Martin Gilbert. Pomper et al.

Patent Trials and Appeals Board

Sep 25, 2019

13881777 - (D) (P.T.A.B. Sep. 25, 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.
13/881,777 06/13/2013 Martin Gilbert Pomper 110551-0102 4135
23524 7590 09/25/2019
FOLEY & LARDNER LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
EXAMINER
MARVICH, MARIA
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
09/25/2019 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):
ipdocketing@foley.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte MARTIN GILBERT POMPER,
HYO-EUN BHANG, and PAUL FISHER
__________

Appeal 2018-007074
Application 13/881,777
Technology Center 1600
__________

Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and
ULRIKE W. JENKS, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134 involving claims to a
method of imaging tumors or cancerous tissue in a subject. The Examiner
rejected the claims as non-enabled and 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. Appellant identifies the Real Party in Interest as “The Johns
Hopkins University and Virginia Commonwealth University” (see App. Br.
2).
2 We have considered and refer to the Specification of Apr. 26, 2013
(“Spec.”); Final Action of Nov. 1, 2016 (“Final Act.”); Appeal Brief of May
19, 2017 (“App. Br.”); Examiner’s Answer of Apr. 30, 2018 (“Ans.”); and
Reply Brief of June 29, 2018 (“Reply Br.”).
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Statement of the Case
Background
“Targeted imaging of cancer remains an important but elusive goal.
Such imaging could provide early diagnosis, detection of metastasis, aid
treatment planning and benefit therapeutic monitoring” (Spec. 1:13–15).
“Indirect methods use a reporter transgene strategy, in analogy to the use of
green fluorescent protein (GFP) in vitro, to provide a read-out on cellular
processes occurring in vivo by use of an external imaging device” (id. 1:23–
25). “Unfortunately, to date, none of these techniques has provided
sufficient specific localization of imaging agents, and unacceptably high
background noise is still prevalent” (id. 1:29–2:2).
The Claims
Claims 1, 3–6, 9–12, 16, 28, and 31–33 are on appeal. Claim 1 is
representative and reads as follows:
1. A method of imaging tumors or cancerous tissue in a
subject, the method comprising the steps of:
(a) administering systemically to the subject a non-
viral plasmid nucleic acid construct comprising an imaging
reporter gene operably linked to a cancer specific or a cancer
selective promoter,
(i) wherein the imaging reporter gene is a
herpes simplex virus 1 thymidine kinase (HSV1-tk) or
a sodium-iodide symporter (NIS) gene, and
(ii) wherein the cancer specific or the cancer
selective promoter is selected from the group
consisting of progression elevated gene-3 (PEG-3)
promoter and astrocyte elevated gene 1 (AEG-1)
promoter;
(b) administering to the subject of part (a) before,
after, or together with the construct an imaging agent that is
complementary to the imaging reporter gene; and
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(c) screening the subject of part (b) for a signal from
the imaging agent, thereby imaging the tumors or the
cancerous tissue if present in the subject, wherein if the
cancer specific or the cancer selective promoter is AEG-1,
the tumors or the cancerous tissue are selected from the
group consisting of hepatocarcinoma, breast cancer, lung
cancer, prostate cancer, colorectal cancer, glioma,
melanoma, and neuroblastoma.

The Issues
A. The Examiner rejected claims 1, 3–6, 9–12, 16, 28, and 31–33 under
35 U.S.C. § 112, first paragraph, enablement (Ans. 5–15).
B. The Examiner rejected claims 1, 3, 6, 11, 12, 16, and 28 under 35
U.S.C. § 103(a) as obvious over Brody,3 Fisher,4 Sarker,5 and Su6 (Ans. 15–
16).
C. The Examiner rejected claims 5, 9, 10, 32, and 33 under 35 U.S.C.
§ 103(a) as obvious over Brody, Fisher, Sarker, Su, Pasqualini,7 and
Nimmagadda8 (Ans. 17–18).
D. The Examiner rejected claim 31 under 35 U.S.C. § 103(a) as obvious
over Brody, Fisher, Sarker, Su, and Chen9 (Ans. 19–20).

3 Brody et al., US 2012/0149647 A1, published June 14, 2012.
4 Fisher et al., US 2011/0313028 A1, published Dec. 22, 2011.
5 Sarkar et al., Eradication of Therapy-Resistant Human Prostate Tumors
Using a Cancer Terminator Virus, 67 Cancer Res. 5434–42 (2007).
6 Su et al., Targeting gene expression selectively in cancer cells by using the
progression-elevated gene-3 promoter, 102 PNAS 1059–64 (2005).
7 Pasqualini et al., US 2010/0254896 A1, published Oct. 7, 2010.
8 Nimmagadda et al., Herpes Simplex Virus Thymidine Kinase Imaging in
Mice with (1-(2’-deoxy-2’-[18F] fluoro-1-β-D-arabinofuranosyl)-5-
iodouracil) and metabolite (1-(2’-deoxy-2’-[18F] fluoro-1-β-D-
arabinofuranosyl)-5-uracil), 36 Eur. J. Nucl. Med. Mol. Imaging 1987–93
(2009).
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E. The Examiner rejected claims 1, 3–6, 9–12, 16, 28, and 31–33 on the
ground of provisional obviousness-type double patenting over claims 1–10
and 14 of US application 14/182,690 (Ans. 18).

A. 35 U.S.C. § 112, first paragraph, enablement
The Examiner finds “because the art of delivering DNA, molecular
imaging i.e. detection of signal and the correlation of small animal models
and humans in this art is proven and known to be unpredictable in the art,
the invention is not enabled” (Ans. 8).
Appellant contends the
Examiner’s reliance on various references in support of the
rejection is wholly misplaced. In some cases, the references
relate to methods of gene therapy, and not cancer imaging, and
are not relevant to the pending claims. In some cases, the
references are outdated and do not represent the current state of
the art. In all cases, the Examiner cites teachings of the
references out of context and exaggerates technical
considerations raised by the authors to the level of impassable
obstacle.
(App. Br. 5–6).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that the
Specification does not enable the claimed invention?

9 Chen et al., The sodium/iodide symporter and radio-iodide therapy, 25
Foreign Medical Sciences. Section of Radiation Medicine and Nuclear
Medicine 258–61 (2001) (abstract only).
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Findings of Fact
Breadth of Claims
1. Claim 1, the sole independent claim, is drawn to systemic
administration of a non-viral plasmid nucleic acid construct with one of two
specific imaging reporter genes, HSV1-tk or NIS, linked to one of two
specific cancer promoters, PEG-3 or AEG-1, in order to image cancers or
tumors.
Presence of Working Examples
2. Example 1 of the Specification teaches systemic DNA delivery
of a plasmid with a PEG-3 promoter and HSV1tk reporter gene by injection
“into the lateral tail vein of an animal” (Spec. 30:15–29). Example 1 teaches
that imaging studies and immunohistochemistry was performed on animals
with induced tumors (Spec. 32:7–27). Example 1 teaches “[e]xpression of
Luc driven by PEG-Prom was observed only in the melanoma metastasis
model (Mel) and not in control animals” (Spec. 33:18–19).
3. Example 1 of the Specification teaches
to exclude the possibility that tumor-specific expression of Luc
. . . might have resulted from the difference in transfection
efficiency between normal and malignant mouse lung tissues,
we quantified the amount of pDNA delivered to the lung of
each animal . . . That result confirmed that the tumor-specific
expression of Luc observed in these models was due to the
tumor-selective activity of PEG-Prom rather than differential
transfection efficiency between normal and malignant lungs.
Poor vascularization and segregated large nodules most likely
contributed to lower transfection efficiency observed in the lung
of the BCa model.
(Spec. 34:18–29).
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4. Example 1 of the Specification teaches bioluminescence
imaging (BLI) “with systemically administered pPEG-Luc also enabled
imaging of small metastatic deposits, i.e., micrometastases, outside of the
lung parenchyma in both the Mel and BCa models. That was confirmed
through harvesting regions producing BLI signal above background and
performing correlative histological analysis” (Spec. 35:8–11).
5. Example 1 of the Specification teaches
we generated a more clinically relevant PEG-Prom-driven gene
expression imaging system, pPEG-HSV1 tk . . . which can be
detected using radionuclide-based techniques, namely, single
photon emission computed tomography (SPECT) or positron
emission tomography (PET), upon administration of a suitably
radiolabeled nucleoside analog. . . . We further confirmed
tumor presence in presumptive extrathoracic metastatic sites
through gross histological analysis after the 48 h imaging
session. Detected on the whole body SPECT-CT images . . .
were multiple metastatic lesions in the dorsal neck of Mel-2
that corresponded to the intact histological specimen.
(Spec. 35:24–36:10).
Amount of Direction or Guidance Presented
6. The Specification provides diagrams of specific imaging
constructs including one of the cancer promoters and both of the imaging
genes recited in claim 1 (see Figures 1A and 1B).
7. The Specification teaches that for “systemic distribution of the
vector, the preferred routes of administration include but are not limited to:
intravenous, by injection, transdermal, via inhalation or intranasally, or via
injection or intravenous administration of a cationic polymer-based vehicle
(e.g. vivo-jetPEI™). Liposomal delivery, which when combined with
targeting moieties will permit enhanced delivery” (Spec. 24:6–10).
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8. The Specification teaches “optimal or effective tumor-inhibiting
or tumor-killing amounts are established e.g. during animal trials and during
standard clinical trials. Those of skill in the art are familiar with conversion
of doses e.g. from a mouse to a human” (Spec. 24:27–29). The Specification
provides conversion factors for relative doses (see Spec. 25:5–15).
Relative skill in the art
9. The Examiner finds the “level of skill is high for this invention.
It requires administration of DNA and agents to a subject in order to detect
cancer cells throughout the body” (Ans. 7).
State of the Prior Art and Unpredictability of the Art
10. Frangioni10 teaches the “goal of this review is to inform the
reader about why current imaging modalities are generally inadequate for
oncology and which new technologies have the potential to improve patient
care” (Frangioni 4013, col. 1).
11. Frangioni teaches imaging technologies including ultrasound,
X-Ray imaging, MRI, SPECT, PET, and optical imaging (see Frangioni
4014–5), but does not discuss the use of nucleic acid constructs with reporter
genes. Frangioni teaches:
the body has many barriers to the effective targeting of contrast
agents (and therapeutics) in vivo, including inhibitors present in
plasma, a relatively small effective endothelial pore size
(hydrodynamic diameter of approximately 5 nm) that constrains
biodistribution, and basement membranes that act as barriers to
preinvasive cancer detection. Finally, many solid tumors have
high hydrostatic pressure, which impedes homogeneous
infiltration of diagnostic agents.

10 Frangioni, New Technologies for Human Cancer Imaging, 26 J. Clin.
Oncology 4012–4021 (2008).
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(Frangioni 4014, col. 1).
12. Frangioni teaches the “detection and imaging of small numbers
of cancer cells anywhere in the human body remains elusive. Although new
technologies, such as optical imaging, will likely play an important role in
certain clinical applications, the field of oncology needs a revolutionary
advance in the physics and chemistry of tumor detection” (Frangioni 4019,
col. 2).
13. Close11 teaches the “challenge of detecting and locating
bioluminescent light emissions from within living subjects has been met by
several commercial suppliers of in vivo imaging equipment . . . When
superimposed, regions of bioluminescence become mapped to the subject’s
anatomy for pinpoint identification of source emissions” (Close 183).
14. Min12 teaches “[n]aked therapeutic genetic molecules are
generally difficult to deliver primarily due to rapid clearance” but explains
that “specialized gene delivery vehicles (GDV) that improve delivery
efficiency and cell-specificity are preferred” (Min 15, col. 2).
15. Min teaches the “HSV1-tk gene has been utilized as an
effective reporter gene for nuclear imaging using PET or a gamma camera”
(Min 20, col. 1).

11 Close et al., In Vivo Bioluminescent Imaging (BLI): Noninvasive
Visualization and Interrogation of Biological Processes in
Living Animals, 11 Sensors 180–206 (2011).
12 Min et al., Molecular Imaging of Biological Gene Delivery Vehicles for
Targeted Cancer Therapy: Beyond Viral Vectors, 44 Nuclear Med.
Molecular Imaging 15–24 (2010).
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16. McCrudden13 teaches “systemic therapeutics bypass the skin,
but encounter further extracellular barriers before reaching their site of
action . . . Whilst in the circulation, however, non-viral agents can be subject
to non-specific binding by serum proteins, which can result in aggregation or
dissociation of nanoparticles” (McCrudden 216).
17. McCrudden teaches:
It is apparent that the field of non-viral gene delivery is making
significant progress in the quest for the ideal gene delivery
vehicle. What is also evident is that the most successful
systems are designed to overcome many biological barriers and
as a consequence the traditional single function systems are
now rendered obsolete. Viruses are nature’s perfect delivery
vehicle and provide the inspiration to many non-viral gene
therapy researchers in the design of state of the art multi-faceted
vehicles. Through a greater understanding and appreciation of
the biological barriers to systemic gene delivery, non- viral
gene therapy researchers are on the cusp of creating a variety of
highly efficient vehicles that will revolutionise cancer gene
therapy.
(McCrudden 234).
18. Thomas14 teaches “[v]ector TROPISM, the duration of
transgene expression and vector immunogenicity are other factors that
influence the suitability of a vector for specific therapeutic applications”
(Thomas 348, col. 2).
19. Thomas teaches “[a]t the present time, viral vectors are the best
available vehicles for efficient gene transfer into most tissues. Nonviral

13 McCrudden et al., Cancer Gene Therapy – Key Biological Concepts in the
Design of Multifunctional Non-Viral Delivery Systems,
http://dx.doi.org/10.5772/54271 213–48 (2013).
14 Thomas et al., Progress And Problems With The Use Of Viral Vectors For
Gene Therapy, 4 Nature Genetics 346–58 (2003).
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gene delivery is potentially safer than viral-mediated delivery, but — with
the exception of a few promising applications, such as vaccines — non-viral
systems are, at present, limited by their inefficiency” (Thomas 356, col. 2).
20. Croft15 teaches “[i]maging of animal tumors may be
accomplished by all of the ordinary techniques for imaging human tumors
. . . Optical techniques have become popular because they require less
expensive equipment and less animal preparation than do the more
instrument-intensive MRI and PET” (Croft 367, col. 2).
21. Croft teaches “HSV-thymidine kinase (TK) often is used for
such purposes, targeting TK receptors, which makes possible the use of anti-
HSV drugs as imaging and targeting agents” (Croft 373, col. 1).
22. Lee16 teaches:
Common transfection techniques were developed for in-vitro,
microscopic volume sample. It can be impractically expensive
to applied to small animal work as well as inefficient, because
the small animal has relatively large body volume but very little
surface area to be exposed to agents (chemical or viral) for
transfection. A second obstacle is that the expression in this
case can often be transient, due to the inability of the living
tissue to regulate the excessive protein and to replicate the
DNA. With the reporter gene not stably incorporated into the
animal genome, the signal can have relatively very short (less
than 2 days) life span.
(Lee 2, col. 1).

15 Croft, Animal models for imaging, 18 Disease Markers 365–74 (2002).
16 Lee, The Advantages of Fluorescent Proteins over Luciferase for In Vivo
Imaging, Focal Points Application Note FP-129 14 (2008).
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Quantity of Experimentation
23. The Examiner finds that the “quantity of experimentation
needed to make or use the invention based on the content of the disclosure is
quite high as there are numerous art provided for obstacles to performing the
metho[do]logy” (Ans. 8).
24. The Specification teaches “[b]ased on these experiments it can
be seen that the systemic delivery of PEG-Prom-driven imaging constructs
will enable tumor-specific expression of reporter genes, not only within
primary tumor, but also in associated metastases in a manner broadly
applicable to tumors of different tissue origin or subtype” (Spec. 30:10–14).
Principles of Law
When rejecting a claim under the enablement requirement of section
112, the PTO bears an initial burden of setting forth a reasonable
explanation as to why it believes that the scope of protection provided
by that claim is not adequately enabled by the description of the
invention provided in the specification of the application.
In re Wright, 999 F.2d 1557, 1561–62 (Fed. Cir. 1993).

Factors to be considered in determining whether a disclosure would
require undue experimentation … include (1) the quantity of
experimentation necessary, (2) the amount of direction or guidance
presented, (3) the presence or absence of working examples, (4) the
nature of the invention, (5) the state of the prior art, (6) the relative
skill of those in the art, (7) the predictability or unpredictability of the
art, and (8) the breadth of the claims.
In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
Analysis
In addressing the Wands factors, we find that the balance of factors
does not support the Examiner’s position. The claims are narrow in scope,
limited to systemic administration with particular imaging reporter genes
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and promoters and limited to particular cancers (FF 1). There are working
examples (FF 2–5) as well as detailed guidance in the Specification (FF 6–8)
in a highly skilled art (FF 9). There is only the Examiner’s statement that a
large quantity of experimentation would be required (FF 23) while the
Specification suggests that the experiments disclosed are sufficient (FF 24).
There is limited evidence of specific unpredictability related to
systemic imaging using the claimed nucleic acid constructs. Frangioni
teaches general imaging difficulties (FF 10–12), while Min teaches issues in
delivery of nucleic acid constructs (FF 14). McCrudden and Thomas teach
that there have been issues with administration of DNA that requires entry
into cells and expression in cells for activity including dissociation of the
particles being administered and non-specific targeting (FF 16–19).
However, Min also teaches HSV1-tk has been used as an effective
reporter gene (FF 15) as does Croft (FF 21). And while Lee teaches
administration may be expensive and transient, there is no showing that the
expense is undue in a medical context. Also, imaging for diagnostic
purposes is desirably transient since there is no need for long term
expression of the reporter genes in patients after the diagnosis is complete
(FF 22). Moreover, the art cited in the obviousness rejection, including
Brody, provides a detailed discussion supporting enablement of the claims
(see FF 25–30 below).
Therefore, in light of the detailed working examples and disclosure in
the Specification, the limited and predictable amount of experimentation
necessary, and the narrow breadth of claim 1, we agree with the Appellant
that the evidence supports the position that the Specification enables the
scope of the claims. See In re Fisher, 427 F.2d 833, 839 (CCPA 1970)
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(“[T]he scope of the claims must bear a reasonable correlation to the scope
of enablement provided by the specification to persons of ordinary skill in
the art.”).

B. 35 U.S.C. § 103(a) over Brody, Fisher, Sarker, and Su
The Examiner finds Brody teaches “methods of imaging tumors in
mice wherein non-viral vectors and luciferase are administered
intravenously (which is a form of systemic administration) . . . The
luciferase was delivered with PEI . . . Delivery can be to any tumor types
such as ovarian or breast” (Ans. 15–16).
The Examiner acknowledges that Brody doesn’t teach the “use of
PEG-3 or AEG-1 as promoters” (Ans. 16). The Examiner finds that Fisher
“teaches delivery of non-viral plasmid vectors with use of PEG-3 and
CCN1/2 linked to reporter/imaging gene for in vivo imaging. The promoter
can be PEG-3 or AEG-1” (id.). The Examiner finds Su teaches “targeted
gene expression using a PEG3-luciferase vector” (id.). The Examiner finds
Sarker teaches the “use of an AEG-1 luciferase vector” (id.).
The Examiner finds it obvious to combine Brody
with the promoters of Sarker, Su and Fisher as Brody is
directed to method of targeting tumor cells wherein expression
is limited to these cells and wherein Sarker, Su and Fisher
teaches that it is within the ordinary skill of the art to deliver
vectors comprising cancer specific promoters for imaging. One
would have been motivated to do so in order to receive the
expected benefit of using proven and reliable imaging
techniques.
(Ans. 16).
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The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Brody, Fisher, Su, and Sarkar
renders the claims obvious?
Findings of Fact
25. Brody teaches a “bioluminescence imaging system (MS™
Imaging System, Xenogen Corp.) can be used to image mice and detect
nanoparticle-delivered Luc gene expression” (Brody ¶ 213).
26. Brody teaches an imaging process in which “C32-MSLN/firefly
luciferase DNA (Fluc) nanoparticles were directly injected into
subcutaneous xenografts derived from MSLN+ ovarian tumor cells, C32, to
poly(β-amino ester) polymer, or PEI was complexed to MSLN/Fluc DNA to
generate nanoparticles. Mice were optically imaged and bioluminescence
was detected in tumors 6 hrs after injection” (Brody ¶ 202).
27. Brody teaches vectors that may contain “the herpes simplex
virus thymidine kinase gene, HSV-tk, and/or a marker gene” (Brody ¶ 61).
28. Brody teaches vectors may express genes using “a cancer
specific promoter” (Brody ¶ 51).
29. Brody teaches “constructs containing the luciferase (Luc)
sequence in place of DT-A allows the use of optical imaging to evaluate
gene expression in multiple organs easily” (Brody ¶ 219).
30. Brody teaches the “pharmaceutical composition may be
administered in a number of ways depending on whether local or systemic
treatment is desired, and on the area to be treated . . . [including]
parenterally, for example by intravenous drip” (Brody ¶ 106).
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31. Brody teaches the “disclosed compositions can be used to treat
cancers including, but not limited to, pancreatic cancer, ovarian cancer,
breast cancer, non-small cell lung cancer, and liver cancer” (Brody ¶ 10).
32. Brody teaches:
There are a number of compositions and methods which can be
used to deliver nucleic acids to cells, either in vitro or in vivo.
These methods and compositions can largely be broken down
into two classes: viral based delivery systems and non-viral
based delivery systems. For example, the nucleic acids can be
delivered through a number of direct delivery systems such as,
electroporation, lipofection, calcium phosphate precipitation,
plasmids, viral vectors, viral nucleic acids, phage nucleic acids,
phages, cosmids, or via transfer of genetic material in cells or
carriers such as cationic liposomes.
(Brody ¶ 48).
33. Fisher teaches the “use of the cancer specific promoter such as
the CCN1/2, PEG-3, or AEG-1 promoter, will allow selective expression of
the gene product in the cancer cell” (Fisher ¶ 100).
34. Su teaches “the use of the PEG-Prom as a means of selectively
targeting gene expression in human tumor cells for directed cancer gene
therapy applications” (Su 1060, col. 1).
35. Su teaches forming a vector comprising PEG-3 promoter linked
to the luciferase gene (see Su 1060, col. 1).
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).

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Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Ans. 15–16; FF 25–35) and agree that the
claims are rendered obvious by Brody, Fisher, Su, and Sarkar. We address
Appellant’s arguments below.
Appellant contends “the combined references do not teach or suggest
methods of imaging tumors or cancerous tissue in a subject comprising
systemic administration of a nonviral plasmid nucleic acid construct” (App.
Br. 17).
We find this argument unpersuasive because Brody teaches
“constructs containing the luciferase (Luc) sequence in place of DT-A
allows the use of optical imaging to evaluate gene expression in multiple
organs easily” (FF 29) and expressly suggests the constructs “may be
administered in a number of ways depending on whether local or systemic
treatment is desired, and on the area to be treated . . . [including]
parenterally, for example by intravenous drip” (FF 30). Brody’s teaching to
optically image multiple organs using a luciferase construct along with the
general suggestion to administer compositions systemically reasonably
suggests systemic administration of the luciferase construct for imaging
multiple organs (FF 25, 29, 30). Brody also teaches both “viral based
delivery systems and non-viral based delivery systems” (FF 32).
Appellant contends that Brody only teaches “‘nanoparticles were
directly injected into subcutaneous xenografts derived from MSLN+
ovarian tumor cells.’ Brody, paragraph [0201] (emphasis added). Hence, the
reference teaches only direct administration of compositions for imaging”
(App. Br. 17).
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While Appellant is correct that Brody only exemplifies imaging using
direct injection of constructs (FF 26), Brody expressly suggests that
constructs may be administered to multiple organs (FF 29) and also suggests
systemic administration of constructs (FF 30). “A disclosure in a reference
is not limited to its specific illustrative examples, but must be considered as
a whole to ascertain what would be realistically suggested thereby to one of
ordinary skill in the art.” In re Uhlig, 376 F.2d 320, 323 (CCPA 1967).
Indeed, “[a]ll the disclosures in a reference must be evaluated, including
nonpreferred embodiments . . . and a reference is not limited to the
disclosure of specific working examples.” In re Mills, 470 F.2d 649, 651
(CCPA 1972). Thus, the issue is not whether Brody provides an example of
systemic administration but rather whether Brody suggests systemic
administration of the nucleic acids. Brody does so (FF 30).
Appellant contends that “[p]aragraph [0010] describes the delivery of
therapeutic agents, not luciferase, to treat, not image, various cancers” (App.
Br. 18). Appellant contends “[p]aragraph [0048] describes the direct
delivery of plasmid vectors to target cells, and not systemic administration.
Paragraph [0107] describes fluid vehicles suitable for in intravenous
administration generally” (id.).
We are not persuaded by this argument as “picking and choosing may
be entirely proper in the making of a 103, obviousness rejection, where the
applicant must be afforded an opportunity to rebut with objective evidence”
In re Arkley, 455 F.2d 586, 587 (CCPA 1972). That is, Brody teaches an
example where nucleic acid constructs were administered into animals in
order to image tumors (FF 26), Brody suggests that nucleic acid constructs
may be used to evaluate and image multiple organs (FF 29), and Brody
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suggests that nucleic acid constructs may be administered systemically (FF
30). We agree with the Examiner that the ordinary artisan, familiar with
these teachings in Brody, would have reasonably found it obvious to
administer Brody’s nucleic acids systemically in order to image tumors in
multiple organs consistent with the disclosures of Brody (FF 25–31).
Appellant’s Appeal Brief does not identify any objective evidence that
would rebut the Examiner’s obviousness position.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that
Brody, Fisher, Su, and Sarkar renders the claims obvious.

C. and D. 35 U.S.C. § 103(a) over Brody, Fisher, Sarker, Su, Pasqualini,
and Nimmagadda and/or Chen
Appellant relies upon the same reasoning regarding the absence of a
teaching of systemic administration as discussed above with regard to
Brody, Fisher, Sarker, and Su for these further rejections. Appellant
contends “the combined references do not teach or suggest methods of
imaging tumors or cancerous tissue in a subject comprising systemic
administration of a nonviral plasmid nucleic acid construct” (App. Br. 19; cf.
Reply Br. 4, 9). We remain unpersuaded by these arguments for the reasons
given above.

E. Provisional Obviousness-Type Double Patenting
We summarily affirm the provisional obviousness-type double
patenting rejections because Appellant does not dispute the merits of this
rejection. See Manual of Patent Examining Procedure § 1205.02 (“If a
Appeal 2018-007074
Application 13/881,777

19
ground of rejection stated by the examiner is not addressed in the appellant’s
brief, that ground of rejection will be summarily sustained by the Board.”)

CONCLUSION
In summary:
Claim(s)
Rejected
Basis Affirmed Reversed
1, 3–6, 9–12,
16, 28, 31–33
§ 112, ¶ 1, enablement 1, 3–6, 9–12, 16,
28, 31–33
1, 3, 6, 11, 12,
16, 28
§ 103(a) Brody, Fisher,
Sarker, Su
1, 3, 6, 11,
12, 16, 28

5, 9, 10, 32, 33 § 103(a) Brody, Fisher,
Sarker, Su, Pasqualini,
Nimmagadda
5, 9, 10, 32,
33

31 § 103(a) Brody, Fisher,
Sarker, Su, Pasqualini,
Nimmagadda, Chen
31
1, 3–6, 9–12,
16, 28, 31–33
Provisional
Obviousness-type
Double Patenting
1, 3–6, 9–12,
16, 28, 31–33

Overall
Outcome
1, 3–6, 9–12,
16, 28, 31–33

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