Gabriela Cezar et al.

Patent Trials and Appeals Board

Jul 22, 2019

12899354 - (D) (P.T.A.B. Jul. 22, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/899,354 10/06/2010 Gabriela Cezar 08-1655-US 5625
81506 7590 07/22/2019
MCDONNELL BOEHNEN HULBERT & BERGHOFF
LLP/WARF
300 S. WACKER DRIVE, SUITE 3100
CHICAGO, IL 60606
EXAMINER
SCHUBERG, LAURA J
ART UNIT PAPER NUMBER
1657
MAIL DATE DELIVERY MODE
07/22/2019 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte GABRIELA CEZAR and ALAN SMITH1
____________

Appeal 2018-004216
Application 12/899,354
Technology Center 1600
____________

Before ERIC B. GRIMES, DEBORAH KATZ, and RYAN H. FLAX,
Administrative Patent Judges.

FLAX, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134(a) involving
claims to a method of assessing cardiotoxicity of a test compound. The
Examiner’s rejection of claims 26–28, 30, 31, and 33–45 under 35 U.S.C.
§ 103(a) is appealed. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1 The Real Parties in Interest are identified as “Stemina Biomarker
Discovery, Inc., and the Wisconsin Alumni Research Foundation.” Appeal
Br. 1.
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STATEMENT OF THE CASE
The Specification states, “[t]here remains a need in th[e] art for in
vitro methods for reliably determining cardiotoxicity of pharmaceuticals,
biologics, and other chemical compounds and environmental agents” and
“[t]he present invention provides reagents and methods for identifying a
plurality of low molecular weight molecules, preferably secreted by
cardiomyocytes or . . . [other] cardiac-specific cells, in response to
pharmaceuticals, biologics, and other chemical compounds or environmental
agents.” Spec. 4.
Independent claim 26, reproduced below, is representative:
26. A method of assessing cardiotoxicity of a test
compound comprising the steps of:
a) contacting a culture of cardiomyocyte cells with a test
compound;
b) physically separating a plurality of candidate cellular
metabolites from one another,
wherein said candidate cellular metabolites have a
molecular weight of from about 10 to about 1500 Daltons and
are secreted from said cardiomyocyte cells in said culture; and
c) comparing the candidate cellular metabolites secreted
from said cardiomyocytes in said culture contacted with the test
compound to a reference metabolic profile characteristic of a
cardiomyocyte cell response to cardiotoxic compound;
wherein said reference metabolic profile characteristic of
a cardiomyocyte cell response to cardiotoxic compound is
comprised of two or more cellular metabolites set forth in
Tables 2A-2D; and
d) identifying the test compound as a cardiotoxic
compound if a plurality of the differentially secreted cellular
metabolites are present in the reference metabolic profile.
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Appeal Br. 20 (Claims Appendix). Independent claim 38 is substantially
similar to claim 26, but requires that a reference metabolic profile include
glutamic acid and at least a second metabolite selected from a list of
metabolites that is similar to those listed in Appellants’ Specification at
Tables 2A–2D, recited by claim 26, and as the list of metabolites of claim 33
(except that claim 38 omits L-Glutamic acid and D-Glutamic acid, which are
subsumed within “glutamic acid” as required by claim 38), which depends
from claim 26.
Appellants present arguments for patentability with respect to claim
26 and do not substantively argue any other claim. Therefore, claims 27, 28,
and 33–35 fall with claim 26, as discussed below. See 37 C.F.R.
§ 41.37(c)(1)(iv); In re Kaslow, 707 F.2d 1366, 1376, (Fed. Cir. 1983)
(commonly argued claims stand or fall together); In re Huai-Hung Kao, 639
F.3d 1057, 1065 (Fed. Cir. 2011) (substantive arguments are needed to
constitute separate arguments).
The following rejections are on appeal:
Claims 26–28 and 33–35 stand rejected under 35 U.S.C. § 103(a) over
Lee,2 McKim,3 Lewis,4 and HMDB.5 Non-Final Action 4.6

2 US 2005/0255491 A1 (published Nov. 17, 2005) (“Lee”).
3 US 2007/0218457 A1 (published Sept. 20, 2007) (“McKim”).
4 Gregory D. Lewis et al., Metabolite profiling of blood from individuals
undergoing planned myocardial infarction reveals early markers of
myocardial injury, 118(10) J. CLIN. INVESTIGATION 3503–12 (2008)
(“Lewis”).
5 Human Metabolome Database: Showing metabocard for D-Glutamic acid
(HMDB03339) (2006), http://www.hmdb.ca/metabolites/HMDB03339,
visited May 2, 2015 (“HMDB”).
6 Non-Final Office Action dated Dec. 29, 2016 (“Non-Final Action”).
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Claims 30, 31, 36, and 37 stand rejected under 35 U.S.C. § 103(a)
over Lee, McKim, Lewis, HMDB, and Cezar.7 Non-Final Action 8.
Claims 26–28, 33–35, 38, 41–43, and 45 stand rejected under
35 U.S.C. § 103(a) over Lee, McKim, Lewis, HMDB, and Yang.8 Non-
Final Action 9.
Claims 30, 31, 39, 40, and 44 stand rejected under 35 U.S.C. § 103(a)
over Lee, McKim, Lewis, HMDB, Yang, and Cezar. Non-Final Action 10.
FINDINGS OF FACT
We agree with and adopt the Examiner’s findings of fact as set forth
in the Non-Final Action and Answer. Non-Final Action 4–12; Answer 4–
17.9 The following claim chart, which highlights evidence of record,
identifies how and where the prior art references cited in the Examiner’s
rejections teach or suggest subject matter corresponding or relevant to the
elements of independent claim 26.

CLAIM LANGUAGE

PRIOR ART DISCLOSURE
26. A method of
assessing
cardiotoxicity of a
test compound
comprising the steps
of:

Lee teaches detected metabolites are surrogate
markers for a condition and that the condition can
be cardiovascular disease and exposure to a toxic
agent or drug candidate. Lee ¶¶ 25–27, 162, 499.

Lee teaches its disclosed subject arrays for
detecting metabolites “can be used to identify
potential biomarkers as surrogate end points in

7 US 2007/0248947 A1 (published Oct. 25, 2007) (“Cezar”).
8 US 2007/0248537 A1 (published Oct. 25, 2007) (“Yang”).
9 Examiner’s Answer dated Jan. 22, 2018 (“Answer”).
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CLAIM LANGUAGE

PRIOR ART DISCLOSURE
developing new drugs . . . and prediction of
clinical outcomes.” Lee ¶ 493.

Lee teaches or suggests assessing cardiovascular
disease and exposure to (and, hence, identification
of) toxic agents by detection of metabolites. Lee
¶¶ 495, 499–500.

McKim similarly teaches “[t]he present invention
provides methods of determining a level of
toxicity of a given compound based on in vitro
assays. The present invention provides particular
methods of determining organ-specific toxicity
and species-specific toxicity of a given compound
based on in vitro assays.” McKim, Abstract
(emphasis added).

a) contacting a
culture of
cardiomyocyte cells
with a test
compound;

Lee teaches that the sample assayed can be “any
body sample” such as isolated cells, aggregates of
cells, muscle tissues, and organs. Lee ¶¶ 201, 229,
452, 456.

Lee teaches “metabolite profiling may be more
advantageous in certain situations, since routine
assays for prediction of drug toxicity often result
in false positive and false negative findings. . . .
Metabolic profiling is an important discipline
focused on the comprehensive analysis of the low
molecular weight biochemicals present in cells,
tissues and biofluids.” Lee ¶ 523.

The Examiner states “Lee et al do not specifically
teach wherein the cell cultures assayed include
cardiomyocytes.” Non-Final Action 6.

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CLAIM LANGUAGE

PRIOR ART DISCLOSURE
McKim is also directed to “methods of
determining a level of toxicity of a given
compound based on in vitro assays,” including
“determining organ-specific toxicity.” McKim,
Abstract.

McKim teaches that its “invention predicts the
cytotoxicity of a given compound by measuring
two or more indicators of cell health in a given
cell. The cell chosen for such an endeavor will
depend on the putative site of in vivo toxicity to be
determined.” McKim ¶ 135.

McKim teaches “a method of determining a level
of cardiac toxicity of a chemical compound. For
such analyses, primary cardiac cells would be
utilized. In particular, freshly isolated
cardiomyocytes . . . .” McKim ¶ 139.

McKim teaches culturing cardiomyocytes and
exposing the cells to the compound being tested
for cardiac toxicity. McKim ¶ 143.

McKim teaches determining toxicity by measuring
a variety of indicators of cell health and viability,
including indicators of metabolic activation and
metabolic stability, i.e., metabolites. McKim ¶¶
132, 148.

b) physically
separating a plurality
of candidate cellular
metabolites from one
another,

Lee teaches “methods for reliably detecting the
presence . . . of small molecules (e.g., metabolites)
. . . in a sample . . . .” Lee, Abstract.

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CLAIM LANGUAGE

PRIOR ART DISCLOSURE
Lee teaches that the target analytes can be
immobilized on a series of distinct addressable
locations on a support. Lee ¶ 19.

Lee teaches immobilizing small molecules, such
as metabolites of interest, for simultaneous
detection, quantitation, and profiling suing
competition arrays and using such arrays in drug
discovery research (such as drug screening) and
disease biomarker discovery. Lee ¶ 162.

Lee teaches that “‘[m]etabolites’ are the end
products of cellular regulatory processes, and their
levels can be regarded as the ultimate response of
biological systems to genetic or environmental
agents including chemicals, drugs and nutritional
factors.” Lee ¶ 225.

Lee teaches “samples to be used for the assay of
the present invention may be drawn from various
physiological, environmental or artificial sources.
In particular, physiological samples such as body
fluids or tissue samples of a patient” and can be
“drawn from cells taken from the patient or grown
in culture,” and “include supernatants, whole cell
lysates, or cell fractions obtained by lysis and
fractionation of cellular material.” Lee ¶ 452
(emphasis added).

Lee teaches fractionation may be performed by
chromatography (size separation, i.e., physical
separation). Lee ¶ 465.

wherein said
candidate cellular
Lee teaches target analytes are 50–5000 Da
molecular weights. Lee ¶ 23.
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CLAIM LANGUAGE

PRIOR ART DISCLOSURE
metabolites have a
molecular weight of
from about 10 to
about 1500 Daltons
and are secreted from
said cardiomyocyte
cells in said culture;
and

McKim teaches “a method of determining a level
of cardiac toxicity of a chemical compound. For
such analyses, primary cardiac cells would be
utilized. In particular, freshly isolated
cardiomyocytes . . .” and determining toxicity by
measuring a variety of indicators of cell health and
viability, including indicators of metabolic
activation and metabolic stability, i.e., metabolites.
McKim ¶¶ 132, 139, 148.

c) comparing the
candidate cellular
metabolites secreted
from said
cardiomyocytes in
said culture contacted
with the test
compound to a
reference metabolic
profile characteristic
of a cardiomyocyte
cell response to
cardiotoxic
compound;

Lee teaches that “metabolites and proteins with a
sample (e.g. serum) may be identified using any of
the art-recognized methods.” Lee ¶ 209.

Lee teaches that “a metabolite knowledge
database” can be created and can include
information on “normal ranges of certain
metabolites in certain tissues or samples, [the]
effects of various agents (such as drugs) on such
ranges,” and “established surrogate markers
associated with certain diseases or conditions.”
Lee ¶ 198 (emphasis added).

Lee teaches that “‘a comparable control sample’
. . . can be derived from physiological normal
conditions and/or can be subjected to different
physical, chemical, physiological or drug
treatments, or can be derived from different
biological stages, etc.” Lee ¶ 231 (emphasis
added).

Lee teaches its disclosed subject arrays for
detecting metabolites “can be used to identify
potential biomarkers as surrogate end points in
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CLAIM LANGUAGE

PRIOR ART DISCLOSURE
developing new drugs . . . and prediction of
clinical outcomes.” Lee ¶ 493.

Lee teaches “‘[b]iological marker (biomarker)’
refers to a physical sign or laboratory
measurement that occurs in association with a
pathological process and that has putative
diagnostic and/or prognostic utility.” Lee ¶ 494.

Lee teaches “‘[s]urrogate endpoint’ (or ‘surrogate
marker’) is a biomarker that is intended to serve as
a substitute for a clinically meaningful endpoint
and is expected to predict the effect of a
therapeutic intervention. It is an objective
biochemical marker which correlates with the
absence or presence of a disease or disorder, or
with the progression of a disease or disorder
(e.g., with the presence or absence of a tumor).
The presence or quantity of such markers is
independent of the causation of the disease.” Lee
¶ 495 (emphasis added).

wherein said
reference metabolic
profile characteristic
of a cardiomyocyte
cell response to
cardiotoxic
compound is
comprised of two or
more cellular
metabolites set forth
in Tables 2A-2D; and

Lee teaches “[i]t is contemplated that either single
small molecule or a combination of several small
molecules can serve as biomarkers or surrogate
endpoints. If a combination of several small
molecules are used, only when all small molecules
have predicted profile changes can a disease
association be implicated.” Lee ¶ 502 (emphasis
added).

The Examiner states, “[t]he combined teachings of
Lee et al and McKim render obvious the claimed
invention as described above, but do not explicitly
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CLAIM LANGUAGE

PRIOR ART DISCLOSURE
teach the claimed metabolites.” Non-Final Action
6.

Lewis teaches several metabolic biomarkers for
myocardial injury, including Glutamic acid and 1-
Methylhistamine. Lewis 3503 (Abstract), 3505,
3507–09.

HMDB teaches that Glutamic acid has two natural
forms: L-glutamic acid and D-glutamic acid.

Table 2D of the Specification (and claim 38) name
L-glutamic acid, D-glutamic acid, and 1-
Methylhistamine as biomarker metabolites for
cardio-toxicity. Spec. 52.

d) identifying the test
compound as a
cardiotoxic
compound if a
plurality of the
differentially secreted
cellular metabolites
are present in the
reference metabolic
profile.

Lee teaches “an assessment of cardiovascular
disease may be made using an analyte
corresponding to a protein associated with a
cardiovascular disease as a surrogate marker
. . . ).” Lee ¶ 495.

Lee further teaches that using biomarkers in such a
way plays an important role in “expediting the
development of new drugs, addressing regulatory
concerns related to dose-exposure-response
relationships, and even assisting with some
aspects of clinical practice.” Lee ¶ 498 (emphasis
added).

Lee teaches “[t]hus, arrays of the present invention
may be used as a tool of identifying and/or
measuring surrogate markers. Specifically, the
subject arrays containing a subset of candidate
small molecules that might be important
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CLAIM LANGUAGE

PRIOR ART DISCLOSURE
biomarkers for certain disease conditions can be
used to rapidly profile a large number of disease
v. normal samples, such that a pattern of profile
changes specific for the disease condition can be
readily identified. Consistent and statistically
significant changes in profile of certain small
molecules are deemed to be associated with such
specific disease conditions, and may serve as
surrogate markers for such diseases. The arrays
of the invention can be used to measure the level
or changes thereof for markers of disorders or
disease states, for markers for precursors of
disease states, for markers for predisposition of
disease states, for markers of exposure to toxic
agents, for markers of drug activity, or for
markers of the pharmacogenomic profile of
protein expression and/or profile of metabolites.”
Lee ¶ 499 (emphasis added).

Lee discloses establishing biomarker profiles for
both or either of disease states or non-disease
states, for comparison to samples, indicated drug
effects. See Lee ¶ 513.

Lee teaches “the present invention may also be
used to study the relationship between a subject’s
metabolite profile (e.g. protein expression profile)
and that subject’s response to a foreign compound
or drug. Differences in metabolism of
therapeutics can lead to severe toxicity or
therapeutic failure by altering the relation between
dose and blood concentration of the
pharmacologically active drug.” Thus, Lee
teaches the “toxicological evaluation of novel
compounds” and the “great need for toxicity
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CLAIM LANGUAGE

PRIOR ART DISCLOSURE
evaluation assays . . . in . . . drug development,”
where “markers [e.g., metabolites,] predictive of
toxicity” are detected. Lee ¶¶ 517, 518.

The above-identified portions of the prior art references are those
specifically cited by the Examiner and, where other portions of the cited
prior art references are identified, they are directly related to the disclosures
cited by the Examiner.
DISCUSSION
“[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting a prima facie case of unpatentability.
[Once] that burden is met, the burden of coming forward with evidence or
argument shifts to the applicant.” In re Oetiker, 977 F.2d 1443, 1445 (Fed.
Cir. 1992). Arguments made by Appellants in the Appeal Brief have been
considered in this Decision (no substantive arguments were presented in the
Reply Brief); arguments not so-presented in the Brief are waived. See
37 C.F.R. § 41.37(c)(1)(iv) (2015); see also Ex parte Borden, 93 USPQ2d
1473, 1474 (BPAI 2010) (informative) (“Any bases for asserting error,
whether factual or legal, that are not raised in the principal brief are
waived.”).
“The combination of familiar elements [or steps] 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). The
reason or motivation to modify the reference may often suggest what the
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inventor has done, but for a different purpose or to solve a different problem;
it is not necessary that the prior art suggest the combination to achieve the
same advantage or result discovered by Applicant. See, e.g., In re Kahn, 441
F.3d 977, 988 (Fed. Cir. 2006).
The Examiner determined that claim 26 (and others) would have been
obvious over the combination of Lee, McKim, Lewis, and HMDB. See
Non-Final Action 4–7, 11–12, and Answer 4–17 (collectively citing Lee
Title, Abstract, ¶¶ 19–27, 162, 198, 201, 231, 451, 452, 456, 516–518, 523–
524; McKim ¶¶ 139, 143, 144, 148; Lewis 3503 (Abstract), 3505, 3507–09;
HMDB generally). As noted above, Appellants present substantive
arguments directed only to claim 26.
To summarize, the Examiner determined that Lee taught or suggested
the general objectives of the claimed invention, that is, using metabolite
profiles to identify, inter alia, drug-compound toxicity, and that Lee taught
or suggested the claimed steps for doing so, but for the specifically claimed
cell-type being analyzed (i.e., cardiomyocytes––cardiac muscle cells) and
the specific metabolites therefrom (e.g., L-Glutamic acid, D-Glutamic acid,
1-Methylhistidine) to be profiled in determining toxicity. The Examiner
combined McKim with Lee for McKim’s teaching that, when focusing on a
particular tissue or organ to analyze toxicity, e.g., in drug development, one
selects cells for testing based on the site of in vivo toxicity to be analyzed;
thus, when testing for cardiac toxicity, one would use cardiomyocytes. The
Examiner reasoned that this combination would have been obvious for the
advantages disclosed in the references and that there would have been a
reasonable expectation of success because the objectives and methodologies
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of the references were so similar. The Examiner further combined Lewis
with Lee and McKim for Lewis’s teaching that myocardial injury is
identified by detecting certain metabolites, including glutamic acid, which is
listed in Appellants’ Specification as a metabolite biomarker for
cardiotoxicity. Again, the motivation for making such a combination was
the applicability of Lewis’s disclosed metabolites to the metabolite-profiling
methods of Lee, as suggested by the references themselves. The Examiner
combined HMDB with Lee, McKim, and Lewis because it identified that
glutamic acid is not just one metabolite, but two: L-Glutamic acid and D-
Glutamic acid.
We find the Examiner has made a prima facie case for the
obviousness of claim 26. We find the Examiner’s rationale for combining
the references to be reasonable and the motivation for doing so to be
apparent from the disclosures of the references themselves. We have
considered Appellants’ arguments for patentability as set forth in the Appeal
Brief (the Reply Brief makes no substantive arguments), but do not find
them persuasive. We address these arguments below.
Appellants argue the Examiner’s rejection fails to consider Lee as a
whole and, so, misapprehends the differences between Lee’s methods and
the claimed invention. Appeal Br. 2–3, 4–7; see also id. at 24 (Appendix II)
(chart indicating differences between Lee’s claimed methods and the
appealed claims’ invention). Appellants argue Lee’s quantitating is not part
of the claimed invention. Appeal Br. 8. Appellants argue Lee teaches
identifying markers for a condition including toxic exposure, while the
invention is directed to assessing toxicity of a compound, not assessing a
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condition resulting from a known toxin. Id. Appellants argue Lee’s
disclosed reference metabolic profile is not the same as the claimed method
of using a reference metabolic profile to assess cardiotoxicity. Id.
Appellants argue Lee’s disclosure of its invention’s applicability to
pharmaceutical compounds (development) does not correspond to any
element recited in Appellants’ claims. Id. Appellants argue Lee’s
comparisons of cellular metabolites with a control sample is not the same as
the metabolites of Appellants’ claims, which are not proteins. Id. at 8–9.
Appellants argue Lee’s disclosed protein separations and fractionations do
not correspond to any element recited in their claims. Id. at 9.
We find none of these arguments persuasive. Upon review of the
Non-Final Action and Answer, we find the Examiner has considered Lee in
its entirety and as a whole (see, e.g., supra Findings of Fact). It appears to
be Appellants that take an overly myopic view of the Lee reference, as
exemplified by the above-noted arguments from their Appeal Brief and
Appendix II of the Appeal Brief, which narrows Lee’s disclosure to
elements of Lee’s claims and specific embodiments disclosed by the
reference. Appellants focus on the invention claimed in Lee or specific
embodiments disclosed in Lee to the exclusion of the greater concepts taught
by the reference, which teach or suggest the steps of appealed claim 26,
except as conceded by the Examiner and as noted above. We will not
discuss each of Appellants’ points of these arguments, noted above, other
than to point to the Findings of Facts section above, which, in agreement
with the Examiner’s determinations, identifies how and where Lee (in
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combination with the other cited prior art) teaches or suggests the steps of
Appellants’ claim.
Regarding McKim, Appellants argue the reference is directed to using
cardiomyocytes to determine the kinetics, pharmacology, and degradation
products of a toxic compound itself, not to detect cellular metabolites from
these cells, per the appealed claims. Appeal Br. 10. This argument is not
persuasive. Regardless of specifically how McKim teaches analyzing
cardiomyocytes, McKim teaches, and the Examiner cites McKim for
teaching that, when analyzing the cardiotoxicity of a compound, such as a
developmental pharmaceutical, one should use cardiomyocytes for such
analysis. Thus, a skilled artisan following the methodology of Lee and
analyzing the toxicity of a developmental pharmaceutical compound upon
the heart would be motivated to analyze cardiomyocytes’ metabolic reaction
to exposure to the compound so that a metabolic biomarker profile could be
established. See supra Findings of Fact.
Regarding Lewis, Appellants argue the Examiner has cherry-picked
the only metabolite (Glutamic acid) common to the reference and the claims
and that the Lewis metabolites result from a different method than
Appellants’ claims. Appeal Br. 11–12. This argument is not persuasive. As
Appellants note, Lewis discloses only a handful of metabolites that serve as
biomarkers for cardiac injury (we do not find cardiac injury to be so
different from cardiotoxicity and Appellants present no persuasive evidence
that they are meaningfully different regarding metabolite output). Glutamic
acid is one such metabolite and Lewis teaches that Glutamic acid is
particularly useful in identifying such cardiac injury at an early stage, e.g.,
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within the first 10 minutes. Thus, it would have been obvious to analyze a
cardiac metabolite sample for Glutamic acid if one were investigating
whether an event had caused cardiac injury. Moreover, Glutamic acid is not
the only metabolite of Appellants’ claims taught by Lewis because Lewis
also teaches 1-Methylhistamine as a biomarker of cardiac injury, which is
also claimed by Appellants.
Regarding HMBD, Appellants argue the reference does not
compensate for the deficiencies of the other references. Appeal Br. 12. This
argument is not persuasive. We do not find Lee, McKim, and Lewis to be
deficient in the ways argued by Appellants; therefore, HMBD need not
compensate for any deficiencies. HMBD does, as determined by the
Examiner, identify that the Glutamic acid taught by Lewis as a cardio-injury
biomarker, is actually two metabolites (L-Glutamic acid and D-Glutamic
acid), as claimed by Appellants.
Regarding each of the above arguments, we note, “[n]on-obviousness
cannot be established by attacking references individually where the
rejection is based upon the teachings of a combination of references. . . .
[Each reference] must be read, not in isolation, but for what it fairly teaches
in combination with the prior art as a whole.” In re Merck & Co., 800 F.2d
1091, 1097 (Fed. Cir. 1986). The rejection is based on the prior art
combination, thus, Appellants’ argument regarding any perceived
shortcoming of any reference individually, without considering the
combination, is not persuasive.
Appellants generally argue there would have been no motivation to
combine the Examiner’s cited references and that the Examiner has not
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identified such motivation. Appeal Br. 13–15. As we noted above, this
argument is not persuasive because the cited references provide motivation
for their combination based on the advantages conveyed in their disclosures.
Appellants’ (essentially restated) argument that the combined prior art
would not have disclosed all elements of the claims (Appeal Br. 15) is also
not persuasive. The Examiner has identified in the Non-Final Action and
Answer how and where the cited prior art teaches and suggests each step of
claim 26; we note the same in the Findings of Fact section above.
As noted above, Appellants present substantive arguments only over
the first rejection and, then, only with regard to independent claim 26.
Therefore, claims 27, 28, and 33–35 fall with claim 26. In addition, while
Appellants also note the three other obviousness rejections and the
additional cited prior art Cezar and Yang (see Appeal Br. 17–18), they have
presented no substantive argument over these other rejections and, so, have
waived arguments based on Cezar and Yang. We therefore affirm the
remaining obviousness rejections for the reasons discussed above. 37 C.F.R.
§ 41.37(c)(1)(iv) (Appeal Brief must include “[t]he arguments of appellant
with respect to each ground of rejection.”); Hyatt v. Dudas, 551 F.3d 1307,
1314 (Fed. Cir. 2008).
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SUMMARY
The four obviousness rejections are each affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED