DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
Acknowledgement is made of Applicant’s claim for benefit under 35 U.S.C. 119(e) to provisional application No. 63/559,544, filed 02/29/2024 and 63/452,206, filed 03/15/2023.
Information Disclosure Statement
The information disclosure statement (IDS) entered 08/13/2024 is considered, initialed and is attached hereto.
Status of the Claims
Claims 1, 2, 4-24 and 26-40 are pending; claims 4-10, 12-14, 16-17, 24, 31-35, 38 and 40 are amended; claims 3 and 41-43 are canceled.
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, 2, 4-24 and 26-40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 at step (a) recites “contacting a population of antibody-producing cells encompassing cells that express antibody molecule to the antigen on the cell surface”, there is insufficient antecedent basis for the recited limitation "the antigen on the cell surface" in line 4. The recited language is confusing because previously the claim merely recites “that express antibody molecules exhibiting high binding affinity for an antigen”, there is no mention previously of antigen that is a cell surface antigen, and as such the recited language is confusing because rather than clearly referring to cell that expresses antibody molecule to an antigen that is a cell surface antigen, the language appears to indicate contacting antibody producing cells to antigen on the cell surface, whereas applicant’s intended meaning based on the originally filed specification and remaining claims appears to be contacting antibody-producing cells with only first labeled form of the antigen (i.e., first labeled antigen conjugated to a first detectable label), wherein the antigen is a cell surface antigen.
Claims 12 and 16 each recite “a timer of a trimerization molecule”, the recite language is indefinite because it is unclear what is an is not considered to be a ‘trimerization molecule”, or further what would be considered a trimer of such (3 units of a “trimerization molecule” that is undefined).
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, 4, 5, 8, 9, 19, 20, 33 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Iverson et al., US PG Pub No. 2003/0036092 in view of Prinz et al., WO2020/018879A1 and UAMS, Department of Microbiology and Immunology, Flow Cytometry Core Facility, “Immunofluorescence Staining for Immunotyping.” Dec. 4, 2021, https://web.archive.org/web/20211204083119/https:/medicine.uams.edu/mbim/research-cores/flow-cytometry-core-facility/protocols-and-reagents/immunofluorescence-staining-for-immunotyping/. Accessed 08/27/2026.
Iverson et al. teach methods of selecting a host cell expressing a desired antibody (such as high affinity antibodies) selecting comprising contacting antibody or antibody fragment-expressing cells with a selected antigen to identify the cells desired (claim 16), the antigen linked to a detectable label (claims 17 and 18), identifying by contacting the cells with fluorescently labeled antigen, then sorting those fluorescently labeled (claims 19 and 20) (also paras [0180]-[0182], [0187]-[0190], [0207]).
Although Iverson et al. teach using labeled antigen to bind and detect desired antibodies (see as cited above), and does teach (paras [0187] and [0195]) examples comprising host cell expressing antibody exposed to labeled antigen, then to sample containing unknown analyte (unlabeled), the purpose of this assay was to detect the unknown amount.
As such, although Iverson et al. teaches a method comprising contacting a population of antibody-producing cells with first labeled antigen to allow binding, Iverson et al. fails to further teach contacting the cells with unlabeled form of the antigen, and further fails to teach wash steps between each contacting step, collecting the cell that remain bound to the first label to obtain high affinity antibody.
However, regarding selecting for high affinity antibodies, it was known in the art that a strategy to test for high affinity binding is to introduce to antibody bound a labeled antigen, additional unlabeled antigen (see Prinz et al., at para [00211], teach selections employing affinity pressure in order to select for and isolate higher affinity antibodies by competing with cold, i.e., unlabeled antigen).
See further, when performing FACs (as in Iverson for example), generally FACs protocols involve wash step after addition of binding reagent and prior to running on cytometer (see for example UAMS for example, FACs staining protocols).
It would have been prima facie obvious to one having ordinary skill in the prior art before the effective filing date of the claimed invention to have modified the methods of Iverson et al., using labeled antigen to bind and detect cells producing high affinity, desirable antibodies, to further wash and perform a step of introducing unlabeled antigen to compete with labeled antigen, further washing before subjecting to a cytometer, one motivated to perform this additional step in order to test for and collect/isolate “higher affinity antibodies” as taught by Prinz et al., since affinity pressure using unlabeled antigen is a technique recognized in the art to screen for high affinity. One would be motivated to select those antibodies most desirable (highest affinity antibodies). One having ordinary skill in the art would have had a reasonable expectation of success using an art recognized technique for its recognized purpose, and further because the primary reference already begins with labeled antigen.
Regarding the wash steps, introducing wash steps following each antigen (labeled and unlabeled antigen) would have been an obvious matter of applying a known technique to an art recognized method, in particular considering wash steps are routine technique performed when performing FACs analysis (see for example, protocols as taught by UAMS, introducing wash steps after binding and before cytometry). One having ordinary skill in the art would have had a reasonable expectation of success performing wash steps as in UAMS because this is an art recognized strategy/step routinely taken by those of ordinary skill when performing this technique (FACs).
Regarding claims 2 and 4, Iverson teach using labeled antigen concentrations within the claimed range (see for example, caption for Fig. 9, para [0030], e.g., 100 nM, 15nM), see as cited presently and above, Iverson et al. teach fluorescent labeled antigen.
Regarding claims 5 and 8-9, Iverson and the cited art addresses the claims, as Iverson is describing single antigen (i.e., monomeric form of antigen) that is a protein (see as cited above), further appears to describe monovalent antigen (e.g., hapten, see para [0239]).
Regarding claims 19, 20, cells are contacted with unlabeled antigen (referring to affinity pressure assay described above).
Regarding claim 33, see as cited above, Iverson teach FACs (fluorescent activated cell sorting, cited above, and paras [0019], [0029], [0030]).
Regarding claims 35-37, Iverson refer to antibody producing host cells that are from any of primary antibody producing cells (paras [0134] and [0135], referring to B-cells, e.g., from spleen, tonsil, lymph; further see describing fused with cells of an immortal myeloma cell for producing hybridomas ), yeast cells (e.g., [0159], immortal cells (para [0135]).
Claim(s) 6, 10-12 and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Iverson et al. in view of Prinz et al. and UAMS, as applied to claim 1 above, and further in view of Franz et al., Ex vivo characterization and isolation of rare memory B-cells with antigen tetramers, Blood, 118(2), (2011), p346-357 (IDS entered 08/13/2024).
Iverson et al. and the cited prior art teach a method substantially as claimed (see as cited in detail previously above), however fail to teach antigen is a protein in multimeric form (claim 6), unlabeled antigen is a multivalent form of the antigen (claim 10), multivalent form provided by a multivalent molecule two which antigen is bound or linked (claim 11), selected from a streptavidin multimer, a dimer of Ig Fc fragment, or a trimer of trimerization molecule (claim 12).
Regarding the labeling of antibody producing cells using fluorescently labeled antigen, Franz et al. teach that the use of fluorescent antigen tetramers (formed using biotinylated antigen and fluorescent labeled streptavidin, i.e. forming a streptavidin multimer with multiple binding sites) result in more sensitive detection via brightly labeled cells as compared to labeling with monomeric antigen, the reference teaching tetrameric antigen as a suitable technique for enabling sensitive detection of low quantity target in a blood sample (see abstract, page 346, end of col. 2, page 349, end of col. 1 to col. 2, Figure 1 and description of Figure 1, page 356, col. 1, para 2)
It would have been prima facie obvious to one having ordinary skill in the art, to have modified the antigen (as such the labeled and unlabeled antigen) of Iverson and the cited art, to utilize the antigen tetramers (antigen tetramer strategy) of Franz et al., because Franz teach this modification enables high sensitivity to detect even in low concentration conditions. The modification would have been an obvious matter of use of a known technique to improve sensitivity, one having ordinary skill would have a reasonable expectation of success because the antigen tetramer would still be expected bind (still achieves binding of antibody to antigen, binding sites are still available, there being an increased number of antigenic binding sites).
Regarding claim 17, the system of Iverson modified by the cited prior art and Franz addresses antigen labeled with biotin and also fluorophore (biotinylated antigen bound to fluorescent labeled streptavidin).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Iverson et al. in view of Prinz et al. and UAMS, as applied to claim 19 above, and further in view of Baruah et al., EP3825326A1.
Regarding claim 21, Iverson et al. and the cited prior art teach a method substantially as claimed (see as cited above, teaching for example affinity pressure using addition of unlabeled antigen), however, fails to teach antigen in the unlabeled form is at least 2-4 fold in molar ratio relative to the first labeled form the antigen in step (a).
See also Baruah et al. teach affinity pressure (paras [0212]-[0213]), see the technique involves competing excess amounts of unlabeled antigen to sort for best affinity).
Although the cited art fails to specify, for the unlabeled antigen, the molar ratio of unlabeled antigen added, the prior art does teach providing in excess (i.e., more than the labeled antigen). See also MPEP 2144.05, Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."
It would have been prima facie obvious to have arrived at the claimed range of 2-4 fold molar ratio as compared to labeled antigen by adding increasing amounts in excess as described by the prior art, one motivated to increase the amount in order to uncover the optimum amount for achieving highest affinity antibodies (which is the desire of the cited art, see for example, Iverson, Prinz, Baruah). One having ordinary skill in the art would have a reasonable expectation of success because the general conditions were already recognized in the prior art (was known in the prior art to provide unlabeled reagent in excess, see for example Baruah).
Claim(s) 38 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Iverson et al., in view of Prinz et al. and UAMS, as applied to claim 1 above, and further in view of Berry et al., WO2013/013323A1.
Regarding claims 38 and 39, Iverson refer to isolation and collection of high affinity antibodies, however, fails to teach antibodies having KD in the range from 0.1pM to about 25nM, or less than 10 nM.
See Berry et al., Berry teach high affinity as being in the range of 10-8 – 10-9, and also as being sub-nanomolar, like picomolar range.
Although Iverson et al. fails to teach KD for what they consider high affinity, it would have been obvious that the antibodies fall within the claimed range because generally high affinity is considered to be nano-molar, down to picomolar, dissociation constants (see Berry et al.).
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Iverson et al. in view of Prinz et al. and UAMS, as applied to claim 1 above, and further in view of Chen et al., WO2022/140494A1.
Iverson et al. and the cited prior art teach a method substantially as claimed, however fails to teach further performing a step of isolating antibody-encoding nucleic acids from the cells collected in step (e).
Chen et al. also teach methods of obtaining antibodies, for example using FACs (like Iverson et al.), Chen further teach (see paras [0025]-[0028]) isolating nucleic acid encoding antibody for further use.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method as taught by Iverson et al. and the cited prior art to further perform a step of isolating the nucleic acid encoding the desired antibody, for further use of the antibody (Chen et al.), this modification an obvious matter of a known technique applied to a known method (Chen as cited above supports it was known when sorting and collecting desired antibody producing cells to further isolate the nucleic acid encoding the antibody for further use). One having ordinary skill would have a reasonable expectation of success because Chen is specifically teaching the ability to perform such isolation (supports its feasibility).
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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