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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/24/2026 has been entered.
Response to Amendment
The Amendment filed 04/24/2026 has been entered. Claims 1, 3, 5, 7-12, 22, and 29-38 remain pending in the application.
New grounds of rejections necessitated by amendments are discussed below.
Claim Objections
Claim 7 is objected to because of the following informalities: In line 1, it is suggested to recite “DiCE” as “the DiCE” if referring to the same DiCE established in claim 1. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3, 5, 7-12, 22, and 29-38 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claim 1 recites “identifying one or more domain-specific charge variants of the one or more reduced and denatured domains”. Claim 31 recites “identifying the charge variants of the one or more reduced and denatured domains, wherein the charge variants are identified as separate peaks in the separation profile.”
In accordance with MPEP 2106, the claims are found to recite statutory subject matter (Step 1: YES) and are analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A: Prong 1).
In the instant application, the limitations of “identifying one or more domain-specific charge variants of the one or more reduced and denatured domains” (claim 1) and “identifying the charge variants of the one or more reduced and denatured domains, wherein the charge variants are identified as separate peaks in the separation profile “ (claim 31) covers performance of the limitations in the mind, i.e. mental process. Accordingly, the claims recite abstract ideas (Step 2A: Prong 1: Yes).
This judicial exception is not integrated into a practical application because the claims do not recite any additional elements that reflects an improvement to technology or applies or uses the judicial exception in some other meaningful way (Step 2A, Prong 2: No).
In claim 1, after “identifying one or more domain-specific charge variants of the one or more reduced and denatured domains”, no further action is performed. In claim 31, after “identifying the charge variants of the one or more reduced and denatured domains, wherein the charge variants are identified as separate peaks in the separation profile”, no further action is performed. Therefore, the claimed limitations do not integrate the abstract idea into a practical application because it does not impose any meaningful limits on practicing the abstract idea. Additionally, the additional steps and limitations of claims 1 and 31 generally link the judicial exception to a particular field of use (MPEP 2106.05(h)) and are used for data gathering in the abstract idea (MPEP 2106.05(g)); wherein, generally linking the use of the judicial exception to a particular field of use and data gathering to be used in the abstract idea is insignificant extra-solution activity, and are not indicative a particular practical application. See MPEP 2106.05(g). Therefore, the claimed limitations do not integrate the abstract idea into a practical application because it does not impose any meaningful limits on practicing the abstract idea. Thus, the claims are directed to an abstract idea that is not integrated into a practical application (Step 2A, Prong 2: No).
The claims 1, 3, 5, 7-12, 22, and 29-38 do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As discussed above with respect to integration of the abstract idea into a practical application, the additional steps and limitations generally link the judicial exception to a particular field of use (MPEP 2106.05(h)) and are used for data gathering or data outputting, wherein data gathering to be used in the abstract idea is an insignificant extra-solution activity, and not a practical application (see MPEP 2106.05(g)), which alone or in combination do not amount to significantly more. Additionally, the limitations of claims 1-7 and 9-10 are well-understood, routine and conventional activities as evidenced by the prior art of 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), Davis et al. (US 20100331527 A1), Lauber et al. (US 20150316515 A1; cited in the office action filed 08/02/2024), Ram et al. (Ram P. Vanam et al., "Rapid quantitative analysis of monoclonal antibody heavy and light chain charge heterogeneity," mAbs 7:6, pages 1118-1127; November/December 2015, Regeneron Pharmaceuticals, Inc.; cited in the IDS filed 11/15/2021), and 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). See MPEP 2106.05(d). The additional elements of the claims 1, 3, 5, 7-12, 22, and 29-38 do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). The claims are not patent eligible.
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 29-30 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), Davis et al. (US 20100331527 A1), Lauber et al. (US 20150316515 A1; cited in the office action filed 08/02/2024), and Ram et al. (Ram P. Vanam et al., "Rapid quantitative analysis of monoclonal antibody heavy and light chain charge heterogeneity," mAbs 7:6, pages 1118-1127; November/December 2015, Regeneron Pharmaceuticals, Inc.; cited in the IDS filed 11/15/2021).
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 a denaturing solution, respectively, 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 solution, 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 denaturing solution 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 domain-specific charge variants are separated into separate peaks (Fig. 11C shows domain-specific charge variants are separated into separate peaks).
An fails to teach the at least one antibody is at least one bispecific antibody; the denaturing solution comprising guanidinium chloride; exchanging denaturing solution with a buffer comprising urea; 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).
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).
Modified An fails to teach: the denaturing solution comprising guanidinium chloride; exchanging denaturing solution with a buffer comprising urea; 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).
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). 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).
Modified An fails to teach: the denaturing solution comprising guanidinium chloride; and exchanging denaturing solution with a buffer comprising urea.
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 denaturing solution of modified An, which includes urea, to incorporate the teachings of 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 denaturing solution comprising guanidinium chloride. Doing so would utilize known denaturants in the art, as taught by Darwish and Lauber, which would have a reasonable expectation of successfully 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 denaturing conditions to use GuHCl and/or Urea, such as 6M GuHCl (Lauber, paragraphs [0438]-[0439]), it would have been obvious to have modified the denaturing solution of modified An to incorporate the teachings of a denaturant, such as guanidine, of Darwish (paragraphs [0328]-[0329]) and the teachings of treating resulting IdeS digested antibodies with 6M GuHCl of Lauber (paragraphs [0438]-[0439]) to provide: the denaturing solution comprising guanidinium chloride. I.e. It would have been obvious to have substituted one known element (An’s use of urea for denaturing) for another (Lauber’s use of 6M GuHCl for denaturing), and the results of the substitution would have been predictable (denaturing of the bispecific antibody). See MPEP 2143(I)(B).
Modified An fails to teach: exchanging denaturing solution with a buffer comprising urea.
Ram teaches a method of characterizing charge heterogeneity of isolated monoclonal antibody heavy and light chains using size-exclusion chromatography and imaged capillary isoelectric focusing (abstract). Ram teaches by incubating the antibodies in the presence of a strong reductant (TCEP) and denaturant (∼6 M guanidinium), they were able to achieve complete reduction and denaturation without the use of elevated temperatures or modifications, which could alter the pI profile; and the SEC step also performs the essential buffer exchange of guanidinium for urea, thereby maintaining the proteins in a denatured state and transferring them into a solvent that is compatible with icIEF (page 1123, left column, first paragraph - page 1124, left column, first paragraph).
Since Ram teaches processing and characterization of charge variants of 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 method of modified An to incorporate Ram’s teachings of performing buffer exchange of guanidinium for urea (page 1123, left column, first paragraph - page 1124, left column, first paragraph) to provide: exchanging denaturing solution with a buffer comprising urea. Doing so would have a reasonable expectation of successfully improving complete reduction and denaturation without the use of elevated temperatures or modifications and ensuring maintaining the proteins in a denatured state prior to electrophoresis as taught by Ram (page 1123, left column, first paragraph - page 1124, left column, first paragraph).
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 the reducing conditions include use of dithiothreitol (DTT) or Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (page 890, section “Reduction” teaches DTT).
Regarding claim 7, An further teaches wherein DiCE comprises a capillary electrophoresis method selected from an isoelectric focusing electrophoresis method, a capillary isoelectric focusing electrophoresis method, an imaged capillary isoelectric focusing electrophoresis method, a chromatography coupled capillary electrophoresis method, 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 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 the reducing conditions include 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 the reducing conditions 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 29, modified An fails to teach wherein the buffer comprises about 8M of urea.
Ram teaches a method of characterizing charge heterogeneity of isolated monoclonal antibody heavy and light chains using size-exclusion chromatography and imaged capillary isoelectric focusing (abstract). Ram teaches by incubating the antibodies in the presence of a strong reductant (TCEP) and denaturant (∼6 M guanidinium), they were able to achieve complete reduction and denaturation without the use of elevated temperatures or modifications, which could alter the pI profile; and the SEC step also performs the essential buffer exchange of guanidinium for urea, thereby maintaining the proteins in a denatured state and transferring them into a solvent that is compatible with icIEF (page 1123, left column, first paragraph - page 1124, left column, first paragraph). Ram teaches a buffer comprises 8M urea (page 1121, right column, section “Charge variant analysis”; page 1125, right column, sections “Size exclusion chromatography” and “Imaged capillary isoelectric focusing”).
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 buffer of modified An to incorporate Ram’s teachings of performing buffer exchange of guanidinium for urea (page 1123, left column, first paragraph - page 1124, left column, first paragraph), the urea being 8M of urea (page 1121, right column, section “Charge variant analysis”; page 1125, right column, sections “Size exclusion chromatography” and “Imaged capillary isoelectric focusing”) to provide: wherein the buffer comprises about 8M of urea. Doing so would have a reasonable expectation of successfully improving complete reduction and denaturation without the use of elevated temperatures or modifications and ensuring maintaining the proteins in a denatured state prior to electrophoresis as taught by Ram (page 1123, left column, first paragraph - page 1124, left column, first paragraph).
Regarding claim 30, modified An fails to teach wherein the denaturing solution comprises about 6M of guanidinium chloride.
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 denaturing solution of modified An to incorporate the teachings of treating resulting IdeS digested antibodies with 6M GuHCl of Lauber (paragraphs [0438]-[0439]) to provide: wherein the denaturing solution comprises about 6M of guanidinium chloride. Doing so would utilize known denaturant concentrations in the art, as taught by Lauber, which would have a reasonable expectation of successfully denaturing the bispecific antibody to analyze charge profiles of individual domains as desired by An (page 887, last paragraph).
Claims 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over An in view of Darwish, Davis, Lauber, and Ram 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-translational modifications.
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 modifications 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-translational modifications. 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 comprise 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 comprise 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 comprise glycation 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 31-35 and 37-38 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 Lauber et al. (US 20150316515 A1; cited in the office action filed 08/02/2024), and Ram et al. (Ram P. Vanam et al., "Rapid quantitative analysis of monoclonal antibody heavy and light chain charge heterogeneity," mAbs 7:6, pages 1118-1127; November/December 2015, Regeneron Pharmaceuticals, Inc.; cited in the IDS filed 11/15/2021).
Regarding claim 31, An teaches a method for identifying one or more charge variants of an 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), the method comprising:
treating the 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 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 of the antibody using reducing conditions and a denaturing solution, respectively, to generate one or more reduced and denatured domains of the 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 solution, 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 denaturing solution to generate one or more reduced and denatured domains as shown in Figs. 1 and 1);
separating the one or more reduced and denatured components of the antibody using electrophoresis to generate a separation profile representing the one or more reduced and denatured components of the antibody (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; page 890, section “cIEF analysis” teaches electropherograms representing the reduced and denatured components of the antibody were produced, i.e. separation profile; 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); and
identifying the 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 charge variants are identified as separate peaks in the separation profile (Fig. 11C shows domain-specific charge variants are separated into separate peaks).
An fails to teach: the denaturing solution comprising guanidinium chloride; and exchanging the denaturing solution with a buffer comprising urea.
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 denaturing solution of An, which includes urea, to incorporate the teachings of treating resulting IdeS digested antibodies with TCEP and 6M GuHCl of Lauber (paragraphs [0438]-[0439]) to provide: the denaturing solution comprising guanidinium chloride. Doing so would utilize known denaturants in the art, as taught by Lauber, which would have a reasonable expectation of successfully denaturing the bispecific antibody to analyze charge profiles of individual domains as desired by An (page 887, last paragraph).
Additionally, since Lauber teaches it is known for denaturing conditions to use GuHCl and/or Urea, such as 6M GuHCl (Lauber, paragraphs [0438]-[0439]), it would have been obvious to have modified the denaturing solution of An to incorporate the teachings of treating resulting IdeS digested antibodies with 6M GuHCl of Lauber (paragraphs [0438]-[0439]) to provide: the denaturing solution comprising guanidinium chloride. I.e. It would have been obvious to have substituted one known element (An’s use of urea for denaturing) for another (Lauber’s use of 6M GuHCl for denaturing), and the results of the substitution would have been predictable (denaturing of the bispecific antibody). See MPEP 2143(I)(B).
Modified An fails to teach: exchanging denaturing solution with a buffer comprising urea.
Ram teaches a method of characterizing charge heterogeneity of isolated monoclonal antibody heavy and light chains using size-exclusion chromatography and imaged capillary isoelectric focusing (abstract). Ram teaches by incubating the antibodies in the presence of a strong reductant (TCEP) and denaturant (∼6 M guanidinium), they were able to achieve complete reduction and denaturation without the use of elevated temperatures or modifications, which could alter the pI profile; and the SEC step also performs the essential buffer exchange of guanidinium for urea, thereby maintaining the proteins in a denatured state and transferring them into a solvent that is compatible with icIEF (page 1123, left column, first paragraph - page 1124, left column, first paragraph).
Since Ram teaches processing and characterization of charge variants of 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 method of modified An to incorporate Ram’s teachings of performing buffer exchange of guanidinium for urea (page 1123, left column, first paragraph - page 1124, left column, first paragraph) to provide: exchanging denaturing solution with a buffer comprising urea. Doing so would have a reasonable expectation of successfully improving complete reduction and denaturation without the use of elevated temperatures or modifications and ensuring maintaining the proteins in a denatured state prior to electrophoresis as taught by Ram (page 1123, left column, first paragraph - page 1124, left column, first paragraph).
Regarding claim 32, 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 33, An further teaches wherein the reducing conditions include use of dithiothreitol (DTT) or Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (page 890, section “Reduction” teaches DTT).
Regarding claim 34, An further teaches wherein the electrophoresis is digestion-assisted imaged capillary electrophoresis (DiCE) (page 890, right column, section “cIEF” teaches profiling of charged variants was performed using cIEF technique, i.e. DiCE; Fig. 11 teaches cIEF electropherograms).
Regarding claim 35, modified An fails to teach: wherein the charge variants of the antibody include variants from post-translational modifications.
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 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 charge variants of the antibody include variants from post-translational modifications. Doing so would have a reasonable expectation of successfully improving identification and modification of commonly observed modifications of antibodies.
Regarding claim 37, modified An fails to teach: wherein the buffer comprises about 8M of urea.
Ram teaches a method of characterizing charge heterogeneity of isolated monoclonal antibody heavy and light chains using size-exclusion chromatography and imaged capillary isoelectric focusing (abstract). Ram teaches by incubating the antibodies in the presence of a strong reductant (TCEP) and denaturant (∼6 M guanidinium), they were able to achieve complete reduction and denaturation without the use of elevated temperatures or modifications, which could alter the pI profile; and the SEC step also performs the essential buffer exchange of guanidinium for urea, thereby maintaining the proteins in a denatured state and transferring them into a solvent that is compatible with icIEF (page 1123, left column, first paragraph - page 1124, left column, first paragraph). Ram teaches a buffer comprises 8M urea (page 1121, right column, section “Charge variant analysis”; page 1125, right column, sections “Size exclusion chromatography” and “Imaged capillary isoelectric focusing”).
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 buffer of modified An to incorporate Ram’s teachings of performing buffer exchange of guanidinium for urea (page 1123, left column, first paragraph - page 1124, left column, first paragraph), the urea being 8M of urea (page 1121, right column, section “Charge variant analysis”; page 1125, right column, sections “Size exclusion chromatography” and “Imaged capillary isoelectric focusing”) to provide: wherein the buffer comprises about 8M of urea. Doing so would have a reasonable expectation of successfully improving complete reduction and denaturation without the use of elevated temperatures or modifications and ensuring maintaining the proteins in a denatured state prior to electrophoresis as taught by Ram (page 1123, left column, first paragraph - page 1124, left column, first paragraph).
Regarding claim 38, modified An fails to teach: wherein the denaturing solution comprises about 6M of guanidinium chloride.
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 denaturing solution of modified An to incorporate the teachings of treating resulting IdeS digested antibodies with 6M GuHCl of Lauber (paragraphs [0438]-[0439]) to provide: wherein the denaturing solution comprises about 6M of guanidinium chloride. Doing so would utilize known denaturant concentrations in the art, as taught by Lauber, which would have a reasonable expectation of successfully denaturing the bispecific antibody to analyze charge profiles of individual domains as desired by An (page 887, last paragraph).
Claims 36 are rejected under 35 U.S.C. 103 as being unpatentable over An in view of Lauber, and Ram as applied to claim 35 above, and further in view of Darwish et al. (US 20170370906 A1).
Regarding claim 36, 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 charge variants comprise glycation or unprocessed C-terminal lysine.
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]). 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 the charge variants modified An to incorporate the teachings of variant modifications, such as glycation, of Darwish (paragraph [0350]) and An (abstract) to provide: wherein the charge variants comprise glycation or unprocessed C-terminal lysine. 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 comprise glycation 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).
Response to Arguments
Applicant’s arguments, see pages 6, filed 04/24/2026, with respect to the rejections under 35 U.S.C. 112 have been fully considered and are persuasive. The rejections under 35 U.S.C. 112 of 09/30/2025 have been withdrawn.
Applicant’s arguments, see pages 6-10, filed 04/24/2026, with respect to the rejection(s) of claims 1, 3, 5, 7, 8, 22, and 24-26 under 35 U.S.C. 103, specifically regarding amended claim 1, have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of 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), Davis et al. (US 20100331527 A1), Lauber et al. (US 20150316515 A1; cited in the office action filed 08/02/2024), Ram et al. (Ram P. Vanam et al., "Rapid quantitative analysis of monoclonal antibody heavy and light chain charge heterogeneity," mAbs 7:6, pages 1118-1127; November/December 2015, Regeneron Pharmaceuticals, Inc.; cited in the IDS filed 11/15/2021).
Conclusion
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/HENRY H NGUYEN/Primary Examiner, Art Unit 1758
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