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
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in INDIA on 03/03/2021. It is noted, however, that applicant has not filed a certified copy of the INDIA 202121009004 application as required by 37 CFR 1.55.
Status of Claims
Claims 3, 16, 18, 21, 23, and 25-35 are cancelled.
Claims 1-2, 4-15, 17, 19-20, 22, 24, and 36 are pending and examined herein.
Withdrawn Rejections
The rejection of claims 1-15, 17-32, and 34-35 on the grounds of 35 U.S.C. 112(a) has been withdrawn, necessitated by amendments filed 10/21/2025.
The rejections of claims 1, 8-13, 15, 17-18, 20-22, 26, 28, and 30-32 on the grounds of 35 U.S.C. 112(b) have been withdrawn, necessitated by amendments filed 10/21/2025.
The rejections of claims 26-30 on the grounds of 35 U.S.C. 112(d) have been withdrawn, necessitated by amendments filed 10/21/2025.
New rejections, necessitated by amendments filed 10/21/2025, are discussed below.
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, 4-15, 17, 20, 22, 24, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Ng (WO 2005042027 A2, published 2005-05-12) in view of Liu, et al. (“A Multiplex Calcium Assay for Identification of GPCR Agonists and Antagonists”, published 2010-06) and an as evidenced by Fattori, et al. (“Design and Synthesis of Novel Sulfonamide-Containing Bradykinin hB2 Receptor Antagonists. 2. Synthesis and Structure−Activity Relationships of α,α-Cycloalkylglycine Sulfonamides”, published 2007-01-06) and the ThermoFisher Fluo-4AM product sheet (https://www.thermofisher.com/order/catalog/product/F14201).
Ng teaches an assay method to determine the efficacy of an antagonist by inhibiting the activity of bradykinin receptors, as in claim 1 (see, e.g., p. 93-95, under “B. In vitro Assay of hB2 Receptor Function using Calcium Flux”). Ng teaches seeding a cell expressing the receptor of interest on a plate, as in step a. of claim 1 (see, e.g., p. 93, line 31 to p. 94, line 2). Ng teaches incubating the cells after seeding on the plate overnight in a 37°C CO2 incubator, as in step b. of claim 1 and claim 8 (see, e.g., p. 94, line 3). It is understood that an overnight incubation is about 12 hours to about 24 hours. Ng teaches washing the cell with Hanks’ Balanced Salt Solution with 20 mM HEPES, as in step c. of claim 1 and claim 36 (see, e.g., p. 94, lines 13-17). Ng teaches mixing a dye to stain the cell and incubating, as in steps d. and e. of claim 1 (see, e.g., p. p. 94, lines 4-13). Ng teaches acclimatizing the cell to room temperature for a time, as in step f. of claim 1 and claim 15 (see, e.g., p. 94, lines 12-13). It is understood that room temperature is from about 20°C to about 25°C because the applicant’s specification states that range in para. [0045]. It is understood that the incubation of the Fluo-4/AM with the cells at room temperature for 1 h hour is equivalent to acclimatizing the cells to a temperature for a time. Ng teaches washing the cells twice, as in step g. of claim 1 (see, e.g., p. 93, lines 26-27). Ng teaches mixing an antagonist diluted in a buffer, as in step h. of claim 1 (see, e.g., p. 94, lines 19-30). Ng teaches incubating the plate for a time and a temperature, as in step i. claim 1 (see, e.g., p. p. 94, line 27 to p. 95, line 2). Ng teaches reading the plate to determine a baseline signal, as in step j. of claim 1 (see, e.g., p. 94, lines 27-28). Ng teaches mixing an agonist diluted in a buffer, as in step k. of claim 1 (see, e.g., p. 95, lines 2-5). Ng teaches reading the plate to determine the receptor of interest inhibition activity of antagonist, as in step m. of claim 1 (see, e.g., p. 95, lines 2-5). Ng teaches the cell is mammalian, specifically Chinese Hamster Ovary cells, as in claims 4 and 5 (see, e.g., p. 93, lines 14-16). Ng teaches the cells are seeded on a plate at seeding density of 25,000, as in claim 6 (see, e.g., p. 93, line 31 to p. 94, line 2). Ng teaches the washing cells with about 200 µL assay buffer, as in claim 9 (see, e.g., p. 94, lines 13-18). It is understood that because Ng states the cells are washed twice and 100 µL is left in the well, the cells are effectively washed with 200 µL assay buffer. Ng teaches the dye is fluo-4AM and the Ex/Em = about 494 nm to about 516 nm, as in claims 10-13 (see, e.g., p. 94, lines 4-7). The Ex/Em of fluo-4AM is 494/506 nm as evidenced by the ThermoFisher product sheet for fluo-4 AM (see, e.g., ThermoFisher product sheet, under “Calcium Indicator (AM Ester) Specifications:”). It is understood that 506 nm is about 516 nm because the applicant’s specification states that “about” is within 10% of the measurable value (see, para. [0034]). Ng teaches incubating the cells in dye for 40 minutes, as in claim 14 (see, e.g., p. 94, lines 12-13). It is understood that the 40 minutes is incubating the cells in dye and then another 20 minutes is acclimatizing the cells at room temperature. Ng teaches the agonist is bradykinin, as in claim 19 (see, e.g., p. 95, lines 2-5). Ng teaches the buffer in step g. is similar to the buffer in step c., as in claim 20 (see, e.g., p. 94, lines 13-17). Ng teaches the receptor is a bradykinin receptor, as in claim 22 (see, e.g., p. 93, lines 14-16). hB2 is a bradykinin receptor as evidenced by Fattori (see, e.g., p. 550 , under “Abstract”). Ng teaches the plate reading is performed in 3 minutes, as in claim 24 (see, e.g., p. 95, lines 3-5).
Ng fails to teach shaking the plate, as in claim 1. However, Liu rectifies this deficiency. In a journal article entitled “A Multiplex Calcium Assay for Identification of ([G-protein)- coupled receptors (GPCR)] Agonists and Antagonists”, Liu discloses assays for identifying GPCR agonists and antagonists with the latest generation of florescence kinetic plate readers. Liu teaches the shaking of assay plates, as in claim 1 (see, e.g., p. 373, col. 1, para. 2).
Ng and Liu are analogous to the field of the claimed invention because they are both in the field of GPCR antagonists. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the assay plate shaking of Liu in the assay of Ng. An artisan would have been motivated to do so because Liu discloses “In this new instrument, the combination of rapidly vertical pin movement and assay plate shaking functions can create effective and rapid mixing of the compound DMSO solution with the assay
plate buffer while the plate is continuously read and recorded. We found that the local high concentration of compounds due to insufficient mixing can be avoided by using these functions in this instrument” (see, e.g., p. 373, col. 1, para. 2). An artisan would have a reasonable expectation of success based on the given disclosures.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Ng (cited above) and Liu (cited above) as applied to claims 1, 4-15, 17, 20, 22, 24, and 36 above, and further in view of Tung (US 20050020659 A1, published 2005-01-27).
Ng and Liu teach as set forth above, but fail to teach the IC50 is 1 nM, as in claim 2. However, Tung rectifies these deficiencies in a patent application on bradykinin receptor antagonists. Tung discloses a cell-based assays where the effectiveness of antagonists for bradykinin receptors is measured (see, e.g., para. [1905]). Tung teaches an antagonist with an IC50 of 1 nM, as in claim 2 (see, e.g., para. [1906]).
Ng, Liu, and Tung are analogous to the field of the claimed invention because they are all in the field of GPCR antagonists. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the antagonists of Tung into the assay of Ng and Liu. An artisan would have been motivated to do so because Tung discloses, “The compounds of this invention have potency in the above assay as demonstrated by results of less than 50 micromolar. It is advantageous that the assay results be less than 1 micromolar, even more advantageous for the results to be less than 0.5 micromolar” (see, e.g., para. [1907]). Tung clearly states the importance of antagonist efficacy. An artisan would have a reasonable expectation of success based on the given disclosures.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Ng (cited above) and Liu (cited above) as applied to claims 1, 4-15, 17, 20, 22, 24, and 36 above, and further in view of Kuohung, et al. (“A High-Throughput Small-Molecule Ligand Screen Targeted to Agonists and Antagonists of the G-Protein-Coupled Receptor GPR54”, published 2018-01-30).
Ng and Liu teach as set forth above, but fail to teach the cell seeding density is 30,000 cells/well, as in claim 7. However, in a journal article on ligand screens to GPCR agonists and antagonists, Kuohung rectifies this deficiency. Kuohung discloses, “We performed optimization experiments of the IP-One HTRF™ assay in 384-well white microplates and tested plating densities of 10,000, 20,000, 30,000, 40,000, and 60,000 cells/well”, as in claim 7 (see, p. 8, under “HTS assay selection and optimization of IP-One HTRF™ assay”, para. 2).
Ng, Liu, and Kuohung are analogous to the field of the claimed invention because they are all in the field of GPCR antagonists. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the 30,000 cells/well density of Kuohung in the assay of Ng and Liu. An artisan would have been motivated to do so because Kuohung discloses, “We found the optimal plating density to be 30,000 cells/well in a volume of 40 µL as this density yielded the most consistent hkiss-10 dose response with the lowest background readings in the smallest amount of media” (see, p. 8, under “HTS assay selection and optimization of IP-One HTRF™ assay”, para. 2). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Ng (cited above) and Liu (cited above) as applied to claims 1, 4-15, 17, 20, 22, 24, and 36 above, and further in view of Paczkowski, et al. ("Pharmacological characterization of antagonists of the C5a receptor", published 1999-12) and Sum, et al. (“Pharmacological Characterization of GPCR Agonists, Antagonists, Allosteric Modulators and Biased Ligands from HTS Hits to Lead Optimization”, published 2019-11-01).
Ng and Liu teach as set forth above, but fail to teach the incubation of the antagonists for 10 minutes at 37°C, as in claim 17. However, in a journal article characterizing antagonists, Paczkowski rectifies this deficiency. Paczkowski teaches incubating an antagonist for 10 min at 37°C, as in claims 17-18 (see, e.g., p. 1462, col. 1, under “Myeloperoxidase release from PMNs”, para. 2). Sum discloses data demonstrating that GPCR receptor response to antagonists is time-dependent (see, e.g., p. 16, under “Figure 7”, panels “A” to “C”).
Ng, Liu, Paczkowski, and Sum are analogous to the field of the claimed invention because they are all in the field of antagonists. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the antagonist incubation time of Paczkowski into the assay of Ng and Liu. An artisan would have been motivated to do so because Sum discloses that receptor occupancy increases with longer incubation time of antagonists (see, e.g., p. 16, under “Figure 7”, panels “A” to “C”). An artisan would have had a reasonable expectation of success based on the given disclosures.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/MICHAEL CAMERON SVEIVEN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678