DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election with traverse of species: Protein digest and Chromatographic separation parameters in the reply filed on 16 January, 2026 is acknowledged.
The traversal is on the following grounds: (I) The species identified by the Restriction Requirement are all directed to the same category of invention, and (II) The Restriction Requirement has not identified any further reasons for a lack of unity; rather the international searching authority found that the unity requirement was satisfied. Applicants’ argument have been fully considered, but are not found persuasive because the test for distinct inventions is whether the product as claimed can be used in a materially different process. Furthermore, the product and method claims raise different and complex issues under 35 U.S.C. 112 and 101.
Group I (Protein digest) and Group II (Chromatographic separation parameters) lack unity of invention because even though the inventions of these groups require the technical feature of antigen binding protein, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of US 2005/0161399. US 2005/0161399 teaches reversed-phase liquid chromatography/mass spectrometry method of analysis of high molecular weight proteins including antibodies.
Claims 6, 7, 10, 15, 16, 19, 24, 27-36 and 38-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Elected species protein digest with trypsin endopeptidase and chromatographic separation parameters as specified in example 5 were searched. These species are not free of the prior art, also is subject to a non-statutory double patenting rejection.
The search was extended and prior art was found, which is included in the scope of claims 1-5, 8, 9, 11-14, 17, 18, 20-23, 25, 26, and 37. The search was not extended further in accordance with MPEP § 803.02.
Priority
The present application filed 05/03/2023 is a 371 of PCT/US2021/57519 filed 11/01/2021 which claims benefit of US Provisional Patent Application 63/110,087 filed 11/05/2020. The benefit is acknowledged and the claims examined herein are treated as having an effective filling date of 11/05/2020.
Status of Claims/Application
Claims 1-5, 11-14, 17-18, 20-23, 25-26, and 43-44 are pending.
Claims 1 and 25 have been amended. Claims 8, 9, and 37 have been canceled. New claims 43 and 44 are added. Claims 1-5, 11-14, 17, 18, 20-23, 25, 26, 43 and 44 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement including foreign patent document filed 06/10/2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because a copy of translated abstract of JP’196 has not been provided. The information disclosure statement requires a legible copy of each cited foreign patent document. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Drawings
The subject matter of this application admits of illustration by a drawing to facilitate understanding of the invention. Applicant is required to furnish a drawing under 37 CFR 1.81(c). No new matter may be introduced in the required drawing. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d).
Objections/Rejections Withdrawn
Objections and/or rejections not reiterated from previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Updated - Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 18, 20, 21, 43 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005, cited in IDS filed June 10, 2026), and in view of U.S. Patent No. 7,765,068 (issued July 27, 2010).
US’399 teaches a method for analyzing an antibody or a fragment comprising: (a) preparing an antibody or fragment for loading onto a reversed-phase chromatography column; (b) separating the antibody or fragment by reversed-phase chromatography using column, where the eluate from the reversed-phase chromatography is introduced into a device in-line with the reversed-phase chromatography column that determines the presence of the antibody or antibody fragment and (c) detecting the presence of antibody or fragment where the mobile phase of reversed-phase chromatography column comprises a water miscible organic solvent (see claim 16). US’399 discloses that the antibody derived fragments may be derived through proteolytic cleavage or chemical cleavage (see [0023]). US’399 teaches the methods of the invention typically may be used to analyze antibodies or fragments of antibodies (e.g., products of disulfide bond reduction, proteolytic or chemical cleavage). The antibody fragments can be any size. Preferably, the antibody fragments are four fragments (two light chains (25 kDa each) and two heavy chains (50 kDa each)) produced by reduction or alternatively or are fragments (Fc (50 kDa), and Fab(50 kDa)) (see [0049]).
Examiner’s Note: This is in correlation with the instant specification which states In some embodiments, the protein processed in any of the methods described herein is a therapeutic protein. In exemplary aspects, the therapeutic protein is an antibody. As used herein, the term "antibody" refers to a protein having a conventional immunoglobulin format, comprising heavy and light chains, and comprising variable and constant regions. For example, an antibody can be an IgG which is a "Y-shaped" structure of two identical pairs of polypeptide chains, each pair having one "light" (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa) (see [0051]).
However, US’399 is silent about “fragmenting the protein, thereby producing at least ten polypeptides” as recited in claim 1.
US’068 discloses a method of determining the structure and origin of a sample protein fragment, comprising: collecting an MS/MS spectrum of the sample protein fragment, identifying the mass of the sample protein fragment, preparing a first set of candidate fragments from the sample protein fragment (see claim 1); further comprising scoring the candidate sequences in the first set of candidate fragments, by comparing mass spectrometry fragment ion masses of the candidate sequences in the first set of candidate fragments, with mass spectrometry fragment ion masses of the sample protein fragment (see claim 4); A method of determining the structure and origin of a sample protein fragment, comprising:
collecting an MS/MS spectrum of the sample protein fragment, identifying the mass of the sample protein fragment, preparing a first set of candidate fragments from the sample protein fragment and a plurality of protein sequences selected from a protein sequence database, comprising: including in the first set of candidate fragments subsequences of the protein sequences in the plurality of protein sequences, wherein the candidate fragments have a mass which is the same as a mass of the sample protein fragment within a tolerance; scoring the candidate fragments, by comparing mass spectrometry fragment ion masses of the candidate fragments with mass spectrometry fragment ion masses of the sample protein fragment;
selecting a subset of candidate fragments (see claim 5); wherein the sample protein fragment is the candidate fragment with the mass spectrometry fragment ion masses most similar to the mass spectrometry fragment ion masses of the sample protein fragment (see claim 6); wherein the sample protein fragment is from a human (see claim 11). US’068 provide specific example of ten fragment ion masses match up to a peptide from 60S ribosomal protein (see col 5, line 49-51, FIG. 4A) where “fragment ions” is defined as referring to fragments of a polypeptide generated by mass spectrometry (col 4, line 21-22); a protein fragment results from degradation ….by intentional use of a protease; a fragment ion is produced in the gas phase by MS/MS (see col 5, line 35-37).
Regarding claim 1, US’399 teaches a method for analyzing an antibody or a fragment, comprising preparing a sample comprising the antibody or fragment for loading onto a high- performance liquid chromatography (HPLC) column; separating the antibody or fragment from the sample by reversed-phase HPLC on the column, where the eluate from the reversed-phase HPLC (see [0025]). US’399 discloses Peaks 1 and 9 are low MW and high MW fragments of the antibody generated after cleavage (see FIG 6) where the deconvoluted electrospray mass spectrum of low MW fragment (peak 1 on FIG. 6) of the IgG2 sample measured MW value of the main fragment 12370.0 Da and (peak 9 on FIG. 6) of the IgG2 sample measured MW value of the main fragment 97928 Da (see [0037-0039]). Additionally, US’068 teaches a method of preparing a first set of candidate fragments from a sample protein fragment and a protein sequence (see abstract), comprising of ten fragment ion masses (see col 5, line 49-50, FIG. 4A).
Additionally, US’399 discloses that the gradient is established comprising introducing a mixture of a first solvent A and a second solvent B as the mobile phase for chromatographic separation, where first solvent A comprises a mixture at pH 2.0 of water and trifluoracetic acid (TFA) and said second solvent B comprises a mixture at pH 2.0 of 70% isopropanol, 20% acetonitrile 9.9% water and 0.1% TFA (see [0174]). Further teaches the solvents useful in the mobile phase of the present invention include alcohols selected from the group consisting of n-propanol, isopropanol, n-butanol and isobutanol (see [0016]). The mobile phase comprises a gradient of isopropanol from 5% propanol to 90% propanol (see claim 10). In other embodiments, the mobile phase comprises a gradient of isopropanol from 10% isopropanol to 60% isopropanol (see [0021]); 20% acetonitrile 9.9% water and 0.1% TFA (see [0022]); the isopropanol is present at least at 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% more of the mobile phase (see [0073]).
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to combine the protein characterization conditions as taught by US’399 to isolate the antigen-antibody binding specific fragments of the complementarity determining region and fragmentation of the protein sample as taught by US’068 to arrive at the presently claimed invention. Based on the teachings of US’399 and US’068 above, it would have been obvious to optimize the experimental conditions/parameters within which the ten fragment separation could be efficiently administered. Prior art range of solvents (TFA, acetonitrile, and alcohol) fully overlaps and is broader than claimed range. Therefore, the claimed invention was prima facie obvious to the artisan of ordinary skill in the art. It would have been prima facie obvious for one of ordinary skill in the art to modify the teachings of US’399 with the expectation to achieve success in enhancing drug efficacy through antigen-antibody mediated binding properties of proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Regarding claims 18 and 43, US’399 teaches protein fragments as used are fragments of a large protein created by cleaving the protein using limited proteolysis with an enzyme or chemical cleavage by reducing the disulfide bonds. For example, an IgG1 antibody can be effectively cleaved by Lys-C protease to generate Fc domain (50 kDa) and two Fab domains (50 kDa each) over a short time period below 1 hour. An IgG2 antibody can be cleaved with pepsin protease to generate Fc domain (50 kDa) and (Fab).sub.2 domain (100 kDa). An IgG1 or IgG2 antibody can be reduced to produce two light chains (25 kDa each) and two heavy chains (50 kDa each). These examples illustrate that the above methods produce antibody fragments, which are, in general, larger than 20 kDa (see [0050]). RP-HPLC is able to separate polypeptides of nearly identical sequences, not only for small peptides such as those obtained through trypsin digestion, but even also for proteins as large as 5,300 Da(see [0055]). The N-terminal (variable) domains of both HCs and LCs contain variable CDRs. These variable CDR domains determine the specificity of interaction of the immunoglobulin with the antigen (see [0126], page 15, col 2 and FIG 12). The selectivity of separation of the antibody variants was increased after the antibody was reduced and alkylated to generate two components: 24 kDa LC and 50 kDa HC (see [0136], Example 5). US’399 discloses high molecular weight protein has a molecular mass of about 90 kDa (see claim 11). US’399 further discloses high molecular weight protein has been cleaved to protein fragments having a molecular mass of 80 kDa (see claim 12).
Regarding claim 20, US’399 teaches the method of determining the presence of the antibody or antibody fragment is a mass spectrometer positioned in-line with reversed-phase chromatography column such that the eluate from the reversed-phase column is introduced into the ion source of said mass spectrometer, and where mass spectrometer provides mass fragmentation data for the antibody or antibody fragments (see claim 17).
Regarding claim 21, US’399 teaches the methods of the invention are particularly useful in determining the integrity of an antibody and in particular a therapeutic antibody (see [0115]).
Regarding claim 44, US’399 isopropyl alcohol as eluotropic solvent (see Table [0070]).
Response to Arguments
II. Applicant’s arguments, see Pg 5-6, filed 6/10/2026, with respect to the rejection of claims 1, 18, 20, and 21 under 35 U.S.C. 102(a)(1) have been fully considered and are persuasive. Specifically, the argument that fragmenting the protein, thereby producing at least ten polypeptides as recited in part of instant claim 1; and on the other hand US 2005/0161399 (hereafter US’399) specifically does not teach digestion into at least ten (smaller) polypeptides. For these reasons, the 35 U.S.C. 102(a)(1) rejection of the above claims have been withdrawn.
Applicant's arguments filed 6/10/2026 have been fully considered but they are not persuasive in view of the modified grounds of rejected necessitated by amendment.
Examiner would like to remind the applicant that US’399 does disclose high molecular weight protein has been cleaved to protein fragments (see claim 12); the antibody derived fragments may be derived through proteolytic cleavage or chemical cleavage (see [0023]); in another embodiment, the chemical cleavage was performed by reducing the disulfide bonds in the protein or fragments thereof (see [0027]). US’399 teaches method directed to analysis of high molecular weight proteins, more specifically, it is directed to a novel reversed-phase LC/MS method of analysis of high molecular weight proteins including antibodies (see Abstract) and antibody conjugates or fragments (see [0003]). US’399 teaches the methods of analyzing the proteins described herein will be particularly useful in determining the structural integrity of a protein (see [0028]). US’399 also presents schematic of LC/MS method of analysis for large proteins (see FIG 1, [0032]). US’399 demonstrated that the RP-HPLC/MS produces that most effective separation and analyses (see [0064]). US’399 teaches that peptide mapping approach involves laborious sample preparation and data interpretation procedures and may introduce artificial disulfide scrambling, and exemplifies reversed-phase HPLC/MS analyses of intact antibodies presented herein does not require any sample preparation, it is quick and the data are easy to interpret and readily provides a method of monitoring disulfide re-arrangement at the hinge region of IgG2 using RP HPLC/MS of intact antibodies (see [0126]). Further, US’399 teaches the characterization and/or consistency of manufacture of a given protein often relies on peptide mapping in order to monitor the amino acid sequence and/or conformational properties of the protein being analyzed. While peptide mapping and analysis of intact proteins are able to detect small changes in small- to moderate-sized proteins (see [0005]), and the analysis of these larger proteins by peptide mapping is thus, hindered by the complexity of the range of peptides generated by timely enzymatic digestion or non-specific catalytic or hydrolytic digestion of the protein and separation of the multiple peptides. Therefore, reversed-phase (RP) HPLC of large proteins is an attractive alternative approach to peptide mapping, because the former method often does not require any sample preparation and is relatively simple in data interpretation (see [0005]).
US’068 teaches a method of preparing a first set of candidate fragments from a sample protein fragment and a protein sequence (see abstract), comprising of ten fragment ion masses (see col 5, line 49-50, FIG. 4A).
For this reason, a new claim rejection under 35 U.S.C. 103 have been modified herein.
Examiner’s Note: Protein digestion/cleavage along with LC-MS mass spectrometry is a standard technique utilized for peptide mapping. See Mouchahoir et.al. Peptide mapping is a component of the analytical toolbox used within the biopharmaceutical industry to aid in the identity confirmation of a protein therapeutic and to monitor degradative events such as oxidation or deamidation (see Abstract), and because peptide mapping can provide a rather comprehensive and specific profile of a biological substance/product in one analytical package, efforts are being made to promote the development of qualified LC-MS peptide mapping assays for extended use in process monitoring and quality control (see page 2112, left col, paragraph 2).
Claims 2, 5, 23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005, cited in IDS filed June 10, 2026), in view of U.S. Patent No. 7,765,068 (issued July 27, 2010), as applied to claims 1, 18, 20, 21, 43 and 44 above, and further in view of Rock et. al. (“CDR3 length in antigen-specific immune receptors”, Journal of Experimental Medicine, 179(1), January 1, 1994, pp. 323–328).
The teachings of US’399 and US’068 are discussed above.
US’399 teaches the methods of analysis of portions of an antibody, such as e.g., an Fab, Fc, heavy chain (HC) and light chain (LC) regions of an antibody or combinations. The antibody derived fragments may be derived through proteolytic cleavage or chemical cleavage (see [0023]). The antibody fragments are four fragments (two light chains (25 kDa each) and two heavy chains (50 kDa each)) produced by reduction or alternatively or are fragments (Fc (50 kDa), and Fab(50 kDa)) produced by limited proteolysis (see [0049]).
US’399 further teaches that the therapeutic function of antibodies is achieved through complementarity defining regions (CDRs) located in the variable region of heavy chain and variable region of light chain. The amino acid sequence of CDRs is chosen such a way as to give the antibody a strong affinity towards a target and block the development of a disease (see [0124], Example 4).
US’399 do not teach about the specific complementarity determining region3 (CDR3) of a variable region of the antigen binding protein that comprise heavy chain (HCDR3) and/or light chain (LCDR3).
Rock et. al. teach CDR3 loops are often critical for antigen binding in Igs (immunoglobulins) and appear to provide the principal peptide binding residues in TCRs (T cell receptors) (see abstract). Structural analysis of antibody-antigen complexes shows that one or both of the CDR3 loops of Ig H and L chains are always involved in antigen contact (see paragraph 1, page 323). Rock et. al. disclose gamma and delta chain CDR3s are more like those of Ig than alpha/beta TCR in both the disparity between heterologous chains of average CDR3 lengths and the pronounced variability of H and delta chain lengths. This suggests that gamma/delta TCRs as a group may recognize antigens in a manner akin to Ig (see paragraph 4, page 326).
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the protein characterization method taught by US’399 and US’068 to isolate the antigen-antibody binding specific fragments of the complementarity determining region taught by Rock et. al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in enhancing drug efficacy through antigen-antibody mediated binding properties of proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Regarding claims 2, 5, and 26, US'399 teach the immunoglobulin molecule consists of two heavy chains (HCs) and two light chains (LCs). The N-terminal (variable) domains of both HCs and LCs contain variable CDRs. These variable CDR domains determine the specificity of interaction of the immunoglobulin with the antigen and are referred to as the VH and VL domains, respectively, for the HC and the LC (see [0126]).
Regarding claim 23, Rock et. al. analyses do indicate that gamma/beta TCRs are much more similar in their CDR3 lengths to Ig (see paragraph 3, page 323).
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Response to Arguments
Applicant's arguments filed 06/10/2026 have been fully considered but they are not persuasive.
Applicant argues modifications to the method of US 2005/0161399 are not obvious over US 2005/0161399 alone, or in view of Dillon I. Rock has been asserted to disclose various regions that may be part of antibodies. The possible existence of such regions does nothing to remedy the deficiencies of US 2005/0161399, nor Dillon I. Thus, Rock has not been shown to remedy the deficiencies of the other references. Examiner reminds the Applicant that for claims 2, 5, 23, and 26 , Dillon et. al. was not used as a prior art. "A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). Also, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). One motivated to combine the teachings of US’399 and Rock et. al. would have a reasonable expectation of success, in isolating the antigen-antibody binding specific fragments of the complementarity determining region.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005, cited in IDS filed June 10, 2026) in view of Dillon et. al. (“Optimization of a reversed-phase high-performance liquid chromatography/mass spectrometry method for characterizing recombinant antibody heterogeneity and stability”, Journal of Chromatography A, 1120, January 30, 2006, pp. 112–120, filed with IDS dated 05/03/2023).
US’399 teaches one LC is connected to one HC at the hinge region by a single disulfide bond. Two HCs are connected together by two disulfide bonds closely positioned in the hinge region between domains CH1 and CH2. In IgG2, one LC is connected to one HC between CH2 and CH2 region by a single disulfide bond. Two HCs are connected together by four disulfide bonds closely positioned in the hinge region between domains CH1 and CH2 (see [0126], FIG. 12). They proposed that the following modifications may be responsible for the heterogeneity: 1) deamidation of asparagine residue into aspartic acid residue (+1 Da); 2) isomerization of aspartic acid residue into isoaspartic acid residue (0 Da); 3) a reduced disulfide bond (+2 Da); 4) disulfide re-arrangement within the cysteine residues at the hinge region of IgG2 (disulfide bond scrambling). Their approach to resolve the disulfide arrangement includes labeling of free cysteine residues at low pH, peptide map of non-reduced protein followed by reduction. This peptide mapping approach involves laborious sample preparation and data interpretation procedures and may introduce artificial disulfide scrambling. The reversed-phase HPLC/MS analyses of intact antibodies presented herein does not require any sample preparation, it is quick and the data are easy to interpret and readily provides a method of monitoring disulfide re-arrangement at the hinge region of IgG2 using RP HPLC/MS of intact antibodies (see [0130]). US’399 teaches RP-HPLC/MS has been used to identify the structure of the antibodies eluted from the HPLC, the elution can be used to monitor disulfide re-arrangement at the hinge region of IgG2 (see [0131]).
Dillon et. al. teaches peptide mapping of collected RP fractions was also used to confirm that no significant differences in chemical modifications were present (see 3.1. Reversed-phase method development, paragraph 7, page 115). Dillon et. al. also teach the protein in the collected fraction has remained soluble, it can then be digested for peptide mapping and/or directly infused into a mass analyzer (see 4.2. Identification of a unique terminal ladder amino acid sequence, page 118). Dillon et. al. further teaches peptide mapping will continue to be a standard method for non-routine antibody analysis, this novel method requires minimal sample preparation and data analysis to determine the molecular weight by deconvolution of electrospray mass spectra (see Discussion, paragraph 1, page 118).
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the protein characterization method taught by US’399 along with implementation of protein structural mapping approach taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success with advanced characterization methods and testing assays with topographical and domain information of proteins in biopharmaceutical research. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005, cited in IDS filed June 10, 2026) in view of Dillon et. al. (“Optimization of a reversed-phase high-performance liquid chromatography/mass spectrometry method for characterizing recombinant antibody heterogeneity and stability”, Journal of Chromatography A, 1120, January 30, 2006, pp. 112–120, filed with IDS dated 05/03/2023).
The teachings of US’399 are discussed above. However, US’399 do not specify the composition of the protein molecules/polypeptides consisting of antibody or antigen-binding fragment, derivative of an antibody or antibody fragment, or a fusion polypeptide.
Dillon et. al. teach the reversed-phase method was required to improve the chromatography of these more hydrophobic antibodies and to resolve the variants and
degradants associated with antibody heterogeneity and stability (see Results, 1st paragraph). The ability to resolve the variants and degradants associated with antibody heterogeneity and stability was a critical factor in column selection (see Results; 3.1 Reversed-phase method development, 4th paragraph). Dillon et al. identified the fragment antigen-binding (Fab) portion of the IgG1 by the unique fragmentation pattern that was identified to be in a conserved region of the upper hinge. Respective peaks were identified as light chain, the N-terminal portion of the heavy chain above the hinge, and the IgG missing one of the Fab regions (see Results; 3.2 Pharmaceutical applications of the method, 2nd paragraph, Fig. 7). Dillon et al. teaches LC/MS analysis of antibodies represents a significant new tool to elucidate the structural basis of antibody heterogeneity and its possible implications on function (see Discussion, 4.4 Mechanism of enhanced chromatography, last paragraph).
At the time before the effective filing date of the claimed invention, it would have been prima facie obvious to one ordinary skill in the art to substitute the types of protein characterized by the method as taught by US’399 with wider range of protein selection from the group consisting of an antibody or antigen-binding fragment, derivative of an antibody or antibody fragment, and a fusion polypeptide taught by Dillon et. al. to arrive at the presently claimed invention. The artisan of ordinary skill would have been motivated to do so with a reasonable expectation of success because protein fragmentation followed by purification method can be utilized for more complex protein structures or other fusion proteins as taught by Dillon et al. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Response to Arguments
Applicant's arguments filed 06/10/2026 have been fully considered but they are not persuasive.
Applicant argues the skilled person in view of US 2005/0161399 would have no reason
to modify the cited method of US 2005/0161399 to digest a larger protein into many smaller polypeptides. Rather, such a modification would be a legally impermissible change to the principle of operation of US 2005/0161399. Examiner reminds the Applicant that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
As discussed above, protein digestion/cleavage along with LC-MS mass spectrometry is a standard technique utilized for peptide mapping. MW measured by US’399 ranges from 12 kDa – 98 kDa. Based on the US’399 FIG 6 data, it is exemplified that lower MW weight fragments have been separated with good resolution. The instantly claimed invention specifies the antibody protein product has a molecular-weight within the range of at least about 12-150 kDa (see instant Specification [0055]), which implies that the 12 kDa – 98 kDa fragments may fall within the fragment size of the instantly claimed invention. It would have been obvious to one of ordinary skill in the art to utilize the protein characterization method taught by US’399 along with implementation of protein structural mapping approach taught by Dillon et. al. to arrive at advanced characterization methods and testing assays with topographical and domain information of proteins in biopharmaceutical research.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005, cited in IDS filed June 10, 2026) in view of Dillon et. al. (“Development of an analytical reversed-phase high-performance liquid chromatography–electrospray ionization mass spectrometry method for characterization of recombinant antibodies”, Journal of Chromatography A, 1053, September 17, 2004, pp. 299–305,).
US’399 teaches the gradient is established comprising introducing a mixture of a first solvent A and a second solvent B as the mobile phase for said HPLC, where the first solvent A comprises a mixture at pH 2.0 of water and trifluoracetic acid (TFA) and the second solvent B comprises a mixture at pH 2.0 of 70% isopropanol, 20% acetonitrile 9.9% water and 0.1% TFA (see [0022]). In the instant claims, the use of TFA as a polar solvent in RP-HPLC for better resolution of peptides and proteins and due to its high polarity, it elutes early in chromatography. Thus the mixture of solvent A constitutes a polar mobile phase solvent.
US’399 do not teach the use of 0.05% - 0.09% of TFA as the mobile phase B solvent in RP-HPLC. However, US’399 also points out that inclusion of TFA in the mobile phase of HPLC suppresses the signal produced in MS analysis (see [0074]).
Additionally, Dillon et. al. teaches 0.09% TFA and 90% acetonitrile for mobile phase B. A lower level of TFA (0.01–0.05%) is preferred when coupled with online mass spectral analysis in order to minimize ion suppression during the electrospray process with a minimal loss
in resolution capabilities (see 3.1. Method development, paragraph 6, page 302). Dillon et al disclose that in order to increase the MS signal intensity, the percentage of the acids
was decreased to 0.05% TFA (see 3.2 Applications, paragraph 1, page 303).
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the protein characterization method taught by US’399 along with optimization mobile phase for characterizing monoclonal antibody taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success with improved chromatography and better resolution of antibody fragment variants. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 11-13, 14, 17, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005, cited in IDS filed June 10, 2026) and U.S. Patent No. 7,765,068 (issued July 27, 2010), as previously applied to claim 1, 18, 20, 21, 43 and 44, and further in view of Dillon et. al. (“Development of an analytical reversed-phase high-performance liquid chromatography–electrospray ionization mass spectrometry method for characterization of recombinant antibodies”, Journal of Chromatography A, 1053, September 17, 2004, pp. 299–305).
The teachings of US’399 and US’068 are discussed above.
US’399 teaches about the using C8 or C18 stationary phase that has been modified such that the radius of curvature inside the pore (120 angstroms) approached the size of the protein molecule being analyzed. In certain embodiments, methods of the invention are employed for the analysis of antibodies. It is contemplated that in such embodiments employing a stationary phase having a pore size of from about 150 .ANG. to about 350 .ANG. may be particularly useful (see [0067]). US’399 discloses commonly used materials are dextran, cellulose, agarose and copolymers of styrene and vinylbenzene in which the divinylbenzene both cross-links the polystyrene strands and contains the charged groups. Table 2 gives the composition of many ion exchangers (see [0088]). In the instant claim, divinylbenzene resin column (AGILENT) are used which has a standard pore size between 3um-10um.
US’399 further teaches that the porosity of the matrix is an important feature because the charged groups are both inside and outside the matrix and because the matrix also acts as a molecular sieve. Large molecules may be unable to penetrate the pores; so the capacity will decease with increasing molecular dimensions. The porosity of the polystyrene-based resins is determined by the amount of cross-linking by the divinylbenzene (porosity decreases with increasing amounts of divinylbenzene) (see [0090]).
US’399 do not teach about the particle size of the column matrix as set forth in claims 11, and 13. Also, US’399 do not disclose the chromatography column height as set forth in claim 14
Dillon et. al. teaches the optimized methods employed a Zorbax SB300 C8 column (150mm × 4.6 mm, 3.5um particle size, 300 °A pore size) and a Polaris C8-ether column (150mm × 4.6 mm, 3.0um particle size, 200 °A pore size) (see 2.2 Reversed-phase HPLC, paragraph 1, page 301). Dillon et al. discloses using the Zorbax SB300 C8 column of 3.5um particle size and 300 °A pore size (see 3.1 Method Development, paragraph 3, page 302). Dillon et al. teaches the preferred columns were a Zorbax SB300 C8 column (150mm × 4.6 mm, 3.5um particle size, 300 °A pore size) and a Polaris C8-ether column (150mm × 4.6 mm, 3.0um particle size, 200 °A pore size) (see 3.1 Method Development, paragraph 6, page 302).
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the parameters of RP-HPLC for characterization of antibodies taught by US’399 and method of determining the structure and origin of a sample protein of ten fragments as taught by US’068, along with enhanced chromatographic column composition and height taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success with enhanced chromatographic separation efficiency, analysis time, and better resolution of antibody variants and hydrophobic proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Response to Arguments
Applicant's arguments filed 06/10/2026 have been fully considered but they are not persuasive.
III. Applicant argues that for each of the noted claims (4, 25, 11-13, 14, and 17), the Office Action alleges that the disclosure of US 2005/0161399 could have been modified with various parameters. For completeness, it is noted that the species elected for search was the digest and chromatography parameters of Example 5, the Office Action at p. 3 asserts that the species were not free of the prior art. However, the Office Action has not identified any art-based teaching comprising every parameter of Example 5, such as an Agilent PLRP-S column and 40% isopropyl alcohol / 40% Acetonitrile / 20% water as mobile phase B. As such, Applicant respectfully disagrees with any allegation that US 2005/0161399 would disclose every feature of Example 5.
However, as set forth in the rejections of record, US’399 shows experimental results with clear drawings of protein fragment eluents with MW labels, and schematic of an exemplary method of analysis. The instantly claimed invention Examples (including Example 5) provides results table, however, no experimental data including protein fragment analysis profiles, chromatograms, identification of cleavage sites, etc. were provided.
Regarding experimental parameter: set forth in instant Example 5, the use of Agilent PLRP-S column is addressed above. US’399 used columns comprising divinylbenzene (DVB) which is a same composition as used in the instantly claimed invention.
Regarding Application teaching a particular method that achieves technically advantageous results: no experimental data including protein fragment analysis profiles, chromatograms, identification of cleavage sites were provided.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
For the Applicant Argument: No reason to decrease the amount of TFA in US’399 in view of Dillon et. al.
As discussed above, US’399 points out that inclusion of TFA in the mobile phase of HPLC suppresses the signal produced in MS analysis (see [0074]). Also, Dillon et al. teaches 0.09% TFA and 90% acetonitrile for mobile phase B; and a lower level of TFA (0.01–0.05%) is preferred when coupled with online mass spectral analysis in order to minimize ion suppression during the electrospray process with a minimal loss in resolution capabilities (see 3.1. Method development, paragraph 6, page 302). Dillon et. al. disclose that in order to increase the MS signal intensity, the percentage of the acids was decreased to 0.05% TFA (see 3.2 Applications, paragraph 1, page 303).
For the Applicant Argument: No reason to fragment a protein into at least ten polypeptides
As discussed above, US’068 teaches a method of determining the structure and origin of a sample protein fragment, comprising: collecting an MS/MS spectrum of the sample protein fragment, identifying the mass of the sample protein fragment, preparing a first set of candidate fragments from the sample protein fragment (claim 1); collecting an MS/MS spectrum of the sample protein fragment, identifying the mass of the sample protein fragment, preparing a first set of candidate fragments from the sample protein fragment (see claim 5); comprising ten fragment ion masses match up to a peptide (see col 5, line 49-51, FIG. 4A)
Additionally, The MW measured by US’399 ranges from 12 kDa – 98 kDa. Based on the US’399 FIG 6 data, it is exemplified that lower MW weight fragments have been separated with good resolution. The instantly claimed invention specifies the antibody protein product has a molecular-weight within the range of at least about 12-150 kDa (see instant Specification [0055]), which implies that the 12 kDa – 98 kDa fragments may fall within the fragment size of the instantly claimed invention.
Also, US’399 teaches the methods of the invention typically may be used to analyze antibodies or fragments of antibodies (e.g., products of disulfide bond reduction, proteolytic or chemical cleavage). The antibody fragments can be any size. Preferably, the antibody fragments are four fragments (two light chains (25 kDa each) and two heavy chains (50 kDa each)) produced by reduction or alternatively or are fragments (Fc (50 kDa), and Fab(50 kDa)) (see [0049]). This is in correlation with the instant specification which states In some embodiments, the protein processed in any of the methods described herein is a therapeutic protein. In exemplary aspects, the therapeutic protein is an antibody. As used herein, the term "antibody" refers to a protein having a conventional immunoglobulin format, comprising heavy and light chains, and comprising variable and constant regions. For example, an antibody can be an IgG which is a "Y-shaped" structure of two identical pairs of polypeptide chains, each pair having one "light" (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa) (see [0051]).
For the Applicant Argument: No reason to import column parameters from Dillon et. al.
The rejections are based on combinations of references and obviousness was not deduced by referring to single references individually. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The instantly claimed invention mentioned use of Agilent PLRP-S column, which has the same composition comprising DVB (see US’399) and column parameters (see US’3099 and Dillon et. al.). Agilent PLRP-S column had a range of products (see PLRP-S for Biomolecules | Polymeric Reversed Phase HPLC Columns | Agilent ), therefore, it is obvious to substitute equivalents known in the art for the same purpose.
For Applicant Argument: Superior and unexpected results further support the non-obviousness of the claims
Applicant argues Examples 3 through 5 provide experimental data demonstrating that the claimed methods, applied to different antibodies and different chromatography columns, achieve superior peptide recovery and superior peptide mapping coverage compared to conventional peptide mapping methods (See Examples 1 through 2). Further emphasizing the superior and unexpected nature of these results, the cited art, US’399 and Dillon I, does not even consider peptide mapping to be advantageous when attempting to obtain information about large molecules such as antibodies, and instead encourages alternative methods directed to whole antibodies or large domains thereof. It is well-established that unexpected results are a hallmark of non-obviousness. As discussed above, Examiner would like to remind the Applicant that "A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). As mentioned above, for instant Examples 3 through 5, no experimental data including protein fragment analysis profiles, chromatograms, identification of cleavage sites, etc. were provided. Results table itself is not sufficient enough to convince the superiority of results achieved. Applicants who allege the inventor discovered the source of a problem must provide evidence substantiating the allegation, either by way of affidavits or declarations, or by way of a clear and persuasive assertion in the specification. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (unsubstantiated statement of counsel was insufficient to show appellants discovered source of the problem); In re Kaslow, 707 F.2d 1366, 217 USPQ 1089 (Fed. Cir. 1983).
Maintained/Modified - Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 18, 20, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 7,329,353, (issued February 12, 2008), in view of US 2005/0161399 (published July 28, 2005, cited in IDS filed June 10, 2026) and U.S. Patent No. 7,765,068 (issued July 27, 2010). Although the claims at issue are not identical, they are not patentably distinct from each other.
US’353 claims a method of determining the presence of an antibody degradation product in an antibody sample, with a method comprising: (a) performing RP-HPLC on said antibody sample under conditions (claim 1); where the mobile phase of the reversed-phase HPLC comprises a water miscible organic solvent having a C18 eluotropic strength coefficient of at least 6.0, and (b) determining the molecular weight data of the components of the antibody sample using ESI-MS (claim 1). US’353 discloses correlating the molecular weight data from the antibody sample to data obtained from known protein standards (claim 2) and the known protein standard is an antibody sample that has not undergone degradation (claim 3). US’353 further claims that product selected from the group consisting of a dimer, a cleavage product, oxidation of the antibody sample, deamidation of the antibody sample, N-terminal pyroglutamation of the antibody sample and disulfide bond scrambling of the antibody sample (claim 4).
The US’353 differ from the instant claims in that they do not claim that TFA was used.
The teachings of US’399 and US’068 are discussed above. US’399 teaches that TFA satisfies requirements for RP-HPLC - the nonspecific interactions of the protein with the solid phase due to the negatively charged silanol groups on the solid phase are typically suppressed by maintaining low pH of the mobile phase and adding anionic pairing reagents to mask basic amino acid residues on the surface of protein (See ¶ [0075]) and a method of determining the structure and origin of a sample protein of ten fragments as taught by US’068.
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the parameters of RP-HPLC for characterization of antibodies taught by US’353 along with the preferred mobile phase solvent taught by US’399 and US’068 to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success with enhanced chromatographic separation efficiency, analysis time, and better resolution of antibody variants and hydrophobic proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Claims 4, 11-13, 14, 17, and 25, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 7,329,353, issued February 12, 2008 as discussed above and in view of Dillon et al. (“Development of an analytical reversed-phase high-performance liquid chromatography–electrospray ionization mass spectrometry method for characterization of recombinant antibodies”, Journal of Chromatography A, 1053, September 17, 2004, pp. 299–305) and U.S. Patent No. 7,765,068 (issued July 27, 2010).
The claims of US’353 and US’068 are as discussed above.
The claims differ from the instant claims in that they do not claim chromatography solvent conditions, column matrix composition and parameters.
The teachings of Dillon et al. are discussed above.
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the parameters of RP-HPLC for characterization of antibodies taught by US’353 along with enhanced chromatographic column composition and height taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success with enhanced chromatographic separation efficiency, analysis time, and better resolution of antibody variants and hydrophobic proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Claims 2, 5, 23, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 7,329,353, (issued February 12, 2008) and US 7,765,068 (issued July 27, 2010)as discussed above in view of Rock et al. (“CDR3 length in antigen-specific immune receptors”, Journal of Experimental Medicine, 179(1), January 1, 1994, pp. 323–328).
The claims of US’353 and US’068 are as discussed above.
The claims of US’353 and US’068 differ from the instant claims in that they do not teach about the specific complementarity determining region3 (CDR3) of a variable region of the antigen binding protein that comprise heavy chain (HCDR3) and/or light chain (LCDR3).
The teachings of Rock et al. are discussed above.
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the protein characterization method taught by US’353 and US’068 to isolate the antigen-antibody binding specific fragments of the complementarity determining region taught by Rock et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in enhancing drug efficacy through antigen-antibody mediated binding properties of proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Claims 3 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 7,329,353, issued February 12, 2008 as discussed above in view of Dillon et al. (“Optimization of a reversed-phase high-performance liquid chromatography/mass spectrometry method for characterizing recombinant antibody heterogeneity and stability”, Journal of Chromatography A, 1120, January 30, 2006, pp. 112–120, filed with IDS dated 05/03/2023).
The claims of US’353 are as discussed above.
The claims of US’353 differ from the instant claims in that they do not teach the structural mapping of the characterized protein fragments/peptides nor specify the composition of the protein molecules/polypeptides consisting of antibody or antigen-binding fragment, derivative of an antibody or antibody fragment, or a fusion polypeptide.
The teachings of Dillon et al are as discussed above.
At the time before the effective filing date of the claimed invention, it would have been prima facie obvious to one ordinary skill in the art to substitute the types of protein characterized by the method as taught by US’353 with wider range of protein selection from the group consisting of an antibody or antigen-binding fragment, derivative of an antibody or antibody fragment, and a fusion polypeptide taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill would have been motivated to do so with a reasonable expectation of success because protein fragmentation followed by purification method can be utilized for more complex protein structures or other fusion proteins as taught by Dillon et al. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Response to Arguments
Applicant argues that claims 1, 18, 20, and 21; 4, 8, 9, 11-13, 14, 17, 25, and 37; 2, 5, 23, and 26; and 3 and 22; were are rejected on the ground of nonstatutory double patenting over claims of U.S. Patent No. 7,329,353 in view of Dillon et. al. and/or Rock et. al. and U.S. Patent No. 7,765,068. Applicant has requested that the claims of U.S. Patent No. 7,329,353 are based on the same disclosure as US’399, the addition of these claims cannot remedy the deficiencies of US’399 as a whole. Examiner reminds the Applicant that "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
The request to hold the rejection has been noted and as no arguments regarding the merits of the rejection have been submitted, the rejection is maintained for reasons of record.
Conclusion
No claims are allowed.
Prior Art of Record
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Mouchahoir et.al. (“Development of an LC-MS/MS peptide mapping protocol for the NISTmAb”; Trina Mouchahoir & John E. Schiel; Analytical and Bioanalytical Chemistry (2018) 410:2111–2126; published February 7, 2018)
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KOYELI BANERJEE/ Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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