Ex Parte Joos et al

Board of Patent Appeals and Interferences

Jul 22, 2010

10426093 (B.P.A.I. Jul. 22, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte THOMAS JOOS and DIETER STOLL
__________

Appeal 2009-013672
Application 10/426,093
Technology Center 1600
__________

Before DONALD E. ADAMS, MELANIE L. McCOLLUM, and STEPHEN
WALSH, Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of detecting proteins. The Patent Examiner rejected the claims on
the ground of obviousness. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.

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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STATEMENT OF THE CASE
Claims 1-2, 5, 19-25, 27, 28, 30 and 35-39, which are all the pending
claims, are on appeal. Claim 1 is representative and reads as follows:
1. A method for detecting plural different proteins in a protein mixture,
comprising:
(1) denaturing and fragmenting said proteins to produce linear
peptide fragments comprising peptide epitopes;
(2) providing an array comprising, at known positions on the
array, first capture molecules produced using synthetic peptides and
being specific for said individual peptide epitopes, whereby the
positions of the first capture molecules produce a spatially resolved
pattern for identifying the linear peptide fragments and thus proteins
that correspond to the linear peptide fragments;
(3) incubating the array with the linear peptide fragments under
conditions whereby the first capture molecules specifically bind to
and thereby form complexes with the linear peptide fragments; and
(4) detecting the linear peptide fragments, if any, bound to the
first capture molecules by contacting said complexes with labeled
second capture molecules selected from the group consisting of
antibodies, antibody fragments, and peptide aptamers.

The Examiner rejected the claims as follows:
• claims 1-2, 5, 19-25, 27, 28, 30 and 35-39 under 35 U.S.C. § 103(a)
as unpatentable over Hutchens2 and Harper3; and
• claims 1-2, 5, 19-25, 27-28, 30 and 36-39 under 35 U.S.C. § 103(a)
as unpatentable over Knowles4 and Maggio5; and

2 US 6,225,047 B1, issued to T. William Hutchens et al., May 1, 2001.
3 Sandra Harper et al., “Two-Dimensional Gel Electrophoresis”,CURRENT
PROTOCOLS IN PROTEIN SCIENCE,. 10.4.1–10.4.36, John Wiley & Sons, Inc
(1998).
4 US 4,658,022, issued to William J. Knowles et al., Apr. 14, 1987.
5 Edward T. Maggio, “Enzymes As Immunochemical Labels” CH. 3
Enzymes-Immunoassay, 53-70 CRC Press, Inc. FL (1980).
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• claim 35 under 35 U.S.C. § 103(a) as unpatentable over Knowles,
Maggio, and Ullman6.
Appellants filed a request for oral hearing in this appeal. We find an
oral hearing unnecessary, and have decided the appeal on the written record
as authorized by 37 C.F.R. § 41.47(f).

OBVIOUSNESS
The Issues
A. The Rejection over Hutchens and Harper
The Examiner’s position is that Hutchens described a method
comprising the steps Appellants claim, but for the denaturing step in claim
part (1). (Ans. 6-7.) Finding that Harper described denaturing as a prelude
to mass spectrometric analysis, the Examiner concluded it would have been
obvious to add denaturing to Hutchens’ method because Harper explains that
“such a ‘denaturing’ step enables dissociation and resolution of protein
subunits in proteins containing interchain disulfide bonds.” (Id. at 7-8.)
Appellants first contend that the claimed method is a sandwich-type
assay but Hutchens describes “a very different technology,” i.e., retentate
chromatography. (App. Br. 9.) Appellants next contend that Harper
describes two dimensional gel electrophoresis, but there is “no logical
connection whatsoever between Harper and Hutchens”, which Appellants
assert “actually teaches away from Harper’s gel electrophoresis method.”
(Id. at 10.) Appellants then argue that the rejection “cobbles together words
and phrases from distinct teachings within Hutchens” (id.), citing the

6 US 5,223,441, issued to Edwin F. Ullman et al., Jun. 29, 1993.
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allegedly distinct portions of Hutchens (id. at 12). According to Appellants,
“even if it were proper to combine words and phrases within and between
Hutchens and Harper,” the combination does not teach or suggest (1)
denaturing and fragmenting proteins and (2) detecting peptides using an
array of labeled capture molecules. (Id. at 12-13.)
The issues with respect to this rejection are:
does the evidence support the finding that Harper’s denaturation step
provided a reason to add denaturing to Hutchens’ process;
does the evidence show that Hutchens taught detecting peptides by
contacting with labeled capture molecules?
B. The Rejections over Knowles and Maggio
The Examiner’s position is that Knowles described a method for
detecting plural different proteins in a protein mixture comprising steps in
Appellants’ method, but without providing “a spatially patterned ‘array’ of
first capture molecules.” (Ans. 11.) Finding that Maggio described
microtiter plates, i.e., spatially patterned arrays, for performing sandwich
assays, the Examiner concluded it would have been obvious to perform
Knowles’ protein detection method with a microtiter plate because Maggio
described the technique as having advantages, e.g., obviation of using
antigen as a reagent. (Id. at 11.)
Claim 35 stipulates that “said second capture molecules are raised
against one of said linear peptide fragments specifically bound to the first
capture molecules.” The Examiner found that although Knowles did not
teach using that kind of second capture molecule, Ullman taught that second
capture molecules raised against bound fragments have “substantially
greater” binding affinity. (Id. at 13.) The Examiner thus, concluded it
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would have been obvious to use Ullman’s second capture molecules in
Knowles’ method. (Id.)
Appellants first contend that the Examiner should not have “re-
applied” this rejection, as Appellants “overcame” a rejection based on
Knowles and Maggio in combination with a third reference earlier in the
prosecution. (App. Br. 17.) Appellants next argue that the combination of
Knowles and Maggio “fails to teach or suggest the core elements of
Appellant’s invention.” (Id. at 18.) Specifically, Appellants argue that
denaturing and fragmenting the proteins in a protein mixture was not taught
in Knowles and nothing in Knowles suggests “multiplexed” protein
detection. (Id. at 18-20.) Appellants argue that Maggio’s “description of an
empty microtiter plate is not an array in accordance with Appellant’s
invention.” (Id. at 19.) As to the rejection of claim 35, Appellants contend
that the combination “still fails to teach or suggest a multiplexed detection of
proteins in a protein mixture.” (Id. at 21.)
The issues with respect to these two rejections are:
did Appellants show there is a valid procedural objection to the
rejections over Knowles and Maggio;
did Knowles teach or suggest detecting plural different proteins in a
protein mixture; and
did the rejection show that the combined teachings of Knowles and
Maggio suggested detecting plural different proteins in a protein mixture on
a microtiter plate?

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Findings of Fact
1. Hutchens described a method related to “separation science and
analytical biochemistry.” (Hutchens, col. 1, ll. 18-19.)
2. Hutchens’ method generally involved: (1) selectively adsorbing
analytes from a sample to a substrate, and (2) detecting the retention
of adsorbed analytes by desorption spectrometry. (Id. at col. 18, ll.
25-29.)
3. Hutchens also taught:
the analytes thus separated remain docked in a retentate map
that is amenable to further manipulation to examine, for
example, analyte structure and/or function. Also, the docked
analytes can, themselves, be used as adsorbents to dock other
analytes exposed to the substrate. In sum, the present invention
provides a rapid, multidimensional and high information
resolution of analytes.

(Id. at col. 18, ll. 41-47.)
4. Harper described two-dimensional gel electrophoresis as combining
“two different electrophoretic separating techniques in perpendicular
directions to provide a much greater separation of complex protein
mixtures than either of the individual procedures.” (Harper 10.4.1.)
5. According to Harper, “[p]rotein subunit compositions and cross-
linked protein complexes can be analyzed by two-dimensional gel
electrophoresis using separation under nonreducing conditions in the
first dimension followed by reduction of disulfide bonds and
separation under reducing conditions in the second dimension.” (Id.
at 10.4.25.)
6. According to Harper, “[t]he most definitive methods for establishing
the identities for proteins of interest detected by computer-assisted
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comparisons are protein sequence analysis and, more recently, mass
spectrometry of tryptic fragments. Both methods are compatible with
the quantities of protein that can be recovered from two-dimensional
gels.” (Id. at 10.4.26-27.)
7. Knowles’ patent is entitled “Binding Of Antibody Reagents To
Denatured Protein Analytes.” (Knowles.)
8. Knowles disclosed:
[i]t has now been found that highly specific immunobinding to
a particular protein can be achieved by forming an antibody
reagent against a linear peptide epitope in the protein and
contacting such antibody reagent with the protein after
denaturing the protein sufficiently to expose or increase the
exposure of the linear peptide epitope therein.

(Id., col. 2, ll. 58-64.)
9. Knowles taught that “[p]hysical or chemical treatments, the latter
including protein digestion, are available for selection of the optimal
denaturation conditions.” (Id. at col. 3, ll. 23-25.)
10. Knowles taught using “the sandwich technique.” (Id. at col. 10, ll. 44-
52.)
11. Maggio listed some solid-phase matrices employed in immunassays,
including polystyrene microtiter plates. (Maggio 64, Table 5.)
12. Maggio described a variety of configurations for immunoassay,
including sandwich assays. (Id. at 61-63 , Table 3.)

Principles of Law
When determining whether a claim is obvious, an Examiner must
make “a searching comparison of the claimed invention – including all its
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limitations – with the teaching of the prior art.” In re Ochiai, 71 F.3d 1565,
1572 (Fed. Cir. 1995).
“There is nothing unusual, certainly, about an examiner changing his
viewpoint as to the patentability of claims as the prosecution of a case
progresses, and, so long as the rules of Patent Office practice are duly
complied with, an applicant has no legal ground for complaint because of
such change in view.” In re Ruschig, 379 F.2d 990, 993 (CCPA 1967),
quoting In re Ellis, 86 F.2d 412, 414 (CCPA 1936); Blacklight Power, Inc.
v. Rogan, 295 F.3d 1269, 1273-74 (Fed. Cir. 2002).

Analysis
A. The Rejection over Hutchens and Harper
Appellants first contend that the claimed method is a sandwich-type
assay but that Hutchens describes “a very different technology,” i.e.,
“retentate chromatography.” (App. Br. 9.) Appellants quote Hutchens col.
18, ll. 24-40, to emphasize that Hutchens’ retentate chromatography was not
a sandwich assay. (Id.) In the paragraph following the one Appellants
quote, Hutchens taught that docked analytes in a retentate map (array) can
themselves be used to dock other analytes. (FF 3.) That paragraph is a
description of a sandwich-type assay, albeit without the label. We are
therefore not persuaded that Hutchens failed to disclose a sandwich-type
assay.
We agree with Appellants’ argument that the evidence does not
support finding that Harper’s denaturation step provided a reason to add
denaturing to the first stage of Hutchens’ process. The Examiner seems to
link Harper and Hutchens because both used mass spectrometry as a last
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step. (Ans. 7.) Harper described using mass spectrometry on protein
fragments after whole proteins were first denatured, then run through two
dimensional gel electrophoresis, then eluted from the gel, and then digested
with trypsin. Hutchens described using mass spectrometry after a protein
was first digested, then docked on an array, then exposed to secondary
capture molecules, and then the secondary capture molecules were subjected
to mass spectrometry. We find these processes dissimilar. There is
insufficient evidence that a person of ordinary skill in the art would have
found the suggestion that the Examiner found.
We also agree with Appellants’ argument that Hutchens did not teach
detecting peptides by contacting with labeled capture molecules. The
Examiner cited various points in Hutchens as disclosing “labeled second
capture molecules selected from the group consisting of antibodies, antibody
fragments, and peptide aptamers” as claimed. (Ans. 7.) We have reviewed
the cited passages. The evidence does not support the finding. The
Examiner argues that the property of mass is itself a label when a molecule
is analyzed by mass spectrometry and that a coat protein is a label. (Id. at
16.) The argument about mass ignores the ordinary meaning of labeled in
this art, and the argument about coat proteins is irrelevant to the claimed
group of second capture molecules. The Examiner further alleges that “it is
not clear how Appellants’ argument distinguishes over Hutchens [] because
Hutchens [] describe antibodies.” (Id.) The Examiner has not pointed to
evidence that Hutchens taught labeled antibodies. The plain language of the
claims distinguishes over Hutchens because it specifies “labeled antibodies,
antibody fragments, and peptide aptamers.” The Examiner has the burden of
accounting for the difference. The Examiner did not carry that burden.
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B. The Rejections over Knowles and Maggio
First, Appellants object to the re-application of these two references as
unreasonable, costly, and counterproductive. (App. Br. 17.) Reapplying
references after both the Examiner and the Applicants had earlier thought
them distinguished can be appropriate when, for example, the Examiner has
a reason to think that a mistake was made. Mistakes may be costly and
counterproductive to the Applicants and to the Office, but a good faith effort
to correct the mistake is not unreasonable. Appellants’ objection here is not
a legal ground for complaint. See Ruschig, 379 F.2d at 993; see also,
Blacklight Power, 295 F.3d at 1273-74 (explaining that the Office may
withdraw a notice of allowability to revisit an earlier patentability decision
before a patent issues). We turn to Appellants’ more persuasive substantive
arguments.
We agree with Appellants that Knowles did not teach detecting plural
different proteins in one protein mixture. The rejection did not address this
limitation or point to evidence in Knowles concerning the limitation. When
Appellants argued this deficiency in the analysis of the scope and content of
the prior art, the Answer responded that “Knowles & Marchesis apply their
method to any biological fluid, see col. 3, line 44.” (Ans. 20.) The sentence
in Knowles at col. 3, line 44 refers to “the highly specific determination of
glucosylated proteins such as glucosylated hemoglobin and albumin, and
particularly Hb A1c in biological fluids such as blood.” While the sentence
indicates that plural proteins can be determined, it does not indicate that the
plural proteins are determined in the same sample at the same time
(“multiplexed” as Appellants put it in their arguments). The Examiner has
not pointed to evidence that Knowles taught or suggested simultaneous
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(multiplexed) determination of plural proteins. Indeed, in Knowles’
Example 1, Knowles determined A1c and AO hemoglobins by a method in
which “[t]he pure A1c and AO hemoglobins are adsorbed onto separate
microtiter plates.” (Knowles, col. 13, l. 67 – col. 14, l. 1.)
We agree with the Examiner’s finding that Knowles and Maggio
together suggest a spatially patterned array of first capture molecules.
However, we also agree with Appellants that the Examiner has not identified
evidence that Maggio taught “multiplexed detection of proteins in a protein
mixture” (App. Br. 19). We conclude that the obviousness rejection did not
account for the claim limitations that define a method “detecting plural
different proteins in a protein mixture, comprising [] denaturing and
fragmenting said proteins . . . .”

CONCLUSIONS
The evidence does not support the finding that Harper’s denaturation
step provided a reason to add denaturing to Hutchens’ process.
The evidence does not show that Hutchens taught detecting peptides
by contacting with the labeled capture molecules defined in the claims.
Appellants did not establish a valid procedural objection to the
rejections over Knowles and Maggio.
Knowles did not teach or suggest detecting plural different proteins in
a protein mixture by the method defined in the claims where fragments of
plural proteins are detected in the same array.
The rejection did not show that the combined teachings of Knowles
and Maggio gave a reason to detect plural different proteins in a protein
mixture on a microtiter plate.
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SUMMARY
We reverse the rejection of claims 1-2, 5, 19-25, 27, 28, 30 and 35-39
under 35 U.S.C. § 103(a) as unpatentable over Hutchens and Harper.
We reverse the rejection of claims 1-2, 5, 19-25, 27-28, 30 and 36-39
under 35 U.S.C. § 103(a) as unpatentable over Knowles and Maggio.
We reverse the rejection of claim 35 under 35 U.S.C. § 103(a) as
unpatentable over Knowles, Maggio, and Ullman.

REVERSED

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