Ex Parte Leicester

Board of Patent Appeals and Interferences

Aug 28, 2008

10947833 (B.P.A.I. Aug. 28, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte STEPHEN LEICESTER
__________

Appeal 2008-3930
Application 10/947,833
Technology Center 1600
__________

Decided: August 28, 2008
__________

Before DEMETRA J. MILLS, LORA M. GREEN, and
FRANCISCO C. PRATS, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of identifying a modified protein. The Examiner has rejected the claims as
anticipated and obvious. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm.

Appeal 2008-3930
Application 10/947,833

STATEMENT OF THE CASE
Claims 1-3, 6-9, and 12-35 stand rejected and appealed (App. Br. 5).
Claim 1 is representative and reads as follows:
1. A method of identifying a modified protein, comprising:
digesting said modified protein to produce a plurality of
peptides;
ionising at least one of said plurality of peptides to form
one or more peptide ions;
mass analysing one or more of said peptide ions to
determine an experimentally measured mass or mass to charge
ratio of at least one of said peptides or peptide ions;
selecting one or more modifications of interest;
adjusting the experimentally measured mass or mass to
charge ratio in response to said one or more modifications of
interest, thereby determining a theoretical unmodified mass or
mass to charge ratio which said at least one peptide or peptide
ion would have, had the protein from which said at least one
peptide or peptide ion is derived not been modified in
association with the one or more modifications of interest;
searching a databank of peptides using said theoretical
unmodified mass or mass to charge ratio; and
determining peptides in said databank which have a mass
or mass to charge ratio which corresponds with said theoretical
unmodified mass or mass to charge ratio.

The Examiner applies the following document in rejecting the claims:
Marc R. Wilkins et al., High-throughput Mass Spectrometric
Discovery of Protein Post-translational Modifications, 289 J. MOL. BIOL.
645-657 (1999).

The following rejections are before us for review:
Claims 1-3, 6-9, and 12-35 stand rejected under 35 U.S.C. § 102(b) as
anticipated by Wilkins (Ans. 2-3).
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Claims 1-3, 6-9, and 12-35 stand rejected under 35 U.S.C. § 103(a) as
being obvious over Wilkins (Ans. 3-4).
ANTICIPATION
ISSUE
The Examiner cites Wilkins as disclosing a method of “identifying a
post-translationally modified . . . protein by digesting the protein, ionizing
and mass analyzing the samples (using matrix-assisted laser ionization time-
of- flight: MALDI-TOF . . .)” (Ans. 3 (citations omitted)). The Examiner
contends that Wilkins’ method includes the steps of “determining the
theoretical unmodified mass; searching a databank of peptides; [and]
correlating data from [a] databank with the theoretical unmodified mass (see
page 647, right column, 2nd full paragraph and also see Table 2)” (id.).
The Examiner contends that Wilkins’ method also includes the steps
of “determining, enumerating and permuting the numbers and sites of
modification (see page 647, right column, 2nd full paragraph),” using an
“allowed mass or mass to charge ratio tolerance of 0.1 Da (see Figs. 2, 4,
6),” as well as “forming a shortlist of possible peptides (see Figs. 2, 4, 6
under ‘known modifications’ column and page 654, left column, 1st full
paragraph, lines 11-13)” (id.).
Appellant contends that Wilkins does not anticipate claim 1 because
“Wilkins relies on the conventional use of experimentally observed peptide
masses when searching a protein database, while claim 1 recites searching
using a theoretical unmodified peptide mass or mass to charge ratio” (App.
Br. 11; see also Reply Br. 1-2).
Appellant does not argue the claims subject to this ground of rejection
separately. We select claim 1 as representative of the rejected claims.
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37 C.F.R. § 41.37(c)(1)(vii). The issue with respect to this rejection, then, is
whether the Examiner erred in finding that Wilkins meets all of the
limitations recited in claim 1.
FINDINGS OF FACT
1. Wilkins discloses “an approach for the systematic characterisation of
proteins using mass spectrometry and a software tool, FindMod. This tool
examines peptide mass fingerprinting data and applies intelligent rules to
predict amino acids in peptides that might carry protein post-translational
modifications” (Wilkins 646).
Wilkins discloses that “FindMod can also check for single amino acid
substitutions,” and that “FindMod predictions can be tested by mass
spectrometry peptide fragmentation techniques” (id.).
2. Wilkins discloses that FindMod applies “rules for the prediction of 22
of the more common post-translational modifications to amino acids . . . .
All of these modifications impart a discrete mass change to a peptide”
(Wilkins 647; see also 648 (Table 1) (“Modification masses and rules used
in FindMod for the prediction of modified amino acids”).)
3. Wilkins discloses that FindMod uses “29 separate rules to address the
22 considered modifications. Simple rules, describing which amino acids
can be modified, were also implemented for the modifications of glycation,
carbamylation, sulphoxide formation and Cys-propionamide formation.
These modifications are artifacts that sometimes occur during protein
preparation” (Wilkins 647).
4. To use FindMod to analyze a protein, Wilkins discloses that the
following initial steps are performed:
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Coomassie-blue stained gel spots of interest were cut
from 2-D polyacrylamide gels using the ARRM-214 excision
robot . . . and automatically placed into 96-well plates. The 96-
well plates were then placed into a Canberra Packard
MultiProbe robot (Downers Grove, Illinois), where they were
digested with trypsin (Promega). Peptides were then extracted,
and samples spotted onto a 100-sample MALDI-TOF MS
sample target with α-cyano-4-hydroxy-cinnamic acid.

(Wilkins 655.)
5. Once the protein’s peptides have been subjected to MALDI-TOF
analysis, the resulting data is analyzed by a procedure described as follows:
In creating FindMod, our rationale has been to dissociate the
peptide mass fingerprinting database matching procedure from
that of protein characterisation. Thus, the user first identifies
the query protein using available peptide mass fingerprinting
search engines, assigning a group of peptide masses to a
particular protein. FindMod is then used to search for protein
post-translational modifications by comparing experimental
peptide masses that did not match with the protein against those
calculated from the assigned protein sequence, seeking mass
differences that may be due to post-translational modifications.
When mass differences corresponding to a post-translational
modification are found between an experimental peptide and a
theoretical peptide for that protein, FindMod applies a set of
intelligent rules to make predictions as to which amino acids
within the peptide, if any, might carry the modification. A flow
diagram for this procedure is shown in Figure 1.

(Wilkins 646.)
6. Figure 1 of Wilkins, reproduced below, is a “[f]low chart for the
discovery of protein post-translational modifications with mass spectrometry
and the FindMod tool” (Wilkins 647 (caption to Figure 1)):
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The figure shows, in flow chart form, the analytical and
decisional steps described on page 646 (see FF 5), which are used in
the Wilkins’ method of characterizing proteins.
PRINCIPLES OF LAW
“To anticipate a claim, a prior art reference must disclose every
limitation of the claimed invention, either explicitly or inherently.” In re
Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997). During examination, the
PTO must interpret terms in a claim using “the broadest reasonable meaning
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of the words in their ordinary usage as they would be understood by one of
ordinary skill in the art, taking into account whatever enlightenment by way
of definitions or otherwise that may be afforded by the written description
contained in the applicant’s specification.” In re Morris, 127 F.3d 1048,
1054 (Fed. Cir. 1997).
ANALYSIS
We do not agree with Appellant that the Examiner erred in finding
that Wilkins discloses a process that meets all of the limitations of claim 1.
Because Wilkins discloses digesting 2-D gel-purified proteins with
trypsin, ionizing the proteins, and subjecting them to MALDI-TOF analysis
(see FF 4), Wilkins’ method has the first three steps -- digesting, ionizing,
and mass analyzing -- recited in claim 1. Moreover, because Wilkins selects
22 modifications that are incorporated into FindMod’s protein analysis (FF
2, 3), Wilkins also discloses the fourth step in claim 1 of “selecting one or
more modifications of interest.”
After obtaining the peptide mass data, Wilkins discloses that “the user
. . . identifies the query [(i.e., tested)] protein using available peptide mass
fingerprinting search engines, assigning a group of peptide masses to a
particular protein”( Wilkins 646 (FF 5)). After assigning an identity to the
investigated protein, Wilkins next determines whether the protein is
modified, by comparing the measured peptide mass data from the “empirical
peptides” with the peptide mass data of the “theoretical peptides” that should
result from digesting the unmodified protein, calculated from a protein
database (FF 6 (first decision box in flow chart)).
Once it is determined that the measured or “empirical” peptides of the
protein carry a modification, Wilkins performs the step of “[c]alculat[ing]
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mass differences between [the measured] peptide and all theoretical
peptides” (Wilkins 647 (Figure 1) (FF 6); see also Wilkins 646 (FF 5)
(“FindMod is then used to search for protein post-translational modifications
by comparing experimental peptide masses that did not match with the
protein against those calculated from the assigned protein sequence, seeking
mass differences that may be due to post-translational modification.”)).
Thus, Wilkins discloses providing a data set of all theoretical
unmodified peptide masses to which the experimentally derived mass data is
compared. In providing the data set of all theoretical unmodified peptides,
Wilkins, in effect, adjusts the experimentally measured mass to yield a
theoretical mass that the peptide would have had in the absence of
modification, as recited in the fifth step of claim 1. Because this adjustment
is made to ascertain whether the peptide has a FindMod modification, the
adjustment is made “in response to said one or more modifications of
interest,” as recited in the fifth step of claim 1. We therefore agree with the
Examiner that Wilkins discloses the fifth step of claim 1.
The sixth, or “searching” step, of claim 1 requires only that a databank
search be conducted “using said theoretical unmodified mass.” Because
Wilkins compares the experimentally derived peptide mass data to the data
set of all theoretical unmodified peptides (see FF 6), Wilkins performs a
search that uses the theoretical unmodified peptide mass. Because Wilkins’
search of the data set of all theoretical unmodified peptides uses the
theoretical unmodified peptide mass, and because that is all that claim 1
requires, we agree with the Examiner that the sixth step in claim 1
encompasses Wilkins’ search of the data set of all theoretical unmodified
peptides.
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Moreover, Wilkins’ search of all theoretically unmodified peptides
provides a determination of which of the unmodified peptides in the data set
corresponds to the experimentally derived peptide (see Wilkins 646 (FF 5)
(“When mass differences corresponding to a post-translational modification
are found between an experimental peptide and a theoretical peptide for that
protein, FindMod applies a set of intelligent rules to make predictions as to
which amino acids within the peptide, if any, might carry the
modification.)). We therefore also agree with the Examiner that Wilkins
meets the seventh, or “determining,” step of claim 1.
Because we agree with the Examiner that Wilkins discloses a process
having all of the steps recited in claim 1, we agree with the Examiner that
Wilkins anticipates claim 1.
Appellant argues that:
Wilkins does not teach adjusting an experimentally
measured mass or mass to charge ratio in response to one or
more modifications of interest to determine a theoretical
unmodified mass or mass to charge ratio of at least one peptide,
and searching a peptide databank with the theoretical
unmodified mass or mass to charge ratio, as recited by claim 1.

(App. Br. 11; see also Reply Br. 2-3.) Rather, Appellant argues, Wilkins’
FindMod method is used after conventional database searching, and Wilkins
explicitly discloses that the FindMod-based method of identifying modified
proteins dissociates the process of identification from conventional database
searching with experimental masses (App. Br. 12, citing Wilkins 646, right
col., ll. 18-29 (first full paragraph) (see also FF 5)).
Appellant’s argument does not persuade us that claim 1 fails to
encompass Wilkins’ process. We agree with Appellant that Wilkins’ initial
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search of the “conventional” database is performed using the experimentally
derived peptide mass data. However, claim 1 is not limited to searching any
particular data set. Thus, in addition to the initial search, Wilkins also
discloses “[c]alculat[ing] mass differences between [the query] peptide and
all theoretical peptides” (Wilkins 647 (FF 6)); see also see also Wilkins 646
(FF 5) (“FindMod is then used to search for protein post-translational
modifications by comparing experimental peptide masses that did not match
with the protein against those calculated from the assigned protein sequence,
seeking mass differences that may be due to post-translational
modification.”) (emphasis added)).
Wilkins therefore searches the data set of all theoretical unmodified
peptides. Moreover, because that search is based on a calculation of the
mass differences between the experimentally measured protein and all
theoretical peptides, that search necessarily “us[es] [the] theoretical
unmodified mass,” which is all that claim 1 requires.
In sum, we agree with the Examiner that Wilkins discloses a process
that meets all of the limitations of claim 1. We therefore affirm the
Examiner’s rejection of claim 1 as anticipated by Wilkins. Because they
were not argued separately, claims 2, 3, 6-9, and 12-35 fall with claim 1.
37 C.F.R. § 41.37(c)(1)(vii).
OBVIOUSNESS
Claims 1-3, 6-9, and 12-35 stand rejected under 35 U.S.C. § 103(a) as
being obvious over Wilkins (Ans. 3-4). The Examiner concedes that
Wilkins does not meet the claim limitations regarding the tolerance between
the experimentally determined masses and the theoretical unmodified
masses (Ans. 3).
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The Examiner nonetheless concludes:
It would have been obvious to one of ordinary skill in the
art at the time the invention was made to choose the mass
tolerance between the theoretical unmodified mass or mass to
charge ratio of the peptide and the mass or mass charge ratio of
peptides listed in the databank falls <0.01 Da, and the mass to
charge ratio tolerance between the theoretical unmodified mass
or mass to charge ratio of the peptide and the mass or mass
charge ratio of peptides listed in the databank falls ≤0.1 mass to
charge ratio units in the method of Wilkins because Wilkins
teaches that one can choose a user-specified mass tolerance
value to predict the modification of the peptides (page 654,
right column, 1st paragraph, lines 10-14[)]. One would have
been motivated to make the modification because Wilkins
described one way to improve the quality of predictions is for
user to choose a specific mass tolerance value, and would
reasonably have expected success because the less the mass
tolerance value the more accurate the prediction will be . . . .
(Ans. 4.)
Appellant limits the argument regarding the Examiner’s conclusion of
obviousness to whether the Examiner erred in finding that Wilkins teaches
or suggests all of the limitations of claim 1 (see App. Br. 15-18).
Specifically, Appellant urges that Wilkins fails to provide motivation for
modifying its process to achieve a process having the steps recited in claim 1
(id. at 17-18), and further notes that Wilkins teaches away from the process
of claim 1 because it teaches that the peptide mass fingerprinting procedure
should be dissociated from protein characterization (id. at 18 (citing Wilkins
646)).
We are not persuaded by these arguments. As discussed above, we
agree with the Examiner that Wilkins meets all of the limitations of claim 1.
It is well settled that “anticipation is the epitome of obviousness.” Connell
v. Sears, Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir. 1983). We
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therefore affirm the Examiner’s obviousness rejection of claim 1. Because
they were not argued separately, claims 2, 3, 6-9, and 12-35 fall with claim
1. 37 C.F.R. § 41.37(c)(1)(vii).

SUMMARY
We affirm the Examiner’s rejection of claims 1-3, 6-9, and 12-35
under 35 U.S.C. § 102(b) as anticipated by Wilkins.
We also affirm the Examiner’s rejection of claims 1-3, 6-9, and 12-35
under 35 U.S.C. § 103(a) as being obvious over Wilkins.
AFFIRMED

clj

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