is no data
in the Chang Declaration to support that assertion. Indeed, what the Chang
Declaration actually says is that such results are “dramatically achieved” at a
molar ratio within the broad range of claim 19––not that such results are
only achieved at a ratio within that range. Chang Decl. ¶ 18. Moreover,
Appellant conceded at the hearing of this appeal that there is no evidence of
record showing that ratios outside the claimed range do not work. See Hr’g
Tr. 7–8 (“[W]e don’t have on the record that ratios outside the range didn’t
work”). Accordingly, there is nothing in the record before us evidencing
that the claimed molar ratio range achieves unexpected results or is
otherwise critical or non-obvious.
Finally, Appellant separately argues that the narrower molar ratios in
claims 218 and 219 are non-obvious. App. Br. 14–15. Like claim 19, both
of these claims encompass a one-to-one molar ratio. Claim 219 is, in fact,
limited to a molar ratio of “about” one-to-one. Id. at 20. For the reasons
explained above, we agree that the record supports Examiner’s finding that
the recitation of these ratios does not distinguish the prior art because the
identification of such ratios would be a matter of routine experimentation
and optimization. Final Act. 4; see also Merck, 874 F.2d at 809; Aller, 220
F.2d at 456 (as discussed above). Again, there is nothing in the record that
demonstrates that a one-to-one ratio achieves unexpectedly good results
relative to those outside the claimed range or that a one-to-one ratio would
not be identified through routine experimentation.
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For these reasons, we determine that the preponderance of the
evidence supports Examiner’s rejection of claims 19–27, 214, and 216–219
as obvious over Chang1 and Chang2 in view of Bot.
DECISION SUMMARY

Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
19–27, 214,
216–219
103 Chang1,
Chang2, Bot
19–27, 214,
216–219

AFFIRMED