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 .
Priority
The present application was filed on March 17, 2023. This application claims benefit of
U.S. Provisional Patent Application 63/269,595 filed on March 18, 2022.
The effective filing date for claims 1-10 and 12-20 of this application is March 18, 2022.
Claim 11 introduces subject matter not supported by the original provisional application. Claim
11 is directed to a method for quantifying a charge variant within an analyte comprising the use
of a sample buffer that includes hydroxyl propyl methyl cellulose. This method is not disclosed
in the provisional application as originally filed. Thus, the effective filing date for claim 11 of
this application is March 17, 2023.
Information Disclosure Statement
Two Information Disclosure Statements (IDS), filed 17 March 2023 and 18 July 2023,
are acknowledged and have been considered.
Status of Claims
Claims 1-20 are pending and examined.
Claim Rejections - 35 USC § 112
Claims 12-15 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.
The term “at” in claims 12-13 is a relative term which renders the claim indefinite. The term “at least” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. A person having ordinary skill in the art would not be able to determine, with a reasonable degree of certainty what is the upper limit for each limitation recited in the instant claims to enable them to make and use the claimed invention. Therefore, the metes and bounds of the claim invention cannot be ascertained.
Claim 14, line 2, recites the limitation "the target molecule" which lacks antecedent basis. “[T]arget molecule” is not previously recited thus referencing “the target molecule” is indefinite because it is unclear what “the target molecule” is.
Claim 15 is rejected as being dependent on rejected claim 14.
Claim Rejections - 35 USC § 102
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.
(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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-8 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Palackal et al., (Palackal et al., PGPub 20200393455 A1, Pub. Date:12/17/2020).
Throughout the disclosure, Palackal teaches methods for separating variants of target contaminating proteins, which involves separating protein components of a sample by charge along an isoelectric gradient, created with carrier ampholytes, in one or more capillaries using capillary electrophoresis: immobilizing the protein components of the sample within capillaries; contacting the protein components within the capillaries with one or more primary antibodies that specifically bind to the charge variant or multiple charge variants in the sample, thereby detecting and/or discriminating between variants in the sample. Palackal further teaches the use of a chemiluminescent detection system comprising of a horseradish enzyme label and luminol-peroxidase agent to detect the detection antibody and thus detect variants in a sample.
Regarding 1, Palackal teaches a method of quantifying charge variants within an analyte, the method comprising: introducing the analyte into a capillary (Palackal et al., 20200393455 A1: paras 0005, 0083-0084, 0086, 0105, 0118; and Fig. 8), wherein the analyte includes charge variants of a target polypeptide (Palackal et al., 20200393455 A1: paras 0005, 0049, 0086; Fig. 8); separating charge variants of the target polypeptide along an isoelectric gradient within the capillary (Palackal et al., 20200393455 A1: paras 0083-0084 and 0095-0096), wherein the charge variants are separated based on their isoelectric points (Palackal et al., 20200393455 A1: paras 0005, 0083-0084, and 0095-0096; and Fig. 8); incubating the separated charge variants within the capillary with a detection antibody to bind the detection antibody to the separated charge variants (Palackal et al., 20200393455 A1: paras 0005, 0050-0051, 0054, 0061, 0083-0084, 0086, 0088, 0117, and Figs. 8-9); and quantifying a relative abundance the charge variants based on a signal that corresponds to the detection antibody (Palackal et al., 20200393455 A1: para 0005, 0083-0084, and Fig. 8).
Regarding 2, Palackal teaches the limitations of claim 1, further comprising incubating the separated charge variants bound to the detection antibody with a reporter molecule (Palackal et al., 20200393455 A1: paras 0005, 0012-0013, 088; and Fig. 8).
Regarding 3, Palackal teaches the method of claim 2, wherein the reporter molecule comprises an antibody conjugated to horseradish peroxidase or streptavidin conjugated to horseradish peroxidase (Palackal et al., 20200393455 A1: para 0089).
Regarding 4, Palackal teaches the method of claim 2, further comprising introducing a detection agent into the capillary (Palackal et al., 20200393455 A1: paras 0088; and Fig. 8).
Regarding 5, Palackal teaches the method of claim 4, wherein the detection agent is luminol- peroxide (Palackal et al., 20200393455 A1: paras 0088-0089).
Regarding 6, Palackal teaches the method of claim 2, further comprising, generating an electropherogram, wherein the electropherogram includes a plot of a strength of a chemiluminescent signal generated by the reporter molecule versus an isoelectric point along the isoelectric gradient where the chemiluminescent signal was detected (Palackal et al., 20200393455 A1: Figs. 9-10).
Regarding 7, Palackal teaches the method of claim 6, wherein quantifying the relative abundance of the charge variants based on the signal that corresponds to the detection antibody includes calculating an area under a peak of the electropherogram that corresponds to each of the charge variants (Palackal et al., 20200393455 A1: para 0084).
Regarding 8, Palackal teaches the method of claim 1, further comprising, after separating charge variants along the isoelectric gradient, and prior to incubating :immobilizing the charge variants within the capillary (Palackal et al., 20200393455 A1: paras 0005, 0083-0084, 0086, and 0050-0051; Fig. 8).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The 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(s) 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Vanam et al., (Vanam et al., Rapid quantitative analysis of monoclonal antibody heavy and light chain charge heterogeneity, 2015, mAbs, 7, 6, 1118-1127, provided in IDS filed 3/17/23, NPL Cite No. 1), in view of Palackal et al., (PGPub 20200393455 A1, Pub. Date: 12/17/2020), Sanchez-Felix et al., (Sanchez-Felix et al., Predicting bioavailability of monoclonal antibodies after subcutaneous administration: Open innovation challenge, 2020, Advanced Drug Delivery Reviews, 167, 66-77), and Kahle et al., (Kahle et al., Determination of protein charge variants with (imaged) capillary isoelectric focusing and capillary zone electrophoresis, 2018, Electrophoresis, 39, 2492-2511).
Throughout the article, Vanam teaches a method, ChromiCE, which combines capillary isoelectric focusing with another analytical chromatographic technique, for separating a diverse set of charged variants under reducing and denaturing conditions. Vanam further teaches a method for quantifying charged variants of isolated analytes of interest, allowing for quantitative assessment of charge heterogeneity of a sample.
Regrading claim 9, Vanam teaches a method of quantifying charge variants within an analyte, the method comprising: reducing and denaturing polypeptides within the analyte to generate reduced and denatured polypeptides, wherein the analyte includes charge variants of a target polypeptide (Vanam et al., 2015, mAbs, 7, 6, pg. 1122, para 1); buffer exchanging the reduced and denatured polypeptides to generate a buffer exchanged sample (Vanam et al., 2015, mAbs, 7, 6, pgs. 1123-1124), wherein the buffer exchanged sample includes the reduced and denatured polypeptides; preparing a sample buffer including the buffer exchanged sample (Vanam et al., 2015, mAbs, 7, 6, pg. 1125, para 5); introducing the sample buffer into a capillary (Vanam et al., 2015, mAbs, 7, 6, pg. 1125, para 5); and separating charge variants of the target polypeptide along an isoelectric gradient within the capillary, wherein the charge variants are separated based on their isoelectric points (Vanam et al., 2015, mAbs, 7, 6, pg. 1121-1122, section "Charge variant analysis"; pg. 1122, section "Discussion"; pg. 1123 Figs. 5A-B; pg. 1125, section "Imaged capillary isoelectric focusing"). Vanam does not teach incubating separated charge variants with detection antibody within capillary and quantifying relative abundance of charge variant based on detecting the detection antibody.
The teachings of Palackal, who is in the same field of endeavor, are discussed herein above. Palackal teaches separating charge variants of the target polypeptide along an isoelectric gradient within the capillary, wherein the charge variants are separated based on their isoelectric points; incubating the separated charge variants within the capillary with a detection antibody to bind the detection antibody to the separated charge variants; and quantifying a relative abundance of the charge variants based on a signal that corresponds to the detection antibody (Palackal et al., US20200393455 A1: paras 0005, 0050-0051, 0054, 0061, 0083-0084, 0088, 0117, and Figs. 9-10 [icIEF-Western]).
It would have been prima facie obvious, at the time of filing, to combine the method of separating and quantifying charge variants under reduced and denaturing conditions, as taught by Vanam, with the method of separating, detecting, and quantifying variants using a detection antibody, as taught by of Palackal. A skilled artisan would have been motivated to combine these teachings because using detection antibodies with specificity for target variants enable selective detection and differentiation between different charge variants of a biopharmaceutical. A person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings amounts to combining known elements/methods, known to perform the same function or be performed the same separately as they do when combined, to yield expected and predictable results.
Regrading claim 10, Vanam and Palackal teach all the limitations of claim 9. Vanam further teaches the method of claim 9, wherein the sample buffer includes urea, carrier ampholytes, and a cellulose (Vanam et al., 2015, mAbs, 7, 6, pg. 1125, para 5).
Regrading claim 11, Vanam and Palackal teach all the limitations of claim 9 and Vanam further teaches the limitation(s) of claim 10. Vanam further teaches wherein the cellulose is hydroxyl propyl methyl cellulose (Vanam et al., 2015, mAbs, 7, 6, pg. 1125, para 5).
Regrading claim 12, c and Vanam further teaches the limitation(s) of claim 10. Vanam further teaches wherein the sample buffer includes a urea concentration of at least 6 M (Vanam et al., 2015, mAbs, 7, 6, pg. 1121, para 1; pg. 1123; and pg. 1125, para 5).
Regrading claim 13, Vanam and Palackal teach all the limitations of claim 9 and Vanam further teaches the limitation(s) of claim 10. Vanam further teaches wherein the sample buffer includes a urea concentration of at least 8 M (Vanam et al., 2015, mAbs, 7, 6, pg. 1125, para 5).
Claim(s) 14 is rejected under 35 U.S.C. 103 as being unpatentable over Vanam et al., (Vanam et al., Rapid quantitative analysis of monoclonal antibody heavy and light chain charge heterogeneity, 2015, mAbs, 7, 6, 1118-1127, provided in IDS filed 3/17/23, NPL Cite No. 1), in view of Palackal et al., (PGPub 20200393455 A1, Pub. Date: 12/17/2020), as applied to claim 9 above, and further in view of Sanchez-Felix et al., (Sanchez-Felix et al., Predicting bioavailability of monoclonal antibodies after subcutaneous administration: Open innovation challenge, 2020, Advanced Drug Delivery Reviews, 167, 66-77), as evidenced by Michels et al., (Michels et al., Charge Heterogeneity of Monoclonal Antibodies by Multiplexed Imaged Capillary Isoelectric Focusing Immunoassay with Chemiluminescence Detection, 2012, Anal. Chem. 84, 5380-5386).
Regarding claim 14, the teachings of Vanam and Palackal are discussed herein above. Vanam and Palackal teach all the limitations of claim 9. Vanam and Palackal do not teach a target molecule is selected from the group consisting of alirocumab, sarilumab, fasinumab, nesvacumab, dupilumab, trevogrumab, evinacumab, rinucumab and aflibercept.
Throughout the review article, Sanchez-Felix, in the same field of endeavor, teaches the current state of the art, known at the time of filing, regarding subcutaneous bioavailability prediction for monoclonal antibodies, including alirocumab (Humira®) and sarilumab (Kevzara®).
Sanchez-Felix teaches wherein the target molecule is selected from the group consisting of alirocumab, sarilumab, fasinumab, nesvacumab, dupilumab, trevogrumab, evinacumab, rinucumab and aflibercept (Sanchez-Felix et al., 2020, Advanced Drug Delivery Reviews, 167, pg. 69 (pI); pg. 75, Table 2 [including alirocumab (Humira®) and sarilumab (Kevzara®)]).
It would have been prima facie obvious, at the time of filing, to combine the method of separating, detecting, and quantifying charge variants, as taught by Vanam, in view of Palackal, with the teachings of FDA-approved therapeutic mAbs, as taught by Sanchez-Felix. Sanchez-Felix teaches a finite group of FDA-approved monoclonal antibodies and fusion proteins for the treatment of disease but with unpredictable bioavailability, a core component of pharmacokinetics, especially when administered via subcutaneous injection. At the time of filing, it was known that charge heterogeneity in lots of therapeutic monoclonal antibodies (mAbs) is critical because of its potential effects on pharmacokinetics, which encompasses bioavailability (see Michels et al., 2012, Anal. Chem. 84, 5380-5386). Thus, a skilled artisan would have been further motivated to combine these teachings because it would enable monitoring of known and commercially available therapeutic mAbs for impurity and charge heterogeneity to ensure safety and efficacy of these therapeutic mAb lots before they are distributed to patients. A person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings amounts to combining known elements/methods, known to perform the same function or be performed the same separately as they do when combined, to yield expected and predictable results.
Further, a skilled artisan would have been motivated to try the biotherapeutics taught by Sanchez-Felix, as part of routine optimization, to determine the optimal target mAb(s) to arrive at the claimed invention. At the time of filing, a skilled artisan would have a reasonable expectation of success in determining the optimal target mAb(s) to arrive at the claimed invention because Sanchez-Felix teaches a finite number of known potential solutions that would yield expected and predictable results.
Claim(s) 15 is rejected under 35 U.S.C. 103 as being unpatentable over Vanam et al., (Vanam et al., Rapid quantitative analysis of monoclonal antibody heavy and light chain charge heterogeneity, 2015, mAbs, 7, 6, 1118-1127, provided in IDS filed 3/17/23, NPL Cite No. 1), in view of Palackal et al., (PGPub 20200393455 A1, Pub. Date: 12/17/2020), Sanchez-Felix et al., (Sanchez-Felix et al., Predicting bioavailability of monoclonal antibodies after subcutaneous administration: Open innovation challenge, 2020, Advanced Drug Delivery Reviews, 167, 66-77), as applied to claims 9 and 14 above, and further in view of Kahle et al., (Kahle et al., Determination of protein charge variants with (imaged) capillary isoelectric focusing and capillary zone electrophoresis, 2018, Electrophoresis, 39, 2492-2511).
Regarding claim 15, the teachings of Vanam, Palackal, and Sanchez-Felix are discussed herein above. Vanam and Palackal teach all the limitations of claim 9 and Sanchez-Felix teaches the limitations of claim 14. Vanam, Palackal, and Sanchez-Felix do not teach a formamide concentration is less than or equal to approximately 30 volume percent.
Throughout the review article, Khale teaches size- and charge-heterogeneity are cornerstone profiles for charge variant characterization. Khale teaches charge-based analysis of biopharmaceutical charge variants using imaged capillary isoelectric focusing (icIEF) and capillary zone electrophoresis (CZE). Khale discusses experimental conditions for sample preparation, capillary properties, anolytes and catholytes, carrier ampholytes, sacrificing agents, solubility enhancement, isoelectric point marker, mobilization techniques, and detection modes.
Khale teaches the limitation(s) of claim 15 reciting wherein a formamide concentration within the sample is less than or equal to approximately 30 volume percent (Kahle et al. Electrophoresis 2018, 39, pg. 2496, Table 2).
It would have been prima facie obvious for a person having ordinary skill in the art to combine in order to modify the method taught by Vanam by adding formamide at a concentration of less than or equal to 30 volume percent to the buffer solution as taught by Kahle. One would be motivated to combine a sample buffer that includes formamide, with a concentration less than or equal to 30 % (v/v) because formamide is a well-known solubility enhancer and denaturant that improves the solubility of difficult-to-solubilize proteins and prevents variant aggregation and precipitation, which could lead to low experimental reproducibility. Kahle teaches adding less than or equal to 30 % (v/v) formamide in a sample buffer for separating charged variants within a capillary successfully, including improved peak resolution with reproducible results. Thus, a skilled artisan would have a reasonable expectation of success in combining the formamide buffer solution taught by Kahle with the method taught by Vanam because it would amount to combining known components/elements, according to known methods, to yield expected and predictable results.
Claim(s) 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cao et al., (Cao et al., Charge variants characterization and release assay development for co-formulated antibodies as a combination therapy, Mabs, 2019, 11, 3, 489–499), in view of Palackal et al., (PG Pub 20200393455 A1, Pub. Date: 12/17/2020).
Throughout the disclosure, Cao teaches a method for characterizing charge variants of
therapeutic antibodies that are combined to make drug co-formulations. Further, Cao teaches
separating charge variants based on charge along a stable pH gradient within a capillary,
detecting variants using a UV detector at 280 nm. Cao further teaches generating charge variant
profiles. Particularly, Cao teaches a method of assessing levels of stress charge variants may be
exposed to throughout the manufacturing process by investigating changes to charge variant
profiles of variants before and after exposure to environmental stress.
Regarding claim 16, Cao teaches a method of assessing a level of environmental stress
perceived by a sample of a target polypeptide, the method comprising: generating a charge
variant profile for the sample, wherein the charge variant profile includes a plurality of peaks,
and where each peak: is associated with a corresponding charge variant of the target polypeptide;
is associated with an isoelectric point that is equivalent to the isoelectric point of the
corresponding charge variant of the target polypeptide; comparing the charge variant profile for
the sample to one or more known charge variant profiles; and based on the comparison of the
charge variant profile for the sample to the one or more known charge variant profiles,
determining a level of environmental stress perceived by the sample (Cao et al., Mabs, 2019, 11, 3, Figs. 1 and pg. 490, full para 3). Further, Cao teaches wherein generating the charge variant profile for the sample includes: separating charge variants of the target polypeptide along an isoelectric gradient within a capillary based on their isoelectric points (Cao et al., Mabs, 2019, 11, 3, pg. 497, section "cIEF for charge profiling"). Cao does not teach the charge variant profile includes a relative peak area that is associated with a relative abundance of the corresponding charge variant of the target polypeptide. Additionally, Cao does not teach incubating separated charge variants with a detection antibody.
The teachings of Palackal are discussing herein above. Palackal, in the same field of endeavor, teaches generating a charge variant profile includes a relative peak area that is associated with a relative abundance of the corresponding charge variant of the target polypeptide (Palackal et al., 20200393455 A1: para 0084, Figs. 8-10); wherein generating the charge variant profile for the sample includes: separating charge variants of the target polypeptide along an isoelectric gradient within a capillary based on their isoelectric points and incubating the separated charge variants within the capillary with a detection antibody to bind the detection antibody to the separated charge variants (Palackal et al., 20200393455 A1: paras 0005, 0050-0051, 0054, 0061, 0083-0084, 0088, and 0117).
It would have been prima facie obvious, at the time of filing, to combine the method of assessing a level of environmental stress perceived by therapeutic proteins, as taught by Cao with the method of separating, detecting, and quantifying variants, as taught by Palackal. Different levels/amounts of charge heterogeneity may impact performance and efficacy of biotherapeutics or therapeutic mAbs. Thus, a skilled artisan would have been motivated to combine these teachings as part of a quality control measure because quantifying charge variants in therapeutic lots would enable a skilled artisan to monitor and determine whether the safety and efficacy of a batch of therapeutic mAbs has been compromised during the manufacturing process. A person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings amounts to combining known elements/methods, known to perform the same function or be performed the same separately as they do when combined, to yield expected and predictable results.
Regarding claim 17, Cao and Palackal teach all the limitations of claim 16. Cao further teaches wherein the level of environmental stress is associated with a level of thermal stress, a level of stress due to a manufacturing process hold time, or a level of stress due to freeze-thaw cycles (Cao et al., Mabs, 2019, 11, 3, Figs. 1-2, pg. 490, full paragraph 4, bottom half).
Regarding claim 18, Cao and Palackal teach all the limitations of claim 16. Cao further teaches wherein the target polypeptide includes an antibody or an adeno-associated virus (Cao et al., Mabs, 2019, 11, 3, Figs. 1, pg. 490, full paragraph 2).
Regarding claims 19-20, Cao and Palackal teach all the limitations of claim 16. Palackal further teaches wherein generating the charge variant profile for the sample includes: immobilizing the charge variants within the capillary [claim 19] (Palackal et al, 20200393455 A1: paras 0083-0084, 0086, Figs. 8-10). Palackal further teaches wherein generating the charge variant profile for the sample further includes: incubating the separated charge variants bound to the detection antibody with a reporter molecule; and generating an electropherogram, wherein the electropherogram includes a plot of a strength of a signal generated by the reporter molecule versus an isoelectric point along the isoelectric gradient where the signal was detected [claim 20] (Palackal et al., 20200393455 A1: paras 0005, 0012-0013, 0083-0084, 0086, 0088-0089, paras 0050-0051, Figs.8-10).
It would have been prima facie obvious, at the time of filing, to combine the method of assessing a level of environmental stress perceived by therapeutic proteins, as taught by Cao with the method of separating, detecting, and quantifying charge variants by generating an electropherogram, as taught by Palackal. A skilled artisan would have been motivated to combine these teachings, as part of quality control in the manufacturing process, because it would enable a skilled artisan to monitor, identify, and quantify charge heterogeneity caused by chemical and physical modifications that impact safety, efficacy, and stability. A person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings amounts to combining known elements/methods, known to perform the same function or be performed the same separately as they do when combined, to yield expected and predictable results.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto- processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Instant claims 1-5 and 7-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 9, and 11-12 of U.S. Patent Application No. 16/880,736 in view of Wang et al (Chemiluminescent Immunoassay and Its Applications, Chin J Anal Chem, 2012, 40(1), 3–10) and evidenced by Yan (Capillary Electrophoresis, 1996, The Chemical Educator, Springer-Veralag New York, Inc, Vol. 1, No. 2). This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 1-4, all limitations in the instant claims are recited by the reference claims 1, 4, 9, and 11-12 except wherein the reporter molecule comprises an antibody conjugated to horseradish peroxidase or streptavidin conjugated to horseradish peroxidase. The reference claims recite a reporter molecule comprised of an antibody and a detectable label wherein the detectable label comprises a chemiluminescent label but fails to specify that the chemiluminescent label is horseradish peroxidase or streptavidin conjugated to horseradish peroxidase label.
However, Wang, in the same field of endeavor, recites that it is known in the art that horseradish peroxidase (HRP) is one of the most commonly used labeling enzymes for chemiluminescent immunoassays (Wang et al, Chin J Anal Chem, 2012, 40(1), pgs.4).
It would have been prima facie obvious to a person having ordinary skill in the art, before the effective filing date of the claimed invention, to have used an HRP chemiluminescent label because it is one of a finite number of known options and using the HRP label would amount to employing a known technique that is applicable to chemiluminescent immunoassay methods. A skilled artisan would have recognized that applying this known technique of conjugating an antibody with the HRP labeling enzyme would have yielded predictable results. A person having ordinary skill in the art would have a reasonable expectation of success because this is known technique routinely practiced in the art.
Regarding instant claim 5, the reference claims fail to recite that the detection agent is luminol-peroxide. However, it is known in the art that the HRP labeling enzyme is only detectable if exposed to hydrogen peroxide. Wang recites that luminol, as the enhancer in luminol-peroxide, is one of a finite number of detection agents routinely used to react with the HRP labeling enzyme for purposes of generating a detectable signal in chemiluminescent immunoassay methods (Wang et al, Chin J Anal Chem, 2012, 40(1), pgs.4).
It would have been prima facie obvious, before the effective filing date, to a person having ordinary skill in the art, to add luminol-peroxide as the detection agent to react with the HRP label conjugated to the detection antibody to generate a detectable signal. A skilled artisan would have recognized that applying luminol-peroxide as a known detection agent, from a finite number of known potential solutions in the art, is required for the HRP label to be detected upon binding to its target. A person having ordinary skill in the art would have a reasonable expectation of success because this is a known technique that is routinely and successfully practiced in the art thus has a known potential solution.
Regarding instant claim 7, all limitations of instant claim 7 are recited by reference claims 1 and 11 except calculating an area under a peak of the electropherogram that corresponds to the charge variant. However, Yan Xu teaches variant concentration is directly related to peak height and a variant concentration can be determined from the peak area (Capillary Electrophoresis, 1996, The Chemical Educator, Springer-Veralag New York, Inc, Vol. 1, No. 2, pg. 13).
It would have been prima facie obvious, before the effective filing date, to a person having ordinary skill in the art, to calculate the area under a peak of an electropherogram, corresponding to a charge variant, to quantify the charge variant. A skilled artisan would have recognized that the amount or abundance of the charge variant is related to the area under its corresponding peak in an electropherogram. A skilled artisan would have a reasonable expectation of success in quantifying the relative abundance by calculating a peak area because this method is routine and common practice in the art.
Regarding instant claim 8, all limitations of instant claims 1 and 8 are recited by reference claim 1.
Response to Arguments
Regarding the 35 U.S.C. 112b rejection of claims 1-8, 11-13, and 20 as being indefinite, rejection is traversed and Applicant amendments to claims 1, 2, 11 and 20 are acknowledged and accepted. The 112b rejection of claims 1-8, 11 and 20 is withdrawn. However, Applicant’s amendments to claims 12-13 do not render the claims definite, thus the 112b rejection of claims 12-13 is maintained.
Regarding the 35 U.S.C. 101 rejection of claims 1, 6, 7, 9, 16, and 20, rejection is traversed and Applicant argues that each independent claim recite steps individually or in combination that are not well-understood, routine, or conventional. Applicant’s arguments have been fully considered, particularly with respect to the use of a detection antibody and reporter molecule in icIEF, are persuasive. The 101 rejection of claims 1, 6, 7, 9, 16, and 20 is withdrawn.
Regarding the 35 U.S.C. 102 rejection of claims 1-8, rejection is traversed and Applicant argues the cited reference, Palackal et al., relates to detecting contaminate polypeptides and does not teach or suggests quantifying charge variants of a target polypeptide.
This is not persuasive. As discussed herein above, Palackal explicitly teaches separating, detecting, and quantifying a relative abundance of target molecules within a capillary based on isoelectric point (pI) [see Palackal et al., paras 0005, 0083-0084, 0095, Figs. 8-10 and remaining citations included in the rejection of claims 1-8 herein above]. Though Palackal does not explicitly state charge variants of a polypeptide, the method steps disclosed by the reference are identical and fundamentally encompass the method steps recited in the instant claims. Performing the method steps taught by Palackal would necessarily and inevitably result in separating charge variants and quantifying a relative abundance of the charge variants. The 102 rejection of claims 1-8 is maintained.
Regarding the 35 U.S.C. 102 rejection of claims 9-13, rejection is traversed by Applicant. Applicant’s arguments have been considered but are moot because amendments to claim 9 necessitated a new ground of rejection that relies on additional references not applied in the prior rejection of record for the teaching or matter specifically challenged in the argument.
Regarding the 35 U.S.C. 103 rejection of claims 14-15, rejection is traversed by Applicant. Applicant’s arguments have been considered but are moot because amendments to claim 14 necessitated a new ground of rejection that relies on additional references not applied in the prior rejection of record for the teaching or matter specifically challenged in the argument.
Regarding the 35 U.S.C. 103 rejection of claims 16-20, rejection is traversed and Applicant argues that the combination of references, Cao and Palackal, do not teach assessing of assessing a level of environmental stress perceived by a sample of a target polypeptide, which includes generating a charge variant profile for the sample, wherein generating the charge variant profile for the sample includes: separating charge variants of the target polypeptide along an isoelectric gradient within a capillary based on their isoelectric points and incubating the separated charge variants within the capillary with a detection antibody to bind the detection antibody to the separated charge variants.
This is not persuasive. As discussed in the rejection of claims 16-20 herein above, Cao teaches assessing levels of environment stress perceived by therapeutic mAbs including generating charge variant profiles for charge variants separated within a capillary based on isoelectric point (pI) along an isoelectric gradient. Palackal explicitly teaches separating charge variants along an isoelectric point and detecting them using a detection antibody, using a method such as icIEF-western which necessarily and inevitably requires incubation between immobilized, separated variants within the capillary and the detection antibody. Further, Palackal explicitly teaches “contacting” the separated variants within the capillary with a (primary/detection) antibody, where the term “contacting” necessarily and inevitably implies incubating the separated variants within the capillary with the [detection] antibody (see Palackal et al.: Abstract, 0083-0084, 0086, 0117). The references, Cao and Palackal, do not explicitly state the target molecule being a polypeptide, however, combining and performing the method steps of Cao and Palackal would necessarily and inevitably result in the exact method steps recited in claims 16-20 when applied to a target polypeptide or to any sample of any target biomolecule that has a population of charge variants. The 103 rejection of claims 16-20 is maintained.
Regarding Non-statutory Double Patenting, rejection is traversed and Applicant argues that Palackal does not teach or suggest quantifying charge variants of a target polypeptide and that Wang and Yan do not remedy the deficiencies of Palackal.
This is not persuasive. As discussed in the rejection herein above, in co-pending Patent Application No. 16/880,736, Palackal teaches separating, immobilizing, detecting variants after incubating them with a detection antibody within a capillary, and quantifying the detected variants (see reference claims 1, 4, 9, and 12 in co-pending application 736’ and “determining a relative or absolute amount,” reference claim 11 in co-pending application 736’). Though Palackal does not explicitly state the target molecule is a polypeptide, combining the method steps and elements taught in reference claims 1, 4, 9, and 11-12 in co-pending application 736’ taught by Palackal with Wang and Yan would result in the method recited in the instant claims of this application when applied to any sample of any target biomolecule that has a population of charge variants. Non-statutory Double Patenting rejection of instant claims 1-5 and 7-8 is maintained.
Conclusion
All examined claims (1-20) are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/MELISSA LIZETTE LIRIANO-NG/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 June 29, 2026
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