ImmuneXpress Pty Ltd

Patent Trials and Appeals Board

Dec 24, 2021

2021000794 (P.T.A.B. Dec. 24, 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.
14/616,565 02/06/2015 Richard Bruce BRANDON DAVI-035/01US
040722-2059
6075
58249 7590 12/24/2021
COOLEY LLP
ATTN: IP Docketing Department
1299 Pennsylvania Avenue, NW
Suite 700
Washington, DC 20004
EXAMINER
SALMON, KATHERINE D
ART UNIT PAPER NUMBER
1634
NOTIFICATION DATE DELIVERY MODE
12/24/2021 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):
zIPPatentDocketingMailboxUS@cooley.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
________________

Ex parte RICHARD BRUCE BRANDON and
LEO CHARLES MCHUGH1
________________

Appeal 2021-000794
Application 14/616,565
Technology Center 1600
________________

Before DONALD E. ADAMS, JOHN G. NEW, and TAWEN CHANG,
Administrative Patent Judges.

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1 We use the term “Appellant” to refer to the “applicant” as defined in
37 C.F.R. § 1.142. Appellant identifies ImmuneXpress Pty Ltd as the real
party-in-interest. App. Br. 3.
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SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 1 and 31. Specifically, claim 1 stands
rejected as unpatentable under 35 U.S.C. § 103 over the combination of Ivey
et al. (US 2004/0097460 A1, May 20, 2004) (“Ivey”), R. Pankla et al.,
Genomic Transcriptional Profiling Identifies a Candidate Blood Biomarker
Signature for the Diagnosis of Septicemic Melioidosis, 10 (R127) GENOME
BIOL. R127:1–22 (2009) (“Pankla”), P. Markoulatos et al., Multiplex
Polymerase Chain Reaction: A Practical Approach, 16 J. CLIN. LAB. ANAL.
47– 51 (2002) (“Markoulatos”), and I.R. Peters et al., Real-time RT-PCR:
Considerations for Efficient and Sensitive Assay Design, 286 J. IMMUNOL.
METHODS 213–17 (2004) (“Peters”).
Claims 31 stands rejected as unpatentable under 35 U.S.C. § 103 over
the combination Ivey, Pankla, Markoulatos, Peters, Brandon et al. (US
2014/0037649 A1, February 6, 2014) (“Brandon”), and Hossain et al (US
2009/0203534 A1, August 13, 2009) (“Hossain”).
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

NATURE OF THE CLAIMED INVENTION
Appellant’s claimed invention is directed to methods, kits, and
apparatus, as well as associated reagents and compositions, for deriving an
indicator for use in diagnosing the presence, absence or degree of at least
one condition in a biological subject or in prognosing at least one condition
in a biological subject. Spec. Abstr.

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REPRESENTATIVE CLAIM
Independent claim 1 and dependent claim 31 are on appeal and recite:
1. A composition comprising a mixture of a DNA
polymerase, a sample of peripheral blood leukocyte cDNA from
a subject with a clinical sign of systemic inflammatory response
syndrome (SIRS), the sample of peripheral blood leukocyte
cDNA comprising a placenta-specific 8 (PLAC8) cDNA and a
phospholipase A2, Group VII (PLA2G7) cDNA and for each of
up to 6 cDNAs, which comprise the PLAC8 cDNA and the
PLA2G7 cDNA, (1) two oligonucleotide primers that hybridize
to opposite complementary strands of the cDNA, and (2) an
oligonucleotide probe that hybridizes to the cDNA, wherein the
oligonucleotide probe comprises a fluorophore and a quencher
for real-time quantification of the cDNA and is free in solution.

31. The composition according to claim 1, wherein the sample
of peripheral blood leukocyte cDNA further comprises a
carcinoembryonic antigen-related cell adhesion molecule 4
(CEACAM4) cDNA and a lysosomal-membrane associated
protein 1 (LAMP I) cDNA and the composition further comprises
for each of the CEACAM4 cDNA and the LAMP I cDNA, (1) two
oligonucleotide primers that hybridize to opposite
complementary strands of the cDNA, and (2) an oligonucleotide
probe hybridizes to the cDNA, wherein the oligonucleotide
probe comprises a fluorophore and a quencher for real-time
quantification of the cDNA and is free in solution.

App. Br. 24, 31.

ISSUE AND ANALYSIS
We agree with and adopt the Examiner’s findings, reasoning, and
conclusion that the claims are obvious over the combined cited prior art. We
address below the arguments raised by Appellant.

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A. Claim 1
The Examiner’s Findings and Conclusions
The Examiner finds that Ivey teaches designing biomarkers for the
detection of sepsis. Final Act. 3 (citing Ivey Abstr.). The Examiner finds
that Ivey teaches that one of the probes is a marker of PLA2G7 (table 1), and
also teaches a method by which an mRNA species is hybridized to an array
of cDNA, and that the probe can be labeled. Id. at 4 (citing Ivey ¶¶ 41, 42).
The Examiner reasons that it would have been obvious to a person of
ordinary skill in the art that the mRNA is converted to cDNA via
hybridization. Id.
The Examiner finds, however, that Ivey does not teach PLAC8,
although Ivey does teach that the cDNA can be derived from the immune
system: viz., leukocytes, and blood cells. Id. (citing Ivey ¶¶ 59 and 62). The
Examiner reasons that a person of ordinary skill in the art would understand
blood cells would include peripheral blood, and that the cells would include
cDNA derived from cells that have peripheral blood components. Id. The
Examiner finds that Ivey teaches mRNA samples taken from a subject with
sepsis (a clinical sign of systemic inflammatory response syndrome
(“SIRS”). Id. (citing Ivey Abstr., ¶ 41).
The Examiner finds that Pankla teaches a composition comprising a
probe (PLAC8) that hybridizes to cDNA. Final Act. 4 (citing Pankla
R127.10, R127.20). The Examiner finds that Pankla also teaches screening
patients with septicemic melioidosis. Id. (citing Pankla Abstr.). As such,
finds the Examiner, both Ivey and Pankla teach regions of cDNA that are of
interest as bioindicators for sepsis, however, these references do not teach a
composition comprising multiplex reaction components. Id.
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However, the Examiner reasons, it was well known in the art to take
known target regions and detect them via a multiplexing polymerase chain
reaction (“PCR”) format, such as one with probes that are free in solution.
Final Act. 4. The Examiner finds that Markoulatos teaches the method of a
one mixture multiplex PCR in solution. Id. (citing Markoulatos, 47).
Specifically, the Examiner finds that Markoulatos teaches the design factors,
including primer design, amount of primer and amount of template. Id.
(citing Markoulatos, 48–49).
The Examiner also finds that Peters teaches that quenchers and
fluorophores can be added to solutions to detect hybridization. Final Act. 4
(citing Peters, 208). The Examiner finds that Peters teaches that use of
quenchers and fluorophores allows for a detection of fluorescence change as
a means of detecting the presence of a biomarker. Id.
The Examiner therefore concludes that it would have been prima facie
obvious to a person of ordinary skill in the art to design a composition that
would include other known probes free in a solution (such as for multiplex
PCR) associated with sepsis. Final Act. 5. The Examiner reasons that,
because Pankla teaches that PLAC8 is associated with sepsis symptoms, an
ordinary artisan would also have been motivated to include this probe, also
for the use of examining biomarkers associated with sepsis. Id.
The Examiner further concludes that it would have been prima facie
obvious to one of ordinary skill in the art to employ the biomarkers of
interest taught by Ivey and Pankla in a multiplex composition, as taught by
Markoulatos. Final Act. 5. The Examiner reasons that a skilled artisan
would have had a reasonable expectation of success, because Markoulatos
teaches that multiple primers can be used in a composition to detect multiple
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regions of a sample, and that such regions can be detected using the
quenchers and fluorophores, taught by Peters. Id. The Examiner further
concludes that a person of ordinary skill in the art would have been
motivated to design such a composition to screen for multiple regions of a
biomarker simultaneously. Id.

Analysis
Issue 1
Appellant argues that the Examiner has not established a prima facie
case of obviousness of claim 1 over Ivey, Pankla, Markoulatos, and Peters,
because the Examiner has failed to identify a proper reason why a person of
ordinary skill in the art would have been prompted to combine the alleged
prior art elements in the manner claimed. App. Br. 9 (citing KSR
International Co. v. Teleflex, Inc., 550 U.S. 398, 418 (2007).
Specifically, Appellant argues first that a person of ordinary skill in
the art would not have used quantitative real-time multiplex PCR merely to
detect or screen for gene expression profiles. Ans. 11. Appellant contends
that there would have been no sound, technical reason to combine, in a
qPCR composition, primers and probes for hybridizing to PLAC8 and
PLA2G7 cDNA targets contained in a sample of peripheral blood leukocyte
cDNA from a subject with a clinical sign of SIRS. Id. Furthermore, argues
Appellant, there would be no reason to combine these in a composition that
would be inherently limited to amplification of up to 6 cDNAs
polynucleotides including PLAC8 and PLA2G7 cDNAs in a single
multiplex reaction. Id. at 11–12.
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Appellant argues that, because the number of target cDNAs in a
multiplex, real-time qPCR amplification reaction is limiting (generally
considered to be limited to 5 targets, plus one reference or control), it is
necessary to carefully choose a small number of target cDNAs, typically five
or less, from a characteristically much larger group of cDNAs identified
from biomarker discovery. App. B. 12 (citing the Declaration of Dr.
Richard Bruce Brandon, filed October 9, 2018 (the 2018 “Brandon
Declaration”). Therefore, contends Appellant, a person of ordinary skill in
the art would have needed a sound technical reason to combine reagents for
amplifying such a small number of cDNAs in a single multiplex, real-time
qPCR reaction, for example, to address a specific clinical question that
requires quantification of multiple target polynucleotides. Id. Appellant
argues that such is not the case in the claims on appeal. Id.
Appellant points to the 2018 Brandon Declaration, in which Dr.
Brandon attests that the Examiner has based rejection of claim 1 on the
allegedly unfounded premise that a person of ordinary skill in the art would
have mixed and matched qualitatively different biomarkers from unrelated
microarray based studies addressing different clinical questions, and placed
them in the same multiplex, real-time qPCR assay merely to detect the
disparate biomarkers. App. Br. 12 (citing 2018 Brandon Decl. ¶ 17).
Appellant notes that Dr. Brandon asserts that such a premise is not founded
on sound scientific principles. Id.
Appellant further points to Dr. Brandon’s testimony that the
biomarkers disclosed in Ivey and Pankla were characterized by the Examiner
in the Office Action, collectively, as “cDNA … known to be associated with
sepsis factors” App. Br. 12 (quoting Final Act. 7). According to Appellant,
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Dr. Brandon interprets this phrase as equating to “sepsis-associated
biomarkers.” Id. However, Appellant argues Dr. Brandon contends that this
characterization is over simplistic, inaccurate, and likely to be over
inclusive. Id. (citing 2018 Brandon Decl. ¶ 18). In support of this position,
Dr. Brandon cites B. Casserly et al., Multimarker Panels in Sepsis, 27(2)
CRIT. CARE CLIN. 391-405 (2011) (“Casserly,” Ex. B) and J. LaBaer, So,
You Want to Look for Biomarkers (Introduction to the Special Biomarkers
Issue), 4 J. PROTEOME RES. 1053–59 (2005) (“LaBaer,” Ex. C), which define
biomarkers as differentiating between two or more biologic states. Id. at 12–
13 (citing 2018 Brandon Decl. ¶ 18, Exs. B, C). Dr. Brandon states that
Casserly cautions the biomarker scientist against the risks of “spectrum
bias,” whereby the inappropriate choice of a control group leads to an
invalid study. Id. Appellant argues that Casserly teaches that an invalid, or
poorly designed, study leads the researcher to believe a biomarker has
diagnostic power when it actually does not. Id. According to Appellant,
such biomarkers ultimately fail at the clinical validation step; the example
presented by Casserly includes the use of healthy subjects (as controls) and
septic shock patients which would most likely lead to “artificial case/control
differences.” Id. (quoting Casserly, 393).
Appellant also notes that Dr. Brandon cites S.E. Kem, Why Your New
Cancer Biomarker May Never Work: Recurrent Patterns and Remarkable
Diversity in Biomarker Failures, 72 CANCER RES. 6097–101 (2012) (“Kem”
Ex. D), which systematically lists reasons why biomarkers fail. App. Br. 13
(citing 2018 Brandon Decl. ¶ 18, Ex. D). Appellant asserts that that Kem
reiterates this problem in biomarker discovery but calls it a “straw-man
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argument (a too easy comparison, a comparison of apples and oranges).” Id.
(quoting Kem, 6100).
Appellant contends that, based upon these references, Dr. Brandon
opines that the biomarkers taught by Ivey differentiate between sepsis and
SIRS (i.e., “sepsis/SIRS biomarkers”), whereas, in contrast, the biomarkers
in Pankla segregate healthy subjects from sepsis patients (i.e.,
“sepsis/healthy biomarkers”). App. Br. 13. Appellant points to Dr.
Brandon’s explanation that, because healthy subjects are never clinically
suspected of having sepsis, biomarkers capable of differentiating between
these two populations do not answer a meaningful clinical question, i.e.,
“does this patient have sepsis?” Id. (citing 2018 Brandon Decl. ¶ 18).
Appellant further notes that Dr. Brandon reasons that the biomarkers
disclosed in Ivey and Pankla are not actually “sepsis-associated biomarkers,”
but are instead separate, qualitatively different combinations of conditions in
which sepsis is the only condition that is shared between the combinations.
App. Br. 14. Appellant argues that Dr. Brandon observes that Pankla uses
septic patients that were blood culture-positive in comparison to healthy
subjects to identify differentially expressed genes. Id. According to
Appellant, Dr. Brandon explains that many septic patients diagnosed by
clinicians are blood culture negative, that is, no organism is ever identified
in up to 90% of septic patients. Id. Additionally, Dr. Brandon notes that
Pankla does not validate PLAC8 as a biomarker for differentiating septic
patients (either blood culture-positive or -negative) from those with SIRS.
Id. On this basis, Appellant contends that Dr. Brandon concludes that to mix
and match Ivey biomarkers with Pankla biomarkers would contravene best
practices for experimental design, at the least because such mixing and
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matching would neither start with an appropriate scientific hypothesis nor
answer a valid clinical question, and thus would likely fail clinical validation
in a relevant patient population to provide clinical utility. Id. (citing 2018
Brandon Decl. ¶ 18).
Appellant notes that Dr. Brandon also cites J. Monforte et al., Strategy
for Gene Expression-Based Biomarker Discovery, 38 BIOTECHNIQUES S25–
S29 (2005) (“Montforte”). App. Br. 15. Dr. Brandon explains that
Montforte discusses that the critical aspects of successful experimental
design include ensuring that potentially confounding factors are controlled.
Id. (citing 2018 Brandon Decl. ¶ 20, Ex. E). According to Appellant,
Monforte teaches that the payoff of adhering to these accepted best practices
is high-quality data that can readily be compared between different studies,
sites, and dates, and more efficient and effective use of resources and
precious patient samples. Id. Appellant contends that a person of ordinary
skill in the art would not have been motivated to combine biomarkers from
different studies (i.e., Ivey and Pankla), using different subject populations,
which not only had different design formats and associated baselines, but
which also attempted to answer different clinical questions. Id. (citing 2018
Brandon Decl. ¶ 20).
Appellant contends that Dr. Brandon attests that Monforte
summarizes the steps involved in a typical biomarker signature discovery
and implementation process including: (i) defining the research need; (ii)
developing a comprehensive and clear experimental design or plan; (iii)
performing global gene expression profiling using microarrays; (iv)
performing a detailed analysis of the microarray data to identify key genes,
patterns, and signatures responsive to the research need; (v) translating the
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signatures into PCR platform assays for confirmation, validation, and
utilization of the signatures in a high sample-throughput platform; and (vi)
developing the final experimental results, conclusions, and validated gene
expression signatures for use as diagnostic and research tools. App. Br. 15.
Dr. Brandon further explains that the use of microarray platforms to profile
global gene expression and identify potential biomarkers followed by PCR
techniques for validation of the biomarkers was accepted by biomarker
researchers as best practice even shortly before the earliest provisional
patent application was filed on February 6, 2014. Id. (citing 2018 Brandon
Decl. ¶ 22 (citing I. Riedmaier et al., Transcriptional Biomarkers - High
Throughput Screening. Quantitative Verification, and Bioinformatical
Validation Methods, 59 METHODS 3–9 (2013) (“Riedmaier”))).
Dr. Brandon opines that there were no multiplex PCR amplification
techniques that were published as transcriptional biomarker discovery
platforms before the earliest priority date. App. Br. 15–16 (citing 2018
Brandon Decl. ¶ 23). Rather, Dr. Brandon attests that PCR platforms,
particularly real-time qPCR, were generally being used for cost-effective
validation of a biomarker signature identified from a microarray discovery
platform, and for clinical validation. Id. at 16 (citing 2018 Brandon Decl.
¶ 23 (citing Monforte and Riedmaier et al)).
Appellant contends that the Examiner has not provided any evidence
of record to explain why a person of ordinary skill in the art would have
used a target-limited assay such as qPCR merely as a screening assay to
detect biomarkers, when the evidence of record allegedly teaches away and
supports the opposite view. App. Br. 16. According to Appellant, the
evidence of record establishes that a person of ordinary skill in the art would
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not have mixed and matched qualitatively different biomarkers from
unrelated microarray-based studies that address different clinical questions.
Id. Nor would such a person use a multiplex PCR assay to screen for
biomarkers, Appellant argues, because it is inherently unsuitable for
biomarker discovery because of the very low number of targets it can detect.
Id. at 16–17.
Rather, Appellant argues, the evidence of record establishes that a
person of ordinary skill in the art would have used a high throughput
microarray-based assay to screen for biomarkers that are differentially
expressed between different patient populations to answer a clinically
relevant question. App. Br. 17. In this regard, contends Appellant, the
Examiner has not provided a clinically relevant question that would have
been addressed by the combined detection of the Ivey and Pankla
biomarkers. Id.
The Examiner disagrees with Appellant’s assertion that the claims are
inherently limited to multiplex real time quantitative PCR because of the
requirement of about five elements with a control. Ans. 7. The Examiner
responds that the claims are interpreted based upon the structure required,
which comprises compositions with particular cDNAs for each, and up to six
cDNAs, two primers and probes. Id. As such, the Examiner finds,
Appellant’s argument does not address the rejection above with regard to the
teachings and suggestions of the art cited by the Examiner. Id. The
Examiner points out that the claims are not towards a method of real-time
quantitative PCR, but rather to a composition that has components that are
capable of being used in a real-time PCR assay. Id.
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The Examiner finds that the claimed composition encompasses an
embodiment that includes routine assay components. Ans. 7. The Examiner
finds that multiplex PCR compositions are routine and conventional for the
use in any combination of known cDNA structures. Id. The Examiner
reasons that an ordinary artisan could have combined any cDNA regions,
using the design constraints of Markoulatos, with the intended result of
detecting those regions. Id. The Examiner finds that the claims are not
limited to any particular number of cDNAs/probes but rather primers and
probes of “the cDNA.”
The Examiner notes that Appellant also argues that a skilled artisan
would not put particular biomarkers together that were gleaned from assays
that are focused on different populations and diagnostic conditions in such a
multiplex method. Ans. 7. However, the Examiner finds that the prior art
teaches that one can make assays to use for detection of known cDNA and
therefore the design choice of particular probes, primers, and cDNAs in such
compositions would have been routine for a person of ordinary skill in the
art. Id.
With respect to the 2018 Brandon Declaration, the Examiner notes
that Appellant asserts that the references cited by the Examiner are different
because Ivey and Pankla answer different clinical questions and have
different subject populations. Ans. 9. However, the Examiner finds, both
references are directed to populations with at least a clinical sign of SIRS
and indicate detection of septic conditions. Id. The Examiner notes that
Appellant argues that a skilled artisan would not have designed a multiplex
PCR amplification with these combinations that would involve a large
combination of potential combinations. Id.
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However, the Examiner finds that the number of combinations of
sepsis biomarkers is finite and that it would have been well within the skill
of an ordinary artisan to make combinations of known biomarkers and
design compositions of the components of real time PCR. Ans. 9. The
Examiner finds that Appellant’s arguments, and the 2018 Brandon
Declaration, are directed against particular reasons for the choice of
populations or clinical outcomes. Id. The Examiner finds that the claimed
cDNA is known to be associated with sepsis factors, and concludes that it
would have been obvious to design primers and probes for compositions in
solution. Id.
Summarizing, the Examiner concludes that it would have been
obvious to a person of ordinary skill in the art that one could design any
number of compositions with known cDNA, primers, and probes in a
solution with the expected outcome of being able to detect a given
biomarker. Ans. 9. The Examiner finds that the Appellant’s arguments that
rely upon the 2018 Brandon Declaration are based upon the use of
biomarkers as detection biomarkers for particular disease phenotypes. Id.
The Examiner finds, however, that the claims are drawn to
compositions that are capable of numerous intended uses, including merely
screening for detection (as the Examiner points out, any probe or primer can
be used). Ans. 9. The Examiner finds that Appellant’s reliance upon the
references cited by the 2018 Brandon Declaration (i.e., Casserly and LaBaer)
as teaching why biomarkers must be validated and a diagnostic power must
be determined to be inapposite. Id. The Examiner notes that, whereas this is
true, these genes were already known to be associated with clinical signs of
SIRs. Id. at 9–10. The Examiner finds that Appellant’s Specification does
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not limit the term “biomarkers” to have any particular limit, but instead
discloses that such biomarkers must be detectable in a patient with a clinical
sign of SIRs. Id. at 10. The Examiner finds that, in the case of both
PLA2G7 and PLAC8 these genes are considered in the art to be biomarkers
of clinical signs of SIRS. Id.
The Examiner finds that Ivey in particular teaches designing
biomarkers for the detection of sepsis. Ans. 10 (citing Ivey, Abstr.). The
Examiner particularly finds that Ivey teaches that one of the probes is a
marker of PLA2G7. Id. (citing Ivey, Table 1). The Examiner also finds that
Ivey further teaches that one can hybridize individual mRNA species to an
array of cDNA. Id. (citing Ivey ¶ 41).
The Examiner finds that Pankla teaches a composition comprising a
probe (PLAC8) that hybridizes to cDNA. Ans. 10 (citing Pankla, R127.10,
R127.20). The Examiner finds that Pankla further teaches screening patients
with septicemic melioidosis. Id. (citing Pankla, Abstr.). As such, the
Examiner finds, having signs of sepsis and septicemic melioidosis both
encompass signs of having SIRS, as each involve clinical signs of
inflammatory responses due to the septic response. Id.
We are not persuaded by Appellant’s arguments. Despite its length,
paragraph 18 of the 2018 Brandon Declaration is worth reproducing in full,
because it constitutes the core of Appellant’s argument with respect to claim
1:
The biomarkers disclosed in Ivey and Pankla are characterized
by the Examiner collectively, as “cDNA … known to be
associated with sepsis factors”. I interpret this phrase as equating
to “sepsis-associated biomarkers”. This characterization is over
simplistic, inaccurate, and likely to be overly inclusive. As
explained in Casserly et al., biomarkers differentiate between
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two or more biologic states. This ability to segregate biological
states distinguishes biomarkers from simple measurements.
Casserly et al. clearly cautions the reader, and biomarker
researcher, of the risks of “spectrum bias” whereby the
inappropriate choice of a control group leads to an invalid study.
An invalid or poorly designed study leads the researcher to
believe a biomarker has diagnostic power when it actually does
not. Such biomarkers ultimately fail at the clinical validation
step. The example presented by Casserly et al. is the use of
healthy subjects (as controls) and septic shock patients which
would most likely lead to “artificial case/control differences”.
Further, in a paper that systematically lists reasons why
biomarkers fail, Kern reiterates this problem in biomarker
discovery but calls it “straw-man argument (a too easy
comparison, a comparison of apples and oranges).”
Consequently, the biomarkers disclosed in Ivey are biomarkers
that differentiate between sepsis and SIRS (i.e., “sepsis/SIRS
biomarkers”), whereas Pankla discloses biomarkers that
segregate healthy subjects from blood culture positive sepsis
patients (i.e., “sepsis/healthy biomarkers”). Since healthy
subjects are never clinically suspected of having sepsis,
biomarkers capable of differentiating these two populations do
not answer a clinical question. That is “does this patient have
sepsis?” Ergo, the biomarkers disclosed in Ivey and Pankla are
not merely “sepsis-associated biomarkers”, instead they separate
qualitatively different combinations of conditions in which
sepsis is the only condition that is shared between the
combinations, Further, Pankla uses septic patients that were
blood culture positive in comparison to healthy subjects to
identify differentially expressed genes. Many septic patients
diagnosed by clinicians are blood culture negative, That is, no
organism is ever identified in up to 90% of septic patients as
described for example by Coburn et al. Pankla does not validate
PLAC8 as a biomarker for differentiating septic patients (either
blood culture positive or negative) from those with SIRS. Thus,
to mix and match Ivey biomarkers with Pankla biomarkers would
contravene best practices for experimental design, would not
start with an appropriate scientific hypothesis, or answer a valid
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clinical question, and would likely fail clinical validation in a
relevant patient population to provide clinical utility.

(References and citations omitted).
Ivey expressly teaches the relationship between sepsis and SIRS:
Sepsis follows a well-described time course, progressing from
systemic inflammatory response syndrome (“SIRS”)-negative to
SIRS-positive to sepsis, which may then progress to severe
sepsis, septic shock, multiple organ dysfunction (“MOD”), and
ultimately death. Sepsis also may arise in an infected individual
when the individual subsequently develops SIRS. “SIRS” is
commonly defined as the presence of two or more of the
following parameters: body temperature greater than 38° C. or
less than 36° C; heart rate greater than 90 beats per minute;
respiratory rate greater than 20 breaths per minute; PCO2 less than
32 mm Hg; and a white blood cell count either less than 4.0x109
cells/L or greater than 12.0x109 cells/L, or having greater than
10% immature band forms. “Sepsis” is commonly defined as
SIRS with a confirmed infectious process.

Ivey ¶ 4. Pankla teaches the same clinical diagnostic indicia. See Pankla
R127.18.
Ivey further teaches that, in its method:
Ideally, diagnosis would be made by a technique that accurately,
rapidly, and simultaneously measures a plurality of biomarkers
at a single point in time, thereby minimizing disease progression
during the time required for diagnosis.… The reference
biomarker profile may also be obtained from various populations
of individuals including those who are suffering from SIRS or
those who are suffering from an infection but who are not
suffering from SIRS. Accordingly, the present invention allows
the clinician to determine, inter alia, those patients who do not
have SIRS, who have SIRS but are not likely to develop sepsis
within the time frame of the investigation, who have sepsis, or
who are at risk of eventually becoming septic.

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Id. at ¶ 8−9.
With respect to its method, Ivey teaches:
A biological sample such as, for example, blood, is taken
immediately upon admission. The complex mixture of proteins
and other molecules within the blood is resolved as a profile of
biomarkers. This may be accomplished through the use of any
technique or combination of techniques that reproducibly
distinguishes these molecules on the basis of some physical or
chemical property.… fragments. In another embodiment,
biomarkers are selected from the various mRNA species
obtained from a cellular extract, and a biomarker profile is
obtained by hybridizing the individual’s mRNA species to an
array of cDNAs. The diagnostic use of cDNA arrays is well-
known in the art.

Ivey ¶ 41. With respect to the oligonucleotide primers recited in claim 1,
Ivey teaches that:
Once isolated, selected RNA species were amplified using
message specific primers or random primers.… Primers were
designed to amplify specific RNA sequences present in the
sample using RT-PCR, using principles generally known by one
of ordinary skill in the art … Amplified RNAs may then be
detected using, for example, fluorescent-tagged detection
primers….”

Id. at 76.
Finally, Ivey teaches that PLA2G7 is a biomarker associated with
both SIRS and sepsis, a result that Ivey teaches is confirmed in WO
03/040404 at 46–52. See Ivey ¶ 98; Table 1. Ivey teaches that PLA2G7 is
expressed in patients who were admitted to hospital with diagnosed SIRS
and who subsequently developed sepsis. Id. at ¶ 119, Table 7.
Pankla teaches the use of “microarray technology to generate genome-
wide transcriptional profiles (>48,000 transcripts) from the whole blood of
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patients with septicemic melioidosis.” Pankla, Abstr. Pankla teaches that
“[u]nsupervised analyses demonstrated the existence of a whole blood
transcriptional signature distinguishing patients with sepsis from control
subjects. The majority of changes observed were common to both septicemic
melioidosis and sepsis caused by other infections, including genes related to
inflammation, interferon-related genes, neutrophils, cytotoxic cells, and T-
cells.” Id. Pankla notes that “[b]lood transcriptional patterns distinguish
patients with septicemic melioidosis from patients with sepsis caused by
other pathogens. Once confirmed in a large scale trial this diagnostic
signature might constitute the basis of a differential diagnostic assay.” Id.
Specifically, Pankla teaches:
To facilitate the biological interpretation of the distinct sepsis
signatures identified in the present study, we applied this
modular analysis strategy. Briefly, differences in expression
levels between uninfected controls (region R1) and septic patients
(regions R2, R4 or R5) for sets of coordinately expressed
transcripts (that is, modules) are displayed on a grid.
….
An increase in the number of altered modules and spot intensities
was observed when comparing region R4 to the uninfected
control region (R1), thereby confirming the increased level of
perturbation quantified through the earlier computation of
cumulative distances (Figure 4). A pronounced overexpression
of transcripts associated with neutrophils (M2.2: BPI, DEFA4,
CEACAM8), myeloid lineage cells (M2.6: PA1L2, FCER1G,
SIPA1L2), and erythrocytes (M2.3: ERAF, EPB49, MXI1) was
observed, together with the under-expression of modules
associated with ribosomal proteins (M2-4), T-cells (M2.8), and
cytotoxic cells (M2.1: CD8B1, CD160, GZMK). This set of
modules was similarly affected in septic patients belonging to R5,
but this time modules composed of interferon-inducible genes
(M3.1: IFITM1, PLAC8, IFI35) and genes related to inflammation
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(M3.2: ICAM1, STX11, BCL3; M3.3: ASAH1, TDRD9, SERPINB1)
were also overexpressed.

Pankla, R127.9–10 (emphasis added). Pankla summarizes:
Increased abundance of transcripts associated with innate
immune responses, including neutrophils, interferon,
inflammation, and myeloid lineage, together with under
expression of transcripts related to T-cells, B-cells, and cytotoxic
cells, indicated substantial dysregulation of the host immune
system in response to infection in those patients. This finding is
in line with a recent report that found over-expression of
transcripts corresponding to inflammation and innate immunity
in the blood of patients with sepsis, while the abundance of
transcripts related to adaptive immunity was decreased.

Id. at 127.10 (internal reference omitted). Pankla concludes:
In addition to providing valuable diagnostic information, blood
transcriptional assays that measure the host response to infection
could potentially serve to monitor disease progression and
response to treatment. A test combining such characteristics
would contribute to improvements in the management of sepsis.
In a context where medical care facilities could be quickly
overwhelmed, a test measuring the host response to infection
would facilitate early diagnosis and an evaluation of disease
severity, thus proving to be particularly valuable as a triage tool.

Id. at R127.17–18.
In summary, Both Ivey and Pankla teach that SIRS and sepsis may
form a spectrum of conditions with a diagnosis of SIRS as a potential
precursor to sepsis, both of which are diagnosed by clinically standardized
indicia. See, e.g., Pankla, 127.18. Both Ivey and Pankla teach well-
controlled studies indicating biomarkers for sepsis, with Ivey specifically
teaching a biomarker for sepsis that developed in patients diagnosed with
SIRS.
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Markoulatos teaches “[m]ultiplex polymerase chain reaction (PCR) is
a variant of PCR in which two or more target sequences can be amplified by
including more than one pair of primers in the same reaction. Multiplex
PCR has the potential to produce considerable savings of time and effort in
the laboratory.” Markoulatos, 47. Markoulatos particularly points to the
usefulness of multiplex PCR in the diagnosis of infectious diseases:
PCR has revolutionized the field of infectious disease diagnosis.
To overcome the inherent disadvantage of cost and to improve
the diagnostic capacity of the test, multiplex PCRs for the
detection of viral, bacterial, and/or other infectious agents in one
reaction tube have been developed. Efforts to enhance sensitivity
and specificity, and to facilitate automation have resulted in
numerous publications regarding the application of multiplex
PCR in the diagnosis of infectious agents, especially those which
target viral nucleic acids.

Id. at 50 (internal citation omitted). In short, Markoulatos would have
provided motivation to a skilled artisan to employ the technique with the
cDNAs taught by Ivey and Pankla for the diagnosis of sepsis.
With respect to the 2018 Brandon Declaration, we find that Appellant
has not demonstrated that Dr. Brandon’s testimony is sufficiently specific to
the teachings of the references cited by the Examiner, nor does Dr.
Brandon’s testimony specifically explain why the combination proposed by
the Examiner as the basis for this rejection would not have provided a skilled
artisan with a reasonable expectation of success.
First, Dr. Brandon cites references that caution the skilled artisan
against the difficulties of designating a specific biomarker as being related to
a specific disease state. The point is indeed well taken, but we find that a
person of ordinary skill in the art would have been aware of these warnings.
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Furthermore, as we have explained, both of the references cited as teaching
PLA2G7 and PLAC8, as biomarkers, Ivey and Pankla, respectively, include
clinical verification of their usefulness as such, and would suggest to a
person of ordinary skill in the art their combined use as sepsis biomarkers.
Dr. Brandon puts great emphasis on the difference between SIRS and
sepsis, however, both cited references expressly teach, as we have explained,
the potential relatedness of the two conditions and further teach that PLAC8
and PLA2G7 are biomarkers for sepsis in patients exhibiting symptoms of
SIRS. See, e.g., Ivey ¶ 98, Table 7; Pankla, R126.16, 18. More importantly,
we acknowledge Appellant’s point that the clinical contexts of Ivey and
Pankla are different and that not all instances of SIRS are indicative of
sepsis. Nevertheless, both studies are expressly directed to identifying
potential sepsis development among SIRS patients who may develop sepsis,
and identifying biomarkers among such patients, which may be indicative of
incipient sepsis.
Finally, Appellant argues that a person of ordinary skill in the art
would not be motivated to employ a multiplex PCR assay to screen for
biomarkers, because it is inherently unsuitable for biomarker discovery due
to the very low number of targets it can detect.
We find that Appellant’s position misunderstands the nature of the
claims. Both claims 1 and 31 recite compositions comprising already known
sepsis biomarkers, as taught by Ivey and Pankla. Markoulatos teaches a
method of multiplexing PCR that is suitable for employing probes for
multiple biomarkers. We agree with the Examiner that a person of ordinary
skill in the art would have been motivated to combine these references to
obtain a reliable diagnosis of sepsis by using the markers taught by Ivey and
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Pankla in the multiplexing PCR method of Markoulatos. This is particularly
so, since multiplexing PCR is practicable for a small number of biomarkers
(i.e., cDNAs) and Ivey an Pankla teach usable biomarkers for sepsis in SIRS
patients from which a person of ordinary skill could choose.
In summary, although we acknowledge the validity of certain of the
points made by Dr. Brandon’s testimony, we do not find that it is sufficient
to overcome the Examiner’s prima facie case of obviousness. See In re
American Academy of Science Tech Center, 367 F.3d 1359, 1370 (Fed. Cir.
2004) (holding that “the Board is entitled to give such weight to declarations
as it deems appropriate”).

Issue 2
Appellant argues that the evidence of record demonstrates that the
combination of PLAC8 and PLA2G7 provides unexpected results that are
greater than expected from the art and provide significant practical
advantages in distinguishing between inSIRS (“infection-negative SIRS” or
“sterile SIRS”) and sepsis (“infection positive SIRS” or “ipSIRS”). App. Br.
17–18.
Appellant points to paragraph 20 of the Declaration of Dr. Brandon,
filed March 2, 2017 (the “2017 Brandon Declaration”) and paragraph [0667]
and Figure 22 of Appellant’s Specification as establishing the effect on the
area under the curve (“AUC”) for separating sterile SIRS (i.e., sterile SIRS)
and infection-positive SIRS (i.e., sepsis) of adding biomarkers to the
diagnostic signature. App. Br. 18. Appellant notes that paragraph 20 of the
2017 Brandon Declaration also highlights that the diagnostic power shown
in Figure 22 significantly increases (adjusted p-value = 0.0175) between
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PLA2G7 (AUC of 0.88, 95% CI 0.79 - 0.97, which is the best performing
single biomarker) compared to the power of the two best performing
biomarkers in combination (in this instance PLA2G7 and PLAC8, AUC of
0.96, 95% CI 0.91 - 1.0). Id. Appellant therefore argues that the
combination of these two biomarkers provides unexpected and unparalleled
diagnostic power to robustly separate patients with sterile SIRS from those
with sepsis. Id.
Similarly, with respect to claim 31, Appellant submits that the
addition of CEACAM4 and LAMPI to the PLA2G7/PLAC8 combination
further elevates the diagnostic power of the assay to an AUC of 0.986, 95%
CI 0.964-1.00, which, Appellant contends is “unparalleled.” App. Br. 18.
Appellant also notes that the 2017 Brandon Declaration draws
attention to Appellant’s F.D.A. clearance for a product that uses RT-qPCR, a
ratio of PLAC8 and PLA2G7, and a ratio of CEACAM4 and LAMPI, to
assist clinicians in determining the probability of a patient having either
sepsis or SIRS (SeptiCyte™ LAB - Kl63260). App. Br. 18 (citing 2018
Second Brandon Declaration, filed October 9, 2018 ¶ 40, Ex. M).
According to Appellant, this is the first gene-expression-based, host-
immune-response sepsis diagnostic assay ever to gain FDA clearance. Id.
Appellant contends that the results of clinical trials using SeptiCyte™ LAB
have also been published as Miller III, R.R., Validation of a Host Response
Assay, SeptiCyte LAB, for Discriminating Sepsis from Systematic
Inflammatory Response Syndrome in the ICU, 198(7) AM. J. RESPIR. CRIT
CARE MED. 903–13 (2018) (“Miller”). Id. at 18–19 (citing 2018 Second
Brandon Decl. ¶ 40, Ex, N). Appellant contends that Miller includes as
authors over 20 key opinion leaders in the field of sepsis, none of whom are
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listed in the Pankla reference. Id. Appellant therefore argues that the
unexpected and improved properties of the claimed subject matters are
commensurate in scope with the claims, and that the secondary
considerations of non-obviousness are sufficient to rebut any assumed prima
facie case of obviousness. Id.
We are not persuaded. The gravamen of Appellant’s argument upon
this issue is that, with respect to claim 1, combining two reliable sepsis
biomarkers in a sepsis assay is unexpectedly more reliable as a diagnostic in
patients exhibiting SIRS than using a single biomarker. Similarly, Appellant
contends with respect to claim 31, the use of additional biomarkers for sepsis
further increases the reliability of sepsis detection and diagnosis.
Appellant provides no argument as to why improved performance in
sepsis detection as a result of increasing the biomarkers in the assay should
be unexpected. “To be particularly probative, evidence of unexpected
results must establish that there is a difference between the results obtained
and those of the closest prior art, and that the difference would not have been
expected by one of ordinary skill in the art at the time of the invention.”
Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977
(Fed. Cir. 2014). Pankla expressly teaches using differential screening
assays with multiple markers as a means of differential and sensitive
diagnostic screening. See Pankla, R127.15. Similarly, Ivey also employs
using multiple biomarkers in a screening assay to differentiate SIRS patients
who developed sepsis from those who did not. See Ivey ¶¶ 98–124, Tables
1–10. Quite apart from the commonsensical notion that using multiple
known biomarkers increases reliability, Appellant has made no express
comparisons between their results and those of the prior art, as required by
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Bristol-Myers, that is persuasive that any observed differences would be
differences of kind, rather than merely of degree, required to show
unexpected results. See In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005).
We are consequently not persuaded by Appellant’s arguments with respect
to the alleged unexpected results.

Issue 3
Appellant argues that the Examiner erred by impermissibly employing
hindsight reasoning. App. Br. 19.
Appellant contends that the Examiner’s suggestion that a person of
ordinary skill in the art would be motivated to assemble:
[A] composition comprising a mixture of: a DNA polymerase; a
sample of peripheral blood leukocyte cDNA from a subject with
a clinical sign of SIRS, comprising PLAC8 cDNA and PLA2G7
cDNA; oligonucleotide primers that hybridize to opposite
complementary strands of the cDNA; and an oligonucleotide
probe that is free in solution and hybridizes to the cDNA,
wherein the oligonucleotide probe comprises a fluorophore and
a quencher for real-time quantification of the cDNA

is hindsight reconstruction because the motivation is based on the
[Appellant’s] Specification, and not based on any suggestion present in the
prior art. App. Br. 19.
Appellant asserts that each of the cited references fails to disclose a
composition as defined in claim 1. App. Br. 20. Furthermore, argues
Appellant, the evidence of record establishes that a person of ordinary skill
in the art would not mix and match qualitatively different biomarkers from
the unrelated microarray based studies of Ivey and Pankla, which address
different clinical questions, nor would such a person use a multiplex PCR
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assay to screen for biomarkers as it is inherently unsuitable for biomarker
discovery because of the very low number of targets it can detect. Id.
Rather, argues Appellant, the evidence or record establishes that a person of
ordinary skill in the art would use a high throughput microarray based assay
to screen for biomarkers that are differentially expressed between different
patient populations to answer a clinically relevant question. Id.
Appellant contends that, without any clinically relevant question to
address, there is no problem to solve, and if there is no problem to solve,
there would be no motivation to combine the references, and if there is no
motivation to combine the references, the Examiner has engaged in
impermissible hindsight reconstruction of the claimed invention. App. Br.
20. According to Appellant, the Examiner has not even provided a credible,
clinically relevant question that would be addressed by the combined
detection of the Ivey and Pankla biomarkers. Id.
Furthermore, Appellant contends, Markoulatos and Peters, either
alone or in combination, fail to supply the requisite motivation to combine
the PLA2G7 biomarker of Ivey and the PLAC8 biomarker of Pankla in a
single composition for multiplex PCR. App. Br. 20.
We are not persuaded. As an initial matter, it is not necessary that a
single reference teach or suggest all of the limitations of the claimed
composition. See In re Keller, 642 F.2d 413, 425 (C.C.P.A. 1981).
Furthermore, we agree with the Examiner’s finding that the references
teach that the biomarkers recited in the claims are known to be associated
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with sepsis. The Examiner has expressly articulated reasoning why a skilled
artisan would have been motivated to combine the references:
Therefore[,] it would be prima facie obvious to one of ordinary
skill in the art to use the biomarkers of interest in Ivey and Pankla
et al in a multiplex composition as described by Markoulatos et
al. The ordinary artisan would have a reasonable expectation of
success as the prior art of Markoulatos et al. teaches that multiple
primers can be used in a composition with the intended result of
detection multiple regions of a sample and detection using
quencher and reporter as taught by Peters et al. The ordinary
artisan would be motivated to design such a composition to
screen multiple regions simultaneously.

Non-Final Act. 5.
It is not necessary for any or all of the references to teach or suggest
the motivation for combining the references; rather, the test for obviousness
is “what the combined teachings of the references would have suggested to
those of ordinary skill in the art.” Keller, 642 F.2d at 425. The Examiner
has articulated a reasonable rationale as to why a person of ordinary skill in
the art would have been motivated to combine the teachings of the cited
references and, as we have explained, we are not persuaded by Appellant’s
arguments that a skilled artisan would not have had a reasonable expectation
of success in combining the references.
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level of
ordinary skill at the time the claimed invention was made and
does not include knowledge gleaned only from applicant's
disclosure, such a reconstruction is proper.

In re McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A. 1971). We are not
persuaded by Appellant’s argument that the Examiner’s reasoning rests on
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knowledge that could have been gleaned only from Appellant’s
Specification. We consequently affirm the Examiner’s rejection of claim 1.

B. Claim 31
Appellant contends that the Examiner erred because the Examiner has
failed to demonstrate why a person of ordinary skill in the art would have
been motivated to combine the teachings of Ivey, Pankla, Markoulatos,
Peters, Brandon, and Hossain to arrive at the claimed invention. App. Br.
22.
Appellant acknowledges that the Examiner finds that CEACAM4 and
LAMPI were regions of interest in sepsis-associated patients. Id. (citing
Non-Final Act. 8–9). Appellant notes that the Examiner finds that Brandon
teaches that CEACAM4 can be used as a probe, and is associated with sepsis
and the use of peripheral blood in expression assays. Id. Appellant further
notes that the Examiner finds that Hossain teaches that LAMP1 can be used
as a probe, and is associated with sepsis and the detection in blood. Id.
Appellant repeats, and incorporates by reference, the arguments
presented supra with respect to claim 1, and argues that Brandon and
Hossain fail to remedy the deficiencies of Ivey, Pankla, Markoulatos, and
Peters. App. Br. 21. According to Appellant, the Examiner has again failed
to explain why a person of ordinary skill in the art would be motivated to use
a target-limited assay such as qPCR merely as a screening assay to detect
biomarkers from disparate studies exploring different clinical questions,
when the evidence of record teaches away and supports the opposite view.
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Id. Appellant contends that the evidence of record establishes that a person
of ordinary skill in the art would not mix and match qualitatively different
biomarkers from unrelated microarray based studies that address different
clinical questions. Id.
Nor, argues Appellant, would a skilled artisan use a multiplex PCR
assay to screen for biomarkers as it is inherently unsuitable for biomarker
discovery because of the very low number of targets it can detect. App. Br.
21. Rather, Appellant asserts, the evidence or record establishes that a
person of ordinary skill in the art would use a high throughput microarray
based assay to screen for biomarkers that are differentially expressed
between different patient populations to answer a clinically relevant
question. Id. In this respect, contends Appellant, the Examiner has not
provided a credible, clinically relevant question that would be addressed by
the combined detection of the Ivey, Pankla, Brandon, and Hossain
biomarkers. Id.
We again do not find Appellant’s arguments persuasive. We remind
Appellant that both claim 1 and 31 are directed to compositions, and not to
methods of performing a specific type of assay. Moreover, although the
references may teach the various biomarkers being identified in different
clinical contexts, all of the contexts are such that the specific biomarker in
each reference is identified as being a biomarker indicating sepsis, or the
possible development of sepsis, particularly in individuals exhibiting
symptoms of SIRS. For example, Brandon teaches:
[M]ethods and apparatus for diagnosis, detection of host
response, monitoring, treatment or management of sepsis,
infection-negative systemic inflammatory response syndrome
(SIRS) and post-surgical inflammation in mammals. More
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particularly, the present invention discloses marker genes and
their splice variant transcripts as well as their expression
products, which are useful for distinguishing between sepsis and
infection-negative SIRS, including postsurgical inflammation,
and to the use of these markers in grading, monitoring, treatment
and management of these conditions.

Brandon, Abstr. Brandon continues “[t]he invention has practical use in
early diagnosis, diagnosis of mild or sub-clinical sepsis or infection-negative
SIRS or post-surgical inflammation, in the detection of specific cell immune
responses as part of active or progressive disease.” Id. at ¶ 1. Brandon
includes CEACAM4 among such markers. See, e.g., id. at ¶¶ 26, 27, 117,
164.
Similarly, Hossain teaches “a procedure for the generation and
evaluation of expression profiles of a specific group of genes, in order to
determine the chance for a sepsis or septic states in the blood sample of a
patient.” Hossain ¶ 1. Hossain teaches that “[t]he procedure according to
the present invention for the diagnosis of sepsis and/or septic states in the
blood of patients with infections allows a considerably earlier detection of
the disease than possible using clinical criteria.” Id. at ¶ 28. In this method,
RNA is extracted from drawn blood samples and “[ex]pression profiles are
established using genes which were, after analysis of clinical, laboratory and
genomic data, recognized as highly relevant for the prediction of sepsis.” Id.
at ¶ 28. Hossain identifies LAMP1 as one such gene, the expression of
which was differentially expressed genes polytraumatized patients with
sepsis, versus a control group of polytraumatized patients without sepsis, 24
hours after admission to hospital. Hossain ¶ 111, Table 1.
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Summarizing, the cited references are directed to identifying
biomarkers for sepsis, particularly in patients exhibiting symptoms of SIRS
who are potentially in danger of developing sepsis. Moreover, by using a
small group of established biomarkers, the assay method taught by
Markoulatos suggests a rapid and inexpensive identification of such
biomarkers. We conclude that the Examiner has established a prima facie
case that the claims are obvious over the cited prior art, and that Appellant
has failed to overcome this prima facie case. We consequently affirm the
Examiner’s rejection of claims 1 and 31.

CONCLUSION
The rejection of claims 1 and 31 as unpatentable under 35 U.S.C.
§ 103 is affirmed.

AFFIRMED

Claim(s)
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1 103 Ivey, Pankla,
Markoulatos, Peters
1
31

103 Ivey, Pankla,
Markoulatos, Peters,
Brandon, Hossain
31
Overall
Outcome

1, 31