Blaze Bioscience, Inc.

Patent Trials and Appeals Board

Apr 26, 2021

2020003677 (P.T.A.B. Apr. 26, 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.
14/855,355 09/15/2015 Stacey J. Hansen 109561-668269 5886
27148 7590 04/26/2021
POLSINELLI PC
900 WEST 48TH PLACE
SUITE 900
KANSAS CITY, MO 64112-1895
EXAMINER
ROGERS, JAMES WILLIAM
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
04/26/2021 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):
patentdocketing@polsinelli.com
rendsley@polsinelli.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD

Ex parte STACEY J. HANSEN,
CLAUDIA JOCHHEIM, DENNIS M. MILLER, NATALIE NAIRN,
JULIA E. NOVAK, MARK STROUD, VALORIE R. WISS,
and KELLY BYRNES-BLAKE

Appeal 2020-003677
Application 14/855,355
Technology Center 1600
BEFORE DONALD E. ADAMS, FRANCISCO C. PRATS, and
TAWEN CHANG, Administrative Patent Judges.
PRATS, Administrative Patent Judge.

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DECISION ON APPEAL
STATEMENT OF THE CASE
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1, 3–10, 31, 32, 34, 35, 37–44, 48, and
49. Oral argument was presented on April 7, 2021. We have jurisdiction
under 35 U.S.C. § 6(b).
We AFFIRM.
CLAIMED SUBJECT MATTER
The claims are directed to compounds in which a polypeptide that
binds preferentially to cancer cells is conjugated to a fluorescent dye. Claim
1, the sole independent claim on appeal, is representative and reads as
follows:
1. A compound of Formula (III), or a
pharmaceutically acceptable salt thereof:

1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R.
§ 1.42(a). Appellant identifies the real party in interest as Blaze Bioscience,
Inc. Appeal Br. 3.
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wherein:
R1, R2, R7, R8, R12, R13, R14, R15, R16, R19, and R20 are each
independently hydrogen;
R3, R4, R5, and R6 are each independently methyl;
R9 is sulfonate;
L1 is C3-C6 alkylene;
L2 is C1-C10 alkylene;
L3 is a bond; and
A4 is a polypeptide comprising at least 90% sequence
identity with SEQ ID NO: 9 or a fragment thereof.
Appeal Br. 34.
In response to a species election requirement, Appellant elected
Appellant’s compound 16 as the species for examination. See Non-Final
Act. 2 (Non-Final Action entered July 13, 2016). We, therefore, limit our
analysis of the rejected claims to the patentability of the elected species, and
the extent to which the rejected claims reads on it. See Ex parte Ohsaka, 2
USPQ2d 1460, 1461 (BPAI 1987).
The structure of compound 16 is shown in the following formula:

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Spec. ¶ 369 (Example 1 showing structure of Appellant’s compound 16); see
also Appeal Br. 37 (Appellant’s claim 37, which depends from claim 1,
reciting compound with structure of Appellant’s compound 16).
REFERENCE(S)
The prior art relied upon by the Examiner is:
Name Reference Date
Susumu Ito et al. (“Ito”) US 5,968,479 Oct. 19, 1999
James M. Olson
(“Olson”)
WO 2011/142858 A2 Nov. 17, 2011
REJECTION(S)
The sole rejection before us for review is the Examiner’s rejection of
claims 1, 3–10, 31, 32, 34, 35, 37–44, 48, and 49, under 35 U.S.C. § 103 as
being unpatentable over Olson and Ito. Final Act. 4 (entered November 5,
2018).
DISCUSSION
The Examiner’s Prima Facie Case
The Examiner’s rationale for rejecting Appellant’s claims appears in
the Non-Final Office Action entered July 13, 2016 (“Non-Final Act.”).
The Examiner cited Olson as disclosing that the polypeptide portion
of Appellant’s compound 16 (polypeptide of SEQ ID NO: 9 recited in
Appellant’s claim 1) is a known variant of the cancer cell binding
polypeptide, chlorotoxin (“CTX”). See Non-Final Act. 4 (noting that SEQ
ID NO: 9 of Appellant’s claim 1 and SEQ ID NO: 4 of Olson describe
identical polypeptides). The Examiner cited Olson as disclosing that it is
useful to conjugate its CTX variant to “imaging agents such as cyanine
dyes[;] specific examples include Cy5.5 and indocyanine green (ICG).” Id.
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The Examiner found that Olson differs from the rejected claims in that
Olson does not disclose conjugating its CTX variant to the elected species of
cyanine dye present in Appellant’s compound 16. Non-Final Act. 4.
The Examiner cited Ito as disclosing that “[s]everal cyanine dyes of
Ito when reacted with the binding amino acid Lys-27 in the SEQ described
in Olson would yield the elected compound, some examples of such dyes
within Ito including [Appellant’s] compound 16.” Non-Final Act. 5.
The Examiner reasoned that, “[s]ince Olson already teaches
attachment of cyanine dyes to the claimed peptide at Lys-27 one of ordinary
skill in the art would have a very high expectation of success in attaching the
cyanine dyes disclosed in Ito.” Non-Final Act. 5. The Examiner reasoned
further that a skilled artisan “would recognize that, based on their close
structural similarity, the cyanine dyes of Olson could be substituted with the
cyanine dyes of Ito with similar results.” Id.
The Examiner explained that an “obviousness rejection based on
similarity in chemical structure and function entails the reason for one of
ordinary skill in the art to make a claimed compound, in the expectation that
compounds similar in structure will have similar properties.” Id. at 5–6.
Analysis
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992); see also In re Jung, 637
F.3d 1356, 1365 (Fed. Cir. 2011) (holding that requiring an applicant to
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identify “reversible error” in an examiner’s rejection is consistent with long
standing Board practice).
Having carefully considered all of the evidence and argument
presented by Appellant and the Examiner, we are not persuaded that
Appellant has shown reversible error in the Examiner’s conclusion of
obviousness as to Appellant’s compound 16 in view of the cited references.
In particular, Appellant does not persuade us that the Examiner erred in
determining that the combined teachings of Olson and Ito would have
suggested preparing a compound with the structure of compound 16.
Olson discloses that chlorotoxin (CTX) is a polypeptide that binds
preferentially to a number of types of cancer cells, which allows detection of
cancer cells when CTX is conjugated to a fluorescent dye, and allowed to
bind to tumor cells. See Olson 1.
Olson’s invention is directed to the preparation of several variants of
CTX, including the polypeptide of SEQ ID NO: 4. See Olson 6 (“In one
embodiment, the modified chlorotoxin peptide has Lys 15 and Lys 23
substituted by arginine (K15R_K23R CTX). In this embodiment, the
modified chlorotoxin peptide has the amino acid sequence set forth in SEQ
ID NO: 4.”).
Appellant does not dispute the Examiner’s finding that the
polypeptide described by Olson’s SEQ ID NO: 4 is identical to the
polypeptide of Appellant’s SEQ ID NO: 9, which is the polypeptide portion
of Appellant’s compound 16. See Ans. 3.
Olson discloses that, for the purposes of detecting cancer cells, its
CTX variants may be conjugated to a variety of fluorescent dyes including
indocyanine green (ICG). See Olson 11 (“[S]uitable NIR fluorophores
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useful in the invention include DyLight-680, DyLight-750, VivoTag-750,
DyLight-800, IRDye-800, VivoTag-680, and indocyanine green.”); see also
id. at 18 (disclosing that when its CTX variants were conjugated to the dye
Cy5.5, “[a]ll of the modified peptide conjugates preferentially illuminated
medulloblastoma cancer tissue compared with normal brain (FIGURES 3A
and 3B)”).
Olson discloses that its CTX variants may be attached to fluorescent
dyes in a number of ways:
Suitable fluorescent compounds include a functional
group that renders the compound chemically reactive toward
the chlorotoxin. Suitable functional groups include the N-
hydroxysuccinimide (NHS) group for covalent coupling to
amine groups, the maleimide group for covalent coupling to
thiol groups, and the hydrazide group for covalent coupling to
aldehyde groups. Preferably, the fluorescent compound useful
in preparing the conjugate of the invention includes a single
reactive functional group (e.g., mono-NHS ester). It will be
appreciated that other conjugating chemistries are suitable for
making the chlorotoxin conjugate of the present invention.
Olson 11; see also id. at 8–9 (“Representative methods for making and using
fluorescent chlorotoxin conjugates are described in U.S. Patent Application
Publication No. 20080279780 A1, Fluorescent Chlorotoxin Conjugate and
Method for Intra-Operative Visualization of Cancer, expressly incorporated
herein by reference in its entirety.”); id. at 18–19 (exemplified embodiment
in which 80% of the dye Cy5.5 was conjugated only to Lys 27 of the CTX
variant).
It is undisputed that the CTX variant conjugate compounds described
in Olson differ from Appellant’s elected compound 16 only in that the dye
portion of the Olson’s conjugates do not have the same structure as the dye
portion of Appellant’s compound 16.
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As the Examiner points out, however, and Appellant does not dispute,
Ito discloses that a dye having the structure of the dye portion of Appellant’s
compound 16 was known in the art to be a derivative of indocyanine green
(ICG), useful for detecting cancer cells when conjugated to a cancer-specific
binding protein, such as a cancer-binding antibody:
The inventors . . . succeeded in preparing indocyanine
green derivatives that emit fluorescence under excitation with
near infrared rays and far infrared rays. They also found that a
diagnostic marker that is directly applicable to a living body
can be prepared by reacting the aforementioned indocyanine
green derivative, as a labeling compound, with an anti-cancer
antigen-antibody and the like, and that the diagnostic marker as
mentioned above is useful for a direct staining of a living tissue
by an immuno-histochemical staining method.
Ito 2:38–49; see also id. at 2:64–5:20 (disclosing dye-detection system
conjugates of formulae (I)–(V)).
Ito discloses an example in which one of its indocyanine derivatives is
conjugated to antibodies specific for Epithelial Membrane Antigen. Ito
24:25–25:2 (Example 7).
Ito discloses an example in which its dye-antibody conjugate was able
to detect the antigen of interest in samples of esophageal cancer tissue. See
Ito 26:40–27:15 (Example 12). Based on the results of Example 12, Ito
concludes as follows:
By using the diagnostic marker of the present invention,
quasi-internal early diagnoses of epithelial neoplasm such as
esophagus cancer, stomach cancer or large bowel cancer by
means of an infrared endoscope, and identification and
diagnosis of foci in surgical operations can be performed
conveniently and accurately. Clinical tests and diagnoses
utilizing the diagnostic marker of the present invention are free
from damages on living tissues and DNAs due to ultraviolet
excitation and can be performed directly to living organisms.
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Accordingly, they are useful as immune-histochemical staining
methods.
Ito 27:6–15; see also id. at 27:16–21 (“In addition, since the labeling
compounds contained in the diagnostic marker of the present invention have
characteristic features of extremely high water solubility, the diagnostic
markers of the present invention are not absorbed in the gastrointestinal tract
and advantageous to achieve highly safe clinical examination and
diagnoses.”).
Thus, on the current record, Olson teaches that, for the purpose of
detecting cancer cells, it is desirable to conjugate, to a variety of fluorescent
dyes including indocyanine green, a CTX polypeptide variant which
preferentially binds to cancer cells, and which is undisputedly identical to
the polypeptide portion of Appellant’s compound 16. Ito, in turn, teaches
that, for the purpose of detecting cancer cells, it is desirable to conjugate, to
a polypeptide (antibody) that preferentially binds to cancer cells, an
indocyanine green derivative, undisputedly identical to the dye portion of
Appellant’s compound 16.
Given these teachings, we agree with the Examiner that a skilled
artisan had good reason for, and a reasonable expectation of success in,
conjugating Olson’s CTX variant to Ito’s indocyanine green derivative,
thereby arriving at a compound having the structure of Appellant’s
compound 16. Appellant does not persuade us, therefore, that the Examiner
erred in determining that a compound having the structure of Appellant’s
compound 16, encompassed by Appellant’s representative claim 1, would
have been prima facie obvious to a skilled artisan.
Appellant argues that the Examiner erred in interpreting Olson’s
disclosure of conjugating its CTX polypeptide variant to indocyanine green
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(see Olson 11 (quoted above)) as teaching conjugation of the polypeptide to
a single discrete dye compound. See Appeal Br. 19–22 (citing Hermanson
Decl. § III, ¶¶ 1–4);2 Reply Br. 5–7 (citing Hermanson Decl. § III, ¶¶ 4–5).
Rather, Appellant argues, a skilled artisan would have understood the term
“indocyanine green” as used in Olson to mean a modestly sized genus of
related compounds with a core structure. See Appeal Br. 22. Therefore,
Appellant argues:
Because the Office failed to recognize that Olson describes a
genus of indocyanine green dyes, it also failed to properly apply
the standard set forth in MPEP § 2144.08 (II) for evaluating a
subgenus encompassed by an earlier-described genus.
According to the MPEP § 2144.08 (II), “The fact that a claimed
species or subgenus is encompassed by a prior art genus is not
sufficient by itself to establish a prima facie case of
obviousness.” (citing In re Baird, 16 F.3d 380, 382[] (Fed. Cir.
1994)).
Appeal Br. 22.
We are not persuaded. In Baird, a skilled artisan had to decipher
through a generic formula encompassing more than 100 million compounds
to arrive at the claimed compound held to be unobvious. See In re Baird, 16
F.3d at 382–83.
Here, in contrast, even if we were to agree that Olson’s disclosure of
the term indocyanine green should be interpreted as describing a genus of
compounds (which we do not for the reasons discussed below), Appellant
points to no persuasive evidence suggesting that a skilled artisan would have
understood the alleged genus to encompass the huge number of potential
species at issue in Baird. Indeed, Appellant identifies only slightly more

2 Declaration of Greg T. Hermanson under 37 C.F.R. § 1.132 (signed August
9, 2018) (“Hermanson Decl.”).
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than a dozen or so compounds belonging to the alleged genus. See
Hermanson Decl. ¶ 5 (Table 1); Hermanson Decl., Appendices B–K.
Moreover, unlike the situation in Baird, in the present case, the
Examiner has advanced the teachings discussed above in Ito, in addition to
the express teachings in Olson of the desirability of conjugating Appellant’s
claimed CTX variant to the alleged genus of indocyanine green dyes. As
discussed above, Ito teaches that its disclosed indocyanine dye derivatives
are useful for precisely the same purpose as the alleged genus of
indocyanine dyes described in Olson—conjugation to a polypeptide that
binds preferentially to cancer cells. See Ito 2:38–49, 2:64–5:20.
Thus, in contrast to the situation in Baird, in the present case the
Examiner has advanced prior art guiding the skilled artisan directly to the
species of dye used in the dye conjugate of Appellant’s compound 16, and
recited in Appellant’s claims. Appellant does not persuade us, therefore,
that the Examiner “failed to properly apply the standard set forth in MPEP
§ 2144.08 (II) for evaluating a subgenus encompassed by an earlier-
described genus.” Appeal Br. 22.
Moreover, other than the testimony of Mr. Hermanson (Hermanson
Decl. ¶¶ 3–5), Appellant points to no specific affirmative statement in the
record supporting its contention that a skilled artisan would have understood
the term “indocyanine green” as used in Olson to mean a genus of related
compounds with a core structure, as opposed to a single discrete dye
compound. To the contrary, the documents cited by Appellant, including
those cited in the Hermanson Declaration, consistently refer to indocyanine
green only in the singular, rather than describing it as a genus, and describe
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it as a discrete dye compound. See Mizrahi3 5175 (“Indocyanine green
(ICG), a water-soluble dye, has been known since the 1950’s. Due to its
biocompatibility, it is widely used as a biomarker in studies involving the
heart, liver, lungs and blood circulation. . . . To date, this is the only NIR
imaging probe approved for human use.”) (citations omitted; emphasis
added); see also Mizrahi 5176 (showing chemical structure of “ICG”); see
also Hermanson Decl., Apps. C and G (“Indocyanine green (ICG) is a
cyanine dye used in medical diagnostics.”) (emphasis added); Hermanson
Decl., Apps. J and K (“ICG is a NIR fluorescent substance . . . .”) (emphasis
added); Velde4 8 (“ICG is a cyanine with a high affinity for protein, causing
a high non-specific binding to proteins. . . . ICG has a remarkably good
safety record and is the only FDA approved fluorescent dye.”) (citations
omitted; emphasis added); Berezin5 2692, 2693 (disclosing purchase of ICG
from “commercial sources” and structural formula of “ICG”); Ogawa6 1268
(“[O]nly indocyanine green (ICG) is clinically approved. Its use in
molecular imaging probes is limited because it loses its fluorescence after
protein binding.”) (emphasis added).

3 Dana M. Mizrahi et al., Synthesis, fluorescence and biodistribution of a
bone-targeted near-infrared conjugate, 46 EUR. J. MED. CHEM. 5175–83
(2011) (“Mizrahi”).
4 E.A. te Velde et al., The use of fluorescent dyes and probes in surgical
oncology, 36 EJSO 6–15 (2010) (“Velde”).
5 Mikhail Y. Berezin et al., Rational Approach To Select Small Peptide
Molecular Probes Labeled with Fluorescent Cyanine Dyes for in Vivo
Optical Imaging, 50 BIOCHEMISTRY 2691–2700 (2011) (“Berezin”).
6 Mikako Ogawa et al., In vivo Molecular Imaging of Cancer with a
Quenching Near-Infrared Fluorescent Probe Using Conjugates of
Monoclonal Antibodies and Indocyanine Green, 69 CANCER RES. 1268–72
(2009) (“Ogawa”).
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Indeed, Appellant’s own Specification describes ICG as a discrete dye
compound that can be conjugated to Appellant’s disclosed CTX variants and
purchased commercially. See Spec. ¶ 141 (“Non-limiting examples of
fluorescent dyes that could be used as a conjugating molecule in the present
disclosure include . . . indocyanine green (ICG) . . . .”); Spec. ¶ 181 (listing
“indocyanine green (ICG)” as near-infrared dye useful with its invention);
Spec. at p. 185 (Appellant’s Table 14 listing “Indocyanine Green” as dye
with single emission and absorbance peaks useful in Appellant’s conjugate
compounds); Spec. ¶ 433 (Appellant’s Example 5 describing “conjugation
with ICG” of PEGylated versions of CTX and Appellant’s compound 76);
Spec. ¶ 437 (Appellant’s Example 5 disclosing that “[f]ree dye experiments
were performed using Cardiogreen (ICG) (Sigma, product # I 2633)”).
We acknowledge Mr. Hermanson’s qualifications and
accomplishments. See Hermanson Decl. § 1, ¶ 1; see also Hermanson Decl.
App. A. Nonetheless, as seen above, the objective evidence of record
supports the Examiner’s determination that a skilled artisan would have
understood the terms indocyanine green and ICG as referring to a specific
discrete dye compound, rather than a genus of compounds, and that a
number of ICG derivatives were known in the prior art, including those
disclosed in Ito, as well as in the documents cited in the Hermanson
Declaration. Accordingly, Appellant does not persuade us that, in
determining that the combined teachings of Olson and Ito would have
suggested conjugating Olson’s CTX variant to Ito’s indocyanine green
derivative to arrive at a compound having the structure of Appellant’s
compound 16, the Examiner “failed to properly apply the standard set forth
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in MPEP § 2144.08 (II) for evaluating a subgenus encompassed by an
earlier-described genus.” Appeal Br. 22.
Appellant argues that a skilled artisan lacked a reasonable expectation
of success in combining Olson and Ito to produce the claimed compounds,
because systemic administration of ICG was known to result in significant
non-selective off-target binding of the dye, and because it was known in the
art that that ICG-bound protein exhibited diminished fluorescence signal
intensity. Appeal Br. 23 (citing Stroud Decl.7 ¶ 3, Berezin, Ogawa).
We are not persuaded. As our reviewing court has explained, “[t]he
reasonable expectation of success requirement refers to the likelihood of
success in combining references to meet the limitations of the claimed
invention.” Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d
1359, 1367 (Fed. Cir. 2016) (emphasis added).
In the present case, the claims under rejection do not recite methods
involving systemic administration of an ICG-conjugate or diagnostic
methods in which reduced fluorescence might become an issue. Rather, the
claimed subject matter at issue is a chemical compound, Appellant’s
compound 16. Thus, the fact that one might expect off-target binding or
reduced fluorescence of the compound, after it is prepared, does not
demonstrate that a skilled artisan lacked a reasonable expectation of success
in preparing the compound, which is all that the claims require.
To the extent Appellant’s arguments implicate an alleged lack of
motivation to prepare the claimed compound at issue, we are also
unpersuaded. We acknowledge the disclosure in Velde that free ICG (i.e.,

7 Declaration of Mark R. Stroud, Ph.D., under 37 C.F.R. § 1.132 (signed
November 16, 2017) (“Stroud Decl.”).
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unconjugated ICG) “is a cyanine with a high affinity for protein, causing a
high non-specific binding to proteins.” Velde 8.
Appellant’s compound 16, however, is not a free dye but instead is a
conjugate of a polypeptide that preferentially binds to cancer cells and an
ICG derivative. As discussed above, Olson discloses that when the claimed
polypeptide is conjugated to a fluorescent dye, the conjugate preferentially
binds cancer tissues (see Olson 18), and Ito discloses that when the claimed
dye is conjugated to a polypeptide that binds preferentially to cancer cells
(an antibody), the conjugate allows visualization of cancer tissues (see Ito
26:40–27:15 (Example 12)). Thus, the fact that free ICG binds non-
specifically to proteins does not persuade us that a skilled artisan lacked
motivation, or a reasonable expectation of success for that matter, in
conjugating Olson’s polypeptide to Ito’s ICG derivative, to arrive at a
compound with the structure of Appellant’s compound 16.
Indeed, Velde discloses that conjugation of ICG to human serum
albumin (HSA) allowed visualization of cancer-bearing sentinel lymph
nodes (SLNs). See Velde 11 (in human trial using ICG:HSA conjugate to
visualize breast cancer tissues “8 of 9 SLNs identified by Tc-99m sulfur
colloid were also identified by fluorescence” and “fluorescence identified an
SLN, confirmed to have cancer in it, that was not identified by Tc-99m
sulfur colloid”). Appellant does not persuade us, therefore, that the non-
specific binding of free ICG described in Velde would have dissuaded the
skilled artisan from preparing an ICG derivative conjugate having the
structure of Appellant’s compound 16, encompassed by Appellant’s rejected
claims.
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Moreover, contrary to Appellant’s contentions, while Berezin tested
the binding of free ICG to HSA, Berezin did not test whether a
polypeptide-ICG conjugate exhibited non-specific/non-target binding. See
Berezin 2695 (Berezin’s list of tested fluorophore conjugates in Table 1 does
not include an ICG-conjugate). Nonetheless, we acknowledge Berezin’s
disclosure that binding affinities of dye-polypeptide conjugates to albumin
was similar to the binding affinities of the free dyes tested. See id.
Appellant, however, points to no disclosure in Berezin suggesting that
the polypeptide portions of its tested conjugates had a target-specific binding
affinity similar to that of Olson’s CTX variant. Given the teachings in both
Olson and Ito discussed above, that conjugates bearing the CTX variant and
ICG derivative of Appellant’s claims preferentially bind to target cancer
cells, we are not persuaded that Berezin’s teachings regarding conjugates,
not shown to be similar to Appellant’s claimed conjugates, would have
dissuaded skilled artisans from preparing an ICG derivative conjugate
having the structure of Appellant’s compound 16.
We acknowledge Ogawa’s disclosure, identified by Appellant, that
“[ICG’s] use in molecular imaging probes is limited because it loses its
fluorescence after protein binding.” Ogawa 1268 (abstract) (emphasis
omitted). In the immediately following sentence, however, Ogawa teaches
that “[t]his property can be harnessed to create an activatable NIR [near-
infrared] probe.” Id. Indeed, several sentences later in the abstract, Ogawa
teaches that ICG-antibody conjugates allowed specific visualization of
cancer tissues in vivo. See id. (“In vivo imaging in mice showed that CD25-
expressing tumors were specifically visualized with Dac-ICG. Furthermore,
tumors overexpressing HER1 and HER2 were successfully characterized in
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vivo by using Pan-ICG(1:5) and Tra-ICG(1:5), respectively.”) (emphasis
omitted). Given Ogawa’s teaching that successful in vivo imaging may be
accomplished using conjugates of ICG and cancer cell-specific polypeptides
(antibodies), Appellant does not persuade us that Ogawa’s teaching
regarding ICG’s loss of fluorescence would have dissuaded a skilled artisan
from conjugating Ito’s ICG derivative to Olson’s cancer cell-specific CTX
variant.
In sum, for the reasons discussed, Appellant does not persuade that
the Examiner erred in determining that, based on the teachings in Olson and
Ito, a skilled artisan had a good reason for, and a reasonable expectation of
success in, conjugating Olson’s CTX variant to Ito’s indocyanine green
derivative, thereby arriving at a compound having the structure of
Appellant’s compound 16. Appellant does not persuade us, therefore, that
the Examiner erred in determining that a compound having the structure of
Appellant’s compound 16, encompassed by Appellant’s representative claim
1, would have been prima facie obvious to a skilled artisan.
Appellant also does not persuade us that it has advanced evidence of
unexpected results sufficient to outweigh the evidence of prima facie
obviousness advanced by the Examiner. We acknowledge Dr. Stroud’s
testimony, based on the results shown in Figures 1 and 2 of the Stroud
Declaration, that compound 16 exhibits unexpected results:
In my opinion, it was unexpected that the ICG derivative
conjugates we tested selectively bound to tumor cells following
systemic administration rather than preferentially binding the
various blood proteins encountered during systemic
administration. This result was surprising because at the time
of filing, a skilled practitioner would have expected that
ICG/ICG derivative conjugates would have been limited by
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non-selective binding to blood proteins. Our determination of
high selectivity for Compound 16 was thus unexpected. Even
more surprising was the result that the sulfonated conjugate
according to the current claims (i.e., Compound 16) exhibited
such a significantly greater selectivity than its desulfonated
counterpart (i.e., DS-Conjugate). Moreover, these results show
a significant and unexpected advantage of the sulfonate form of
the claimed compounds relative to the desulfonated form that
could not have been contemplated by Olson and Ito.
Stroud Decl. ¶ 13; see also id. ¶ 12 (“The average background fluorescence
in muscle was greater than four-fold higher in mice injected with Compound
16 compared to the DS-Conjugate injected group. These significant
differences can be attributed to the considerably lower selectivity for the DS-
Conjugate relative to that of Compound 16.”).
We agree with the Examiner that the selectivity of compound 16 for
tumor cells over blood proteins would not have been unexpected, given Ito’s
disclosure that conjugation of the ICG derivative of Appellant’s compound
16 to a cancer cell-specific antibody allowed specific visualization of cancer
tissues, and further given Olson’s teaching that the CTX variant used in
Appellant’s compound 16 binds preferentially to cancer cells.
We agree with the Examiner, moreover, that Appellant has not
explained sufficiently why the comparison in the Stroud Declaration
between Appellant’s compound 16 and the conjugate composed of the
claimed CTX variant and a desulfonated ICG derivative (“the DS-
Conjugate”) represents a comparison between compound 16 and the closest
prior art.
As the Examiner notes, Olson expressly discloses that the CTX
variant of Appellant’s claims may be conjugated to ICG (see Olson 11), and
Olson identifies a number of methodologies for attachment (see id. at 8–9,
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11). As the Examiner also notes, ICG includes a sulfonate group. See, e.g.,
Berezin 2693 (Fig. 1 showing structure of ICG). In contrast, the DS-
Conjugate used in the comparison in Stroud Declaration undisputedly does
not include a sulfonate group, like ICG.
We note, moreover, the disclosure in Ogawa of conjugating an ICG
derivative, which has a sulfonate group, to three different antibodies (i.e.,
polypeptides) that bind preferentially to cancer cells, allowing for in vivo
visualization of tumors. See Ogawa 1268 (describing conjugation of
“ICG-sulfo-OSU” to daclizumab (Dac), trastuzumab (Tra), and
panitumumab (Pan)); see also Hermanson Decl., App. C (structural formula
of ICG-sulfo-OSU showing sulfonate group). Indeed, a number of the ICG
derivatives identified by Appellant as belonging to the alleged ICG genus
also have sulfonate groups. See Hermanson Decl., Apps. C, D, E, G, H, I, J,
K.
Given Olson’s express disclosure that its CTX variant may be
conjugated to ICG, which includes sulfonate groups, and given that a
number of the ICG derivatives in the prior art identified by Appellant
include a sulfonate group despite being conjugated to a polypeptide, we are
not persuaded that Appellant has explained sufficiently why the comparison
of Appellant’s compound 16 to a desulfonated derivative (“the DS-
Conjugate”) represents a comparison of Appellant’s compound 16 to the
closest prior art.
We acknowledge Appellant’s contention that ICG itself cannot be
conjugated to a peptide. See, e.g., Appeal Br. 20; Reply Br. 12. Even
assuming for argument’s sake that Appellant’s contention in that regard is
accurate, however, we are not persuaded that comparison to a conjugate
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entirely lacking sulfonate groups (the DS-Conjugate) represents a
comparison to the closest prior art, because Olson expressly discloses
conjugating its CTX variant to ICG, which contains sulfonate groups, and
because a number of ICG derivatives containing sulfonate groups were
known in the art to be capable of conjugation to cancer-binding
polypeptides.
In sum, for the reasons discussed, Appellant does not persuade us of
error in the Examiner’s determination that Olson and Ito would have
suggested preparing a compound having the structure of Appellant’s
compound 16. For the reasons discussed, Appellant also does not persuade
us of error in the Examiner’s determination that the evidence of unexpected
results advanced by Appellant is not sufficient to outweigh the prior art
evidence of obviousness, because it does not compare Appellant’s
compound 16 to the closest prior art. Appellant does not persuade us,
therefore, that the Examiner erred in concluding that Appellant’s compound
16, encompassed by Appellant’s representative claim 1, would have been
obvious to a skilled artisan. Accordingly, we affirm the Examiner’s
rejection of claim 1. The remaining rejected claims fall with claim 1.
DECISION SUMMARY
In summary:
Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 3–10, 31,
32, 34, 35,
37–44, 48,
49
103 Olson, Ito 1, 3–10, 31,
32, 34, 35,
37–44, 48,
49

Appeal 2020-003677
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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). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED