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 07/14/2023. This application claims benefit of U.S. Provisional Patent Application 63/368,483 filed on 07/14/2022.
Election/Restrictions
Applicant’s election with traverse of Group I (claims 1-2) in the reply filed on 07/13/2026 is acknowledged. Applicant canceled claims 3-26. Applicant added new claims 27-39 and requested for examination with the elected invention. The request is accepted because the new claims are directed to the subject matter of Group I.
Claim status
Claims 1-2 and 27-39 are pending and examining.
Claim Objections
Claims 3-26 are objected to because of the following informalities: while claims 3-26 are canceled, they should be noted in the claim set following Manner of making amendments in application rule. See MPEP 714, 37 C.F.R. 1.121 (c).
For example, right below claim 2 Applicant should write: Claims 3-26. (Canceled)
Claims 1, 2 and 35 are objected to because of the following informalities:
Claims 1 and 2 read “cFlour” in Fluorochrome column when it should read as -cFluor-.
Claim 35 read “a nineth vial containing…” in paragraph 10 when it should read as -ninth-.
Appropriate correction is required.
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.
Claims 27 and 31 are 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.
Claims 27 and 31 do not further limit the subject matter of the claims 1 and 2 because the limitation “antibodies specific to the markers listed under the SPECIFICITY/MARKER column” in claims 27 and 31 has been recited in claims 1 and 2.
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.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, and 27-39 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Scope of the invention
Claims 1-2 and 35 recite a reagent kit for analysis of blood cells comprising antibodies specific to cell markers listed in the claimed table.
The claimed antibody may be any of a genus of antibody where the antibody is defined only in terms of desired functions (e.g., desired binding properties) and not by structure or sequence. The claim scope is potentially enormous depending on how many of the products meet the functional requirements.
MPEP § 2163 states that written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics) or through a sufficient description of a representative number of species. Either is considered sufficient to show the applicant was in possession of the claimed genus.
“When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)) (emphasis added).
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number* of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
In the present case, however, there is insufficient evidence of such an established structure-function correlation in the case of antibodies having the function of binding to the claimed cell markers. Reciting that the antibodies are specific for the cell markers only sets forth what the antibodies do and not what they are.
Regarding structure-function correlation, it is noted that one of skill in the art was aware that there is a lack of structure-function correlation in antibody molecules. Evidence of such in the form of publications in the art include the following.
First, the prior art recognizes that the full six CDR sequences are required to form the part of an antibody, i.e., the paratope, that specifically binds the target antigen. See Janeway et al. (Immunobiology: the Immune System in Health and Disease (2001), Elsevier Science Ltd/Garland Publishing, New York, NY, Fifth Edition, see sections 3-6 and 3-7) and Almagro et al. ("Humanization of Antibodies", Frontiers in Bioscience 13, 1619-1633, 2008) at introduction and section 4. While antibody CDRs are necessary for binding, they are highly diverse in structure, and their sequence does not correlate to binding in a predictable fashion.
The prior art also recognizes that a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes). For example, Edwards et al. (2003, JMB 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well.
Lloyd et al. (2009, Protein Engineering, Eng. Design & Selection 22(3): 159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding. Said reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen. Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (See entire reference.)
Goel et al. (“Plasticity within the Antigen Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response”, The Journal of Immunology 173(12):7358-7367, 2004) made three antibodies that bind to the same 12-mer but have very different CDRs (see Figures 2-3 in particular).
Vajdos et al. (“Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis” J Mol Biol. 2002 Jul 5;320(2):415-28, DOI: 10.1016/S0022-2836(02)00264-4) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (see especially at 416). Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen.
In view of the above, one cannot visualize or recognize the identities of the members of the genus that exhibit the claimed functional properties. Given the highly diverse nature of antibodies, and particularly the highly variable structure of antibodies in their CDR regions which are responsible for antigen binding, one cannot envision the structure of an antibody merely by knowing its binding characteristics.
Regarding a representative number of species, the instant specification fails to describe a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163. While the specification provides the antibody clones that produce monoclonal antibodies specific to the claimed cell markers (par.11, 273), only one species of antibody within the claimed genus is described with sufficient identifying characteristics using precise definitions such as structure, formula, chemical name, or physical properties that one skilled in the art could visualize or recognize the identity of the claimed subject matter. The disclosed antibodies do not cover all antibodies that bind to the claimed targets, given the potential variability in antibody generation (see discussion of Edwards and Lloyd above for the structurally diverse genus of antibodies that can bind to a protein). The disclosure does not reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation."
Moreover, Applicant’s attention is directed to the recent decision in Amgen Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The court discussed whether an antibody is adequately described by describing a newly characterized antigen. Specifically, the court referred to the decision in Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011). In that case, the patentee claimed a genus of antibodies containing a human variable region that has particularly desirable therapeutic properties: high affinity, neutralizing activity, and A2 specificity. Despite the fact that the specification disclosed human TNF-α protein, and despite the disclosure of the structures of more than one species of antibody related to the genus, the court ruled that the generic antibody claims at issue were invalid for lack of written description. Similarly, the instant claims recite a genus of antibodies that are specifically reactive with the claimed cell markers but the specification discloses one species of the antibodies. Following the finding in Centocor, the instant claims are found to lack adequate written description.
Level of skill and knowledge in the art/predictability in the art
The level of skill in the art is high. In particular, methods for making and/or screening monoclonal antibodies with desired binding properties were well known in the art at the time of the invention. At the same time, however, it was not within the skill of the art to predict whether a given antibody would bind specifically to a particular epitope.
All dependent claims are also rejected based on their dependency of the defected parent claims.
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 1-2, and 27-39 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, 2 and 35 recite the antibodies that bind to the claimed cell markers. The claims encompass a genus of antibodies that can do the claimed function. The prior arts (Edwards and Lloyd) above teach that a single protein can be bound by a very large and structurally diverse genus of antibodies. The claims are indefinite because there is more than one reasonable interpretation of what species are included in the claims.
Claims 1 and 2 contain the trademark name “cFluor” from Cytek Biosciences. 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 “cFluor”, accordingly, the identification/description is indefinite.
All dependent claims are also rejected based on their dependency of the defected parent claims.
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.
Claim(s) 1-2, 27-28 and 31-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wood (9-Color and 10-Color Flow Cytometry in the Clinical Laboratory, Arch Pathol Lab Med—Vol 130, May 2006) in view of Cytek (Cytek® Aurora, 2019) and Omana-Zapata et al. (Accurate and reproducible enumeration of T-, B-, and NK lymphocytes using the BD FACSLyric 10-color system: A multisite clinical evaluation, PLOSONE January 28, 2019).
For claim 1, Wood teaches that the 9-color, 10-color, or more than 10-color flow cytometry offers the possibility for increased accuracy in abnormal cell identification, the ability to obtain detailed information from paucicellular specimens, improved laboratory efficiency, and the means to consistently detect abnormal populations at low levels (see Abstract, page 680 col.1 par.1-2 and col.2 par.1). There is no specific answer for how many fluorochromes are optimal for use in a clinical laboratory setting. The number of simultaneous fluorescent signals can be detected in a test depends on the availability of the instruments and the objective of the evaluation (see page 680 col.2 par.1 and page 681 How many colors are enough?). Wood states that the instrument manufacturers have begun to produce benchtop instruments capable of the simultaneous detection of 10 or more fluorochromes and with the advent of an increasing variety of fluorochromes suitable for immunophenotyping, the possibility of high level multicolor flow cytometry is rapidly becoming a reality (see page 680 col.2 par.1).
Wood teaches that a single tube or plurality of tubes comprising antibodies or reagents is/are used to do multicolor flow cytometry analysis (see page 681 col.1 par.3, page 682 col.1 par.3). The antibodies are fluorochrome-conjugated antibodies, which are the pairing of fluorochromes and antibodies to cell markers of interest (see page 680 col.1 par.2: disclosing that flow cytometric immunophenotyping is performed using 2 to 4 simultaneous fluorochrome-conjugated antibodies; see Reagents page 685: disclosing that most reagents for high-level multicolor immunophenotyping consist of monoclonal antibodies coupled to a wide range of fluorochromes; see page 681 col.2 par.4 and page 682 col.1 par.3: disclosing that the fluorochrome-conjugated antibodies should be able to identify the presence of an abnormal population for all categories of neoplastic disease within a given lineage, e.g., a generic evaluation of B cells includes CD45, CD19, CD20, CD10, CD5, CD38, CD34 etc.) Each fluorochrome having different excitation or emission spectra and euphemistically referred to as a ‘‘color’’, e.g., blue, red (see page 680 col.1 par.2, Table 1 on page 682: disclosing a variety of fluorochromes having different emission spectra which are detected using different laser wavelengths, e.g., blue 488 nm, red 635 nm). Wood provides a multicolor panel for immunophenotyping comprising fluorochromes excited by two blue and red lasers (see Table 1 page 682 and Table 2 page 687).
The pairing of antibodies and fluorochromes must be evaluated first individually and then in combination to assure adequate signal intensity across the range to be detected (see page 685 col.1 par.1). A fluorochrome should be associated with each target, wherein the basic principle to be used is that highly expressed antigens should be coupled with dim fluorochromes and that dimly expressed antigens should be coupled with bright fluorochromes. This pairing principle generally provides reasonable signal intensities and avoids compensation problems due to excessively bright fluorescence. See page 686 Assign a Fluorochrome to Each Target. This teaching means that the particular antibody-fluorescent pairs in the multicolor reagent are the consequence of the optimizing step to make sure the combination of antibody-fluorescent pairs provides a good signal intensity for analysis.
Wood teaches a 4-laser flow cytometer having multiple detector arrays that allowing for the simultaneous detection of the fluorochromes (see page 682 col.2 Instrumentation).
Wood does not specifically teach a 13-color reagent. Wood does not teach a kit. Wood does not teach a flow cytometer instrument having at least twenty-two (22) detectors.
Omana-Zapata teaches that multicolor reagent kits for flow cytometry can simplify laboratory workflow, reduce the time or expertise required for analysis, and improve performance with high sensitivity and specificity, which enables improvement in sample testing throughput and cost reduction (see Introduction par.1-3 on page 2). For example, the BD FACSLyric system, e.g., Multitest IMK kit and BD Multitest 6-color TBNK kit, has been designed to address the increasing complexity of clinical flow cytometry assays by simplifying instrument setup and by facilitating assay transfer across different instruments to improve efficiency and simplify the cell phenotyping workload (see Introduction par.3 on page 2).
Cytek discloses a five-laser system having 5 lasers and 64 fluorescence detectors, which is able to run more than 30 colors (see page 1 par.1). This is a full spectrum cytometer which can detect fluorescent blue and red lights as recited in claim 1 (e.g., cFluor B515 and cFluor R668) (see page 3 and 4).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the multicolor reagent taught by Wood by a thirteen-color reagent, because the high-level multicolor flow cytometry increases accuracy in identifying small populations of abnormal cells in smaller amount of sample (see page 680 col.2 par.2). One of ordinary skill in the art would have had a reasonable expectation of success in analyzing high-level multicolor flow cytometry because Wood states that instruments capable of the simultaneous detection of 10 or more fluorochromes are available in the market (see page 680 col.2 par.1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make a kit for detecting abnormal blood cells comprising a 13-color reagent taught by Wood for the benefit of simplifying instrument setup and by facilitating assay transfer across different instruments to improve efficiency and simplify the cell phenotyping workload as taught by Omana-Zapata.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the Cytek system with 5 lasers and 64 fluorescence detectors to detect the fluorochromes from the test tube of Wood, because the Cytek system can detect fluorescent blue and red lights which are emitted from the blue and red fluorochrome, i.e., fluorochrome-labeled antibodies specific to cell markers taught by Wood. One of ordinary skill in the art would have had a reasonable expectation of success in using the Cytek system to analyze the multicolor test tube of Wood because the Cytek system and the analysis system taught by Wood are structurally and functionally equivalent, e.g., those instruments have more than 2 lasers and multiple detectors, and simultaneously detect multiple fluorochromes.
For claim 2, Wood, Omana-Zapata, and Cytek teach the 13-color reagent kit for analysis of blood cells by a spectral flow cytometer. See the discussion of Wood, Omana-Zapata, and Cytek in claim 1.
Wood in view of Cytek also teach a spectral flow cytometer having at least two (2) lasers and at least twenty-eight (28) detectors (Wood teaches a 4-laser flow cytometer having multiple detector arrays that allowing for the simultaneous detection of the fluorochromes (see page 682 col.2 Instrumentation); Cytek discloses a five-laser system having 5 lasers and 64 fluorescence detectors, which is able to run more than 30 colors (see page 1 par.1)). See the discussion of Wood, Omana-Zapata, and Cytek in claim 1.
Wood, Omana-Zapata, and Cytek also teach a plurality of tubes having one or more reagents of the reagent composition with the pairing of fluorochromes and antibodies specific to listed cell markers to attach to blood cells as recited in the table of claim 2. See the discussion of Wood, Omana-Zapata, and Cytek in claim 1.
One or more antibodies to the cell marker to attach to blood cells comprise antibodies to CD38, CD19, CD45, CD20 (see Wood page 681 col.2 par.4 and page 682 col.1 par.3).
Wood does not clearly teach that the 13-color reagent kit is used for monitoring B subsets of anti-CD20 treated autoimmune patients. However, Wood teaches the multicolor reagent flow cytometry is used for diagnosis and monitoring of patients with a specific disease (see Abstract, page 681 Disease Specific). For instance, the reagent combination ideally should be able to identify the presence of an abnormal population for all categories of neoplastic disease within a given lineage, e.g., B cells (see page 682 Lineage-Specific Screening). Wood discloses one or more antibodies to the claimed cell markers for monitoring B cells (see page 681 col.2 par.4 and page 682 col.1 par.3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the multicolor reagent kit taught by Wood, Omana-Zapata, and Cytek for monitoring B subsets of anti-CD20 treated autoimmune patients with a reasonable expectation of success, because Wood teaches that the reagent combination is able to monitor an abnormal population of B cells in the patients with a specific disease and Wood also discloses one or more antibodies to the claimed cell markers for monitoring B cells.
For claims 27 and 31, Wood, Omana-Zapata, and Cytek teach the 13-color reagent kit as in claims 1 and 2 above. Wood, Omana-Zapata, and Cytek also teach the reagent comprising antibodies specific to the cell markers listed under the SPECIFICITY/MARKER column. See the discussion of Wood, Omana-Zapata, and Cytek in claim 1.
For claims 28 and 32, Wood, Omana-Zapata, and Cytek teach the 13-color reagent kit as in claim 27 above. Wood, Omana-Zapata, and Cytek teach each antibody, specific to a particular cell marker, is conjugated to a fluorochrome forming a conjugated fluorescent labeled antibody (see page 680 col.1 par.2, Table 1 on page 682). Wood does not clearly teach the antibody is conjugated to a fluorochrome in the same row as the marker as in the table of claim 1.
However, Wood teaches that the pairing of antibodies and fluorochromes must be evaluated first individually and then in combination to assure adequate signal intensity across the range to be detected (see page 685 col.1 par.1). A fluorochrome should be associated with each target, wherein the basic principle to be used is that highly expressed antigens should be coupled with dim fluorochromes and that dimly expressed antigens should be coupled with bright fluorochromes. This pairing principle generally provides reasonable signal intensities and avoids compensation problems due to excessively bright fluorescence. See page 686 Assign a Fluorochrome to Each Target. This teaching means that the particular antibody-fluorescent pairs in the multicolor reagent are the consequence of the optimizing step to make sure the combination of antibody-fluorescent pairs provides a good signal intensity for analysis.
At the time of invention, it would have been obvious to one of ordinary skill in the art to select each pair of antibodies and fluorochromes to form fluorochrome labeled antibodies by an optimization procedure taught by Wood to arrive the claimed pairs of antibodies and fluorochromes in order to provide a good signal intensity for analysis.
Claim(s) 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wood in view of Cytek and Omana-Zapata, as applied in claim 28, and further in view of BioLegend (Alexa Fluor® 647 anti-human CD19 Antibody, 2014).
For claim 29, Wood, Omana-Zapata, and Cytek teach the 13-color reagent kit as in claim 28 above. Wood teaches the conjugated fluorescent labeled antibodies are combined into a reagent cocktail (see page 690 col.1 par.1).
Wood does not teach that the reagent cocktail is supplied in phosphate-buffered saline.
BioLegend teaches a commercial product comprising a fluorescent conjugated antibody supplied in phosphate-buffered saline (see page 1 Product Details/Formulation).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to supply the conjugated antibodies cocktail in phosphate-buffered saline as taught by BioLegend, because BioLegend supports the success of using the conjugated antibody in PBS for immunofluorescent staining and analyzing with flow cytometry (see page 1 Product Details/ Recommended Usage).
Claim(s) 30 and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wood in view of Cytek and Omana-Zapata, as applied in claim 1, and further in view of R&D (H/M Pluripotent Stem Cell Multi-Color Flow Cytometry Kit, 2015).
For claims 30 and 34, Wood, Omana-Zapata, and Cytek teach the 13-color reagent kit as in claims 1 and 2 above. Wood does not teach the kit further comprising a buffer solution.
R&D teaches a multicolor flow cytometry kit comprising 4 pairs of fluorochromes and antibodies and buffer solutions (see page 4 Kit components). The kit offers users an efficient and quantitative method to verify the cells of interest in flow cytometry (see page 4 par.3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a buffer solution in a kit of Wood, Omana-Zapata, and Cytek, because the buffer is essential to perform the test (see R&D pages 4-5 Kit components). Since the kit includes enough reagents to perform the test, the cell phenotyping is more efficient and simple.
Claim(s) 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wood in view of Cytek and Omana-Zapata, as applied in claim 32, and further in view of R&D (H/M Pluripotent Stem Cell Multi-Color Flow Cytometry Kit, 2015) and BioLegend (Alexa Fluor® 647 anti-human CD19 Antibody, 2014).
For claim 33, Wood, Omana-Zapata, and Cytek teach the 13-color reagent kit as in claim 32 above. Wood does not teach that the conjugated fluorescent labeled antibodies are supplied in individual vials of phosphate-buffered saline.
R&D teaches a multicolor flow cytometry kit comprising a plurality pairs of fluorochromes and antibodies and buffer solutions (see page 4 Kit components). The conjugated antibodies are supplied in individual vials (see page 6 Materials Provided & Storage). The kit offers users an efficient and quantitative method to verify the cells of interest in flow cytometry (see page 4 par.3). The kit is used for single-step staining of pluripotent stem cells (see page 5 Product description). R&D teaches adding 10ul of each antibody to the cells for staining, which means that the antibody is supplied in a solution. R&D does not clearly teach what the solution is.
BioLegend teaches a commercial product comprising a fluorescent conjugated antibody supplied in phosphate-buffered saline (see page 1 Product Details/Formulation).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to keep the conjugated antibodies in individual vials as taught by R&D for single-step staining the cell of interest. One of ordinary skill in the art would have been motivated to do this with a reasonable expectation of success, because the kit offers users an efficient and quantitative method to verify the cells of interest in flow cytometry as shown by R&D (see R&D page 4 par.3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to supply the conjugated antibodies in phosphate-buffered saline as taught by BioLegend, because BioLegend supports the success of using the conjugated antibody in PBS for immunofluorescent staining and analyzing with flow cytometry (see page 1 Product Details/ Recommended Usage).
Claim(s) 35-39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wood (9-Color and 10-Color Flow Cytometry in the Clinical Laboratory, Arch Pathol Lab Med—Vol 130, May 2006) in view of Cytek (Cytek® Aurora, 2019), Omana-Zapata et al. (Accurate and reproducible enumeration of T-, B-, and NK lymphocytes using the BD FACSLyric 10-color system: A multisite clinical evaluation, PLOSONE January 28, 2019), R&D (H/M Pluripotent Stem Cell Multi-Color Flow Cytometry Kit, 2015), Day et al. (The utility of monitoring peripheral blood lymphocyte subsets by flow cytometric analysis in patients with rheumatological diseases treated with rituximab, Autoimmunity Reviews 16 (2017) 542–547), and Gatti et al. (The ISCCA flow protocol for the monitoring of anti-CD20 therapies in autoimmune disorders, Cytometry. 2021;100:194–205).
For claim 35, Wood, Omana-Zapata, and Cytek teach the 13-color reagent kit for analysis of blood cells by a spectral flow cytometer. See the discussion of Wood, Omana-Zapata, and Cytek in claim 1 above.
Wood in view of Cytek also teach a spectral flow cytometer having at least two (2) lasers and at least twenty-eight (28) detectors (Wood teaches a 4-laser flow cytometer having multiple detector arrays that allowing for the simultaneous detection of the fluorochromes (see page 682 col.2 Instrumentation); Cytek discloses a five-laser system having 5 lasers and 64 fluorescence detectors, which is able to run more than 30 colors (see page 1 par.1)). See the discussion of Wood, Omana-Zapata, and Cytek in claim 1.
Wood, Omana-Zapata, and Cytek also teach a plurality of tubes having one or more reagents of the reagent composition with the pairing of fluorochromes and antibodies specific to cell markers. See the discussion of Wood, Omana-Zapata, and Cytek in claim 1.
Wood, Omana-Zapata, Cytek, and R&D teaches the conjugated fluorescent labeled antibodies are supplied in individual vials. See the discussion of Wood, Omana-Zapata, Cytek, and R&D in claim 33.
Wood teaches that each antibody is conjugated with a fluorochrome, wherein each fluorochrome has a different excitation or emission spectra, e.g., blue, red (see page 680 col.1 par.2, page 685 Reagents, page 680 col.1 par.2, Table 1 on page 682). Wood discloses that the fluorochrome-conjugated antibodies are able to identify the presence of a cell population of interest. In particular, a generic evaluation of B cells includes CD45, CD19, CD20, CD38 etc. (see page 681 col.2 par.4 and page 682 col.1 par.3); an evaluation of blast cells includes CD45, CD19, CD33, CD15, CD38 etc. (see page 687 Table 2); an evaluation of T cells includes CD45, CD3, CD8 etc. (see page 687 Table 2); an evaluation of myeloid cells includes CD45, CD38, CD14 etc. (see page 687 Table 2).
Wood teaches that the fluorochromes used to conjugate to the antibodies have a variety of maximum emission wavelengths, e.g., 530/30nm, 575/26nm, 610/20nm, 780/60nm etc. (see Table 1 Filter column on page 682). The signal from these fluorochromes are detected using the instruments containing 4 lasers having excitation maxima at 407, 488, 594, and 635 nm, with spatially separated stream intersection points (see page 682 Instrumentation). This teaching implies that the fluorochromes used to conjugate to the antibodies are selected based on the availability of the instruments (see page 680 col.2 par.1).
Wood teaches that the pairing of antibodies and fluorochromes must be evaluated first individually and then in combination to assure adequate signal intensity across the range to be detected (see page 685 col.1 par.1). A fluorochrome should be associated with each target, wherein the basic principle to be used is that highly expressed antigens should be coupled with dim fluorochromes and that dimly expressed antigens should be coupled with bright fluorochromes. This pairing principle generally provides reasonable signal intensities and avoids compensation problems due to excessively bright fluorescence. See page 686 Assign a Fluorochrome to Each Target. This teaching means that the particular antibody-fluorescent pairs in the multicolor reagent are the consequence of the optimizing step to make sure the antibody-fluorescent pairs can provide good signal intensity for analysis when they are used individually or in a combination.
Wood teaches the multicolor reagent flow cytometry is used for diagnosis and monitoring of patients with a specific disease (see Abstract, page 681 Disease Specific). For instance, the reagent combination ideally should be able to identify the presence of an abnormal population for all categories of neoplastic disease within a given lineage, e.g., B cells (see page 682 Lineage-Specific Screening).
Wood does not specifically teach the antibodies to the cell markers conjugated to the fluorochromes as in claim 35. Wood does not teach all the fluorochromes having emission maximum wavelengths as claimed.
Wood does not teach the antibodies specific for cell markers: IgM, IgG, IgD, CD27.
Wood does not clearly teach that the 13-color reagent kit is used for monitoring B subsets of anti-CD20 treated autoimmune patients.
Cytek discloses a five-laser system having 5 lasers and 64 fluorescence detectors, which is able to run more than 30 colors (see page 1 par.1). This is a full spectrum cytometer which can detect fluorochromes having a variety of maximum emission wavelengths as claimed (see Table on page 3 and 4).
Day teaches that B cells contribute to the development of autoimmune disease, and B cell depletion with agents such as rituximab (RTX) is being increasingly employed to treat refractory or severe autoimmune and inflammatory diseases (see page 542 Introduction). RTX is a chimeric murine/human monoclonal antibody targeting the B cell-specific antigen CD20 (see page 543 col.1 par.1). Day teaches that monitoring individual B cell and T cell subpopulations during immune reconstitution following rituximab therapy may correlate with disease relapse in autoimmune conditions (see page 544 section 5). The cell subpopulations include cells expressing IgD+; CD27+; IgM + IgD + CD38hi; CD8+T cells; CD3+T cells (see at least page 544 col.1 par.2 col.2 par.2; see page 545 col.2 par.2, page 546 col.1 par.1-2).
Gatti discloses an immune monitoring procedure for the clinical decision-making process during anti-CD20 therapies in autoimmune diseases, by identifying B cells, plasma cells/blasts, naïve and memory B cells, sIgM+ and sIgG-switched memory B cells, T and NK cells, with high-sensitivity analysis (>106 CD45+ cells). The procedure comprises a multicolor 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). See Abstract. The 8-color procedure was designed to be implemented on flow cytometer system (see page 196 section 2.6).
Gatti teaches that the disappearance of memory B cells and the repopulation by naïve cells correlate with good clinical response, while the reappearance of memory B cells and plasma blasts correlates with relapse or resistance to therapy. See Abstract.
Therefore, at the time of the invention, it would have been obvious to one of ordinary skill in the art to select each pair of antibodies and fluorochromes to form fluorochrome-labeled antibodies using an optimization procedure taught by Wood to arrive the claimed pairs of antibodies and fluorochromes in order to provide a good signal intensity for analysis. Users should select the fluorochromes having maximum emission wavelengths based on the availability of the analysis instrument so that the signal from the fluorochromes can be detected ,as taught by Wood. It would have been obvious to one of ordinary skill in the art to use fluorochromes having maximum emission wavelengths as claimed, because Cytek flow cytometry system can detect fluorochromes having a variety of maximum emission wavelengths as claimed.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the multicolor reagent kit taught by Wood, Omana-Zapata, and Cytek by using the antibodies to the claimed cell markers (IgM, CD15, CD38, CD33, CD27, CD14, CD19, CD3, CD8, CD20, and CD45) taught by Wood, Day and Gatti, because these markers are helpful to monitor B subsets of anti-CD20 treated autoimmune patients in order to assist the safe and rational usage of anti-CD20 therapies (see the teachings of Day and Gatti). One of ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Wood teaches that the reagent combination is able to monitor an abnormal population of B cells in patients with a specific disease, and Day and Gatti specifically teach that monitoring the B cell subsets supports a safe and rational administration of anti-CD20 in clinical settings (see Gatti page 202 col.2 par.2).
For claim 36, Wood, Omana-Zapata, Cytek, R&D, Day, and Gatti teach the 13-color assay kit of claim 35. Wood teaches that fluorochromes are excited by at least two lasers comprising a blue laser with a center wavelength of emission at 488 nm and a red laser with a center wavelength of emission at 635 nm. See Table 1 page 682.
Cytek teaches a full spectrum cytometer comprising a blue laser with a center wavelength of emission at 488 nm and a red laser with a center wavelength of emission at 640 nm (see Table pages 3-4).
While Wood and Cytek do not teach the same center wavelength of emission of the red laser as recited in the claim (638 nm), one of ordinary skill in the art would have had a reasonable expectation of success in using the system of Wood and Cytek to detect the signals from the claimed fluorochromes, because the Cytek system is the full spectrum cytometer that can detect fluorochromes having a wide range of maximum emission wavelengths as claimed.
For claims 37-38, Wood, Omana-Zapata, Cytek, R&D, Day, and Gatti teach the 13-color assay kit of claim 36.
Wood, Omana-Zapata, Cytek, R&D, Day, and Gatti do not specifically teach the fluorochromes in the vials. However, Wood discloses a combination of fluorochrome-conjugated antibodies for multicolor analysis with flow cytometry system comprising blue and red lasers (see Table 2 page 687). Wood also discloses a variety of fluorochromes excited to emit fluorescent light by the blue laser or the red laser (see Table 1 page 682 and Table 2 page 687).
Wood teaches that the pairing of antibodies and fluorochromes must be evaluated first individually and then in combination to assure adequate signal intensity across the range to be detected (see page 685 col.1 par.1). A fluorochrome should be associated with each target, wherein the basic principle to be used is that highly expressed antigens should be coupled with dim fluorochromes and that dimly expressed antigens should be coupled with bright fluorochromes. This pairing principle generally provides reasonable signal intensities and avoids compensation problems due to excessively bright fluorescence. See page 686 Assign a Fluorochrome to Each Target. This teaching means that the particular antibody-fluorescent pairs in the multicolor reagent are the consequence of the optimizing step to make sure the antibody-fluorescent pairs can provide good signal intensity for analysis when they are used individually or in a combination.
Therefore, it would have been obvious to one of ordinary skill in the art to select the fluorochromes for each vial of fluorochrome-conjugated antibody by an optimization procedure taught by Wood to arrive the claimed pairs of antibodies and fluorochromes in order to provide a good signal intensity for analysis. It would have been obvious to one of ordinary skill in the art to select fluorochromes based on the availability of the analysis instrument so that the signal from the fluorochromes could be detected.
For claim 39, Wood, Omana-Zapata, Cytek, R&D, Day, and Gatti teach the 13-color assay kit of claim 35. Wood does not teach the kit comprising a buffer solution.
R&D teaches a multicolor flow cytometry kit comprising 4 pairs of fluorochromes and antibodies and buffer solutions (see page 4 Kit components). The kit offers users an efficient and quantitative method to verify the cells of interest in flow cytometry (see page 4 par.3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a buffer solution in the kit of Wood, Omana-Zapata, Cytek, R&D, Day, and Gatti, because the buffer is essential to perform the test (see R&D pages 4-5 Kit components). Since the kit includes enough reagents to perform the test, the cell phenotyping is more efficient and simple.
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.
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Claims 1-2, 27-28, 31-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6 and 7 of copending Application No. 18/491,742 (‘742) in view of Cytek (Cytek® Aurora, 2019) . Although the claims at issue are not identical, they are not patentably distinct from each other because:
For claim 1, claim 6 of ‘742 discloses a thirteen color reagent kit for analysis of blood cells by a full spectrum flow cytometer comprising a sample test tube having a reagent composition with the following pairing of fluorochromes and antibodies specific to cell markers as in claim 1. The respective fluorochromes are excited by the respective two lasers blue and red. Claim 6 of ‘742 does not teach a spectral flow cytometer having at least two ill lasers and at least twenty-two detectors.
Cytek discloses a five-laser system having 5 lasers and 64 fluorescence detectors, which is able to run more than 30 colors (see page 1 par.1). This is a full spectrum cytometer which can detect fluorescent blue and red lights as recited in claim 1 (e.g., cFluor B515 and cFluor R668) (see page 3 and 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the Cytek system with 5 lasers and 64 fluorescence detectors to detect the fluorochromes from the test tube of ‘742 with a reasonable expectation of success, because the Cytek system can detect fluorescent blue and red lights which are emitted from the blue and red fluorochrome, i.e., fluorochrome-labeled antibodies specific to cell markers taught by ‘742. Cytek system is also a full spectrum flow cytometer, which is functionally equivalent as the system of ‘742.
For claim 2, claim 7 of ‘742 discloses a thirteen color reagent kit for analysis of blood cells by a full spectrum flow cytometer, comprising a plurality of test tubes having one or more reagent composition with the following pairing of fluorochromes and antibodies specific to cell markers as in claim 2. The respective fluorochromes are excited by the respective two lasers blue and red. Claim 7 of ‘742 does not teach a spectral flow cytometer having at least two ill lasers and at least twenty-eight detectors.
Cytek discloses a five-laser system having 5 lasers and 64 fluorescence detectors, which is able to run more than 30 colors (see page 1 par.1). This is a full spectrum cytometer which can detect fluorescent blue and red lights as recited in claim 2 (e.g., cFluor B515 and cFluor R668) (see page 3 and 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the Cytek system with 5 lasers and 64 fluorescence detectors to detect the fluorochromes from the test tube of ‘742 with a reasonable expectation of success, because the Cytek system can detect fluorescent blue and red lights which are emitted from the blue and red fluorochrome, i.e., fluorochrome-labeled antibodies specific to cell markers taught by ‘742. Cytek system is also a full spectrum flow cytometer, which is functionally equivalent as the system of ‘742.
For claims 27-28, claim 6 of ‘742 discloses the limitations of the claims.
For claims 31-32, claim 7 of discloses the limitations of the claims.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 18/491,742 (‘742) in view of Cytek (Cytek® Aurora, 2019), Wood (9-Color and 10-Color Flow Cytometry in the Clinical Laboratory, Arch Pathol Lab Med—Vol 130, May 2006) and Day et al. (The utility of monitoring peripheral blood lymphocyte subsets by flow cytometric analysis in patients with rheumatological diseases treated with rituximab, Autoimmunity Reviews 16 (2017) 542–547). Although the claims at issue are not identical, they are not patentably distinct from each other because:
For claim 35, claim 7 of ‘742 and Cytek discloses a 13 reagent kit for analysis of blood cells by a full spectrum flow cytometer having at least two lasers and at least twenty-eight (28) detectors. See the discussion of claim 7 of ‘742 and Cytek in claim 2 above. The kit comprises a plurality of test tubes having one or more reagent composition with the following pairing of fluorochromes and antibodies specific to cell markers, e.g., a 1st vial, a 5th vial to a 13th vial as in claim 35. Claim 7 of ‘742 does not teach a 2nd vial to 4th vial. Claim 7 of ‘742 does not teach using antibodies specific for CD33.
Wood teaches a multiple color flow cytometer for analysis of blood cells. Wood discloses that a single tube or plurality of tubes comprising antibodies or reagents is/are used to do multicolor flow cytometry analysis (see page 681 col.1 par.3, page 682 col.1 par.3). Wood teaches that the fluorochromes used to conjugate to the antibodies have a variety of maximum emission wavelengths (see Table 1 Filter column on page 682). The pairing of antibodies and fluorochromes must be evaluated first individually and then in combination to assure adequate signal intensity across the range to be detected (see page 685 col.1 par.1). A fluorochrome should be associated with each target, wherein the basic principle to be used is that highly expressed antigens should be coupled with dim fluorochromes and that dimly expressed antigens should be coupled with bright fluorochromes. This pairing principle generally provides reasonable signal intensities and avoids compensation problems due to excessively bright fluorescence. See page 686 Assign a Fluorochrome to Each Target. This teaching means that the particular antibody-fluorescent pairs in the multicolor reagent are the consequence of the optimizing step to make sure the combination of antibody-fluorescent pairs provides a good signal intensity for analysis.
Wood teaches a generic evaluation of B cell subsets including cells having CD45, CD19, CD20, CD38 markers (see page 681 col.2 par.4 and page 682 col.1 par.3); an evaluation of blast cells includes cells having CD45, CD19, CD33, CD15, CD38 etc. (see page 687 Table 2); an evaluation of T cells includes cells having CD45, CD3, CD8 etc. (see page 687 Table 2); an evaluation of myeloid cells includes cells having CD45, CD38, CD14 etc. (see page 687 Table 2).
Day teaches that B cells contribute to the development of autoimmune disease, and B cell depletion with agents such as rituximab (RTX) is being increasingly employed to treat refractory or severe autoimmune and inflammatory diseases (see page 542 Introduction). RTX is a chimeric murine/human monoclonal antibody targeting the B cell-specific antigen CD20 (see page 543 col.1 par.1). Day teaches that monitoring individual B cell and T cell subpopulations during immune reconstitution following rituximab therapy may correlate with disease relapse in autoimmune conditions (see page 544 section 5).
Therefore, at the time of the invention, it would have been obvious to one of ordinary skill in the art to modify the kit of ‘742, by selecting each pair of antibodies and fluorochromes to form fluorochrome-labeled antibodies using an optimization procedure taught using Wood to arrive the claimed pairs of antibodies and fluorochromes in order to provide a good signal intensity for analysis. Users should select the fluorochromes having maximum emission wavelengths based on the availability of the analysis instrument so that the signal from the fluorochromes can be detected, as taught by Wood. It would have been obvious to one of ordinary skill in the art to use fluorochromes having maximum emission wavelengths as claimed, because Cytek flow cytometry system can detect fluorochromes having a variety of maximum emission wavelengths as claimed.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the multicolor reagent kit taught by ‘742, Cytek, Wood, by replacing anti-CD4 antibody in the kit of 742 with anti-CD33 antibody as taught by Wood, because the antibody helps to evaluate of blast cells which is one of B cell subsets. One of ordinary skill in the art would have been motivated to evaluate blast cells with a reasonable expectation of success, because Day teaches that monitoring B subsets in anti-CD20 treated autoimmune patients will assist the safe and rational usage of anti-CD20 therapies (see the teachings of Day in claim 35 above).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/CHAU N.B. TRAN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 September 21, 2026
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