Ex Parte LeicesterDownload PDFBoard of Patent Appeals and InterferencesAug 28, 200810947833 (B.P.A.I. Aug. 28, 2008) Copy Citation 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). 2 Appeal 2008-3930 Application 10/947,833 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. 3 Appeal 2008-3930 Application 10/947,833 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: 4 Appeal 2008-3930 Application 10/947,833 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)): 5 Appeal 2008-3930 Application 10/947,833 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 6 Appeal 2008-3930 Application 10/947,833 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] 7 Appeal 2008-3930 Application 10/947,833 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. 8 Appeal 2008-3930 Application 10/947,833 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 9 Appeal 2008-3930 Application 10/947,833 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). 10 Appeal 2008-3930 Application 10/947,833 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 11 Appeal 2008-3930 Application 10/947,833 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 WATERS INVESTMENTS LTD. c/o WATERS CORPORATION 34 MAPLE STREET - LG MILFORD, MA 01757 12 Copy with citationCopy as parenthetical citation