DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
This is a U.S. application that claims priority to U.S. Provisional Application No. 63/434,516 filed on 12/22/2022 and to U.S. Provisional Application No. 63/431,131 filed on 12/08/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/06/2024 has been received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner and all references are considered except where they were lined through.
Claim Objections
Claim 6 is objected to because of the following informalities: claim 6 recites “a homodimer the second heavy chain” in line 3. To move the prosecution, claim 6 is read to recite “a homodimer of the second heavy chain” . Appropriate correction is required.
Claim 20 is objected to because of the following informalities: claim 20 recites “Th method of claim 15” in line 1. The claim is read to recite “The method of ” Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-22 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.
Claim 1 recites the limitation "d. … determine a mass of deuterium-labeled peptides" in line 7, and similarly, claim 15 recites the limitation “d. … determine a mass of deuterium-labeled peptides” in line 11. There is no mention of deuterium in the previous steps of claims 1 and 15, and it is not clear where the deuterium label is being introduced. And thus, it is not clear how deuterium-labeled peptides would result from the method.
To overcome this rejection, it is suggested to add the term “deuterium” before “a. …labeling buffer” in claims 1 and 15 to read “a. … deuterium labeling buffer”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5, 7-11 and 13-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al. (Anal. Chem. 2020, 92, 1582−1588; Supporting Information, S1-S6).
Liu reference incorporates supporting information, and therefore it is treated as a single prior art reference.
Claim 1 recites:
“A method of characterizing a Fe domain of a bispecific antibody, comprising:
a. incubating a sample comprising said bispecific antibody with a labeling buffer;
b. contacting the labeled sample with a quenching buffer;
c. contacting the quenched sample with a hydrolyzing agent to form a digested
sample;
d. contacting the digested sample to a liquid chromatography - mass spectrometer to
determine a mass of deuterium-labeled peptides; and
e. analyzing the mass of deuterium-labeled peptides to characterize the Fc domain”.
Regarding claim 1, Liu teaches a method of characterizing a Fc domain of a bispecific antibody (Abstract). Liu further teaches incubating a sample comprising the bispecific antibody with a deuterium labeling buffer (Page 1584, left column, first paragraph, “For deuterium labeling, three samples were incubated in deuterium buffer”). And Liu teaches contacting the labeled sample with a quenching buffer (Supporting Information, S2, second paragraph, “The exchange reaction was quenched …”). Liu also teaches contacting the quenched sample with a hydrolyzing agent to form a digested sample (Supporting Information, S2, second paragraph, “Each quenched sample was immediately injected onto an immobilized protease XIII/pepsin column … for on-line digestion in 0.1 % formic acid”). Liu further teaches contacting the digested sample to a liquid chromatography - mass spectrometer to
determine a mass of deuterium-labeled peptides (Supporting Information, S2, second paragraph, “the digested peptides were desalted on a trapping column … and further separated on an analytical column … A separation gradient from 5% to 50% B (A: 0.1 % formic acid and 0.04 % TFA in H2O, B: 0.1 % formic acid, 0.04 % TFA in acetonitrile) over 12 mins was provided by a Thermo Ultimate 3000 HPLC (Thermo Fisher Scientific, San Jose, CA). On-line digestion and separation were performed at 0 °C to minimize back-exchange. The eluate was introduced into an Orbitrap Elite for mass measurement”). And Liu teaches analyzing the mass of deuterium-labeled peptides to characterize the Fc domain (Abstract; Page 1584, left column, first paragraph “Peptide identifications were based on accurate masses together with MS/MS fragmentation by Mascot search. Deuterium incorporation was determined by use of EXMS, followed by a python script. Averaged deuterium uptake difference (ARDD) was calculated by a modified python script and mapped onto homologous crystal structures to visualize overall H/D exchange MS results”; Supporting Information, S2, second paragraph, “Mass spectra were collected over a range of m/z 300 ~1800 at a Thermo resolving power setting of 60,000 at m/z 400”)
Regarding claim 2, Liu teaches that the digested sample is desalted prior to contacting it to
the liquid chromatography (Supporting Information, S2, second paragraph, “the digested peptides were desalted on a trapping column).
Regarding claim 3, Liu teaches that the characterizing comprises identifying site-specific mutations on the Fc domain (Abstract; page 1583, right column, second paragraph “To the best of our knowledge, this study is the first to provide a comprehensive view of the impact of the knob-into-hole mutations on the full-length solution structure and function of an antibody.”; page 1585, left column, third paragraph, “For the two peptides that are close to the hole mutation site Y407 V (HC377−402 and HC 411−423), the H/D exchange data from the WT and the knob-into-hole antibodies correlated well”). Regarding claim 4, Liu teaches that characterizing comprises identifying a glycosylation profile of the Fc domain (Page 1583, left column, fourth paragraph). Regarding claim 5, Liu teaches that characterizing comprises identifying an oxidation profile of the Fc domain (Page 1586, right column, second paragraph).
Regarding claim 7, Liu teaches that the hydrolyzing agent is pepsin (Supporting Information, S2, second paragraph, “Each quenched sample was immediately injected onto an immobilized protease XIII/pepsin column … for on-line digestion in 0.1 % formic acid”).
Regarding claim 8, Liu teaches that characterizing comprises identifying site-specific
mutations on the Fc domain (Abstract; page 1583, right column, second paragraph “To the best of our knowledge, this study is the first to provide a comprehensive view of the impact of the knob-into-hole mutations on the full-length solution structure and function of an antibody.”; page 1585, left column, third paragraph, “For the two peptides that are close to the hole mutation site Y407 V (HC377−402 and HC 411−423), the H/D exchange data from the WT and the knob-into-hole antibodies correlated well”).
Regarding claim 9, Liu teaches that characterizing comprises identifying a glycosylation profile of the Fc domain (Page 1583, left column, fourth paragraph).
Regarding claim 10, Liu teaches that the liquid chromatography is coupled to the mass
Spectrometer (Supporting Information, S2, second paragraph, “the digested peptides were desalted on a trapping column … and further separated on an analytical column … A separation gradient from 5% to 50% B (A: 0.1 % formic acid and 0.04 % TFA in H2O, B: 0.1 % formic acid, 0.04 % TFA in acetonitrile) over 12 mins was provided by a Thermo Ultimate 3000 HPLC (Thermo Fisher Scientific, San Jose, CA). On-line digestion and separation were performed at 0 °C to minimize back-exchange. The eluate was introduced into an Orbitrap Elite for mass measurement”).
Regarding claim 11, Liu teaches that the hydrolyzing agent is immobilized over a resin (Supporting Information, S2, second paragraph, “Each quenched sample was immediately injected onto an immobilized protease XIII/pepsin column … for on-line digestion in 0.1 % formic acid”).
Regarding claim 13, Liu teaches that the quenching buffer comprises a reducing agent (Supporting Information, S2, second paragraph, “The exchange reaction was quenched by reducing the pH to 2.2 with a dilution with 8 M urea (Sigma, Prod #: U6504-500G), 1 M TCEP·HCl (Thermo Scientific, Prod #: PG82089), pH 2.2”).
Regarding claim 14, Liu teaches a mobile phase used for the liquid chromatography of
step (d) comprises formic acid in acetonitrile (Supporting Information, S2, second paragraph, “A separation gradient from 5% to 50% B (A: 0.1 % formic acid and 0.04 % TFA in H2O, B: 0.1 % formic acid, 0.04 % TFA in acetonitrile) over 12 mins was provided by a Thermo Ultimate 3000 HPLC (Thermo Fisher Scientific, San Jose, CA).”).
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.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Anal. Chem. 2020, 92, 1582−1588; Supporting Information, S1-S6) as applied to claim 1 above, and further in view of Muthusamy et al. (US 12,158,473 B2) and Zhang et al. (Anal. Chem. 2017, 89, 13494−13501).
Claim 6 recites:
“The method of claim 1, wherein the analysis is performed by comparing said mass of
deuterium-labeled peptides with masses of deuterium-labeled peptides obtained from
characterizing a homodimer of the first heavy chain and a homodimer the second heavy
chain using steps ( a)-( e) of claim 1”.
Regarding claim 6, the teachings of Liu are previously discussed.
Moreover, regarding claim 6, Liu teaches incubating a first sample of a bispecific antibody with a deuterium labelling buffer (Page 1584, left column, first paragraph, “For deuterium labeling, three samples were incubated in deuterium buffer”).
Regarding claim 6, Liu does not teach that the analysis is performed by comparing the mass of deuterium-labeled peptides with masses of deuterium-labeled peptides obtained from characterizing a homodimer of the first heavy chain and a homodimer the second heavy chain using steps ( a)-( e) of claim 1.
Zhang teaches incubating two samples with homodimers with a deuterium labeling buffer (Page 13495, right column, last two paragraphs).
Muthusamy further teaches three antibodies of (e.g., bsAb or hetero-AB, homo-A, homo-B) in which each homodimer is a monospecific antibody having a distinct specificity, and the heterodimer is a bispecific antibody specific for both the cognate antigen of the first homodimer and the cognate antigen of the second homodimer (Column 2, lines 63-67; column 3, lines 1-3).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine hydrogen exchange method of homodimers of Zhang with the hydrogen exchange method of heterodimer of Liu because Zhang characterized the homodimers by hydrogen exchange chromatography to further develop a safe and efficacious bispecific antibody (Abstract; page 13495, left column, second paragraph). A skilled artisan would have been motivated to further combine the heterodimer characterization method of Muthusamy of purifying bispecific antibody with the combined method of Zhang and Liu because Muthusamy differentiated homodimer side products from the desired heterodimer bispecific antibody (bsAb) (Column 1, lines 56-58). A skilled artisan would have been motivated to use the method of Muthusamy of differentiating homodimers from heterodimers in the hydrogen exchange methods of Liu and Zhang because the combined methods would have resulted in a purification method with high sensitivity and specificity. A PHOSITA would have had a reasonable expectation of success in combining the methods of Muthusamy, Zhang and Liu based on the methods being in the field of structural and functional characterization of heterodimers and homodimers.
It would have been obvious for a PHOSITA to further detect and characterize bispecific antibodies from homodimer impurities by using the differentiation method of Muthusamy in the hydrogen exchange methods of Zhang and Liu to produce an effective bispecific antibody.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Anal. Chem. 2020, 92, 1582−1588; Supporting Information, S1-S6) as applied to claim 1 above, and further in view of Huang et al. (Anal. Chem. 2020, 92, 10709−10716).
Claim 12 recites:
“The method of claim 1, wherein the labeling buffer comprises deuterated phosphate
buffer”.
Regarding claim 12, the teachings of Liu are previously discussed.
Regarding claim 12, Liu does not teach that the deuterium labeling buffer comprises deuterated phosphate buffer.
Regarding claim 12, Huang teaches that the deuterium labeling buffer comprises deuterated phosphate buffer.
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the deuterium phosphate buffer of Huang with the method Liu for detecting and characterizing the Fc domain of a bispecific antibody because Huang’s method further improved the characterization of bispecific antibodies by providing molecular details on the binding mechanisms of bispecific antibodies (abstract). A PHOSITA would have had a reasonable expectation of success in combining the methods of Huang and Liu based on the methods being in the field of Structural and Functional Characterization of heterodimers and homodimers.
It would have been obvious for a PHOSITA to further detect and characterize bispecific antibodies by using the hydrogen exchange method of Liu and the deuterated phosphate buffer of Huang to produce an effective bispecific antibody.
Claims 15-19 and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Muthusamy et al. (US 12,158,473 B2, priority to 05/12/2015) in view of Liu et al. (Anal. Chem. 2020, 92, 1582−1588; Supporting Information, S1-S6) and Zhang et al. (Anal. Chem. 2017, 89, 13494−13501).
Claim 15 recites:
“A method of identifying site-specific mutations on Fe domain of a bispecific antibody
with a first heavy chain and a second heavy chain, comprising:
a. incubating a first sample, a second sample and a third sample with a labelling
buffer, wherein the first sample comprises said bispecific antibody, the second
sample comprises a homodimer of the first heavy chain, and the third sample
comprises a homodimer of the second heavy chain;
b. contacting each of the three labeled samples of with a quenching buffer;
c. contacting the quenched samples with a hydrolyzing agent to form a digested
sample;
d. contacting the digested samples to a liquid chromatography - mass spectrometer
to determine a mass of deuterium-labeled peptides; and
e. analyzing the mass of deuterium-labeled peptides to characterize the Fe domain
by comparing said mass of deuterium-labeled peptides obtained using the first
sample with masses of deuterium-labeled peptides obtained from the second
sample and the third sample”.
Regarding claim 15, Muthusamy teaches a method of identifying site-specific mutations on Fc domain of a bispecific antibody with a first heavy chain and a second heavy chain (Column 3, lines 7-11, “In a specific embodiment, the first heavy chain can bind to protein A, and the second heavy chain contains the H95R and Y96F substitutions of the CH3 domain, which abrogates protein A binding”; column 10, lines 55-61, “In another embodiment, wherein (a) the heterodimer is a bispecific antibody, (b) the first subunit is an immunoglobulin heavy chain containing the CH3 domain that binds protein A, ( c) the second subunit is an immunoglobulin heavy chain containing the CH3 domain that does not bind
protein A (e.g., the CH3* containing the H95R and Y96F amino acid substitutions)”). Muthusamy further teaches three antibodies of (e.g., bsAb or hetero-AB, homo-A, homo-B) in which each homodimer is a monospecific antibody having a distinct specificity, and the heterodimer is a bispecific antibody specific for both the cognate antigen of the first homodimer and the cognate antigen of the second homodimer (Column 2, lines 63-67; column 3, lines 1-3).
Regarding claim 15, Muthusamy does not teach incubating a first sample of a bispecific antibody, a second sample of a homodimer of the first heavy chain and a third sample of a homodimer with a second heavy chain with a labelling buffer. Muthusamy does not teach contacting each of the three labeled samples of with a quenching buffer. Muthusamy does not teach contacting the quenched samples with a hydrolyzing agent to form a digested sample. Muthusamy does not teach contacting the digested samples to a liquid chromatography - mass spectrometer to determine a mass of deuterium-labeled peptides. Muthusamy does not teach analyzing the mass of deuterium-labeled peptides to characterize the Fc domain by comparing said mass of deuterium-labeled peptides obtained using the first sample with masses of deuterium-labeled peptides obtained from the second sample and the third sample.
Regarding claim 16, Muthusamy does not teach that the digested samples are desalted prior to contacting it to the liquid chromatography. Regarding claim 17, Muthusamy does not teach that the hydrolyzing agent is pepsin. Regarding claim 18, Muthusamy does not teach that the liquid chromatography is coupled to the mass spectrometer. Regarding claim 19, Muthusamy does not teach that the hydrolyzing agent is immobilized over a resin. Regarding claim 21, Muthusamy does not teach that the quenching buffer comprises sodium phosphate, guanidine hydrochloride, tris(2-carboxyethyl)phosphine, a reducing agent, or any combination thereof. Regarding claim 22, Muthusamy does not teach that a mobile phase used for the liquid chromatography of step (d) comprises formic acid in acetonitrile.
Regarding claim 15, Liu teaches incubating a first sample of a bispecific antibody with a deuterium labelling buffer (Page 1584, left column, first paragraph, “For deuterium labeling, three samples were incubated in deuterium buffer”). Liu further teaches contacting the labeled sample of bispecific antibody with a quenching buffer (Supporting Information, S2, second paragraph, “The exchange reaction was quenched …”). And Liu teaches contacting the quenched sample of bispecific antibody with a hydrolyzing agent to form a digested sample (Supporting Information, S2, second paragraph, “Each quenched sample was immediately injected onto an immobilized protease XIII/pepsin column … for on-line digestion in 0.1 % formic acid”). Liu also teaches contacting the digested sample of bispecific antibody to a liquid chromatography - mass spectrometer to determine a mass of deuterium-labeled peptides (Supporting Information, S2, second paragraph, “the digested peptides were desalted on a trapping column … and further separated on an analytical column … A separation gradient from 5% to 50% B (A: 0.1 % formic acid and 0.04 % TFA in H2O, B: 0.1 % formic acid, 0.04 % TFA in acetonitrile) over 12 mins was provided by a Thermo Ultimate 3000 HPLC (Thermo Fisher Scientific, San Jose, CA). On-line digestion and separation were performed at 0 °C to minimize back-exchange. The eluate was introduced into an Orbitrap Elite for mass measurement”). Liu further teaches analyzing the mass of deuterium-labeled peptides of the bispecific antibody to characterize the Fc domain (Abstract; Page 1584, left column, first paragraph “Peptide identifications were based on accurate masses together with MS/MS fragmentation by Mascot search. Deuterium incorporation was determined by use of EXMS, followed by a python script. Averaged deuterium uptake difference (ARDD) was calculated by a modified python script and mapped onto homologous crystal structures to visualize overall H/D exchange MS results”; Supporting Information, S2, second paragraph, “Mass spectra were collected over a range of m/z 300 ~1800 at a Thermo resolving power setting of 60,000 at m/z 400”).
Regarding claim 16, Liu teaches that the digested sample of bispecific antibody is desalted prior to contacting it to the liquid chromatography (Supporting Information, S2, second paragraph, “the digested peptides were desalted on a trapping column).
Regarding claim 17, Liu teaches that the hydrolyzing agent is pepsin (Supporting Information, S2, second paragraph, “Each quenched sample was immediately injected onto an immobilized protease XIII/pepsin column … for on-line digestion in 0.1 % formic acid”).
Regarding claim 18, Liu teaches that the liquid chromatography is coupled to the mass
Spectrometer (Supporting Information, S2, second paragraph, “the digested peptides were desalted on a trapping column … and further separated on an analytical column … A separation gradient from 5% to 50% B (A: 0.1 % formic acid and 0.04 % TFA in H2O, B: 0.1 % formic acid, 0.04 % TFA in acetonitrile) over 12 mins was provided by a Thermo Ultimate 3000 HPLC (Thermo Fisher Scientific, San Jose, CA). On-line digestion and separation were performed at 0 °C to minimize back-exchange. The eluate was introduced into an Orbitrap Elite for mass measurement”).
Regarding claim 19, Liu teaches that the hydrolyzing agent is immobilized over a resin (Supporting Information, S2, second paragraph, “Each quenched sample was immediately injected onto an immobilized protease XIII/pepsin column … for on-line digestion in 0.1 % formic acid”).
Regarding claim 21, Liu teaches that the quenching buffer comprises a reducing agent (Supporting Information, S2, second paragraph, “The exchange reaction was quenched by reducing the pH to 2.2 with a dilution with 8 M urea (Sigma, Prod #: U6504-500G), 1 M TCEP·HCl (Thermo Scientific, Prod #: PG82089), pH 2.2”).
Regarding claim 22, Liu teaches that a mobile phase used for the liquid chromatography of
step (d) comprises formic acid in acetonitrile (Supporting Information, S2, second paragraph, “A separation gradient from 5% to 50% B (A: 0.1 % formic acid and 0.04 % TFA in H2O, B: 0.1 % formic acid, 0.04 % TFA in acetonitrile) over 12 mins was provided by a Thermo Ultimate 3000 HPLC (Thermo Fisher Scientific, San Jose, CA).”).
Regarding claim 15, Zhang teaches incubating second sample of a homodimer with a deuterium labeling buffer (Page 13495, right column, last two paragraphs). Zhang teaches contacting the labeled sample of a homodimer with a quenching buffer (Page 13495, right column, last paragraph). Zhang teaches contacting the quenched sample of a homodimer with a hydrolyzing agent to form a digested sample (Page 13495, right column, last paragraph). Zhang teaches contacting the digested sample of a homodimer to a liquid chromatography - mass spectrometer to determine a mass of deuterium-labeled peptides (Pages 13495, right column, last paragraph and page 13496, left column, first paragraph). Zhang teaches analyzing the mass of deuterium-labeled peptides of the homodimer to characterize the Fc domain (Abstract; page 13496, left column, first paragraph).
Regarding claim 16, Zhang teaches that the digested sample of a homodimer is desalted prior to contacting it to the liquid chromatography (Pages 13495, right column, last paragraph).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the hydrogen exchange method of heterodimer of Liu with the characterization method of Muthusamy to improve the detection and characterization of a heterodimer of a bispecific antibody because Liu obtained high-resolution structural information at the peptide level by using hydrogen exchange mass spectrometry (Page 1583, left column, last paragraph). A skilled artisan would have been motivated to further combine the hydrogen exchange method of homodimers of Zhang with the combined methods of Liu and Muthusamy because Zhang characterized the homodimers by hydrogen exchange chromatography to develop a safe and efficacious bispecific antibody (Page 13495, left column, second paragraph; page 13500; right column, fourth paragraph). A PHOSITA would have had a reasonable expectation of success in combining the methods of Zhang, Liu and Muthusamy based on the methods being in the field of Structural and Functional Characterization of heterodimers and homodimers.
It would have been obvious for a PHOSITA to further detect and characterize bispecific antibodies from homodimer impurities by using the hydrogen exchange methods of Zhang and Liu in the differentiation method of Muthusamy to produce an effective bispecific antibody.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Muthusamy et al. (US 12,158,473 B2, priority to 05/12/2015), Liu et al. (Anal. Chem. 2020, 92, 1582−1588; Supporting Information, S1-S6) and Zhang et al. (Anal. Chem. 2017, 89, 13494−13501) as applied to claim 15 above, and further in view of Huang et al. (Anal. Chem. 2020, 92, 10709−10716).
Claim 20 recites:
“Th method of claim 15, wherein the labeling buffer comprises deuterated phosphate
buffer”.
Regarding claim 20, the teachings of Muthusamy, Liu and Zhang are previously discussed.
Regarding claim 20, Muthusamy does not teach that the labeling buffer comprises deuterated phosphate buffer.
Regarding claim 20, Huang teaches that the labeling buffer comprises deuterated phosphate
buffer.
It would have been It would have been obvious for a PHOSITA before the effective filing date of the application to combine the deuterium phosphate buffer of Huang with the combined methods of Muthusamy, Liu and Zhang for detecting and characterizing the Fc domain of a bispecific antibody because Huang’s method further improved the characterization of bispecific antibodies by providing molecular details on the binding mechanisms of bispecific antibodies (abstract). A PHOSITA would have had a reasonable expectation of success in combining the methods of Huang, Zhang, Liu and Muthusamy based on the methods being in the field of structural and functional characterization of heterodimers and homodimers.
It would have been obvious for a PHOSITA to further detect and characterize bispecific antibodies from homodimer impurities by using the hydrogen exchange methods of Zhang and Liu and the deuterated phosphate buffer of Huang in the differentiation method of Muthusamy to produce an effective bispecific antibody.
Conclusion
No claims are allowed.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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