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 .
Status of the Claims
Claims 1-20 are pending and examined herein.
Priority
This application is a DIV of 15/824,905, now US Patent Number 11733237, filed on November 28, 2017 and claims benefit of provisional application 62/447,772 filed on January 18, 2017. The effective filing date of this application is January 18, 2017.
Information Disclosure Statement
The Information Disclosure Statement filed June 30th, 2023 are acknowledged and have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6 depends upon claim 1 which recites “transferring a plurality of cell samples to an assay plate having a plurality of sample wells, wherein each sample well contains a cell sample that is an undiluted cell culture expressing a target IgG antibody and mixing the plurality of cell samples with analysis reagents to generate a plurality of analysis mixtures”.
This limitation establishes that 1) The cell samples are added to the assay plate wells, and 2) the cell samples are mixed with analysis reagents. Therefore, claim 6 fails to further limit the subject matter of claim 1, as it merely recites this already existing limitation taught in claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1, 8 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Maranon et al. (1994). "A Competitive Enzyme Immunoassay Subclass® for the Determination of Total IgG—Subclass Levels in Human Serum". Journal of Immunoassay and Immunochemistry, 15(2), 147-156, in view of Tyagarajan et al. (WO 2007/067680 A2 - IDS dated 6/30/23).
Regarding instant claims 1, 8 and 10, Maranon teaches a method for quantifying human immunoglobulin gamma (IgG) antibody levels in biological samples via competitive binding immunoassay. In this method, biological samples expressing IgG antibodies are incubated for a time and under conditions with detection reagents that consist of a labeled target IgG protein isotypes that binds to the target IgG antibodies (abstract; page 148, paragraph 2). Maranon discloses the use of microtiter strips of flat-bottom wells in the method (page 149, first full paragraph).
While Maranon discloses the use of assay plate comprising individual wells, Maranon does not recite that the cell samples are transferred to an assay plate with sample wells wherein each sample well contains a cell sample that is an undiluted cell culture in each well. Maranon also does not recite the use of a capture bead that binds to IgG antibody or the use of flow cytometry.
However, Tyagarajan discloses a similar assay using particle-based methods for detecting analytes. Tyagarajan teaches that the samples can be placed in a multiwell plate (page 4, line 28). Tyagarajan also teaches a particle-based competitive immunoassay for measuring antibodies in a sample and in one embodiment, no dilution of the sample is needed - (page 34, line 9). Tyagarajan teaches an immunoassay using capture beads that bind to an IgG antibody of interest (page 33, examples 1 and 2) that can quantify antibody levels via cytometry (page 10, line 23). Tyagarajan specifically teaches many advantages of particle-based assay including increased surface area for reaction and increased capacity of binding. The smaller size of the particles permits their retention in solution for a longer period of time which promotes better contact and reactivity with analytes. The better suspension properties of these beads can allow the use of automated sample preparation and maybe used without vigorous shaking and wash step (page 10, line 24 through page 11, line 14).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Maranon to mix the reagents in plate wells, as disclosed in Tyagarajan, because it allows the avoidance of a transfer step and reduces the possibility of human error. A person of ordinary skill would have had a reasonable expectation of success in placing and mixing the cell samples in uncoated wells instead of test tubes as they serve the same purpose and the results of the substitution would have been predictable.
It also would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Maranon to forgo a sample dilution step, as disclosed in Tyagarajan, because it reduces the possibility of additional human error. The skilled artisan would have been motivated to modify the method to use an undiluted sample in order to save time and reduce costs.
Additionally, it would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Maranon to use beads as the antibody binding substrate and to use flow cytometry analysis, for the advantages disclosed in Tyagarajan as discussed above, such as beads “provide the advantage of increased surface area for reaction and increased capacity of binding. Further, the smaller size of these particles permits their retention in solution for a longer period of time, which promotes better contact and reactivity with analytes”.
The skilled artisan would have been motivated to modify the method in Maranon to use beads as the antibody binding substrate and flow cytometry analysis because beads allow for the use of automated sample preparation that can be used without vigorous shaking and/or wash steps”. Tyagarajan makes obvious that the use of automated detection methods such as flow cytometry allows for a multiplex format which can assay from 2 to more than 1000 different analytes and/or cells using different particles and detection moieties simultaneously (page 11, lines 20-23), which saves time.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon and Tyagarajan as applied to claim 1 above, and further in view of McFarland (2000). “Preparation of pure cell cultures by cloning”. Methods in cell science, 22(1), 63-66, as evidenced by Brezski et al. (2016), "Immunoglobulin isotype knowledge and application to Fc engineering." Current opinion in immunology 40 (2016): 62-69.
Regarding instant claim 2, Maranon and Tyagarajan recites all of the limitations of claim 1 of the instant application but does not recite “wherein the cell culture is propagated from a single clone”.
However, McFarland (2000) teaches multiple strategies to produce cell cultures through cloning for use in biological assays, in order to avoid the use of cultures with multiple cell types that may confound results (abstract). McFarland teaches the preparation of cell cultures through cloning can “insure the purity of cell cultures” (abstract), which can make data interpretation easier such as by avoiding paracrine interactions between different cell types (page 1, column 1, paragraph 1). Such a cloning method for antibody screening purposes in order to insure efficient antibody production.
Therefore, it would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to apply the isotyping method recited in Maranon and Tyagarajan to test a cell sample from a cell culture propagated from a single clone because it is well known in the art that antibody screening, tittering and isotyping are important in-process and final antibody-testing steps in any custom antibody production project and cloned cell cultures. This is further evidenced by Brezski, which teaches the identifying of cell clone lines that produce IgG isotypes in pursuit of efficient production (abstract). A skilled artisan would have been motivated to use the method of the patented claims to identify different IgG isotypes from a single clone for the advantage taught by McFarland, that interpretation of data is clearer than those arising from cell cultures with more than one type of cell (“Interpretation of data arising from studies using these mixed cultures can lead to difficulties, because it may not be possible to ascertain which of the cell types present may have responded to a given treatment” – abstract).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon and Tyagarajan as applied to claim 1 above, and further in view of Mali et al. (2016). “Observations on different resin strategies for affinity purification mass spectrometry of a tagged protein”. Analytical Biochemistry, 515, 26-32.
Regarding instant claim 3, Maranon and Tyagarajan recites all of the limitations of claim 1 of the instant application but does not recite “wherein the capture bead is covalently linked with Protein G or Protein A”.
However, Mali et al. (2016) teaches the use and effect of different support resins (e.g. agarose and paramagnetic capture beads) for immobilization of the antibody in methods for identifying and isolating proteins (abstract). Mali teaches capture beads covalently coupled to Protein A or Protein G for use in mass spectrometry of a tagged protein (Figure 1). Furthermore, Mali teaches that Protein A and Protein G are commonly used for immobilization of antibodies and attached to resin matrices, which confers the advantage of allowing for covalent or non-covalent attachment to antibodies (page 26, paragraph 1).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Maranon and Tyagarajan to use capture beads linked to Protein A or protein G, as disclosed in Mali, because the use of Protein A or Protein G “…enables non-covalent attachment to antibodies (Condition B) or the addition of crosslinkers including BS3 for covalent attachment through Protein A and G (Condition C)” – Figure 1 caption. A person of ordinary skill would have had a reasonable expectation of success in selecting Protein A or protein G as the binding molecule in the method of Maranon and Tyagarajan because Mali teaches that A or protein G can be successfully covalently attached to beads in order to bind target proteins and because these agents are well known in the art as being specific binding agents for immunoglobulins.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon and Tyagarajan as applied to claim 1 above, and further in view of Bangs (1990)."New developments in particle-based tests and immunoassays". Journal of the International Federation of Clinical Chemistry, 2(4), 188-193.
Regarding instant claim 4, Maranon and Tyagarajan recites all of the limitations of claim 1 of the instant application but does not recite that the capture bead is a magnetic bead or an agarose bead.
However, Bangs (1990) recites the use of particle immunoassays for quantitative measurements, done in 96-well plates or tubes (abstract). Bangs teaches that polymers of many types may be utilized as the binding substrate in particle-based tests, (page 193, column 3), and that magnetic particles in particular have speed and convenience advantages and are used in immune- and chemiluminescent assays (page 193, column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen a magnetic bead or an agarose bead as the bead recited in the method of Maranon and Tyagarajan. The skilled artisan would have been motivated to make the selection because Bangs teaches that magnetic particles give the advantage of permitting fast and easy separation of solid and liquid phases (page 193, column 2, lines 11-13). Furthermore, these magnetic and agarose beads are well known in the art as being widely used binding substrates used for immunoassays.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon and Tyagarajan as applied to claim 1 above, and further in view of Belouski et al. (2010). "Utility of lyophilized PMA and ionomycin to stimulate lymphocytes in whole blood for immunological assays". Cytometry Part B: Clinical Cytometry: The Journal of the Int. Society for Analytical Cytology, 78(1), 59-64.
Regarding instant claim 5, Maranon and Tyagarajan recites all of the limitations of claim 1 of the instant application but does not recite “the assay plate contains lyophilized analysis reagents before the plurality of samples are transferred”.
However, Belouski et al. (2009) teaches the efficacy of lyophilized immunoassay reagents used in assay plates, in comparison with the standard liquid formulation equivalency (abstract). Belouski teaches the use of plates for immunoassays preloaded with lyophilized reagents prior to the addition of samples that can provide the advantage of reducing the potential for error that can occur when adding reagents to the wells (Discussion, paragraph 2).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have the assay plate contain lyophilized analysis reagents before the plurality of samples are transferred, as disclosed in Belouski, within the method of Maranon and Tyagarajan, to prolong the stability of the reagents and potentially reduce human error (“the lyophilised reagent plates offer long reagent stability, even at room temperature (>1 year), and a potential reduction in errors caused by incorrect reagent addition.” – Discussion, paragraph 2).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon and Tyagarajan as applied to claim 1 above, and further in view of Dunne et al. (2004), “Automation of cytokine flow cytometry assays”. JALA: Journal of the Association for Laboratory Automation, 9(1), 5-9.
Regarding instant claim 7, Maranon and Tyagarajan recites all of the limitations of claim 1 of the instant application but does not recite “wherein the assay plate is centrifuged before reading the plurality of analysis mixtures in the assay plate in a flow cytometer”.
However, Dunne (2004) teaches a method of flow cytometry assays with elements that facilitate their automation to increase sample analysis output. In the method of this assay, Dunne teaches the centrifugation of assay plates prior to analysis via flow cytometry to avoid transfer steps which allows for more streamlined protocols and increased efficiency (page 6, column 2, second full paragraph).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Maranon and Tyagarajan to include a step where the assay plate is centrifuged prior to the samples are read via flow cytometry, as disclosed in Dunne, to decrease the potential of human error during vessel transfer and increase reproducibility (page 6, column 2, second full paragraph). The skilled artisan would have been motivated to modify the method of Maranon and Tyagarajan to have the assay plate centrifuged because it can allow for an entirely plate-based assay which Dunne teaches produces comparable results to tube-based methods while having higher throughput (page 6, column 2, first full paragraph).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon and Tyagarajan as applied to claim 1 above, and further in view of Widjojoatmodjo et al. (1993). "Comparison of immunomagnetic beads coated with protein A, protein G, or goat anti-mouse immunoglobulins Applications in enzyme immunoassays and immunomagnetic separations". Journal of immunological methods, 165(1), 11-19.
Regarding instant claim 9, Maranon and Tyagarajan recites all of the limitations of claim 1 of the instant application but does not recite the mixing and stepwise addition process of the capture beads and first detection molecule.
However, Widjojoatmodjo et al. (1993) teaches the use of different proteins coupled to magnetic beads for binding IgG antibodies in immunoassays, and comparisons of their binding capacity (abstract). Widjojoatmodjo teaches mixing the samples with the beads to promote IgG antibody binding (“magnetic bead suspension coupled either with GaM, PA, or PG, was incubated with 50 /zl diluted hybridoma culture supernatant for 15 min with continuous shaking” – page 13, column 1, paragraph 4), adding the first detection molecules to this mixture (“GaM IgG conjugated with horseradish peroxidase was used to detect bound Igs at 37°C for 1 h” – page 13, column 2, paragraph 1), and determining IgG antibody concentration based on the amount of the first detection molecule bound (“The formula used for calculating the percentage of bound Igs to the beads was as follows” - page 13, column 2, paragraph 1).
Maranon, Tyagarajan, and Widjojoatmodjo are considered to be analogous to the claimed invention because both are in the same field quantifying IgG via bead-based immunoassay techniques. It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Maranon and Tyagarajan to include this mixing via stepwise addition process, as it is merely applying a known technique to a known method ready for improvement to yield the predictable result of providing accurate quantification of IgG in a biological sample through proper binding conditions and steps.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon and Tyagarajan as applied to claim 10 above, and further in view of Kaleem et al. (2000). "Lack of expression of surface immunoglobulin light chains in B-cell non-Hodgkin lymphomas". American journal of clinical pathology, 113(3), 399-405.
Regarding instant claim 11, Maranon and Tyagarajan recites all of the limitations of claim 10 of the instant application but does not recite “wherein the first detection molecule lacks immunoglobulin light chains and is capable of binding to the capture bead”.
However, Kaleem et al. (2000) recites the identification of patients with non-Hodgkin lymphoma with cells that do not express immunoglobulin kappa or lambda light chains (abstract). Kaleem teaches that an assay having the ability to measure immunoglobulin has invaluable diagnostic purposes (page 404, column 1, paragraphs 2-3). Kaleem teaches the detection of cells lacking immunoglobulin light chain expression using flow cytometry (abstract).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Maranon and Tyagarajan to allow for the detection of molecules that lack immunoglobulin light chains, as disclosed in Kaleem, in order to correctly identify and differentiate lymphoma cells in order to avoid misdiagnosis (page 404, column 1, paragraphs 2-3).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon, Tyagarajan and Kaleem as applied to claim 11 above, and further in view of Manning et al. (2012). "Benefits and pitfalls of secondary antibodies: why choosing the right secondary is of primary importance". PloS one, 7(6), e38313.
Regarding instant claim 12, Maranon and Tyagarajan in view of Kaleem recites all of the limitations of claim 11 of the instant application but does not recite the use of a detectably labeled anti-IgG light chain secondary antibody.
However, Manning et al. (2012) teaches labeling multiple antibodies in one sample in order to provide robust measurement of target protein amounts (abstract). Manning also teaches that using IgG subclass-specific secondary antibodies are superior to using general anti-mouse IgG secondary antibodies when quantifying IgG subclasses (abstract). Manning teaches the use of IgG secondary antibodies (including those binding to light chains) for multiplex labeling of IgG protein subclasses for use in multiple detection applications (page 2, column 1, paragraph 2; Figure 6).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to use a labeled anti-IgG light chain antibody, as disclosed in Manning, within the method of Maranon and Tyagarajan and Kaleem, to allow for robust, reliable, and simultaneous detection of different IgG subclasses in one sample (page 7, column 2). The skilled artisan would have been motivated to modify the method to have a secondary detection molecule (anti-IgG light chain secondary antibody) to distinguish different sites of primary antibody labeling and avoid sample heterogeneity issues (abstract; page 7, column 2).
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon, Tyagarajan, Kaleem, and Manning as applied to claim 12 above, and further in view of Shah et al. (2008). "Flow cytometric measurement of microparticles: pitfalls and protocol modifications". Platelets, 19(5), 365-372.
Regarding instant claim 13, Maranon, Tyagarajan, Kaleem, and Manning recites all of the limitations of claim 12 of the instant application but does not recite “wherein the plurality of analysis mixtures are centrifuged and subjected to a wash step before the labeled anti-light chain antibody is added”.
However, Shah et al. (2008) teaches how variation in sample preparation can significantly influence the results of flow cytometry measurements, and how to optimize sample preparation for the best results through contamination removal (abstract). Shah teaches that centrifugation of biological samples for flow cytometry sample preparation is “...considered to be the primary contributor to variation in microparticle isolation” (page 368, column 2, paragraph 2) and that “most protocols advocate microparticle isolation via washing and centrifugation to reduce background signals” (page 370, column 1, paragraph 1).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Maranon, Tyagarajan, Kaleem, and Manning to include a step where the analysis mixtures are centrifuged and subjected to a wash step before the labeled anti-light chain antibody is added, as disclosed in Shah, in order to reduce background signal and improve results. The skilled artisan would have been motivated to perform these steps for assay standardization to have consistent measurements that can be compared across labs.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon and Tyagarajan as applied to claim 1 above, and further in view of Adan et al. (2017). "Flow cytometry: basic principles and applications". Critical reviews in biotechnology, 37(2), 163-176 (Published online: 14 Jan 2016).
Regarding instant claim 14, Maranon and Tyagarajan recites all of the limitations of claim 1 of the instant application but does not recite “wherein the analysis reagents further comprises one or more of a cell viability dye, a cell surface biomarker, or a marker of apoptosis”.
However, Adan (2017) teaches applications of flow cytometry such as immunophenotyping and apoptosis analysis, as well as general principles including the importance viability analysis for accurate data (abstract; page 171, first full paragraph). Adan recites that in the context of flow cytometry, there are dyes and/or markers used to detect cell viability, cell surface biomarkers, and apoptosis (page 170, column 1, paragraph 3; page 170, column 2, paragraph 2; page 170, column 2, paragraph 3).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Maranon and Tyagarajan to include a cell viability dye, a cell surface biomarker, or a marker of apoptosis, as disclosed in Adan, in order to phenotype and characterize aspects of cells for analysis (“Size, granularity and fluorescent features of the cells, derived from either antibodies or dyes, are also examples of parameters used to analyze and differentiate the cells - (page 163, paragraph 1). The skilled artisan would have been motivated to make this modification because it allows for the identification and avoidance of non-viable cells in the samples which can “non-specifically bind to your antibodies resulting in false positives and ultimately inaccurate results” - page 171, first full paragraph.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Maranon and Tyagarajan as applied to claim 1 above, and further in view of Shenkin et al. (2007). "Accurate assessment of cell count and viability with a flow cytometer". Cytometry Part B: Clinical Cytometry, 72(5), 427-432.
Regarding instant claim 15, Maranon and Tyagarajan recites all of the limitations of claim 1 of the instant application but does not recite “further comprising determining one or more of: (i) a number of cells in each analysis mixture; (ii) a percentage of viable cells in each analysis mixture; (ii) a concentration of target IgG antibody per cell in each analysis mixture; and/or (iii) a concentration of target IgG antibody per viable cell in each analysis mixture”.
However, Shenkin et al. (2007) teaches a method of avoiding using specimens for studies that are low quality and cellularity in order to improve immunophenotypic analysis (page 427, paragraph 1), which could be used in the context of antibody screening. Shenkin recites a method of assessing cell count and viability using flow cytometry to assess specimen quality which is important for accurate results (abstract).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Maranon and Tyagarajan to measure the total and viable cell counts and to quantify the amount of antibody per cell and viable cell, as disclosed in Shenkin, in order to ensure specimen quality and provide accurate data and analysis (“An accurate assessment of specimen quality is an important parameter when performing flow cytometric…” – abstract; “Use of a cell count and viability measurement prior to leukemia and lymphoma assessment by flow cytometry and cytogenetics helps to increase the rate of successful immunophenotypic and cytogenetic analysis.” – abstract).
Claims 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Maranon and Tyagarajan in view of Zuk et al. (U.S. Patent No. 4208479).
In addition to the details of Maranon and Tyagarajan discussed above, Tyagarajan also teaches a kit used to perform particle-based immunoassays to measure antibodies.
Furthermore, Zuk et al. teaches the convenience and accuracy enhancement associated with combining all necessary reagents for an assay together in a kit (column 22, lines 20-68).
Therefore, it would have been obvious to one of ordinary skill in the art to assemble together the reagents (capture bead, control IgG antibody, first detectable moiety, etc.) in the form of a kit, in order to create an assay kit for analyzing IgG antibody production that can be quantified via flow cytometry as described in Maranon and Tyagaraja. A skilled artisan would have had a reasonable expectation of success in assembling the reagents of the patented claims into kits as taught by Zuk because kits are well known as being convenience and economical.
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.
Although there is a restriction in the parent application, 15/824,905 now USP 11,733,237, the prohibition against nonstatutory double patenting rejections under 35 U.S.C. 121 does not apply because the claims of the application under examination (18/345,170) and claims of the patented application are not consonant with the restriction requirement made in the parent application, since the claims have been changed in material respects from the claims at the time the requirement was made. The divisional application, 18/345,170 includes additional claims not consonant in scope with the original claims subject to restriction in the parent (MPEP § 804.01).
Claims 1, 8, and 10 of the instant application are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of Liu et al. (U.S. Patent No. 11733237).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1, 8, and 10 under examination are anticipated, respectively, by claims 1 and 2 of the reference patent Liu `237. The instant application and reference patent both teach a method of quantifying immunoglobulin gamma (IgG) antibody levels, and every limitation in the application under examination claims is recited in the conflicting reference patent claims.
Regarding instant claims 1 and 10, claims 1 and 2 of Liu `237 also teaches a method for analyzing a plurality of cell samples for immunoglobulin gamma (IgG) antibody production, the method comprising:
(a) transferring a plurality of cell samples to an assay plate having a plurality of sample wells (`237 claim 1, line 3), wherein each sample well contains a cell sample that is an undiluted cell culture expressing a target IgG antibody (`237 claim 1, lines 4-5) and mixing the plurality of cell samples with analysis reagents to generate a plurality of analysis mixtures, wherein the analysis reagents comprise:(i) a capture bead, wherein the capture bead binds to IgG antibody (`237 claim 1, lines 13-15); and (ii) a first detection molecule comprising (A) a control IgG antibody or fragment thereof (`237 claim 2, lines 8-10), and (B) a first detectable moiety;
(b) incubating the plurality of analysis mixtures for a time and under conditions to promote binding of the target IgG antibody and the first detection molecule to the capture bead (`237 claim 2, lines 16-20); and
(c) determining the target IgG antibody concentration in each analysis mixture of the plurality of analysis mixtures by flow cytometry analysis (`237 claim 1, lines 21-23).
Regarding instant claim 8, claim 2 of Liu `237 teaches:
The method of claim 1, wherein the mixing comprises simultaneously mixing the plurality of cell samples and all of analysis reagents, wherein the first detection molecule (`237 claim 2, lines 8-10) competes with the target IgG antibody for binding to the capture bead (`237 claim 2, paragraph 2); and wherein the amount of the first detection molecule bound to the capture bead in each analysis mixture provides a measure of the target IgG antibody concentration in a given analysis mixture (`237 claim 2, paragraph 2).
Claim 2 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11 of Liu et al (U.S. Patent No. 11733237) in view of McFarland (1999), “Preparation of pure cell cultures by cloning”. Methods in cell science, 22(1), and further evidenced by Brezski et al. (2016), "Immunoglobulin isotype knowledge and application to Fc engineering." Current opinion in immunology 40 (2016): 62-69.
Regarding instant claim 2, claim 1 of Liu `237 recites all of the limitations of claim 1 of the instant application but does not recite “wherein the cell culture is propagated from a single clone”. However, McFarland (1999) teaches the preparation of cell cultures through cloning “in order to insure the purity of cell cultures” .
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to apply the isotyping method recited in claim 1 of Liu `237 to test a cell sample from a cell culture propagated from a single clone because it is well known in the art that antibody screening, tittering and isotyping are important in-process and final antibody-testing steps in any custom antibody production project and cloned cell cultures, as further evidenced by Brezski et al. A skilled artisan would have been motivated to use the method of the patented claims to identify different IgG isotypes from a single clone for the advantage taught by McFarland, that interpretation of data is clearer than those arising from cell cultures with more than one type of cell (“Interpretation of data arising from studies using these mixed cultures can lead to difficulties, because it may not be possible to ascertain which of the cell types present may have responded to a given treatment” – abstract).
Claim 3 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11 of U.S. Patent No. 11,733,237 in view of Mali et al (2016) “Observations on different resin strategies for affinity purification mass spectrometry of a tagged protein. Analytical Biochemistry, 515, 26-32.
Regarding instant claim 3, claim 1 and 11 of Liu `237 recites all of the limitations of claim 1 of the instant application but does not recite “wherein the capture bead is covalently linked with Protein G or Protein A”.
However, Mali et al. (2016) teaches capture beads covalently coupled to Protein A or Protein G for use in mass spectrometry of a tagged protein (Figure 1).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in claims 1 and 11 of Liu `237 to use capture beads linked to Protein A or protein G, as disclosed in Mali et al., because it “…enables non-covalent attachment to antibodies (Condition B) or the addition of crosslinkers including BS3 for covalent attachment through Protein A and G (Condition C)” – Figure 1 caption. A person of ordinary skill would have had a reasonable expectation of success in selecting Protein A or protein G as the binding molecule in the method of Liu `237 because Mali et al teaches that A or protein G can be successfully covalently attached to beads in order to bind target proteins.
Claim 4 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,733,237 in view of Bangs (1990)."New developments in particle-based tests and immunoassays". Journal of the International Federation of Clinical Chemistry, 2(4), 188-193.
Regarding instant claim 4, claim 1 of Liu `237 recites all of the limitations of claim 1 of the instant application but does not recite that the capture bead is a magnetic bead or an agarose bead.
However, reference Bangs (1990) teaches that polymers of many types may be utilized as the binding substrate in particle-based tests and immunoassays (page 193, column3). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen a magnetic bead or an agarose bead as the bead recited in Liu `237. The skilled artisan would have been motivated to make the selection because Bangs teaches that magnetic particles give the advantage of permitting fast and easy separation of solid and liquid phases (page 193, column 2, lines 11-13).
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,733,237 in view of Belouski et al. (2010). "Utility of lyophilized PMA and ionomycin to stimulate lymphocytes in whole blood for immunological assays". Cytometry Part B: Clinical Cytometry: The Journal of the Int. Society for Analytical Cytology, 78(1), 59-64.
Regarding instant claim 5, claim 1 of Liu `237 recites all of the limitations of claim 1 of the instant application but does not recite “the assay plate contains lyophilized analysis reagents before the plurality of samples are transferred”. However, Belouski et al. (2009) teaches the use of plates with lyophilized reagents for immunoassays (Discussion, paragraph 2).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have the assay plate contain lyophilized analysis reagents before the plurality of samples are transferred, as disclosed in Belouski et al., within the method of claim 1 of Liu `237, to prolong the stability of the reagents and potentially reduce human error (“the lyophilised reagent plates offer long reagent stability, even at room temperature (>1 year), and a potential reduction in errors caused by incorrect reagent addition.” – Discussion, paragraph 2).
Claim 7 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,733,237 in view of Shah et al. (2008). "Flow cytometric measurement of microparticles: pitfalls and protocol modifications". Platelets, 19(5), 365-372.
Regarding instant claim 7, claim 1 of Liu `237 recites all of the limitations of claim 1 of the instant application but does not recite “wherein the assay plate is centrifuged before reading the plurality of analysis mixtures in the assay plate in a flow cytometer”. However, Shah et al. (2008) teaches that centrifugation of biological samples for flow cytometry sample preparation is “...considered to be the primary contributor to variation in microparticle isolation” (page 368, column 2, paragraph 2).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in claim 1 of Liu `237 to include a step where the assay plate is centrifuged prior to the samples are read via flow cytometry, as disclosed in Shah et al., in order to reduce background microparticle levels and noise to improve the quality of flow cytometry analysis (“Additional centrifugation was critical for removing platelet contamination, which significantly affected microparticle counts” - abstract; “Most protocols advocate microparticle isolation via washing and centrifugation to reduce background signals contributed by plasma proteins. Concentrating microparticles also improves the signal-to-noise ratio, which can become problematic when using the limited resolution of flow cytometry” – page 370, column 1, paragraph 1).
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,733,237 in view of Widjojoatmodjo et al. (1993). "Comparison of immunomagnetic beads coated with protein A, protein G, or goat anti-mouse immunoglobulins Applications in enzyme immunoassays and immunomagnetic separations". Journal of immunological methods, 165(1), 11-19.
Regarding instant claim 9, claim 1 of Liu `237 recites all of the limitations of claim 1 of the instant application but does not recite the mixing and stepwise addition process of the capture beads and first detection molecule.
However, Widjojoatmodjo et al. (1993) teaches mixing the samples with the beads to promote IgG antibody binding (“magnetic bead suspension coupled either with GaM, PA, or PG, was incubated with 50 /zl diluted hybridoma culture supernatant for 15 min with continuous shaking” – page 13, column 1, paragraph 4), adding the first detection molecules to this mixture (“GaM IgG conjugated with horseradish peroxidase was used to detect bound Igs at 37°C for 1 h” – page 13, column 2, paragraph 1), and determining IgG antibody concentration based on the amount of the first detection molecule bound (“The formula used for calculating the percentage of bound Igs to the beads was as follows” - page 13, column 2, paragraph 1).
Liu `237 and Widjojoatmodjo et al. are considered to be analogous to the claimed invention because both are in the same field quantifying IgG via bead-based immunoassay techniques. It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in claim 1 of Liu `237 to include this mixing via stepwise addition process, as it is merely applying a known technique to a known method ready for improvement to yield predictable results.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,733,237 in view of Kaleem et al. (2000). "Lack of expression of surface immunoglobulin light chains in B-cell non-Hodgkin lymphomas". American journal of clinical pathology, 113(3), 399-405.
Regarding instant claim 11, claim 1 of Liu `237 recites all of the limitations of claim 10 of the instant application but does not recite “wherein the first detection molecule lacks immunoglobulin light chains and is capable of binding to the capture bead”. However, Kaleem et al. (2000) teaches the detection of cells lacking immunoglobulin light chain expression using flow cytometry (abstract).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in claim 1 of Liu `237 to allow for the detection of molecules that lack immunoglobulin light chains, as disclosed in Kaleem et al., in order to correctly identify and differentiate lymphoma cells in order to avoid misdiagnosis (page 404, column 1, paragraphs 2-3).
Claim 12 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,733,237 in view of Kaleem et al. and Manning et al. (2012). "Benefits and pitfalls of secondary antibodies: why choosing the right secondary is of primary importance". PloS one, 7(6), e38313.
Regarding instant claim 12, claim 1 of Liu `237 in view of Kaleem et al. (2000) recites all of the limitations of claim 11 of the instant application but does not recite the use of a detectably labeled anti-IgG light chain secondary antibody. However, Manning et al. (2012) teaches the use of IgG secondary antibodies (including those binding to light chains) for multiplex labeling of IgG protein subclasses for use in multiple detection applications (page 2, column 1, paragraph 2; Figure 6).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to use a labeled anti-IgG light chain antibody, as disclosed in Manning et al., within the method of claim 1 of Liu `237 and in view of Kaleem et al. (2000), to allow for robust, reliable, and simultaneous detection of different IgG subclasses in one sample (page 7, column 2). The skilled artisan would have been motivated to modify the method to have a secondary detection molecule (anti-IgG light chain secondary antibody) to distinguish different sites of primary antibody labeling and avoid sample heterogeneity issues (abstract; page 7, column 2).
Claim 13 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,733,237 in view of Shah et al. (2008). "Flow cytometric measurement of microparticles: pitfalls and protocol modifications". Platelets, 19(5), 365-372.
Regarding instant claim 13, claim 1 of Liu `237 recites all of the limitations of claim 12 of the instant application but does not recite “wherein the plurality of analysis mixtures are centrifuged and subjected to a wash step before the labeled anti-light chain antibody is added”. However, Shah et al. (2008) teaches that centrifugation of biological samples for flow cytometry sample preparation is “...considered to be the primary contributor to variation in microparticle isolation” (page 368, column 2, paragraph 2) and that “most protocols advocate microparticle isolation via washing and centrifugation to reduce background signals” (page 370, column 1, paragraph 1).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in claim 1 of Liu `237 to include a step where the analysis mixtures are centrifuged and subjected to a wash step before the labeled anti-light chain antibody is added, as disclosed in Shah et al., in order to reduce background signal and improve results.
Claim 14 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,733,237 in view of Adan et al. (2017). "Flow cytometry: basic principles and applications". Critical reviews in biotechnology, 37(2), 163-176, (Published online: 14 Jan 2016).
Regarding instant claim 14, claim 1 of Liu `237 recites all of the limitations of claim 1 of the instant application but does not recite “wherein the analysis reagents further comprises one or more of a cell viability dye, a cell surface biomarker, or a marker of apoptosis”. However, Adan (2017) recites that in the context of flow cytometry, there are dyes and/or markers used to detect cell viability, cell surface biomarkers, and apoptosis (page 170, column 1 paragraph 3; page 170, column 2 paragraph 2; page 170, column 2 paragraph 3).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in claim 1 of Liu `237 to include a cell viability dye, a cell surface biomarker, or a marker of apoptosis, as disclosed in Adan, in order to phenotype and characterize aspects of cells for analysis (“Size, granularity and fluorescent features of the cells, derived from either antibodies or dyes, are also examples of parameters used to analyze and differentiate the cells - (page 163, paragraph 1).
Claim 15 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,733,237 in view of Shenkin et al. (2007). "Accurate assessment of cell count and viability with a flow cytometer". Cytometry Part B: Clinical Cytometry, 72(5), 427-432.
Regarding instant claim 15, claim 1 of Liu `237 recites all of the limitations of claim 1 of the instant application but does not recite “further comprising determining one or more of: (i) a number of cells in each analysis mixture; (ii) a percentage of viable cells in each analysis mixture; (ii) a concentration of target IgG antibody per cell in each analysis mixture; and/or (iii) a concentration of target IgG antibody per viable cell in each analysis mixture”. However, Shenkin et al. (2007) recites a method of assessing cell count and viability using flow cytometry (abstract).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in claim 1 of Liu `237 to measure the total and viable cell counts and to quantify the amount IgG antibody per cell and viable cell, as disclosed in Shenkin et al., in order to ensure specimen quality and provide accurate data and analysis (“An accurate assessment of specimen quality is an important parameter when performing flow cytometric…” – abstract; “Use of a cell count and viability measurement prior to leukemia and lymphoma assessment by flow cytometry and cytogenetics helps to increase the rate of successful immunophenotypic and cytogenetic analysis.” – abstract).
Claims 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of Liu et al. (U.S. Patent No. 11733237) in view of Zuk et al. (U.S. Patent No. 4208479).
Liu `237 is discussed above. However, Liu `237 does not specifically recite an assay “kit” or describe their invention using this terminology, as is done in claims 16-20 of the instant application.
However, Zuk et al. teaches the convenience and accuracy enhancement associated with combining all necessary reagents for an assay together in a kit (column 22, lines 20-68).
Therefore, it would have been obvious to one of ordinary skill in the art to assemble together the reagents (capture bead, control IgG antibody, first detectable moiety, etc.) in the form of a kit, in order to create an assay kit for analyzing IgG antibody production that can be quantified via flow cytometry as described in claims 1-2 of Liu `237. A skilled artisan would have had a reasonable expectation of success in assembling the reagents of the patented claims into kits as taught by Zuk because kits are well known as being convenience and economical.
Conclusion
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/A.J.H./ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 February 18, 2026