Markus Kostrzewa et al.

Patent Trials and Appeals Board

Jul 17, 2020

13582372 - (D) (P.T.A.B. Jul. 17, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/582,372 12/26/2012 Markus Kostrzewa 1138-0045 8385
50811 7590 07/17/2020
O''''Shea Getz P.C.
10 Waterside Drive, Suite 205
Farmington, CT 06032
EXAMINER
PATURY, SRIKANTH
ART UNIT PAPER NUMBER
1657
NOTIFICATION DATE DELIVERY MODE
07/17/2020 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):
shenry@osheagetz.com
uspto@osheagetz.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MARKUS KOSTRZEWA,
KARSTEN MICHELMANN, and KATRIN SPARBIER
Appeal 2020-001611
Application 13/582,372
Technology Center 1600
Before RICHARD M. LEBOVITZ, FRANCISCO C. PRATS, and
TAWEN CHANG, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1, 3–12, 14, and 17–23. We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as Bruker
Daltonik GmbH. Appeal Br. 3.
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STATEMENT OF THE CASE
“[A]ntibiotic resistance categorizes characteristics of microorganisms
. . . which allow them to weaken or completely neutralize the effect of
antibiotically active substances.” Spec. ¶ 8. “An important type of bacteria
resistance to ß-lactam[ antibiotics, such as penicillin,] consists in the
formation of enzymes (ß-lactamases), which catalytically break open the ß-
lactam ring by hydrolysis and thus render it ineffective.” Id. ¶¶ 10–11.
According to the Specification, “[t]he invention provides a method whereby
a microbial resistance due to ß-lactamases can be very easily and quickly
measured with a mass spectrometer.” Id. ¶ 20. More particularly, the
Specification states that the method of the invention determines the
resistance of the bacteria by making a “direct mass spectrometric
measurement” after bringing the bacteria together with an appropriate
substrate (i.e., a ß-lactam antibiotic or derivative), wherein “hydrolytic
attack of the ß-lactamases on the substrate” would lead to a decrease in the
amount of the substrate and the appearance of the hydrolyzed cleavage
product. Id.
CLAIMED SUBJECT MATTER
The claims are directed to a method for the determination of a ß-
lactam resistance of microbes. Claim 1 is illustrative:
1. Method for the determination of a ß-lactam resistance of
microbes based on the production of ß-lactamases by the
microbes, comprising bringing the microbes together with a
substrate in a solution, the solution is partly applied onto a mass
spectrometric support, and the enzymatic breakdown of the
substrate by the ß-lactamases of the microbes is measured mass
spectrometrically by acquiring a mass spectrum of the
remaining substrate and the breakdown product using a time of
flight mass spectrometer with ionization by matrix-assisted
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laser desorption, wherein the molecules of the substrate
comprises a ß-lactam ring.
Appeal Br. 14 (Claims App.).
REJECTION(S)
A. Claims 1, 3, 8, 11, 12, 14, and 17–23 are rejected under pre-AIA 35
U.S.C. § 103(a) as being unpatentable over Citri,2 Yazawa,3 Lidgard,4
Liesener,5 and Saves,6 as evidenced by Kitchen.7 Ans. 4.
B. Claims 1, 3, 4, 6–8, 11, 12, 14, and 17–23 are rejected under pre-AIA
35 U.S.C. § 103(a) as being unpatentable over Citri, Yazawa, Lidgard,
Liesener, Saves, Dargis,8 and Thermo Scientific.9 Ans. 7.

2 Citri, US 2011/0245105 A1, published Oct. 6, 2011.
3 Katsukiyo Yazawa et al., Inactivation of Kanamycin A by Phosphorylation
in Pathogenic Nocardia, 35 MICROBIOLOGY & IMMUNOLOGY 39 (1991).
4 Ray Lidgard & Mark W. Duncan, Utility of Matrix-assisted Laser
Desorption/Ionization Time-of-flight Mass Spectrometry for the Analysis of
Low Molecular Weight Compounds, 9 RAPID COMM. IN MASS
SPECTROMETRY 128 (1995).
5 André Liesener & Uwe Karst, Monitoring Enzymatic Conversions by Mass
Spectrometry: A Critical Review, 382 ANALYTICAL & BIOANALYTICAL
CHEMISTRY 1451 (2005).
6 Isabelle Saves et al., Mass Spectral Kinetic Study of Acylation and
Deacylation during the Hydrolysis of Penicillins and Cefotaxime by ß-
Lactamase TEM-1 and the C238S Mutant, 34 BIOCHEMISTRY 11660 (1995).
7 D. K. Kitchen & C. R. Rein, Time-Dosage Relation in Penicillin Therapy
with Special Reference to Yaws, 8 BULL. WORLD HEALTH ORG. 77 (1953).
8 M. Dargis & F. Malouin, Use of Biotinylated ß-Lactams and
Chemiluminescence for Study and Purification of Penicillin-Binding
Proteins in Bacteria, 38 ANTIMICROBIAL AGENTS & CHEMOTHERAPY 973
(1994).
9 Thermo Scientific, Overview of Affinity Purification, INTERNET ARCHIVE:
WAYBACK MACHINE (Jan. 14, 2010)
http://web.archive.org/web/20100114044337/http://piercenet.com/browse.cf
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C. Claims 1, 3, 5, 8–12, 14, and 17–23 are rejected under pre-AIA 35
U.S.C. § 103(a) as being unpatentable over Citri, Yazawa, Lidgard,
Liesener, Saves, and Neu.10 Ans. 8.

OPINION
A. Issue
The same issue is dispositive for all of the rejections; we therefore
discuss them together. With respect to claim 1, the Examiner finds that Citri
teaches “methods of detection of the resistance profiles of bacteria by
directly determining hydrolysis [products] of ß-lactam antibiotic substrate in
a test sample.” Ans. 4. Thus, Citri teaches a “[m]ethod for the
determination of a ß-lactam resistance of microbes based on the production
of ß-lactamases by the microbes, comprising bringing the microbes together
with a substrate . . . compris[ing] a ß-lactam ring” and measuring “the
enzymatic breakdown of the substrate by the ß-lactamases of the microbes,”
as recited in claim 1.
Although Citri does not discuss determining ß-lactam resistance using
a “time of flight mass spectrometer with ionization by matrix-assisted laser
desorption” as recited in claim 1, the Examiner finds Lidgard teaches that
MALDI-TOF (Matrix-Assisted Laser Desorption Ionization — Time of
Flight) mass spectrometry, in which “the sample to be analyzed is applied to

m?fldID=E9F29426-E119-45F2-9625-8A5296BF3E92 (accessed April 30,
2013).
10 Harold C. Neu, Structure-Activity Relations of New ß-Lactam Compounds
and in Vitro Activity Against Common Bacteria, 5 REV. INFECTIOUS
DISEASES S319 (1983).
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a support matrix . . . and mass spectrometric peaks are measured with a
laser,” is “a simple, rapid and inexpensive technique to monitor low-
molecular weight compounds including antibiotics.” Id. at 4–5. The
Examiner also finds that Yazawa teaches that “bacteria inactivate antibiotics
by enzymatically modifying antibiotics” and further teaches “monitoring the
parent antibiotic and the modified antibiotic using mass spectrometry and
NMR of cell free extracts.” Id. at 5.
The Examiner concludes that it would have been obvious to a skilled
artisan to modify Citri’s method of determining bacterial resistance to ß-
lactam antibiotics via detection of the hydrolysis products of ß-lactam
substrates in a test sample, by using MALDI mass spectrometry to detect
such hydrolysis products, as suggested by Yazawa and Lidgard. Ans. 5.
The Examiner finds that a skilled artisan would have been motivated to
make the proposed modification to Citri because the modification merely
“substitut[es] one known method of detecting small molecules with another
to yield predictable results.” Id. The Examiner notes that the result of the
modification would have been predictable because Lidgard teaches that
“low-molecular weight compounds including antibiotics can be detected
using MALDI mass spectrometry,” and Saves teaches using mass
spectrometry “to kinetically detect hydrolysis of lactam based antibiotics . . .
after they are hydrolyzed by lactamases.” Id.
With respect to the limitation of “acquiring a mass spectrum of [both]
the remaining substrate and the breakdown product,” as recited in claim 1,
the Examiner finds that Yazawa teaches “monitoring the parent antibiotic
and the modified inactivated antibiotic in an NMR spectra” and Liesener
teaches “monitoring enzymatic conversions of substrates using mass
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spectrometry,” monitoring “low-molecular weight products and substrates
. . . using MALDI-TOF,” and “monitoring both substrate and product
concentrations.” Ans. 5–6.
The Examiner concludes that it would have been obvious to a skilled
artisan, when using the method rendered obvious by the combination of
Citri, Yazawa, and Lidgard, “to acquire the spectrum of the parent substrate
and/or the hydrolysis (enzymatic) products as taught by Yazawa/Liesener,”
because in doing so the skilled artisan is merely “combining prior art
elements according to known methods.” Ans. 6.
Appellant argues that none of the references teach or suggest
“detecting break down products of beta-lactam antibiotics using MALDI
mass-spectrometry.” Appeal Br. 11. Appellant argues that “it would not be
obvious to a person skilled in the art that break down products of beta-
lactam antibiotics can be detected using MALDI mass-spectrometry, even if
the beta-lactam antibiotics can be detected,” because “as known to a person
of ordinary skill in the art, the breakdown products are chemically modified
so that they are not automatically charged during the ionization process used
in the spectrometric measurement.” Id.
The same issues are dispositive for all of the rejections. We therefore
discuss them together. Similarly, Appellant does not separately argue the
claims. We therefore focus our analysis on claim 1 as representative. The
issue with respect to the rejections is whether the combination of Citri,
Yazawa, Lidgard, Liesener, and Saves would have suggested to a skilled
artisan the limitation of “acquiring a mass spectrum of . . . the breakdown
product using a time of flight mass spectrometer with ionization by matrix-
assisted laser desorption [(MALDI)],” as recited in claim 1.
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B. Findings of Fact
1. Citri teaches that “[b]eta-lactamases are bacterial enzymes that
inactiv[ate] beta-lactam antibiotics by hydrolysis of the beta-lactam bond.”
Citri ¶ 6.
2. Citri teaches “methods . . . for the rapid and direct detection of
beta-lactam resistant bacteria in a test sample . . . by directly determining
hydrolysis product/s of beta-lactam antibiotic substrates in the tested
sample.” Id. at Abstract.
3. Lidgard teaches that “[m]atrix-assisted laser
desorption/ionization (MALDI) combined with time-of-flight (TOF) mass
spectrometry has found general acclaim as an approach to synthetic and bio-
polymer analysis.” Lidgard 128.
4. Lidgard examines “[a] range of low molecular weight
compounds (<800 Da) . . . by matrix-assisted laser desorption time-of-flight
mass spectrometry to demonstrate the general analytical utility of this
technique. The compound classes investigated included: . . . antibiotics
. . . .” Id. at Abstract.
5. Lidgard teaches preparing samples of the antibiotics ampicillin,
a ß-lactam, and tetracycline to be analyzed using MALDI spectrometry,
using dichloromethane as a solvent and cyano-4-hydorxycinnamic acid
(4HCCA) and dihydroxybenzoic acid (DHB) as matrices. Id. at 128–129.
6. Lidgard teaches that, “[i]n all instances the ions detected could
be assigned, and excellent agreements between calculated and experimental
mass values were obtained.” Id. at Abstract; see also id. at Tables 1 and 2.
7. Lidgard teaches that its studies demonstrate that “a linear
MALDI-TOF system can provide reliable molecular weight information on a
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diverse selection of analytes,” that “the majority of compounds give
interpretable data,” that “most compound types generate a stable ion related
to the molecular ion,” and that “MALDI is a reproducible, sensitive and
reliable analytical tool.” Id. at 132.
8. Lidgard teaches that, based on its findings, “MALDI-TOF is a
possible substitute for chemical ionization and FAB mass spectrometry in
the routine chemical analysis laboratory.” Id.
9. Liesener teaches that “the demand for a label-free, non-
radioactive assay scheme [for enzymatic activities] is high.” Liesener 1452.
Liesener further teaches advantages of mass spectroscopy include that (1)
“no modification [of the analyte] is required and the native substrates may
be applied for enzyme assays” and (2) it may be possible “to simultaneously
monitor the fate of multiple analytes during an enzyme-catalysed reaction.”
Id.; see also id. at Abstract (teaching that “[i]ts applicability for monitoring
the conversion of naturally occurring substrates and its overall versatility
make MS an especially promising tool for the study of enzyme-catalysed
processes”).
10. Liesener teaches that “[s]everal approaches using MALDI-MS
for the monitoring of enzymatic conversions have been reported.” Id. at
1456.
11. In particular, Liesener describes a prior art “high-throughput
protocol for the automated determination of enzymatic activities by MALDI-
MS” that adds a deuterium-labelled substrate to the matrix as an internal
standard to achieve reliable quantification. Id. at 1457.
12. Liesener further describes a prior art “MALDI-MS-based assay
scheme for the quantification of low molecular weight products and
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substrates directly from the reaction mixtures,” wherein “[t]ime-resolved
reaction profiles for [glucose oxidase-based conversion of glucose to
gluconolactone and carboxypeptidase A-mediated cleavage of hippuryl-L-
phenylalanine] were obtained by simultaneous determination of the
respective substrate and product concentrations without the need for time-
consuming sample preparation steps,” as well as a refinement of the scheme
wherein MALDI-MS “was applied to screen the enzymatic activity of ten
pyranose oxidase variants towards glucose” by “generating reaction profiles
by the simultaneous determination of product and substrate concentrations
for each enzyme variant.” Id. Liesener teaches that the latter study “clearly
shows the suitability of the MALDI-MS-based assay schemes for . . .
application in rapid, enzyme activity screening procedures.” Id.
13. Yazawa teaches that the resistance of certain Nocardia species
to an aminoglycoside antibiotic, kanamycin A, results from the bacteria’s
production of the enzyme aminoglycoside 3’-phosphotransferase APH(3’).
Yazawa Abstract.
14. Yazawa teaches using “[s]tructural studies by mass and NMR
[(nuclear magnetic resonance)] spectroscopy on the inactivated substance
produced by a cell-free extract of the Nocardia [to] confirm[] the conversion
of kanamycin A to an inactive substance, kanamycin A 3’-phosphate,”
wherein the inactive substance was obtained by combining kanamycin with
the cell-free extract. Yazawa Abstract, 40–41 (Materials and Methods).
15. Yazawa teaches that “[a] fast atom bombardment (FAB) mass
spectrum of the inactivated substance showed a 565 (M+H) peak, suggesting
a molecular ion peak of phosphorylated kanamycin A,” and further teaches
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using two-dimensional NMR analyses “to make definitive assignments of
kanamycin A and its phosphate derivative.” Id. at 44; see also id. at Fig. 3.
16. Saves teaches that “[t]he production of ß-lactamase . . . is the
major mechanism used by Gram-negative bacteria to develop resistance to
ß-lactam antibiotics.” Saves 11660.
17. Saves teaches “[a] method to determine the elementary rate
constants of hydrolysis . . . based on electrospray mass spectrometry
(ESMS) and UV spectrophotometry,” in order to study “[t]he effect of th[e]
ß-lactamase amino acid mutation [G238S] on acylation and deacylation
steps . . . with both penicillins and cefotaxime” and better “understand the
global effect of the G238S substitution on the hydrolysis of B-lactams.” Id.
18. In particular, Saves teaches that “[e]nzymatic reactions were
carried out . . . by mixing the enzyme solution . . . with an aqueous solution
of antibiotic and quenched after various times,” that “[r]eaction mixtures
were directly introduced into the electrospray source,” that acylation and
deacylation rate constants were determined by quantitative evaluation of the
acyl-enzyme (i.e., reaction intermediate), and that “[t]he acyl-enzyme
concentration . . . [was] determined by the initial enzyme concentration and
the evaluation of the ratio of free enzyme to acyl-enzyme in solution by
electrospray mass spectrometry.” Id. at 11662–63; see also id. at Figs. 1 &
2, 11665.
19. Saves teaches that monitoring the antibiotic (e.g., oxacillin,
cloxacillin, and cefotaxime) and their hydrolysis product(s) “provided a way
to follow the course of the [ß-lactamase enzymatic] reaction.” Id. at 11662;
see also id. at 11663–64, Figs. 3 & 4.
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C. Analysis
Citri teaches that ß-lactamase, a bacterial enzyme, confers resistance
to ß-lactam antibiotics by inactivating such antibiotics through the
hydrolysis of the ß-lactam bond. FF1. Citri further teaches determining the
ß-lactam resistance of a microbe by determining whether the microbe
produces ß-lactamase, which is in turn determined by “bringing the microbe
together with a substrate . . . compris[ing] a ß-lactam ring” and detecting the
hydrolysis product(s) of a ß-lactam antibiotic (i.e., measuring “the enzymatic
breakdown of the substrate by the ß-lactamase,” as recited in claim 1). FF2.
We agree with the Examiner that, in light of Yazawa, Lidgard,
Liesener, and Saves, it would have been prima facie obvious to a skilled
artisan to detect the hydrolysis product(s) of a ß-lactam antibiotic, as
discussed in Citri, by using “a time of flight mass spectrometer with
ionization by matrix-assisted laser desorption” (i.e., MALDI-TOF) to
“acquir[e] a mass spectrum of the remaining [ß-lactam] substrate and the
breakdown product,” as recited in claim 1.
Specifically, Yazawa, Liesener, and Saves all teach using mass
spectrometry to monitor enzymatic reactions by detecting the breakdown
product and the initial enzyme substrate. FF9–FF12, FF14, FF15, FF17–
FF19. Yazawa and Saves in particular teach the use of mass spectrometry to
monitor bacterial enzymatic reactions that confer resistance to certain
antibiotics, FF13–FF19, with Saves even more particularly teaching the use
of mass spectrometry to analyze the hydrolysis of ß-lactam antibiotics by ß-
lactamase. FF16–FF19. With respect to the recited use of MALDI-TOF,
Liesener specifically discusses the use of MALDI mass spectrometry for
monitoring enzymatic conversions, FF10, FF12, and Lidgard, another
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reference in the prior art combination cited by the Examiner, teaches that
MALDI-TOF has general analytical utility for detecting low molecular
weight compounds, including antibiotics such as ampicillin, a ß-lactam.
FF4–FF8.
In short, using MALDI-TOF to determine the presence of ß-lactamase
in a microbe sample by combining the sample with a ß-lactam substrate and
then acquiring a mass spectrum of the ß-lactam and the breakdown product
of the enzymatic reaction is no more than using a known “technique” for its
“predictable” and “established function[ ],” which the Supreme Court has
held is “is obvious unless its actual application is beyond” the skill of one of
ordinary skill in the art. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417
(2007). Appellant has not argued that the claimed subject matter yielded any
unexpected results.
A skilled artisan also would have had further reason to combine Citri
and Yazawa, Liesener, Saves and Lidgard to arrive at the invention of claim
1, with a reasonable expectation of success, by bringing a microbe sample
together with a ß-lactam substrate in solution and then using MALDI-TOF
to acquire mass spectrum of breakdown products and the remaining
substrate. Liesener, for example, teaches that mass spectroscopy provides
certain advantages in assaying enzymatic activities, namely that no
modification of the analyte is required and native substrates may be used,
and that multiple analytes may be monitored simultaneously. FF9.
Similarly, Lidgard teaches that MALDI-TOF is “a reproducible, sensitive
and reliable analytical tool” that “can provide reliable molecular weight
information on a diverse selection of analytes.” FF7.
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Appellant contends that “the combination of Yazawa and Lidgard
[does not] teach[] analyzing the hydrolysis of antibiotic substrates using
MALDI mass spectrometry.” Appeal Br. 10. In particular, Appellant
contends that Yazawa only teaches acquiring a spectrum using fast atom
bombardment mass spectrometry and nuclear magnetic resonance, not
MALDI mass spectrometry, and also does not teach monitoring both the
enzyme substrate and the breakdown products of an enzymatic reaction
using mass spectrometry. Id. Appellant contends that Lidgard only teaches
using MALDI mass spectrometry to acquire a spectrum of a ß-lactam
antibiotic and does not teach “detecting breakdown products of the
antibiotics using MALDI mass-spectrometry or monitoring breakdown
products and the remaining substrate.” Id. Appellant further argues that
Saves “teaches using electrospray mass spectrometry for detecting
hydrolyzed beta-lactam antibiotics” but “neither teaches detecting the
antibiotics . . . or . . . break down products . . . using MALDI.” Id.
Appellant contends that, without “a proper teaching” or the claimed
feature of “detecting break down products of beta-lactam antibiotics using
MALDI mass-spectrometry,” “it would not be obvious to a person skilled in
the art that break down products of beta-lactam antibiotics can be detected
using MALDI mass-spectrometry, even if the beta-lactam antibiotics can be
detected,” because “the breakdown products are chemically modified so that
they are not automatically charged during the ionization process used in the
spectrometric measurement.” Id. at 11.
We are not persuaded. We agree with the Examiner that Appellant’s
arguments attack references individually, which cannot establish non-
obviousness where the rejection is based upon the teachings of a
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combination of references. In re Merck & Co., 800 F.2d 1091, 1097 (Fed.
Cir. 1986). As discussed above, the references, when read in combination,
suggest using MALDI-TOF mass spectrometry to monitor the activity of
microbial ß-lactamase enzymes by acquiring spectrum of ß-lactam substrates
and breakdown products when microbes are brought together with ß-lactam
substrates.
Neither are we persuaded by Appellant’s apparent argument that a
skilled artisan would not have had a reasonable expectation of success of
using MALDI-TOF to detect breakdown products even if prior art teaches
that ß-lactam antibiotics themselves can be detected. Appeal Br. 11.
Our reviewing court has explained that “expectation of success need
only be reasonable, not absolute.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1364 (Fed. Cir. 2007). In this case, Lidgard teaches that MALDI-TOF
is generally useful as an analytical tool for low molecular weight compounds
such as antibiotics. FF4–8. Liesener teaches that MALDI mass
spectrometry is able to detect both the substrate and the product of several
enzyme-mediated reactions. FF12. Yazawa and Saves both teach that other
types of mass spectrometry (fast atom bombardment mass spectrometry and
electrospray mass spectrometry, respectively) are capable of acquiring
spectrums of enzymatic reaction products, including in the case of Saves the
hydrolysis product(s) of ß-lactam antibiotics such as oxacillin and
cloxacillin. FF14, FF15, FF18, FF19. We find that these disclosures would
have provided a skilled artisan with a reasonable expectation of success of
using MALDI-TOF to detect the breakdown products of ß-lactam antibiotics
as a result of its hydrolysis by ß-lactamase. Neither has Appellant provided
persuasive evidence that a skilled artisan would not have reasonably
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expected the products of ß-lactam hydrolysis to be detectable by MALDI-
TOF mass spectrometry. “Attorneys’ argument is no substitute for
evidence.” Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989).
In the Reply Brief, Appellant argues that the arguments in the Appeal
Brief did not separately attack individual prior art references but rather
“includes technical rationale/reasoning regarding why a skilled person
would not combine the references as the Examiner contends.” Reply Br. 1–
2.
We are not persuaded. As an initial matter, Appellant’s arguments
with respect to Yazawa and Lidgard in the Appeal Brief were explicitly
made while “[a]ssuming . . . without admitting that Citri, Yazawa, Lidgard,
Liesener, and Saves are combinable.” Appeal Br. 10. Neither did Appellant
address all of the references cited in the combination. For example,
Appellant failed to discuss Liesener, which uses MALDI mass spectrometry
to monitor enzymatic conversions by detecting enzyme substrates and
products.
More importantly, even assuming Appellant timely raised arguments
regarding the lack of motivation to combine, we agree with the Examiner
that a skilled artisan would have had reason to combine the cited prior art
references to arrive at the invention of claim 1, for the reasons already
discussed.
Appellant argues in the Reply Brief that, while “[t]he Examiner is
contending because NMR and mass spectrometry are both known that a
skilled person would have modified Yazawa based upon the teaching in
Lidgard to replace NMR with mass spectrometry,” “[a] skilled person in the
art at the time of the . . . invention would NOT look to Yazawa because it
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teaches NMR” and there is no teaching of record suggesting that “a skilled
person would replace the NMR in Yazawa with the mass spectrometry of
Lidgard.” Reply Br. 2. Appellant argues that, accordingly, the Examiner
has failed to provide an articulated reasoning with some rational
underpinning to support the legal conclusion of obviousness. Id. at 2–3.
Once again, however, Appellant fails to address the combination of
the prior art cited in the rejection. As an initial matter, Yazawa also teaches
using fast atom bombardment (FAB) mass spectrometry (in addition to
NMR) to detect an antibiotic inactivated by bacterial enzyme, and Lidgard
teaches that MALDI-TOF is a possible substitute for FAB mass
spectrometry. FF8, FF13–FF15.11 Moreover, Appellant fails to address
Liesener, which as the Examiner points out teaches that MALDI mass
spectrometry may be used to monitor enzymatic conversions by detecting
both the substrate and the product from the conversion. Ans. 5–6, 10; FF10,
FF12.
Accordingly, Appellant does not persuade us that the Examiner failed
to establish a prima facie case of obviousness, and we affirm the Examiner’s
rejection of claim 1 as obvious over the combination of Citri, Yazawa,
Lidgard, Liesener, and Saves, as evidenced by Kitchen. Claims 3, 8, 11, 12,
14, and 17–23 are not separately argued and fall with claim 1. See 37 C.F.R.

11 Appellant contends that “the Examiner is improperly using the
Applicant’s specification to support his obviousness rejections.” Reply Br.
3. To the extent the Examiner’s rejection is based on statements in the
Specification suggesting that different types of mass spectrometry are
functionally equivalent to MALDI-TOF in detecting the breakdown products
of ß-lactam antibiotics, we disagree with that portion of the rejection and do
not rely on such statements in the Specification in affirming the rejection.
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§ 41.37(c)(1)(iv). Likewise, Appellant makes no additional arguments with
respect to the rejections over the combination of Citri, Yazawa, Lidgard,
Liesener, Saves, and either Dargis and Thermo Scientific or Neu. We
therefore affirm those rejections for the same reasons.

CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/
Basis
Affirmed Reversed
1, 3, 8, 11,
12, 14, 17–23
103(a) Citri, Yazawa,
Lidgard,
Liesener,
Saves,
Kitchen
1, 3, 8, 11,
12, 14, 17–23

1, 3, 4, 6–8,
11, 12, 14,
17–23
103(a) Citri, Yazawa,
Lidgard,
Liesener,
Saves, Dargis,
Thermo
Scientific
1, 3, 4, 6–8,
11, 12, 14,
17–23

1, 3, 5, 8–12,
14, 17–23
103(a) Citri, Yazawa,
Lidgard,
Liesener,
Saves, Neu
1, 3, 5, 8–12,
14, 17–23

Overall
Outcome
1, 3–12, 14,
17–23

Appeal 2020-001611
Application 13/582,372

18
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