Ex Parte Pentyala

Board of Patent Appeals and Interferences

Mar 2, 2011

11516385 (B.P.A.I. Mar. 2, 2011)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte SRINIVAS N. PENTYALA
__________

Appeal 2010-007616
Application 11/516,385
Technology Center 1600
__________

Before DEMETRA J. MILLS, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL1

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
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This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s rejection of claims 4, 5, 7-9, 12, and 13. 2 We have jurisdiction
under 35 U.S.C. § 6(b).

STATEMENT OF THE CASE
Claim 4 is representative of the claims on appeal, and read as follows:
4. A device for detection of the presence or absence of cerebrospinal
fluid in a sample from a human subject, comprising
an absorbent membrane comprising:
a sample zone comprising a first purified monoclonal antibody
to lipocalin-type prostaglandin D2 synthase (L-PGDS), said first
purified monoclonal antibody conjugated to a mobile particle, wherein
the first purified monoclonal antibody is suitable for specifically
detecting the presence or absence of an L-PGDS antigen, and wherein
the purified monoclonal antibody binds to native and denatured L-
PGDS antigen;
a second zone comprising a fixed antibody to lipocalin-type
prostaglandin D2 synthase,
wherein the presence of a detectable band in the second region
indicates the presence of cerebrospinal fluid in the sample from the
human subject.

The following grounds of rejection are before us for review:
I. Claims 4, 5, 7, 8, 12, and 13 stand rejected under 35 U.S.C.
§ 103(a) as being rendered obvious by the combination of May,3
Bachmann,4 Harlow,5 and Nagata.6

2 Claims 14-20 are also pending, but stand withdrawn from consideration.
(App. Br. 2.)
3 May et al., US 5,602,040, Feb. 11, 1997.
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II. Claims 4, 5, 7, 8, 12, and 13 stand rejected under 35 U.S.C.
§ 103(a) as being rendered obvious by the combination of
Remington,7 Bachmann, Harlow, and Nagata.
III. Claim 9 stand rejected under 35 U.S.C. § 103(a) as being rendered
obvious over the combination of May or Remington and
Bachmann, Harlow, and Nagata, as further combined with Davis.8
IV. Claims 4, 12, and 13 stand provisionally rejected on the ground of
nonstatutory obviousness-type double patenting as being
unpatentable over claims 1-11 of copending Application No.
12/102,091 as combined with Harlow and Nagata.
V. Claims 5, 7, and 8 stand provisionally rejected on the ground of
nonstatutory obviousness-type double patenting as being
unpatentable over claims 1-11 of copending Application No.
12/102,091 as combined with Harlow and Nagata, and as further
combined with May.
VI. Claim 9 stands provisionally rejected on the ground of
nonstatutory obviousness-type double patenting as being
unpatentable over claims 1-11 of copending Application No.

4 Bachmann et al., Predictive Values of β-Trace Protein (Prostaglandin D
Synthase) by Use of Laser-Nephelometry Assay for the Identification of
Cerebrospinal Fluid, 50 NEUROSURGERY 571-577 (2002).
5 Ed Harlow and David Lane, ANTIBODIES: A LABORATORY MANUAL 54-61,
72-74, 124, 153, 173-174, 474-478 (Cold Spring Harbor Laboratory Press
1988).
6 Nagata, US 2002/0141997 A1, Oct. 3, 2002.
7 Remington et al., US 2004/0002168 A1, Jan. 1, 2004.
8 Davis et al., US 6,352,862 B1, Mar. 5, 2002.
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12/102,091 as combined with Harlow and Nagata, and as further
combined with Davis.
As Appellant does not present any arguments as to rejections IV, V,
and VI, we summarily affirm those rejections. We also affirm Rejections I,
II, and III for the reasons set forth below.

PRINCIPLES OF LAW
Obviousness is determined in from the context of a person of ordinary
skill in the art at the time the invention was made. “[T]he level of skill in
the art is a prism or lens through which a judge, jury, or the Board views the
prior art and the claimed invention. This reference point prevents these
factfinders from using their own insight or, worse yet, hindsight, to gauge
obviousness.” Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001)
(citation omitted). Therefore, the evidence of record must be viewed
through the lens of a person of ordinary skill in the art with consideration of
common knowledge and common sense. Graham v. John Deere, 383 U.S.
1, 17-18 (1966); DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H.
Patrick Co., 464 F.3d 1356, 1367 (Fed. Cir. 2006).
Therefore, it is proper to “take account of the inferences and creative
steps that a person of ordinary skill in the art would employ.” KSR Int’l Co.
v. Teleflex Inc, 550 U.S. 398, 418 (2007). See also id. at 421 (“A person of
ordinary skill is also a person of ordinary creativity, not an automaton.”).
“In determining whether obviousness is established by combining the
teachings of the prior art, the test is what the combined teachings of the
references would have suggested to those of ordinary skill in the art.” In re
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GPAC Inc., 57 F.3d 1573, 1581 (Fed. Cir. 1995) (internal quotations
omitted). Similarly, “[I]f a technique has been used to improve one device,
and a person of ordinary skill in the art would recognize that it would
improve similar devices in the same way, using the technique is obvious
unless its actual application is beyond his or her skill.” KSR, 550 U.S. at
417.
One way for a patent applicant to rebut a prima facie case of
obviousness is to make a showing of “unexpected results,” i.e.,
to show that the claimed invention exhibits some superior
property or advantage that a person of ordinary skill in the
relevant art would have found surprising or unexpected. The
basic principle behind this rule is straightforward-that which
would have been surprising to a person of ordinary skill in a
particular art would not have been obvious.

In re Soni, 54 F.3d 746, 750 (Fed. Cir.1997).
“When prima facie obviousness is established and evidence is
submitted in rebuttal, the decision-maker must start over.” In re Rinehart,
531 F.2d 1048, 1052 (CCPA 1976); In re Hedges, 783 F.2d 1038, 1039
(Fed. Cir. 1986) (“If a prima facie case is made in the first instance, and if
the applicant comes forward with reasonable rebuttal, whether buttressed by
experiment, prior art references, or argument, the entire merits of the matter
are to be reweighed”).
In addition, “when unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art.” In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed.
Cir. 1991). A showing of unexpected results must also be commensurate in
scope with the breadth of the claims. In re Grasselli, 713 F.2d 731, 743
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(Fed. Cir. 1983).

ISSUE (Rejections I and III)
Has the Examiner established by a preponderance of the evidence that
the combination of May, Bachmann, Harlow, and Nagata renders obvious
the assay device of claim 4?
And if yes, has Appellant presented evidence of secondary
considerations, that when weighed with the evidence of obviousness,
sufficient to support a conclusion of non-obviousness?

FINDINGS OF FACT
FF1 The Examiner’s statement of Rejection I may be found at pages 6-11
of the Answer. As Appellant does not argue the claims separately, we focus
our analysis on claim 4, and claims 5, 7, 8, 12, and 13 stand or fall with that
claim. 37 C.F.R. § 41.37(c)(1)(vii).
FF2 The Examiner finds that May teaches the claimed device, except that
May does not teach or suggest that the device may be used to detect L-
PGDS, or that the first antibody is reactive with both native and denatured
L-PGDS (Ans. 6-7).
FF3 Specifically, May teaches that the “invention relates to assays
involving specific binding, especially immunoassays” (May, col. 1, ll. 13-
14).
FF4 May teaches further that the disclosed test devices “are quick and
convenient to use and . . . require the user to perform as few actions as
possible” (id. at col. 1, l. 67-col. 2, l. 2).
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FF5 The Examiner finds that Bachmann teaches that β-trace protein (β-TP,
i.e., L-PDGS) “is the most abundant protein in human CSF, and can be used
as an immunological marker to detect the presence of cerebrospinal fluid
traces” (Ans. 7).
FF6 Specifically, Bachmann used specimens from patients with otorrhea
or rhinorrhea to look for CSF using a laser-nephelometric assay for β-TP
(Bachmann, Abstract).
FF7 Bachmann teaches that β-TP “is the most abundant protein in human
CSF, with a concentration of 17 mg/L” (id. at 571, second col.).
FF8 Bachmann teaches further that β-TP has been found in urine, aqueous
humor, and inner ear fluids, and that severe renal filtration dysfunction can
cause elevated levels in serum (id.).
FF9 Bachmann teaches further that β-TP has a CSF to serum level of 33,
the highest of all CSF proteins (id.).
FF10 The laser-nephelometric assay for β-TP used immunaffinity-purified
polyclonal antibodies against β-TP purified from rabbit (id. at 572, first
column).
FF11 The Examiner cites Harlow for teaching methods for producing
antibodies, and the antibodies that bind both the native and denatured forms
of a protein antigen may be produced (Ans. 7-8).
FF12 The Examiner further cites Harlow for teaching that it is known that
different applications require antibodies that recognize either the native or
denatured form of the protein antigen (id. at 8). The Examiner further finds
that Harlow teaches that in techniques such as immunoblotting the
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antibodies that work best are those that recognize denaturation resistant
epitopes (id.).
FF13 The Examiner thus finds that such technical considerations as whether
or not an antibody recognizes both the native and denatured forms, and what
antibody will work best in certain applications “were known and would have
been appreciated by those of skill in the art at the time of the instant
invention” (id. at 9).
FF14 The Examiner cites Nagata for teaching antibodies that recognize both
the native and denatured forms of a protein, and that such an antibody is
“‘versatile’” (id.).
FF15 Specifically, Nagata is drawn to “the construction and characterization
of mouse monoclonal antibodies against western equine encephalitis virus
(WEE)” (Nagata, ¶1).
FF16 Nagata found that certain of, but not all, of the monoclonal antibodies
produced were able to recognize both the native and denatured forms of the
antigen (id. at ¶49). Nagata found that one of the most reactive antibodies
was the most “versatile,” as it could recognize both the native and denatured
forms in a number of different assays (id. at ¶52).
FF17 The Examiner concludes that it would have been obvious to use the
device of May to detect the L-PGDS antigen as taught by Bachmann as
Bachmann teaches “that detection of L-PGDS in a sample can be used to
detect trace amounts of CSF with high sensitivity and accuracy” (Ans. 9).
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FF18 The Declaration of Srinivas Pentyala, dated April 21, 2008,9 states
that based on Bachmann, “one would expect that L-PDGS is an abundant,
but not a unique marker for CSF” (Pentyala Declaration, ¶4).
FF19 The Declaration further states that their studies have shown that L-
PGDS is a selective and specific marker for CSF (id. at ¶5). The Declarant
obtained a polyclonal antibody to L-PGDS, and found, that “[i]n contrast to
the results shown in Bachmann . . ., a polyclonal antibody specific for L-
PGDS identifies L-PGDS . . . in CSF, but not with other fluids including
urine and amniotic fluid with immunoblot technique” (id. at ¶6).
FF20 The Declaration of Vincent Pieribone, dated February 3, 2009,10 states
that the “production of antibodies for use in experimental biology remains a
difficult and undetermined process” (Pieribone Declaration, ¶2).
FF21 The Declaration further states:
4. Antibodies for use in lateral flow devices must be IgG,
highly stable over time and under various environmental
conditions, highly specific, recognize native and denatured
proteins and have high affinity.

These qualities cannot be simple ‘designed’ into a particular
antibody preparation a priori but rather are realized after trial
and error and with an informed and experientially- and
experimentally-driven process. It is not a given that an
antibody with a particular set of qualities can be easily and
reliably produced by any person practiced at the art.

9 The Pentyala Declaration was submitted with the Amendment dated April
28, 2008 (see App. Br. 23, Evidence Appendix).
10 The Pieribone Declaration was submitted with the Amendment dated
February 5, 2009 (see App. Br. 23, Evidence Appendix).
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5. The production of monoclonal antibodies that recognize
native, non denatured antigens (as is necessary in lateral flow
devices), is very difficult and in no way guaranteed. The nature
of the mono specificity and method of isolating clones does not
ensure identifying clones that express antibodies with the
necessary properties.

(Id. at ¶¶4 and 5.)
FF22 The Declaration of Glenn Ford, dated February 4, 2009,11 reiterates
that the “selection of a single antibody that binds both native and denatured
antigen is not guaranteed” (Ford Declaration, ¶4). The Declaration further
states that “[p]roducing a purified antibody with the most optimal properties
requires the expertise and work of a highly skilled researcher” (id. at ¶5).
FF23 Jemmerson,12 cited by Appellant, a reference published in 1987,
looked at the ability of monoclonal antibodies to react with both the native
and denatured forms of the protein (Jemmerson, Abstract). Jemmerson
found that the “vast majority” of the several hundred monoclonal antibodies
examined to native protein did not bind to peptides, but those to the
denatured protein did bind to the peptides (id.).
FF24 Prud’homme,13 cited by Appellant, produced monoclonal antibodies
to estrogen-induced breast cancer protein (Prud’homme, Abstract).

11 The Ford Declaration was submitted with the Amendment dated February
5, 2009 (see App. Br. 23, Evidence Appendix).
12 Ronald Jemmerson, Antigenicity and native structure of globular proteins:
Low frequency of peptide reactive antibodies, 84 PROC. NATL. ACAD. SCI.
USA 9180-9184 (1987).
13 Prud’homme, Monoclonal Antibodies against Native and Denatured
Forms of Estrogen-induced Breast cancer protein (BCEI/pS2) Obtained by
Expression in Escherichia coli, 50 CANCER RESEARCH 2390-2396 (1990).
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Prud’homme teaches that two classes of monoclonal antibodies were
obtained, those that recognized the denatured protein and those that
recognized the native protein (id.).
FF25 André,14 cited by Appellant, produced antibodies against muscarinic
acetylcholine receptors (André, Abstract). André also teaches that two
classes of monoclonal antibodies were obtained, those that recognized the
denatured protein and those that recognized the native protein (id.).
FF26 Varshney,15 cited by Appellant, is an Abstract, teaches that 21
monoclonal antibodies were developed against either native or heat
denatured ovalbumin.
FF27 Melegos,16 cited by Appellant, teaches a two-site sandwich assay for
L-PGDS (β-trace) (Melagos, Abstract). Using the assay, L-PGDS
concentrations were measured in serum, urine, amniotic fluid, CSF, seminal
plasma, breast cyst fluid, breast discharge fluid, breast milk, and breast
tumor extracts, with the highest concentration being found in CSF (id.).
FF28 Spangler,17 cited by Appellant, is an Abstract, teaches that anti-
peptide antibody against cholera toxin, myohemerythrin, and sickle

14 André et al., Monoclonal antibodies against the native or denatured forms
of muscarinic acetylcholine receptors, 3 THE EMBO JOURNAL 17-21 (1984).
15 Varshney et al., Structure of Native and Heat-denatured Ovalbumin as
Revealed by Monoclonal Antibodies: Epitopic Changes during Heat
Treatment, 56 J. FOOD SCIENCE 224-227 (2006).
16 Melegos et al., Immunofluorometric assay of prostaglandin D synthase in
human tissue extracts and fluids, 42 CLINICAL CHEMISTRY 1984-1991
(1996).
17 BD Spangler, Binding to native proteins by antipeptide monoclonal
antibodies, 146 J. IMMUNOLOGY 1591-1595 (1991).
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hemoglobin, were able to recognize the denatured form of each of the
protein, but not the native form. (Did not screen for cross-reactive)
FF29 Arrer,18 cited by Appellant, teaches that L-PGDS (β-trace) is abundant
in CSF, but is also found in other body fluids, such as serum, although in
much lower quantities (Arrer, p. 939, second col.; see also, p. 940, Table 1).
Arrer thus explored an appropriate cut-off for L-PGDS such that its presence
would be indicative of the presence of CSF (id. at 941).
FF30 Arrer specifically teaches:
The rationale for using βTP [L-PGDS] to detect CSF in nasal
secretions is based on observations showing a 30- to 40-fold
higher concentration in CSF than in serum Compared with
β2Tr [beta-2 transferrin] testing, isoform separation is not
required. Hence, βTP testing can be automated, has a higher
analytical sensitivity, and is less time-consuming.

(Id.)
FF31 Oda,19 cited by Appellant, is drawn to a monoclonal antibody that
specifically binds to L-PGDS (Oda, Absttract). Oda then used the antibody
to detect L-PGDS in various tissues, such as CSF, blood, and urine (Oda,
col. 14, Example 3).
FF32 The Anesthesiology News article,20 cited by Appellant, notes that
New York researchers are working on a lateral flow device, much like a
home pregnancy test, that will alert doctors in five minutes “to the presence

18 Arrer et al., β-Trace protein as a marker for cerebrospinal fluid
rhinorrhea, 48 CLIN. CHEM. 939-941 (2002).
19 Oda et al., US 6,605,705 B1, Aug. 12, 2003.
20 Anesthesiology News Technology, New Device Finds CSF Leaks in
Minutes Issue: 5/2007.
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of even tiny traces of . . . (CSF) in body excretions” (News Article, first
page).
FF33 The FDA Letter,21 also cited by Appellant, states that “we have not
seen previously a device with an intended use similar to yours.”

ANALYSIS
We conclude that the preponderance of the evidence of record
supports the Examiner’s conclusion that the combination of May,
Bachmann, Harlow, and Nagata renders obvious the assay device of claim 4.
Claim 4 is drawn to an assay device. Thus, the recitation of detecting
the presence or absence of CSF in a sample of a human patient in the
preamble, and the wherein clause, which recites “wherein the presence of a
detectable band in the second region indicates the presence of cerebrospinal
fluid in the sample from the human subject,” are both statements of intended
use.
As to the limitation that “the first purified monoclonal antibody is
suitable for specifically detecting the presence or absence of an L-PGDS
antigen,” we note that the Specification does not define “specifically
detecting.” We therefore give it its broadest reasonable interpretation, which
is that the first purified monoclonal antibody is able to specifically detect,
that is, specifically bind, to an L-PGDS antigen from any source.
Appellant argues that the recitation of “‘wherein the presence of a
detectable band in the second region indicates the presence of cerebrospinal

21 Letter from Dr. Steven I. Gutman, M.D., M.B.A., (USDA) dated July 9,
2006.
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fluid in the sample’” is not a statement of intended use, as it requires that the
use of antibodies specific to L-PGDS, and specific to cerebral spinal fluid
(App. Br. 12). Thus, Appellant asserts, the “wherein” clause is a functional
limitation, limiting the device to the detection of CSF (id. at 13). We do not
agree. While Appellant argues that the wherein clause is functional, they do
not point to how it changes the structure of the device. Specifically,
Appellant has not demonstrated how detection of the L-PGDS antigen in
CSF changes the structure of the device or the monoclonal antibodies that
specifically bind the L-PGDS antigen.
Appellant argues that based on the teachings of May, “one would
select a marker that is specific for the fluid of interest and that for which
highly specific antibodies can be produced, that is, antibodies with relatively
low cross-reactivity” (App. Br. 5). Appellant argues that while Bachmann
suggests that L-PGDS is a marker for CSF, they do not suggest that it is an
appropriate analyte for a lateral flow device (id.). Appellant asserts further
that Bachmann teaches that L-PGDS may be found in other fluids, such as
urine, inner ear fluids, among others, and thus does not teach that L-PGDS is
specific for CSF, nor does Bachmann teach that highly specific monoclonal
antibodies for L-PGDS can be produced (id. at 5-6). Appellant argues
further that the ordinary artisan would not be motivated by Bachmann to
select L-PGDS as an analyte for detection on a lateral flow device, as
Bachmann does not teach that L-PGDS is specific to CSF, and May is drawn
to the detection of analytes that can be detected selectively with specific
bind reagents (id. at 4-5). Appellant thus asserts that neither May nor
Bachmann teach or suggest “‘a first purified monoclonal antibody [that] is
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suitable for specifically detecting the presence or absence of an L-PGDS
antigen’ and a device ‘wherein the presence of a detectable band in the
second region indicates the presence of cerebrospinal fluid in the sample’”
(id. at 6 (alteration in original)).
May teaches a lateral flow assay device that may be used to detect an
antigen, and all that it required is a specific binding reagent for the antigen,
such as a monoclonal antibody for the antigen (see, e.g., FF3). May also
teaches the advantages of such a device, such that it is easy, quick, and
convenient. Bachmann teaches a laser-nephelometric assay for β-TP, that is,
L-PGDS, that uses immunaffinity-purified polyclonal antibodies against β-
TP purified from rabbit (FF10). As found by the Examiner, Bachmann
teaches further that L-PGDS is the most abundant protein in human CSF,
and can be used as an immunological marker to detect the presence of
cerebrospinal fluid traces. Thus, in view of the teachings of Bachmann that
L-PGDS is a marker for CSF, and that it may be detected using a specific
binding reaction, it would have been well within the level of skill of the
ordinary artisan to use the device of May to detect the L-PGDS antigen of
Bachmann. As to Appellant’s argument that as Bachmann teaches that L-
PGDS may be found in fluids other than CSF, Bachmann teaches that the
CSF to serum ratio of L-PGDS is 33, the highest of all CSF specific
proteins, making it the “ideal marker” for CSF fluid traces (Bachmann,
p571, second column). Thus, while recognizing that L-PGDS may be found
in other fluids, Bachmann still identifies L-PGDS as an “ideal marker” for
CSF.
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Appellant argues further that the Examiner has not provided a reason
as to why the ordinary artisan would have used an antibody that binds both
the native and denatured forms of L-PGDS in the lateral flow device of May
(App. Br. 11).
Appellant also argues that, as to the limitation that the monoclonal
antibodies bind to both the native and denatured forms of L-PGDS, the
Examiner acknowledges that Harlow teaches that antibodies that recognize
both the native and denatured forms may be produced by known methods,
but that there is no teaching that the can be definitively produced to every
antigen (App. Br. 6). Appellant relies on the Pieribone and Ford
Declarations to support the assertion that it is unpredictable as to whether
antibodies may be obtained with the desired binding characteristics (id. at 6-
7).
Appellant argues further that the Examiner’s reliance on Harlow is
misplaced, as it is a general laboratory manual and “has no teachings
regarding L-PGDS, the specific antigen in the present application” (id. at 7).
Nagata, Appellant asserts, is limited to antibodies to western equine
encephalitis (WEE) antigen, and “is not a general teaching that antibodies
that bind native and denatured antigens can be produced for all antigens”
(id.). Thus, according to Appellant, “while the procedures for producing and
screening antibodies are relatively routine, the production of an antibody
with desired properties is a trial and error process and there is no guarantee
that a particular desired antibody will be obtainable for a particular protein
antigen” (id. at 8).
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Appellant cites Jemmerson, Prud’homme, André, Varshney, and
Spangler, as well as the Pieribone Declaration as evidence that it is not
predictable to be able to obtain antibodies that bind both the native and
denatured forms of a protein (id. at 8-9). Appellant further asserts that other
workers, as demonstrated by Arrer, Melegos, Oda, and Bachmann,22 have
had difficulty in producing antibodies specific for L-PGDS, “there was no
guarantee that the art-recognized antibody production techniques would be
successful” (id. at 10). Thus, Appellant asserts “the prior art does not fairly
teach or suggest that it is routine to generate antibodies to native and
denatured L-PGDS, and in fact suggests that it can be challenging to produce
such antibodies for any antigens” and it is only the present inventor who has
demonstrated that such antibodies to L-PGDS may be produced (id. at 9-10).
Appellant’s arguments have been carefully considered, but are not
deemed to be convincing. First, as to Appellant’s argument that the
Examiner would have used an antibody that binds both the native and
denatured forms of L-PGDS in the lateral flow device of May, we note that
Harlow is evidence of the state of the art and the level of skill of the ordinary
artisan. Harlow demonstrates that the ordinary artisan would have
understood the advantages of such a monoclonal antibody, such that it could

22 It is unclear to which Bachmann reference Appellant is referring. If it is
the Bachmann reference relied upon by the Examiner, Appellant does not
point, nor can we find, any section which discusses that it was difficult in
producing antibodies specific to L-PGDS. If Appellant is referring to the
mention in Bachmann that L-PGDS (β-TP) has been found in urine, inner
ear fluids, aqueous humor, inner ear fluids, and serum (see FF8), that is in
the introduction to the study, and is not referring to the laser-nephelometric
assay for β-TP.
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recognize both the native form of the antigen, as well as of the antigen that
may have denatured when placed on the solid phase of the assay device of
May. Harlow, a general laboratory manual, is also evidence that the
ordinary artisan would understand that antibodies that recognize both the
native and denatured forms of an antigen may be produced.
We also find that it would have been well within the level of skill of
the ordinary artisan to specifically screen for an antibody that binds both the
native and denatured forms of L-PGDS. We have considered the Pieribone
and Ford Declarations, but they do not convince us to the contrary. The
Declarations appear to be asserting that there is no guarantee of success, but
that is not the standard by which obviousness is measured. All that is
required is a reasonable expectation of success, not absolute predictability of
success. See In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988).
We have also considered the Jemmerson, Prud’homme, André,
Varshney, and Spangler references. None of those references are drawn to
the antigen here, that is L-PGDS, nor do any of Prud’homme, André,
Varshney, and Spangler references teach that it is difficult to obtain
antibodies that recognize both the native and denatured forms of the antigen.
The references do not appear to screen specifically for antibodies that bind
both the native and denatured forms of the antigens involved, the references
just recognize that separate antibodies that recognized either the native and
denatured forms of the antigen were produced. As to Jemmerson, the
reference found that the “vast majority” of the several hundred monoclonal
antibodies examined to native protein did not bind to peptides, but those to
the denatured protein did bind to the peptides (FF23), but as Jemmerson
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stated that the “vast majority” of the several hundred monoclonal antibodies
examined did not bind to peptides, Jemmerson appears to be inferring that
some of the antibodies to the native antigen also bound to peptides.
As to the Arrer, Melegos, and Oda references, those references do not
teach that antibodies to both the native and denatured forms of L-PGDS
could not be obtained, but are evidence that antibodies that specifically bind
to L-PGDS were known in the art. In addition, while those references teach
that L-PGDS may be found in samples other than CSF, Arrer recognizes that
given the appropriate cut-off, the presence of L-PGDS in a sample may be
used as a marker for CSF. Moreover, as discussed above, we interpret the
limitation that “the first purified monoclonal antibody is suitable for
specifically detecting the presence or absence of an L-PGDS antigen,” as
encompassing a first purified monoclonal antibody is able to specifically
detect, that is, specifically bind, to an L-PGDS antigen from any source.
Appellant argues further that they have presented data demonstrating
unexpected results, as Bachmann, Arrer, Melagos, and Oda all showed
production of antibodies that detected fluids other than CSF (App. Br. 14).
Appellant’s arguments have been considered, but are again not found
to be convincing. We assume Appellant is referring to the Pentyala
Declaration. We agree with the Examiner (see Ans. 41-43) that the
Declaration does not present evidence of unexpected results, that when
weighed with the combination of references as cited by the Examiner,
sufficient to support a conclusion of unobviousness. First, for a
demonstration of unexpected results, the results must be shown to be
unexpected compared with the closest prior art. In this case, while we
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understand that the prior art antibodies may not be available for comparison,
the Declaration does not point to how the results obtained compare to those
of the prior art. For example, Appellant has not demonstrated how the same
or similar samples as those used in the prior art are comparable to those used
to obtain the results shown in the Declaration. That is, as taught by
Bachmann, severe renal dysfunction causes elevated levels of L-PGDS in
serum, whereas in healthy patients the ratio is at least 33 (FFs 8 and 9), and
thus L-PGDS is present in much greater levels in CSF than serum in patients
who do not suffer from severe renal dysfunction. In that regard, we note that
multiple references of record teach that L-PGDS may be found in samples
other than CSF (see, e.g., FFs 8, 27, 29, and 30), and that may be due to the
source of the samples that were analyzed.
Appellant also argues that the invention meets a long felt need, as
evidenced by Anesthesiology News, as well as the letter from the FDA
(App. Br. 16). As noted by the Examiner, however (Ans. 44-45), that
evidence, however, does not show that there was a persistent need that was
recognized by those of ordinary skill. In re Gershon, 372 F.2d 535, 538
(CCPA 1967).
As to the rejection over claim 9, Appellant argues that Davis does not
remedy the deficiencies of the combination of Bachmann, Harlow, Nagata,
and Davis (App. Br. 20). Those arguments are not found to be convincing
for the reasons set forth above.

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CONCLUSIONS OF LAW
To reiterate, we conclude that the Examiner has established by a
preponderance of the evidence that the combination of May, Bachmann,
Harlow, and Nagata renders obvious the assay device of claim 4. We further
conclude that Appellant has not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness,
sufficient to support a conclusion of non-obviousness.
We thus affirm the rejection of claim 4 under 35 U.S.C. § 103(a) as
being rendered obvious by the combination of May, Bachmann, Harlow, and
Nagata. As claims 5, 7, 8, 12, and 13 stand or fall with claim 4, we affirm
the rejection as to those claims as well. We also affirm the rejection of
claim 9 rejected under 35 U.S.C. § 103(a) as being rendered obvious over
the combination of May, Bachmann, Harlow, and Nagata, as further
combined with Davis.

ISSUE (Rejection II)
Has the Examiner established by a preponderance of the evidence that
the combination of Remington, Bachmann, Harlow, and Nagata renders
obvious the assay device of claim 4?

FINDINGS OF FACT
FF34 The Examiner’s statement of Rejection I may be found at pages 12-17
of the Answer. As Appellant does not argue the claims separately, we focus
our analysis on claim 4, and claims 5, 7, 8, 12, and 13 stand or fall with that
claim.
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FF35 The Examiner relies on Remington for teaching a test strip device for
detecting the presence or absence of CSF (Ans. 12).
FF36 Specifically, Remington teaches:
The present invention provides methods for detection and
diagnosis of cerebrospinal fluid (CSF) leakage and associated
conditions using antibodies that specifically bind to CSF-
specific proteins. In particular, the present invention provides
for monoclonal antibodies that specifically bind to CSF-specific
proteins. Apparatus and methods for assaying and detecting
CSF-specific proteins in a sample are also disclosed. Such
apparatus can be used for inpatient (e.g., in surgery) and/or
outpatient conditions (e.g., in clinic). In preferred embodiment,
an easy-to-use apparatus can be operated by a physician or by
any other individual. Prior experience is not necessary as the
apparatus is simple to use and no special timing, dilutions or
concentrations are required prior to using the apparatus herein,
such that the same apparatus can be used to detect low and high
concentrations of CSF-specific protein in a test sample.

(Remington, ¶38.)
FF37 Remington defines “CSF-specific proteins” as “proteins that under
normal healthy conditions are present in the CSF and possibly in the humor
and/or perilymph, but which are not present significantly (or in similar
amounts) in other bodily fluids such as blood, serum, tears, nasal discharge,
ear drainage, saliva, urine, etc.” (id. at ¶51).
FF38 According to Remington, an example of such a protein is beta-2
transferrin (id.). Remington teaches that “[u]nlike the other transferrin
isoforms, beta-2 transferrin is normally present only in cerebrospinal fluid,
aqueous and vitreous humors, and perilymph” (id. at ¶46).
FF39 The Examiner notes that Remington fails to teach that the CSF
specific protein is L-PGDS.
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FF40 Bachmann, Harlow, and Nagata are relied upon as set forth above.
FF41 The Examiner concludes that “given that the teachings of Bachman[n]
[ ] establish that like the protein transferrin studied by Remington [ ], L-
PGDS was also recognized in the art to be a marker of CSF, it would have
been obvious to one of ordinary skill in the art to substitute the known
marker L-PGDS for transferrin as the CSF-specific protein because both of
these proteins and their functions as markers of CSF were recognized in the
art” (Ans. 15).

ANALYSIS
Appellant argues that, as does May, Remington “clearly discloses that
for a device such as a lateral flow device, it is essential that the marker must
be highly specific for the fluid to be detected, in this case CSF” (App. Br.
17). Appellant argues that the “beta-2 transferrin of Remington et al. is not
present in nasal fluids, aural fluids, saliva, tears or serum,” whereas
Bachmann teaches that L-PDGS may be present in urine, aqueous humor,
inner ear fluids, and serum (id.). Thus, Appellant asserts, the ordinary
artisan “would not replace the specific CSF marker beta-2 transferrin with
the apparently non-specific CSF maker L-PGDS” (id.).
Appellant’s arguments are not convincing. Remington teaches that
“CSF-specific proteins” are proteins that under normal healthy conditions
are present in the CSF but which are not present in similar amounts in other
fluids, such as serum. Bachmann specifically teaches that CSF is present in
much greater quantities in CSF than serum, making it the “ideal marker” for
CSF (Bachmann, p. 571, second column). That finding is supported by
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Arrer, cited by Appellant, who teaches the advantages of L-PGDS over beta-
2 transferrin (FF30), the preferred antigen of Remington (FF38).
As to the addition of Harlow and Nagata, Appellant reiterates the
arguments made with respect to the previous rejection (App. Br. 17-19).
Appellant also reiterates the argument that the present invention fulfills a
long-felt need in the art (id. at 20).
Those arguments are not found to be convincing for the reasons set
forth above with respect to Rejection I.

CONCLUSION OF LAW
We conclude that the Examiner established by a preponderance of the
evidence that the combination of Remington, Bachmann, Harlow, and
Nagata renders obvious the assay device of claim 4.
We thus affirm the rejection of claim 4 under 35 U.S.C. § 103(a) as
being rendered obvious by the combination of Remington, Bachmann,
Harlow, and Nagata. As claims 5, 7, 8, 12, and 13 stand or fall with claim 4,
we affirm the rejection as to those claims as well. We also affirm the
rejection of claim 9 rejected under 35 U.S.C. § 103(a) as being rendered
obvious over the combination of Remington, Bachmann, Harlow, and
Nagata, as further combined with Davis as Appellant do not argue the merits
of that rejection.

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TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with this
appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).

AFFIRMED

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