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 .
Response to Amendment
The Amendment filed 09/12/2025 has been entered. Claims 1, 3, 5, 7-12, 14-22, and 24-28 remain pending in the application. Claims 14-21 are withdrawn.
New grounds of rejections necessitated by amendments are discussed below.
Claim Objections
Claim 1 is objected to because of the following informalities: In line 18, “the one or more one or more” should read “the one or more”. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: In line 1, it is suggested to recite “DiCE” as “the DiCE”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 5, 7-12, 22, and 24-28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, claim 1 recites “ANTIGENB-Fd’ domain” and “ANTIGENA-Fd’ domain” in lines 19-20. It is unclear if “ANTIGENB-Fd’ domain” and “ANTIGENA-Fd’ domain” are specific and particular antigen domain structures or if the terms are used to denote two different types of antigen domains, such as a first antigen domain, i.e. antigen A, and a second antigen domain, i.e. antigen B. Claims 3, 5, 7-12, 22, and 24-28 are rejected by virtue of their dependency on claim 1.
Regarding claim 24, claim 24 recites “ANTIGENB” and “ANTIGENA” in lines 2-3. It is unclear if ANTIGENB and ANTIGENA are specific and particular antigens or if the terms are used to denote two different types of antigens, such as a first antigen, i.e. antigen A, and a second antigen, i.e. antigen B. Claim 25 is rejected by virtue of its dependency on claim 24.
Regarding claim 24, claim 24 recites “wherein the ANTIGENB-Fd' targets an ANTIGENB and the ANTIGENA-Fd' targets an ANTIGENA”. It is unclear if the method is further defining a positive step of the ANTIGENB-Fd' and ANTIGENA-Fd' physically targeting or interacting with ANTIGENB and ANTIGENA respectively, or if the term of “targets” is related to the function of the ANTIGENB-Fd' and ANTIGENA-Fd', i.e. configured to target. Since claim 1 digests, reduces, and denatures the bispecific antibody, is claim 24 requiring the separated ANTIGENB-Fd' and ANTIGENA-Fd' to target or interact with ANTIGENB and ANTIGENA after being separated? Claim 25 is rejected by virtue of its dependency on claim 24.
Claim Rejections - 35 USC § 103
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, 3, 5, 7-8, 22, and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over An et al. (Yan An et al., "A new tool for monoclonal antibody analysis, Application of IdeS proteolysis in LgG domain-specific characterization," mAbs 6:4, pages 879-893; July/August 2014; Landes Bioscience; cited in the IDS filed 11/15/2021) in view of Darwish et al. (US 20170370906 A1) and Davis et al. (US 20100331527 A1).
Regarding claim 1, An teaches a method for identifying one or more domain-specific charge variants of at least one antibody (abstract teaches techniques for characterization of antibody products, such as fragments from antibodies and antibody domains, i.e. identifying domain-specific charge variants of a protein, wherein analysis includes profiling of charge heterogeneity; Fig. 9 shows identifying acidic, main, and basic species, i.e. domain-specific charge variants; Fig. 10 shows identification of LC and HC, i.e. domain-specific charge variants; Fig. 11C shows identification of LC-A, Fc-A, LC+Fc, Fd-A, Fd, i.e. domain-specific charge variants; page 890, section “cIEF” teaches profiling, interpreted as including identifying, charge variants using cIEF), comprising:
treating the at least one antibody (page 889, section “Materials and Methods”, IgGs) with one or more digestion enzymes (page 889-890, section “IdeS digestion” teaches treating IgG with IdeS, i.e. digestion enzyme), to generate two or more components of the at least one antibody (Fig. 1 teaches digestion of IgG with IdeS, which generates two or more components, i.e. F(ab’)2 and Fc/2);
reducing and denaturing the two or more components using one or more reducing conditions and one or more denaturing conditions to generate one or more reduced and denatured domains of the at least one antibody (page 890, section “Reduction” teaches for cIEF analysis, DTT reduction as conducted, i.e. reducing, and section “cIEF analysis” teaches urea was added to the partially reduced samples, wherein urea is interpreted as a denaturing agent, i.e. denaturing; Fig. 10 teaches the effect of urea on partially reduced mAb A1; page 884, second full paragraph teaches determination of charge profiles after IdeS digestion and partial reduction, wherein when analyzing the IdeS digest by cIEF, urea is present at 7M, i.e. denaturing; thus, the combination of DTT and urea is interpreted as reducing and denaturing the IdeS digested sample, which comprise two or more components as shown in Fig. 1, using one or more reducing conditions and one or more denaturing conditions to generate one or more reduced and denatured domains as shown in Figs. 1 and 10);
separating the one or more reduced and denatured domains of the at least antibody according to the intrinsic charge of the one or more reduced and denatured domains using digestion-assisted imaged capillary electrophoresis (DiCE) (page 890, section “cIEF analysis” teaches profiling charged variants was performed using imaged cIEF technique, which performs separation, wherein cIEF is an electrophoresis method involving separating based on intrinsic charge; Fig. 11; page 884, second full paragraph teaches determination of charge profiles after IdeS digestion and partial reduction, wherein when analyzing the IdeS digest by cIEF, urea is present at 7M, i.e. denaturing, therefore cIEF is performed on one or more reduced and denatured domains as claimed; note that since IdeS digestion is performed prior to cIEF analysis, see pages 889-890, the cIEF electrophoresis is interpreted as being digestion-assisted), wherein a separation profile is generated (page 890, section “cIEF analysis” teaches electropherograms were produced, i.e. separation profile); and
identifying one or more domain-specific charge variants of the one or more reduced and denatured domains (Fig. 9 shows identifying acidic, main, and basic species, i.e. domain-specific charge variants; Fig. 10 shows identification of LC and HC, i.e. charge variants of the one or more reduced and denatured domains; Fig. 11C shows identification of LC-A, Fc-A, LC+Fc, Fd-A, Fd, i.e. charge variants of the one or more reduced and denatured domains; page 884, second full paragraph teaches determination, i.e. identifying, of charge profiles after IdeS digestion and partial reduction; page 890, section “cIEF” teaches profiling, interpreted as including identifying, charge variants of the one or more reduced and denatured domains using cIEF),
wherein the one or more one or more domain-specific charge variants are separated into separate peaks (Fig. 11C shows domain-specific charge variants are separated into separate peaks) comprising one or more light chains (Fig. 11C, “LC-A”), a Fd-A domain (Fig. 11C), a Fd domain (Fig. 11C), and the first Fc domain (Fig. 11C, “Fc-A”), and the second Fc domain (Fig. 11C, “LC+Fc”).
An fails to teach the at least one antibody is at least one bispecific antibody; wherein the at least one bispecific antibody comprises a first Fc domain and a second Fc domain, wherein the first Fc domain comprises HNRFTQKSLSLSLGK (SEQ ID NO: 2), and the second Fc domain comprises HNHYTQKSLSLSLGK (SEQ ID NO: 1), wherein the one or more one or more domain-specific charge variants are separated into separate peaks comprising an ANTIGENB-Fd' domain and an ANTIGENA-Fd' domain.
Darwish teaches methods to rapidly and accurately detect, characterize, measure, and quantify antibody drug conjugates (ADCs) (abstract), wherein the methods provides for consistent, reliable, efficient, high-resolution and highly sensitive methods of assessing stability, post-translational and chemical modifications during production, formulation, storage, and administration during the development of site-specific ADCs by combining site specific and controlled proteolytic digestion matched with the analysis of homogenous and site specific ADC to reduce the size of the ADC analytes (paragraph [0012]). Darwish teaches the ADC may be an IgG antibody (paragraph [0014]), and the antibody portion of the ADC may bind to one or more antigens or receptors (paragraph [0014]). Darwish teaches an antibody may be a bispecific antibody (paragraphs [0066],[0168]-[0171]). Darwish teaches an “antibody” includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity (paragraph [0045]). Darwish teaches an antibody is purified and purity is determined by electrophoretic methods, such as capillary electrophoresis or isoelectric focusing (paragraph [0164]). Darwish teaches that a sample containing the ADC for analysis/quantification is subjected to digestion and optionally reduction and denaturation (paragraph [0328]). Darwish teaches that ADC may be reduced by at least one reductant, such as DTT or TCEP (paragraph [0329]). Darwish teaches digestion comprises the uses of enzymes such IdeS (paragraph [0318]). Darwish teaches the method allows for reproducible, accurate, and efficient analytical methods for quantification and analysis of characteristics of antibody and drug components of site specific ADC therapeutic constructs (paragraph [0315]).
Since Darwish teaches digestion of ADC such as an IgG, similar to An, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the at least one antibody of An to incorporate the teachings of ADCs binding to multiple antigens or receptors and bispecific antibodies of Darwish (paragraphs [0014], [0066],[0168]-[0171]) to provide: the at least one antibody as at least one bispecific antibody. Doing so would have a reasonable expectation of successfully improving characterizing and analyzing known types of antibodies as discussed by Darwish (paragraph [0012], [0315]).
Furthermore, since Darwish teaches a desire to choose an antibody that exhibit desired antigen-binding activity (paragraph [0045]), and a finite number of identified, predictable types of antibodies (paragraph [0045]), it would have been obvious to choose at least one bispecific antibody from a finite number of identified, predictable antibodies for characterization and analysis as discussed by Darwish (paragraph [0045]), i.e., it would have been obvious to try the specific structure of a bispecific antibody to improve analysis of a desired type of antibody with a reasonable expectation of success. See MPEP 2143(I)(E).
Furthermore, the claimed limitations are obvious because all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements (i.e. bispecific antibody) by known methods with no change in their respective functions (i.e. identifying one or more charge variants of the bispecific antibody), and the combinations yielded nothing more than predictable results (i.e. having An’s antibody be an bispecific antibody would yield nothing more than the obvious and predictable result of enabling characterization and analysis of a known type of antibody). See MPEP 2143(A).
While An teaches domain-specific charge variants are separated into separate peaks (Fig. 11C), modified An fails to explicitly teach: wherein the at least one bispecific antibody comprises a first Fc domain and a second Fc domain, wherein the first Fc domain comprises HNRFTQKSLSLSLGK (SEQ ID NO: 2), and the second Fc domain comprises HNHYTQKSLSLSLGK (SEQ ID NO: 1), wherein the one or more one or more domain-specific charge variants are separated into separate peaks comprising an ANTIGENB-Fd' domain and an ANTIGENA-Fd' domain.
Davis teaches a bispecific antibody format providing ease of isolation comprising immunoglobulin heavy chain variable domains that are differentially modified in the CH3 domain, and at least one of the modifications results in a differential affinity for the bispecific antibody (abstract). Davis teaches antigen-binding proteins or antibodies having heterodimers of heavy chains, i.e., two immunoglobulin heavy chains that differ by at least one amino acid, that allows isolation of the antigen-binding protein based on a differential affinity of an immunoglobulin heavy chain and a modified or mutated immunoglobulin heavy chain toward an affinity reagent (paragraph [0002]). Davis teaches the antigen-binding protein comprises a first and second CH3 region, i.e. Fc domains (paragraphs [0024]-[0026]), wherein one CH3 region comprises the nucleic acid sequence of HNRFTQKSLSLSLGK (SEQ ID NO: 2) (paragraph [0026] and Fig. 3 teaches SEQ ID NO: 6, which comprises the claimed SEQ ID NO:2), and a different CH3 region comprises the nucleic acid sequence of HNHYTQKSLSLSLGK (SEQ ID NO: 1) (paragraphs [0025],[0029] and Fig. 3 teaches SEQ ID NO:5, which comprises the claimed SEQ ID NO: 1).
Since Davis teaches bispecific antibodies, similar to modified An, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the at least one bispecific antibody of modified An to incorporate the teachings of examples of bispecific antibodies having Fc domains of specific sequences of Davis (paragraphs [0024]-[0026]; Fig. 3) and the teachings of separating domain-specific charge variants into separate peaks for analysis of an antibody fragment of An (Fig. 11C), to provide: wherein the at least one bispecific antibody comprises a first Fc domain and a second Fc domain, wherein the first Fc domain comprises HNRFTQKSLSLSLGK (SEQ ID NO: 2), and the second Fc domain comprises HNHYTQKSLSLSLGK (SEQ ID NO: 1), wherein the one or more one or more domain-specific charge variants are separated into separate peaks comprising an ANTIGENB-Fd' domain and an ANTIGENA-Fd' domain. Doing so would have a reasonable expectation of successfully improving characterizing and analyzing known types of antibodies in the art and their charge variants via separate peaks for the different domains of the bispecific antibody as discussed by Davis (paragraphs [0024]-[0026]).
Furthermore, the claimed limitations are obvious because all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements (i.e. bispecific antibody having the claimed first and second Fc domains) by known methods with no change in their respective functions (i.e. identifying separate peaks of the one or more charge variants of the bispecific antibody having the claimed first and second Fc domains), and the combinations yielded nothing more than predictable results (i.e. having An’s antibody be an bispecific antibody having the claimed first and second Fc domains would yield nothing more than the obvious and predictable result of enabling characterization and analysis of separate peaks of charge variants a known type of antibody). See MPEP 2143(A).
Regarding claim 3, An further teaches wherein the one or more digestion enzymes is an immunoglobulin G-degrading enzyme of Streptococcus pyogenes, sialidase, cysteine protease, endopeptidase, papain, endoproteinase Lys-C, pepsin, trypsin, carboxypeptidase B, protease, exoglycosidase or a combination thereof (page 889, section “IdeS digestion” teaches IdeS, i.e. an immunoglobulin G-degrading enzyme of Streptococcus pyogenes and an endopeptidase).
Regarding claim 5, An further teaches wherein reducing and denaturing includes use of urea, guanidinium chloride, dithiothreitol (DTT), Tris(2-carboxyethyl)phosphine hydrochloride (TCEP), organic solvents, alkaline solution, acid solution or a combination thereof (page 890, section “Reduction” teaches DTT; page 890 teaches, section “cIEF analysis”, teaches “urea”).
Regarding claim 7, An further teaches wherein DiCE comprises a capillary electrophoresis method, wherein the capillary electrophoresis method is selected from the group comprising isoelectric focusing electrophoresis method, a capillary isoelectric focusing electrophoresis method, an imaged capillary isoelectric focusing electrophoresis method, a chromatography coupled capillary electrophoresis method, capillary electrophoresis or a chromatography coupled imaged capillary electrophoresis method (page 890, right column, section “cIEF” teaches profiling of charged variants was performed using cIEF technique, i.e. a capillary isoelectric focusing electrophoresis method; Fig. 11 teaches cIEF electropherograms).
Regarding claim 8, modified An further teaches the method further comprising quantifying or identifying the separated one or more reduced and denatured domains of the at least one bispecific antibody (see above claim 1 regarding “bispecific” antibody; An, abstract teaches “mAb product characterization” and identifying domain-specific modifications of antibody products; page 886, right column, first paragraph, “The procedure outlined here can therefore be used as an identification test of IgG and Fc fusion protein products”; Fig. 10 shows identification of LC and HC, i.e. separated components; Fig. 11C shows identification of LC-A, Fc-A, LC+Fc, Fd-A, Fd, i.e. separated components).
Regarding claim 22, modified An fails to teach wherein reducing and denaturing includes use of Tris(2-carboxyethyl)phosphine hydrochloride (TCEP).
Darwish teaches methods to rapidly and accurately detect, characterize, measure, and quantify antibody drug conjugates (ADCs) (abstract), wherein the methods provides for consistent, reliable, efficient, high-resolution and highly sensitive methods of assessing stability, post-translational and chemical modifications during production, formulation, storage, and administration during the development of site-specific ADCs by combining site specific and controlled proteolytic digestion matched with the analysis of homogenous and site specific ADC to reduce the size of the ADC analytes (paragraph [0012]). Darwish teaches the ADC may be an IgG antibody (paragraph [0014]). Darwish teaches that a sample containing the ADC for analysis/quantification is subjected to digestion and optionally reduction and denaturation (paragraph [0328]). Darwish teaches that ADC may be reduced by at least one reductant, such as DTT or TCEP (paragraph [0329]). Darwish teaches digestion comprises the uses of enzymes such as trypsin, papain, pepsin, endoproteinase LysC, endoproteinase ArgC, staph aureus V8, chymotrypsin, Asp-N, Asn-C, PNGaseF, endoproteinase GluC, LysN (paragraph [0044]), and IdeS (paragraph [0318]).
Since Darwish teaches digestion of ADC, wherein the ADC may be an IgG, similar to An, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified An to incorporate the teachings of a reductant, such as TCEP of Darwish (paragraph [0328]) to provide: wherein reducing and denaturing include use of Tris(2-carboxyethyl)phosphine hydrochloride (TCEP). Doing so would utilize known reductants in the art, as taught by Darwish, which would have a reasonable expectation of successfully reducing the at least one peptide or protein. Furthermore, it would have been obvious to choose TCEP from a finite number of identified, predictable reductants to reduce the at least one peptide or protein as discussed by Darwish (paragraph [0329]), i.e. it would have been obvious to try the specific TCEP to optimize the reducing and denaturing conditions to thus optimize identification of the charge variants.
Regarding claim 24, modified An fails to explicitly teach: wherein the ANTIGENB-Fd' targets an ANTIGENB and the ANTIGENA-Fd' targets an ANTIGENA.
An teaches the LC and Fd regions are responsible for the antigen binding specificity (page 879, left column).
Darwish teaches an antibody may be a bispecific antibody (paragraphs [0066],[0168]-[0171]). Darwish teaches an “antibody” includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity (paragraph [0045]). Darwish teaches the method allows for reproducible, accurate, and efficient analytical methods for quantification and analysis of characteristics of antibody and drug components of site specific ADC therapeutic constructs (paragraph [0315]). Darwish teaches embodiments wherein the multispecific antibodies comprise two different binding domains that may bind to two different epitopes on the same molecule (paragraph [0169]). Darwish teaches a bispecific antibody refers to a multispecific antibody comprising an antigen-binding domain that is capable of binding to two different epitopes on one molecule or is capable of binding to epitopes on two different molecules (paragraph [0171]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ANTIGENB-Fd' domain and the ANTIGENA-Fd' domain of the at least one bispecific antibody modified An to incorporate the teachings of Fd regions responsible for antigen binding specificity of An (page 879, left column) and the teachings of bispecific antibodies with different binding domains to bind to different epitopes of Darwish (paragraph [0169]) to provide: wherein the ANTIGENB-Fd' targets an ANTIGENB and the ANTIGENA-Fd' targets an ANTIGENA. Doing so would have a reasonable expectation of successfully improving characterizing and analyzing known bispecific antibodies with different Fd domains that targets different antigens as discussed by Darwish (paragraph [0012], [0315]).
Regarding claim 25, modified An fails to explicitly teach wherein the ANTIGENB and the ANTIGENA are within the same antigen or within two different antigens.
Darwish teaches an antibody may be a bispecific antibody (paragraphs [0066],[0168]-[0171]). Darwish teaches an “antibody” includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity (paragraph [0045]). Darwish teaches the method allows for reproducible, accurate, and efficient analytical methods for quantification and analysis of characteristics of antibody and drug components of site specific ADC therapeutic constructs (paragraph [0315]). Darwish teaches embodiments wherein the multispecific antibodies comprise two different binding domains that may bind to two different epitopes on the same molecule (paragraph [0169]). Darwish teaches a bispecific antibody refers to a multispecific antibody comprising an antigen-binding domain that is capable of binding to two different epitopes on one molecule or is capable of binding to epitopes on two different molecules (paragraph [0171]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the first Fd domain and second Fd of modified An to incorporate the teachings of Fd regions responsible for antigen binding specificity of An (page 879, left column) and the teachings of bispecific antibodies with different binding domains to bind to different epitopes, such as epitopes on one molecule or epitopes on two different molecules of Darwish (paragraphs [0169],[0171]) to provide: wherein the ANTIGEN B and the ANTIGENA are within the same antigen or within two different antigens. Doing so would have a reasonable expectation of successfully improving characterizing and analyzing known bispecific antibodies with different Fd domains as discussed by Darwish (paragraph [0012], [0315]).
Regarding claim 26, An further teaches wherein the one or more reducing conditions and the one or more denaturing conditions includes the use of urea, guanidinium chloride, dithiothreitol (DTT), Tris(2-carboxyethyl)phosphine hydrochloride (TCEP), organic solvents, alkaline solution, acid solution or a combination thereof (page 890, section “Reduction” teaches DTT; page 890 teaches, section “cIEF analysis”, teaches “urea”).
Claims 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over An in view of Darwish and Davis as applied to claim 1 above, and further in view of Ahluwalia et al. (AHLUWALIA DEEPTI ET AL: "A three-point identity criteria tool for establishing product identity using icIEF method", JOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL, vol. 1083, 1 March 2018 (2018-03-01), pages 271-277, cited in the IDS filed 10/15/2021).
Regarding claim 9, modified An fails to explicitly teach the method further comprising identifying the components of the at least one bispecific antibody based on a comparison of a separation profile for at least one bispecific antibody with a different domain-specific charge variant.
Ahluwalia teaches product identity is one of the release testing requirements that needs to be established to ensure that there is no misidentification of drugs (abstract) and teaches a product identity method for monoclonal antibodies using icIEF method (abstract). Ahluwalia teaches comparing representative profile of mAb1 (Fig. 2) and visually comparing charge variants as a product identify approach for mAb1 against other mAbs, i.e. different charge variant (Fig. 3; sections 3.1-3.3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified An to incorporate the teachings of comparing profiles of antibodies with different antibodies of Ahluwalia (Figs. 2-3; sections 3.1-3.3) to provide: the method further comprising identifying the components of the at least one bispecific antibody based on a comparison of a separation profile for at least one bispecific antibody with a different domain-specific charge variant. Doing so would have a reasonable expectation of successfully identifying components of said at least one bispecific protein and ensure that there is no misidentification of the at least one bispecific protein as discussed by Ahluwalia (abstract).
Regarding claim 10, while An teaches it is important to use quantitative and convenient approaches to obtain a comprehensive assessment of glycoform distribution (page 888, right column, first paragraph), modified An fails to explicitly teach: the method further comprising quantifying the level of the domain-specific charge variants.
Ahluwalia teaches product identify testing using icIEF charge variant profile (page 274, section 3.1). Ahluwalia teaches selection of peaks when identifying charge variants is critical to develop a robust identity method and that peak area is used to quantify level of variants (page 274, section 3.1 teaches that peaks that are well resolved with area % greater than a limit should be selected). Ahluwalia teaches grouping charge variant profiles based on the closeness of peak profile (section 3.1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified An to further incorporate the teachings of quantifying level of variants of Ahluwalia (page 274, section 3.1) to provide: the method further comprising quantifying the level of the domain-specific charge variants. Doing so would have a reasonable expectation of successfully improving characterization and analysis of charge variants and properly identify the charge variants as discussed by Ahluwalia (page 274, section 3.1)
Regarding claim 11, modified An fails to teach wherein the domain-specific charge variants of the at least one bispecific antibody include variants from post-translation modification.
An teaches identifying and monitoring of domain-specific modifications of antibody molecules, i.e. post-translational modification (abstract). An teaches that charge variants are commonly observed and that many of the post-translational modifications could lead to charge variants (page 887, right column). An teaches N-glycosylation is a common post-translational modification that is studied (page 888, left column).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the at least one bispecific antibody of modified An to incorporate the teachings of identifying and monitoring of post-translational modification of antibody molecules of An (abstract; Page 887, right column; page 888, left column) to provide wherein the domain-specific charge variants of the at least one bispecific antibody include variants from post-translation modification. Doing so would have a reasonable expectation of successfully improving identification and modification of commonly observed modifications of antibodies.
Regarding claim 12, while An teaches monoclonal antibody products, i.e. variants, are extraordinarily heterogenous due to modifications, such as glycation and terminal cyclization (abstract), modified An fails to teach wherein the domain-specific charge variants of the at least one bispecific antibody include variants from glycation or unprocessed C-terminal lysine of the components.
Darwish teaches analysis of ADCs with glycations and/or other modifications (paragraph [0350]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified said variants of said at least one bispecific antibody of modified An to incorporate the teachings of variant modifications, such as glycation, of Darwish (paragraph [0350]) and An (abstract) to provide: wherein the domain-specific charge variants of the at least one bispecific antibody include variants from glycation or unprocessed C-terminal lysine of the components. Doing so would have a reasonable expectation of successfully characterizing and analyzing known types of antibodies as discussed by Darwish (paragraph [0012], [0315]), and thus improving characterization and identification of variants by analyzing known variants observed from antibodies.
Furthermore, the claimed limitations are obvious because all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements (i.e. said variants of said at least one bispecific antibody include variants from glycation or unprocessed C-terminal lysine of said components) by known methods with no change in their respective functions (i.e. identifying one or more domain-specific charge variants of the bispecific antibody), and the combinations yielded nothing more than predictable results (i.e. providing the variants of the bispecific antibody with modifications, such as glycation of the components would yield nothing more than the obvious and predictable result of enabling characterization and analysis of a known type of antibody). See MPEP 2143(A).
Claims 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over An in view of Darwish and Davis as applied to claims 26 and 1 above, and further in view of Lauber et al. (US 20150316515 A1; cited in the office action filed 08/02/2024).
Regarding claim 27, while An teaches DTT reductions without GuHCl (page 890, section “Reduction”) and charge profiling of individual LC and Fd domains can only be achieved under somewhat denaturing conditions (page 887, last paragraph), modified An fails to teach: the one or more reducing conditions and the one or more denaturing conditions includes the use of 6M guanidinium chloride and Tris(2- carboxyethyl)phosphine hydrochloride (TCEP).
Darwish teaches that a sample containing the ADC for analysis/quantification is subjected to digestion and optionally reduction and denaturation (paragraph [0328]). Darwish teaches that ADC may be reduced by at least one reductant, such as DTT or TCEP (paragraph [0329]), and the ADC may be denatured by guanidine (paragraph [0329]).
Lauber teaches methods for characterization of large biological molecules and separation of proteins (abstract). Lauber teaches analysis or analyzing using methods such as electrophoresis (paragraph [0153]). Lauber teaches reduction can be performed by heat-denaturing, adding a surfactant, or adding a denaturing agent, e.g., guanidine HCl (6M), in the presence of a reducing agent, e.g. TCEP (paragraph [0219]); enzymatic degradation is a digestion of the protein with a protease or trypsin (paragraph [0219]); and immunoglobulin degrading enzyme from S. pyogenes (IdeS) is commonly used for antibody subunit fragmentation (paragraph [0219]). Lauber teaches an embodiment of IdeS digestion of antibodies (paragraph [0438]) and then the resulting IdeS digested antibodies were denatured and reduced using TCEP and 6M GuHCl, and incubated for 1 hour (paragraph [0439]). Lauber teaches a denaturant can be GuHCl or urea (paragraph [0085]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the one or more reducing conditions and the one or more denaturing conditions of modified An, which included DTT and urea, to incorporate the teachings of a reductant, such as TCEP, and a denaturant, such as guanidine, of Darwish (paragraphs [0328]-[0329]) and the teachings of treating resulting IdeS digested antibodies with TCEP and 6M GuHCl of Lauber (paragraphs [0438]-[0439]) to provide: the one or more reducing conditions and the one or more denaturing conditions includes the use of 6M guanidinium chloride and Tris(2- carboxyethyl)phosphine hydrochloride (TCEP). Doing so would utilize known reductants and denaturants in the art, as taught by Darwish and Lauber, which would have a reasonable expectation of successfully reducing and denaturing the bispecific antibody to analyze charge profiles of individual domains as desired by An (page 887, last paragraph).
Additionally, since Darwish and Lauber teaches it is known for reducing and denaturing conditions to use GuHCl, TCEP, DTT, and/or Urea, such as the combination of 6M GuHCl and TCEP (Darwish, paragraphs [0328]-[0329]; Lauber, paragraphs [0438]-[0439]), it would have been obvious to have modified the one or more reducing conditions and the one or more denaturing conditions of modified An to incorporate the teachings of a reductant, such as TCEP, and a denaturant, such as guanidine, of Darwish (paragraphs [0328]-[0329]) and the teachings of treating resulting IdeS digested antibodies with TCEP and 6M GuHCl of Lauber (paragraphs [0438]-[0439]) to provide: the one or more reducing conditions and the one or more denaturing conditions includes the use of 6M guanidinium chloride and Tris(2- carboxyethyl)phosphine hydrochloride (TCEP). I.e. It would have been obvious to have substituted one known element (An’s use of DTT and urea for reduction and denaturing) for another (Darwish and Lauber’s use of 6M GuHCl and TCEP), and the results of the substitution would have been predictable (reduction and denaturing of the bispecific antibody). See MPEP 2143(I)(B).
Regarding claim 28, modified An further teaches wherein the one or more reducing conditions or one or more denaturing conditions includes incubating the two or more components of the at least one bispecific antibody for 10 minutes to obtain the one or more reduced and denatured domains (An, page 890, section “Reduction” teaches reduction includes incubating for 10 minutes). While An teaches charge profiling of individual LC and Fd domains can only be achieved under somewhat denaturing conditions (page 887, last paragraph), modified An fails to teach: wherein the one or more reducing conditions or one or more denaturing conditions includes incubating the two or more components of the at least one bispecific antibody for 1 hour to obtain the one or more reduced and denatured domains.
Darwish teaches that a sample containing the ADC for analysis/quantification is subjected to digestion and optionally reduction and denaturation (paragraph [0328]). Darwish teaches that ADC may be reduced by at least one reductant, such as DTT or TCEP (paragraph [0329]), and the ADC may be denatured by guanidine (paragraph [0329]).
Lauber teaches methods for characterization of large biological molecules and separation of proteins (abstract). Lauber teaches analysis or analyzing using methods such as electrophoresis (paragraph [0153]). Lauber teaches reduction can be performed by heat-denaturing, adding a surfactant, or adding a denaturing agent, e.g., guanidine HCl (6M), in the presence of a reducing agent, e.g. TCEP (paragraph [0219]); enzymatic degradation is a digestion of the protein with a protease or trypsin (paragraph [0219]); and immunoglobulin degrading enzyme from S. pyogenes (IdeS) is commonly used for antibody subunit fragmentation (paragraph [0219]). Lauber teaches an embodiment of IdeS digestion of antibodies (paragraph [0438]) and then the resulting IdeS digested antibodies were denatured and reduced using TCEP and 6M GuHCl, and incubated for 1 hour (paragraph [0439]). Lauber teaches a denaturant can be GuHCl or urea (paragraph [0085]). Lauber teaches an embodiment of an antibody mixed with a denaturing buffer and incubated for 2 hours (paragraph [0441]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the one or more reducing conditions and the one or more denaturing conditions of modified An, which included DTT and urea, to incorporate the teachings of a reductant, such as TCEP, and a denaturant, such as guanidine, of Darwish (paragraphs [0328]-[0329]) and the teachings of treating resulting IdeS digested antibodies with TCEP and 6M GuHCl of for 1 hour Lauber (paragraphs [0438]-[0439]) to provide: wherein the one or more reducing conditions or one or more denaturing conditions includes incubating the two or more components of the at least one bispecific antibody for 1 hour to obtain the one or more reduced and denatured domains. Doing so would have a reasonable expectation of successfully ensuring adequate time for reducing and denaturing the bispecific antibody to analyze charge profiles of individual domains as desired by An (page 887, last paragraph).
Response to Arguments
Applicant’s arguments, see pages 7-8, filed 09/12/2025, with respect to the rejections under 35 U.S.C. 112(a) and 112(b) have been fully considered and are persuasive. The rejections under 35 U.S.C. 112(a) and 112(b) of 05/05/2025 have been withdrawn.
Applicant's arguments, see pages 9-10, filed 09/12/2025, regarding the rejection under 35 U.S.C. 103, specifically regarding claim 1, have been fully considered but they are not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references of An, Darwish and Davis to arrive at the new limitations of “wherein the one or more one or more domain-specific charge variants are separated into separate peaks comprising one or more light chains, an ANTIGENB-Fd' domain, an ANTIGENA-Fd' domain, the first Fe domain and the second Fe domain” (Remarks, pages 9-18), the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
More specifically, in response to applicant’s argument that An failing to teach: “wherein the one or more one or more domain-specific charge variants are separated into separate peaks comprising one or more light chains, an ANTIGENB-Fd' domain, an ANTIGENA-Fd' domain, the first Fe domain and the second Fe domain” (Remarks, pages 12-14), the examiner partially disagrees. An teaches wherein the one or more one or more domain-specific charge variants are separated into separate peaks (Fig. 11C shows domain-specific charge variants are separated into separate peaks) comprising one or more light chains (Fig. 11C, “LC-A”), a Fd-A domain (Fig. 11C), a Fd domain (Fig. 11C), and the first Fc domain (Fig. 11C, “Fc-A”), and the second Fc domain (Fig. 11C, “LC+Fc”). The BRI of “one or more light chains” includes the interpretation of one light chain (Fig. 11C, LC-A). The LC+Fc reads on a Fc domain separate from the Fc-A as shown in Fig. 11C of An. However, An fails to teach: wherein the one or more one or more domain-specific charge variants are separated into separate peaks comprising an ANTIGENB-Fd' domain and an ANTIGENA-Fd' domain.
Additionally, in response to applicant’s argument that Darwish and Davis fails to provide teachings and motivation for a person of skill in the art to have modified An to arrive at the claimed limitations, specifically wherein the one or more one or more domain-specific charge variants are separated into separate peaks comprising one or more light chains, an ANTIGENB-Fd' domain, an ANTIGENA-Fd' domain, the first Fe domain and the second Fe domain, the examiner disagrees.
Davis provides teachings and suggestions of bispecific antibodies having Fc domains of specific sequences of Davis (paragraphs [0024]-[0026]; Fig. 3). An provides teachings and suggestions of separating domain-specific charge variants into separate peaks for analysis of an antibody fragment (Fig. 11C).
Since Davis teaches bispecific antibodies, similar to modified An, it would have been obvious to one of ordinary skill in the art to have modified the at least one bispecific antibody of modified An to incorporate the teachings of examples of bispecific antibodies having Fc domains of specific sequences of Davis (paragraphs [0024]-[0026]; Fig. 3) and the teachings of separating domain-specific charge variants into separate peaks for analysis of an antibody fragment (Fig. 11C), to provide: wherein the at least one bispecific antibody comprises a first Fc domain and a second Fc domain, wherein the first Fc domain comprises HNRFTQKSLSLSLGK (SEQ ID NO: 2), and the second Fc domain comprises HNHYTQKSLSLSLGK (SEQ ID NO: 1), wherein the one or more one or more domain-specific charge variants are separated into separate peaks comprising an ANTIGENB-Fd' domain and an ANTIGENA-Fd' domain. Doing so would have a reasonable expectation of successfully improving characterizing and analyzing known types of antibodies in the art and their charge variants via separate peaks for the different domains of the bispecific antibody as discussed by Davis (paragraphs [0024]-[0026]).
Furthermore, the claimed limitations are obvious because all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements (i.e. bispecific antibody having the claimed first and second Fc domains) by known methods with no change in their respective functions (i.e. identifying separate peaks of the one or more charge variants of the bispecific antibody having the claimed first and second Fc domains), and the combinations yielded nothing more than predictable results (i.e. having An’s antibody be an bispecific antibody having the claimed first and second Fc domains would yield nothing more than the obvious and predictable result of enabling characterization and analysis of separate peaks of charge variants a known type of antibody). See MPEP 2143(A).
Therefore, there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art to have combined An, Darwish, and Davis to arrive at the claimed invention. Specifically, one of ordinary skill in the art would be motivated to characterize the different domains of a bispecific antibody with different Fd and Fc domains via separate peaks. Additionally, since modified An teaches an identical bispecific antibody, it would be obvious for one of ordinary skill to recognize that the intended result of separating the bispecific antibody would be separated peaks of each charge variants. Additionally note, if the limitation of “wherein the one or more one or more domain-specific charge variants are separated into separate peaks comprising one or more light chains, an ANTIGENB-Fd' domain, an ANTIGENA-Fd' domain, the first Fe domain and the second Fe domain” is merely an intended result of the process steps, a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) (MPEP 2111.04(I)).
In response to applicant’s arguments regarding claims 9-12 and 27-28 (Remarks, pages 18-22), specifically that it also would not have been obvious to one of ordinary skill in the art to have combined Ahluwalia or Lauber to cure the defects of An of claim 1, the examiner disagrees. As discussed above, An in view of Darwish and Davis teaches all of the limitations of claim 1. Ahluwalia or Lauber are not utilized to arrive at the specific limitations of claim 1.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HENRY H NGUYEN whose telephone number is (571)272-2338. The examiner can normally be reached M-F 7:30A-5:00P.
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/HENRY H NGUYEN/Primary Examiner, Art Unit 1758
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