DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Status of the Claims
Claims 1-7 are pending and examined herein. Claim 8 is cancelled.
Priority
This application, filed 10/20/2023, claims benefit of provisional application 63/418,013 filed on 10/20/2022. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of 10/20/2022.
Claim Objections
Claims 1, and 5-7 are objected to because of the following informalities:
Claim 1 states "…and thirteen (20) clones…" when it should read as "…and thirteen (13) clones…". Appropriate correction is required.
Furthermore, claims 1, 6, and 7 contain tables in the claims, which lists fluorochromes, cell markers, and clones. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). See MPEP §§ 2173.05(s). Appropriate correction is required.
Claim 5 recites several abbreviations being used for the first time (“EDTA”, “Cyto- Chex BCT “). The first recitation of an abbreviation should be accompanied with the full term/terminology in the interest of improving clarity of the record. Appropriate correction is required.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The drawings in color are objected to because there was no petition under 37 CFR 1.84(a)(2).
Specification
The use of the terms “Cyto-Chex”, “cFluor”, which is a trade name or a mark used in commerce, has been noted in this application (see, e.g., pages 2, 7, 25). The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-7 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.
Claims 1, 6 and 7 all recite a table which lists various fluorochromes, markers, and clones. Claim 1 also recites selecting 13 cell markers, selecting 13 clones, identifying 13 fluorochromes, and conjugating the 13 clones with the 13 fluorochromes, all from the claimed table. The claim is indefinite because there are multiple possible conflicting interpretations based on the claim language and table provided. For example, it is unclear if the claim language is to be interpreted as each row of the table being a set combination, and therefore, for example, if IgM was chosen as the marker to be measured then the CH2 antibody clone must be used and must be conjugated with CFluor B515. Or alternatively if interpretation of the claim language would be that after a marker to measure is chosen from the “Marker” column, then any fluorochrome is chosen from the “Fluorochrome” column to conjugate with any antibody clone from the “Clone” column (as is suggested by the language “assigning”, for example, at claim 2). Similarly, claims 6 and 7 recite a combination of fluorochromes and clones specific to cell markers in reference to the table recited in the claims. Based on the claim language and the recitation of tables in the claims, it is not clear how the claim is to be interpreted. As there are multiple potential conflicting interpretations of the claim language, these claims are indefinite.
Furthermore, claims 1, 6, and 7 contain the trademark/trade name “cFluor” (Serial num. 88958780). Claim 5 contains the trademark/trade name “Cyto-Chex” (Serial num. 77479291). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe commercially available fluorophore-conjugated antibodies in the instances of “cFluor” and a direct draw blood collection tube that maintains cellular morphology and surface antigen expression in the instances of “Cyto-Chex”, accordingly, the identification/description is indefinite.
Claim 2 recites “…assigning the dimmest fluorochromes to the highest expressing antigens; assigning tertiary markers to bright fluorochromes…”. The term “the highest expressing antigens” lacks antecedent basis because it is not recited or defined previously in claim 2 or in claim 1 from which it depends, nor does the recited language make evident that “antigens” is specifically a further limitation of “cell markers” recited in claim 1. The claim language is indefinite because it is not readily apparent which cell marker/antigen are those considered to be “highest expressing” such that one can readily visualize which antigen is to be assigned to each fluorochrome. Additionally, “highest” is relative terminology, and as such the claim is indefinite because it is not readily clear what is encompassed by “highest expressing” (i.e., compared to what standard is considered highest expressing, for example, highest expressing relative to some specific specimen, since a particular marker could be highly expressed in one cell/tissue type and not another).
The term “tertiary markers” also lacks antecedent basis because it is not recited or defined previously in claim 2 or in claim 1 from which it depends, nor is it clear whether “tertiary markers” is a further limitation of “cell markers” recited in claim 1. As a result, the scope of the claim is unclear because one having ordinary skill cannot readily determine which cell markers are and are not considered “tertiary”. The originally filed specification fails to provide further context or definition regarding what is meant by the recited language.
Appropriate correction is required.
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 1-2, 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Gatti et al. (2021). “The ISCCA flow protocol for the monitoring of anti‐CD20 therapies in autoimmune disorders”. Cytometry Part B: Clinical Cytometry, 100(2), 194-205, (herein referred to as Gatti), in view of Park et al. (2020). “OMIP‐069: forty‐color full spectrum flow cytometry panel for deep immunophenotyping of major cell subsets in human peripheral blood”. Cytometry Part A, 97(10), 1044-1051, (herein referred to as Park), Jaimes et al. (US 20220082488 A1), (herein referred to as Jaimes), Streicher et al. (2014). “The plasma cell signature in autoimmune disease”. Arthritis & rheumatology, 66(1), 173-184, Kim et al. (2018). “Human extrafollicular CD4+ Th cells help memory B cells produce Igs”. The Journal of Immunology, 201(5), 1359-1372, (herein referred to as Kim), Ferreira-Gomes et al. (2021). “SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself”. Nature communications, 12(1), 1961, (herein referred to as Ferreira-Gomes), Krejsek et al. (2015). “Increase of Intracellular BAFF in B Cells of Sjögren’s Patients Is Not Affected by Decrease of BAFFR”. Acta medica, 58(1), 25-31, (herein referred to as Krejsek), Tipton et al. (2015). “Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus”. Nature immunology, 16(7), 755-765, (herein referred to as Tipton), Baart et al. (2023). (Published: 12 October 2021). “Side-by-side comparison of uPAR-targeting optical imaging antibodies and antibody fragments for fluorescence-guided surgery of solid tumors”. Molecular Imaging and Biology, 25(1), 122-132, (herein referred to as Baart), Heidt et al. (2012). “B cell repopulation after alemtuzumab induction—transient increase in transitional B cells and long-term dominance of naïve B cells”. American Journal of Transplantation, 12(7), 1784-1792, (herein referred to as Heidt), Cytek A (Cytek® 25-Color Immunoprofiling Assay. Technical Data Sheet, R8-50002 Rev. G, Effective Date: 06/15/2022), and Cytek B (cFluor® B532 Anti-Human CD4 (SK3). Technical Data Sheet, R8-50037 Rev. B, Effective Date: 05/04/2022).
Regarding claim 1, Jaimes et al. teaches a method of building an optimized color flow cytometry panel using a full spectrum flow cytometer with five excitation lasers and five corresponding detection modules (Abstract). Jaimes teaches that when constructing the panel, 30 or more cell markers are selected from cell lines such as CD4 T cells, CD8 T cells, regulatory T cells (Tregs), yd T cells , NKT - like cells , B cells , 2 NK cells , monocytes , and dendritic cells. The cell markers are selected from cell lines that can be used for studies aimed at characterizing the immune response in the context of infectious or autoimmune diseases ([0150]). The antigens listed by Jaimes as B cell markers include CD19, CD20, CD27, CD38, CD95, IgD, CD24, IgM, CXCR5, and IgD (Fig. 19).
The workflow for panel construction includes identifying commercially available fluorochromes to be used in the flow cytometry panel, covering as many possible peak emission wavelengths as possible across all available lasers (Figure 7A, Block 2, page 31; paragraph [0151]). Jaimes et al. further teaches that the workflow includes calibrating the laser and detectors in the flow cytometer (Figure 7A, Block 3, page 31), and specifically a full spectrum cytometer with 5 laser and 64 detectors is calibrated for use (paragraph [0152]).
Furthermore, Jaimes et al. discloses that in the workflow, the biological cells of interest are stained with the fluorochrome conjugated antibodies according to best practice staining protocols (paragraph [0166], page 75; Figure 7B, Block 10, page 32), and the stained biological cells of interest are collected in a multicolor sample tube and run through a full spectrum flow cytometer (paragraph [0167], page 76; Figure 7B, Block 11, page 32). Additionally, Jaimes et al. teaches that the plurality of scatter detectors are typically used to control data capture by the detector modules in the flow cytometer and data storage in a storage device, and each of the detector modules can capture a plurality of raw digital data for a given particle/cell as each laser beam of the plurality of lasers strike the same particle (paragraph [0123], page 71). Lastly, Jaimes et al. discloses that the raw data collected by detectors is processed and analyzed using computational methods including gating, clustering, and visualization (paragraph [0168], page 76; Figure 7B, Block 12, page 32). Hence, Jaimes et al. teaches a structured workflow for building a flow cytometry panel which directly correspond to the claimed workflow steps.
However, Jaimes does not teach creating the panel for monitoring B cells specifically for analyzing subsets in anti- CD20 treated autoimmune patients, nor does Jaimes teach selecting exactly thirteen (13) cell markers for biological cells of interest, selecting exactly thirteen (13) clones related to the thirteen (13) cell markers, and identifying exactly thirteen (13) fluorochromes to be used in the flow cytometry panel, nor does Jaimes teach the exact matching of markers with specific fluorochrome-conjugated antibody clones as recited in the table of claim 1.
Gatti teaches a flow cytometry protocol for the monitoring of anti-CD20 therapies in autoimmune disorders using an immunophenotypic panel (Abstract-Background). Specifically, Gatti discloses the measurement of B cells, plasma cells/blasts, naïve and memory B cells, sIgM+ and sIgG-switched memory B cells, T and NK cells in order to provide a standardized method for the clinical decision-making process during anti-CD20 therapies used for autoimmune diseases (Abstract-Background). To do this, Gatti teaches the use of a 10-marker, 8-color staining panel (CD20-V450, CD45-V500c, CD4-FITC + sIgM-FITC, CD38-PE, CD3-PerCP Cy5.5, CD19-PE-Cy7, CD27-APC, CD8-APC H7 + sIgG-APC-H7) to quantify the cells mentioned above (Abstract-Methods). The only markers from claim 1 that Gatti does not teach are CD15, CD14, and IgD. Furthermore, Gatti teaches that the 10-marker staining panel was based on a preconfigured and commercially available lyophilized reagent tube, and explicitly recites the cell markers and corresponding antibody clones and conjugated fluorochromes the tube contains.
Gatti teaches the use of several marker/clone matches recited in claim 1 but with different fluorochromes, regarding the matching clones, Gatti teach CD45 (clone 2D1)-V500c, CD4 (clone SK3)-FITC, CD38 (clone HB7)-PE, CD3 (clone SK7)- PerCP Cy5.5, CD19 (clone SJ25C1)-PE-Cy, CD8 (clone SK1)-APC H7 (page 196, column 1, 5th paragraph). Gatti also teaches the use of several other markers recited in claim 1, but with different antibody clones. This includes CD20 (clone L27)-V450, CD27 (clone L128)-APC, anti-IgM (clone G20-127)-FITC, and anti-IgG (clone G18-145)-APC H7 (page 196, column 1, 5th paragraph). Furthermore, Gatti teaches the use of flow cytometers that can house up to 3 lasers (“FACSCanto II and BD FACSLyric flow cytometers”, page 196, column 2, 2nd paragraph).
Park teaches a 40-color full spectrum flow cytometry-based panel for in-depth immunophenotyping of the major cell subsets present in human peripheral blood (Purpose). Park also recites that “The panel can be used for studies aimed at characterizing the immune response in the context of infectious or autoimmune diseases, monitoring cancer patients on immuno- or chemotherapy, and discovery of unique and targetable biomarkers”. In addition, Park teaches that the use of the full spectrum flow cytometer allows for 40 fluorescent markers to be used effectively in a single panel, and that the panel was developed using cryopreserved human peripheral blood mononuclear cells (PBMC) (Purpose). Park teaches the use of all the markers recited in the panel of claim 1 except CD15, and also teaches the use of several of the exact marker/clone matches recited in claim 1 but with different fluorochromes (Table 2). This includes CD3 (clone SK7)-BV510, CD4 (clone SK3)-cFluor YG584, and CD8 (clone SK1)-BUV805 (Table 2). The other markers recited by claim 1 that are taught by Park use different antibody clones. This includes CD45 (clone HI30)-PerCP, CD14 (clone 63D3)-Spark Blue 550, CD19 (clone HIB19)-Spark NIR 685, CD20 (clone HI47)-Pacific Orange, IgD (IA6-2)-BV480, IgG (clone G18-145)-BV605, IgM (clone MHM-88)-BV570, CD27 (clone M-T271)-APC-H7, and CD38 (HIT2)-APC-Fire810 (Table 2). Park recites that their full spectrum cytometry panel protocol produces excellent population resolution (page 1049, column 1, 5th paragraph).
Regarding claim 1, Ferreira-Gomes teaches the use of IgM antibody clone CH2 for flow cytometry analysis (page 10, column 2, 2nd full paragraph).
Regarding claim 1, Streicher teaches the use of CD15 antibody clone HI98 for flow cytometry analysis (page 175, column 1, 1st full paragraph).
Regarding claim 1, Kim teaches the use of CD27 antibody clone O323 for flow cytometry analysis (page 1360, column 2, 3rd full paragraph; page 1367, column 1, 1st paragraph; Supp. Fig. 2E).
Regarding claim 1, Krejsek teaches the use of CD14 antibody clone MEM-15 for flow cytometry analysis (page 26, column 2, 1st paragraph).
Regarding claim 1, Tipton teaches the use of IgD antibody clone IgD26 for flow cytometry analysis (page 766, column 1, 2nd paragraph).
Regarding claim 1, Baart teaches the use of IgG antibody clone 4A11 for flow cytometry analysis (page 124, column 1, 3rd full paragraph).
Regarding claim 1, Heidt teaches the use of CD20 antibody clone 2H7 for flow cytometry analysis (page 1785, column 1, 5th paragraph).
Regarding claim 1, Cytek A teaches an immunoprofiling assay designed and optimized by for identifying major human immune subpopulations for T, B, NK cells, monocytes, dendritic cells, and basophils using flow cytometry (Product Description, page 2). The assay contains fluorochrome conjugated antibodies in individual tubes, which includes a list of the specific fluorochromes used (table, page 2-3). Cytek A teaches many of the fluorochromes of claim 1, including cFluor® B515, cFluor® B548, cFluor® BYG575, cFluor® BYG610, cFluor® BYG667, cFluor® BYG710, cFluor® BYG781, cFluor® R659, cFluor® R668, cFluor® R685, cFluor® R720, cFluor® R780 (table, page 2).
Regarding claim 1, Cytek B teaches the cFluor® B532 conjugated Anti-Human CD4 (SK3) monoclonal antibody for use in flow cytometry (table, page 1).
It would have been prima facie obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of building an optimized color full spectrum flow cytometry panel to measure cell markers as taught by Jaimes, to be used for monitoring anti-CD20 therapies in autoimmune patients as disclosed by Gatti, using the cell markers and clones as disclosed by Gatti and Park, the antibody clones recited by Ferreira-Gomes, Streicher, Kim, Krejsek, Tipton, Baart, and Heidt, and the specific fluorochromes recited by Cytek A and B, in order to achieve a method of building a B cell monitoring panel for analyzing subsets in anti- CD20 treated autoimmune patients (as in Gatti) that is optimized due to the inclusion of additional markers influenced by anti-CD20 treatments, because the fluorochromes and antibody clones used are commercially available and known to be used in the field of immunophenotyping with regards to disease state.
One of ordinary skill would be motivated to improve the method of building an optimized color full spectrum flow cytometry panel to measure cell markers taught by Jaimes, to include the markers taught by Gatti, Park, and Streicher in order to create a more comprehensive panel for monitoring B cells to analyze the effects of anti-CD20 treatments on immune cell subsets in autoimmune patients, by providing more data in order to assist the safe and rational usage of anti-CD20 therapies (Gatti, page 195, column 2, paragraphs 2 and 3).
One of ordinary skill would also be motivated to modify the method of Jaimes using the markers taught by Gatti, Park, and Streicher because these inventions aim to better characterize immune subpopulations to allow for more informed decisions regarding the identification of targetable biomarkers and the development of new therapeutic approaches. One having ordinary skill would also be motivated to substitute the antibody clones and fluorophores taught by Gatti, Park, Streicher, Ferreira-Gomes, Streicher, Kim, Krejsek, Tipton, Baart, and Heidt with those of the claimed invention because the prior art references demonstrate that these antibody clones were effectively used to target the same markers as listed in claim 1 for use with flow cytometry and are commercially available, and therefore their use would represent a mere simple substitution of similar features that serve the same purpose. Similarly, a skilled artisan would also be motivated to modify the method of Jaimes, Gatti, Park, Streicher, Ferreira-Gomes, Streicher, Kim, Krejsek, Tipton, Baart, and Heidt to instead use the claimed fluorochromes as a matter of simple substitution, as for example, the staining panel of Gatti and Park fluororeagent tubes with fluorochromes that are commercially available for use with flow cytometry, similar to the claimed fluorochromes as documented by the Cytek references discussed above.
A person of ordinary skill would have had a reasonable expectation of success in modifying the method of Jaimes to achieve the method of claim 1, because all the aspects of the modification are known in the art and have been used in similar flow cytometry methods with success as described above, creating immunophenotypic panels to monitor immune cell subsets.
Regarding claim 2, Jaimes et al teaches that the dimmest fluorochromes were assigned to markers with high expression levels and high co-expression levels in the panel to reduce spread [0165]. Jaimes further teaches that tertiary cell markers were assigned to bright fluorochromes to maximize resolution, and that for fluorochromes with the same primary excitation laser or similar emission wavelengths, avoid highly expressed antigens being placed in cells adjacent to co-expressed antigens with lower expression [0165]. It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to adopt the fluorochrome assigning protocol recited by Jaimes in order to maximize resolution.
One would be motivated to maximize resolution because Park teaches that such high-quality signals, low noise, and excitation specific full-emission profiles are needed to distinguish fluorochromes whose spectral signatures, particularly their peak emissions, are similar (page 1045, column 1, 1st full paragraph). Park also teaches that such high quality also requires extremely careful panel design and optimization. A person of ordinary skill would have had a reasonable expectation of success in making this modification because the methods represented in Gatti, Jaimes, and Park are all in the same field of endeavor which is multicolor flow cytometry panels and rely on the same well-understood, routine, and conventional methodologies and concepts, such that the result of maximizing resolution would be predictable.
Regarding claim 4, Gatti teaches wherein the biological cells comprise peripheral blood cells (page 196, column 1, 1st paragraph).
Regarding claim 5, Gatti teaches wherein the biological cells are collected in EDTA (page 196, column 1, 1st paragraph).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Jaimes in view of Gatti, Park, Streicher, Kim, Ferreira-Gomes, Krejsek, Tipton, Baart, Heidt, Cytek A and Cytek B as applied to claims 1-2 and 4-5 above, and in further view of Ferrer-Font et al. (2019). “Design and optimization protocol for high-dimensional immunophenotyping assays using spectral flow cytometry”. bioRxiv, 784884.
The teachings of Jaimes in view of Gatti Park, Streicher, Kim, Ferreira-Gomes, Krejsek, Tipton, Baart, Heidt, Cytek A and Cytek B are incorporated herein.
In addition to the details of Jaimes, Gatti, Park,, Streicher, Kim, Ferreira-Gomes, Krejsek, Tipton, Baart, Heidt, Cytek A, and Cytek B discussed above, Park also teaches the use of an “Aurora full spectrum flow cytometer”, manufactured by Cytek Biosciences, to perform the studies (“Conflict of Interest”, page 1049). However, Park is silent on whether the recited cytometer was a 3-laser flow cytometer.
Ferrer-Font teaches the design and optimization protocol for high-dimensional immunophenotyping assays using spectral flow cytometry. Specifically, Ferrer-Font teaches the use of a 3-laser Aurora (Cytek) full spectrum flow cytometer (Fig. 4, Fig. 6), and that the 3-laser unit is the base unit (Introduction, page 2, 3rd paragraph). Furthermore, Ferrer-Font teaches an example of markers and fluorochromes in a 24-color panel designed for identification of circulating cell subsets in blood using the 3-laser system (Table 3, page 17).
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 taught by Jaimes in view of Gatti, Park, Streicher, Kim, Ferreira-Gomes, Krejsek, Tipton, Baart, Heidt, Cytek A and Cytek B to use a 3-laser full spectrum flow cytometer, as taught by Ferrer-Font, because it would have been “obvious to try”, as there are a finite number of possible laser configurations of the full spectrum flow cytometer taught by Park (3, 4, or 5 lasers). A skilled artisan would also be motivated to use a 3-laser full spectrum flow cytometer because it come as the standard of the base model, and therefore provides convenience and economy by avoiding cytometer upgrades to a 4 or 5-laser system. A person of ordinary skill would have had a reasonable expectation of success in using a 3-laser full spectrum within the method taught by the above references as the claimed invention only requires a 13-color panel, and Ferrer-Font resides in the same field of invention as Gatti, Park, etc. of identifying circulating cell subsets in peripheral blood, and provides an example of a panel that measures many of the same markers as the claimed invention.
Claims 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Jaimes, Gatti Park, Streicher, Kim, Ferreira-Gomes, Krejsek, Tipton, Baart, Heidt, Cytek A, and Cytek B in view of Zuk et al. (U.S. Patent No. 4208479).
In addition to the details of Jaimes, Gatti, Park, Streicher, Kim, Ferreira-Gomes, Krejsek, Tipton, Baart, Heidt, Cytek A, and Cytek B discussed above, Gatti also teaches the use of a commercially available tube on which the staining panel is based on, and which contains preconfigured fluorochrome conjugated antibody clone combinations, and also contains further fluorochrome conjugated antibody clones added to the tube by the authors (page 196, column 1, 5th paragraph). Additionally, Kim teaches the use of multiple tubes to which samples and reagents were added to (page 1361, column 1, 3rd full paragraph).
While Jaimes, Gatti, Park, Streicher, Kim, Ferreira-Gomes, Krejsek, Tipton, Baart, Heidt, Cytek A, and Cytek B makes obvious the method of claims 1-5 as discussed above, they do not recite all the reagents together in a kit
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 (test tubes, fluorochromes, antibody clones, etc.) in the form of a kit, in order to create a reagent kit for a full spectrum flow cytometer for B cell monitoring for analyzing subsets in anti-CD20. 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.
Claims 1-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 6 and 7 of copending Application No. 18/491,741 in view of Jaimes, Gatti, Park, Streicher, Kim, Ferreira-Gomes, Krejsek, Tipton, Baart, Heidt, Cytek A, Cytek B, Ferrer-Font, and Zuk.
Copending claim 1 teaches a method of building a color flow cytometry panel for detecting aberrant cells in Acute Myeloid Leukemia (AML) using a full spectrum flow cytometer, including selecting cell markers, selecting corresponding clones, identifying fluorochromes, conjugating clones to create a multicolor single tube sample, staining biological cells, and analyzing the multicolor sample. This corresponds to the panel-building workflow recited in instant claim 1.
However, copending claim 1 differs from instant claim 1 in that it does not expressly teach: selecting thirteen (13) specific cell markers from a predefined list directed to B cell monitoring panel for analyzing subsets in anti- CD20 treated autoimmune patients, selecting thirteen (13) specific clones corresponding to those markers, identifying thirteen (13) specific fluorochromes from a predefined list, and forming the specific one-to-one fluorochrome-marker-clone combinations recited in instant claim 1. Gatti teaches constructing an immunophenotypic panel by selecting cells relevant to autoimmune patients treated with ant-CD20 such as B cells, plasma cells/blasts, naïve and memory B cells, sIgM+ and sIgG-switched memory B cells, T and NK cells, and selecting the necessary fluorochromes and antibody clones to quantify them.
Jaimes et al. teaches a structured workflow for building optimized full spectrum flow cytometry panels, including fluorochrome identification, detector calibration, staining, acquisition, and data processing. Park teaches the use of a full spectrum flow cytometry to measure major cell subsets in human peripheral blood, and Ferrer-Font teaches a 3-laser full spectrum flow cytometer. The additional references (Streicher, Kim, Ferreira-Gomes, Krejsek, Tipton, Baart, Heidt) teach the use of the specific claimed antibody clones targeting the same markers, and Cytek technical documents teach the claimed fluorochromes and their use in multiplex flow cytometry panels.
Together, these references would have suggested modifying the panel construction method of copending claim 1 to incorporate the specific AML marker set, clone selections, fluorochrome selections, and one-to-one combinations recited in instant claim 1, as these represent known and interchangeable panel components selected from a finite set of well-characterized markers, clones, and fluorochromes used in multiplex flow cytometry.
Instant claim 2 recites fluorochrome assignment strategies. Copending claim 2 recites
substantially the same assignment principles.
Instant claim 3 recites that the full spectrum flow cytometer is a 3-laser flow cytometer. The copending claims do not expressly teach the number of lasers used by the full spectrum flow cytometer. However, Park and Ferrer-Font teach the use of a 3-laser full spectrum flow cytometer for immunotyping of cell subsets for characterizing the immune response in the context of autoimmune diseases. Incorporating these into the copending method would have been an obvious refinement, rendering instant claim 3 not patentably distinct.
Instant claim 4 recites that the biological cells comprise peripheral blood cells. Copending claim 5 recites wherein the biological cells comprise blood and bone marrow cells, but does not teach that the blood cells are peripheral blood cells. However, Gatti teaches wherein the biological cells comprise peripheral blood cells specifically, rendering instant claim 4 not patentably distinct.
Instant claim 5 recites that the biological cells are collected in EDTA, Cyto- Chex BCT, or heparin tubes. The copending claims do not expressly teach that the biological cells are collected in EDTA, Cyto- Chex BCT, or heparin tubes. However, Gatti teaches the use of EDTA which is well-understood, routine, conventional method of preventing clotting of blood samples, making its use obvious and rendering instant claim 4 not patentably distinct.
Instant claim 6 and 7 recite a reagent kit comprising a sample test tube and test tubes respectively, containing fluorochrome- clone-marker combinations. Copending claims 6 and 7 similarly recite a reagent kit comprising a sample test tube(s) containing a reagent composition including fluorochromes and clones specific to cell markers; but does not expressly recite the specific B cell monitoring panel combinations for anti- CD20 treated autoimmune patients. Gatti teaches the use of a 10-marker, 8-color staining panel with markers for cells affected by antiCD20 treatments in a single tube, while Cytek A teaches providing such panels in reagent kit formats with predefined fluorochrome-clone-marken combinations in tube-based containers. Accordingly, modifying the kit of copending claims 6 and 7 to include the specific combinations for cells depleted by anti-CD20 recited in instant claims 6 and 7 would have been an obvious selection of known panel components, rendering instant claims 6 and 7 not patentably distinct.
Conclusion
For all the reasons discussed above, claims 1-7 are rejected and therefore no claims are allowed.
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/ALEXANDER J. HOFFMAN/ Examiner, Art Unit 1677
/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677
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