DETAILED ACTION
This action is in reply to papers filed 2/17/2026. Claims 1-19 are pending and examined herein.
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 .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230288403A1, Published 9/14/2023.
Maintained Rejection(s)
Applicant's arguments filed 2/17/2026, with respect to the 103 (a) rejection of claims 1-9 and 11-12 as being unpatentable over Behnen et al. in view of Teng et al. have been fully considered but they are not persuasive. Applicant’s arguments will be addressed following maintained rejection.
Applicant's arguments filed 2/17/2026, with respect to the 103 (a) rejection of claims 10 and 14-17 as being unpatentable over Behnen et al. in view of Teng et al. as applied to claims 1-9 and 11-12 and further in view of Anders et al. have been fully considered but they are not persuasive. Applicant’s arguments will be addressed following maintained rejection.
Applicant's arguments filed 2/17/2026, with respect to the 103 (a) rejection of claims 17-19 as being unpatentable over Behnen et al. in view of Teng et al. as applied to claims 1-9 and 11-12 and further in view of Ruiz-Opazo et al. have been fully considered but they are not persuasive. Applicant’s arguments will be addressed following maintained rejection.
Claim Rejections - 35 USC § 103
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.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-9 and 11-12 remain rejected under 35 U.S.C. 103 as being unpatentable over Behnen et al. (J Immunol. 2014 Aug 15;193(4):1954-65.) in view of Teng et al. (WO2017055604A1, Published 4/6/2017).
Claim interpretation: Para. 86 teaches “Polyvalent immunoglobulins” or “intravenous immunoglobulins” or “IVIg” refers to preparations of pooled normal polyspecific immunoglobulins, mostly IgG, obtained from large numbers of donors. The rejection below is made in view of this teaching.
Behnen et al. teach plymorphonuclear neutrophil granulocytes are key players in the antimicrobial defense. One important antimicrobial effector mechanism is the release of extracellular fibrous structures, the so-called neutrophil extracellular traps (NETs). Behnen teaches NETs are composed of chromatin, histones, and antimicrobial proteins and contribute to pathogen containment. To release NETs, Behnen teaches activated neutrophils undergo a form of cell death that is distinct from apoptosis and necrosis, the so-called NETosis (Pg. 1954, Col. 1, para. 1).
Regarding claim 1, in-part, Behnen et al. teach surface-bound immobilized immune complexes (iICs) were generated by using HSA and rabbit anti–HSA IgG Abs. Briefly, 20 μg/ml HSA in 50 mM carbonate/bicarbonate buffer (pH 9.6) was coated overnight at 4°C to 96-well Lumitrac 600 (for chemiluminescence-based ROS detection) or Fluotrac 600 (for fluorescence-based NET detection using the non–cell-permeable DNA dye Sytox Green (as in claim 7, claim 8 and claim 9)). After washing with PBS plus 0.05% Tween 20 (wash buffer), wells were blocked with 10% biotin-free BSA in PBS for 1 h at room temperature following 1 h incubation with anti–HSA IgG1 diluted 1:400 in PBS (∼10 μg/ml HSA-specific IgG) (as in claim 5, in-part) (Pg. 1955, Col. 1). Behnen teaches immune complexes formed with rabbit IgG have been used previously in several studies with neutrophils. Rabbit IgGs bind to human Fcγ receptors in a similar pattern as human IgG, and they activate human neutrophils (Pg. 1956, Col. 1). Thus, rabbit IgGs can be used as an equivalent alternative to human IgG. Behnen assessed the effect of iICs on the formation of NETs (as in claim 1, in-part). Behnen teaches iICs significantly induced NET release (as in claim 11) by human neutrophils (as in claim 2 and claim 3) as detected by real-time kinetics. Preincubation of neutrophils, at a seeding density of 10^6 cells/ml (as in claim 6) () with TNF-α significantly increased iIC-induced NET production (Fig. 2B; . 1956, Col. 1) (as in claim 4). When compared with PMA, a well-characterized inducer of ROS-dependent NETosis, NETs induced by iICs/TNF-α occurred later and to a lesser extent (Fig. 2A) (as in claim 12). Behnen notes that their study was the first to show that NETs contribute to pathology in autoimmune inflammatory disorders associated with surface-bound ICs (Abstract).
And although Behnen teaches IgG, Behnen fails to teach a human polyvalent immunoglobulin (as further in claim 1).
Before the effective filing date, Teng et al. taught a method for quantifying, analysing or detecting NET inducing capacity, ETosis and/or ET-like structures, said method comprising: providing cells; contacting the cells with a cell membrane stain and subjecting the cells to inducers which induce ETosis such as IVIG (as further in claim 1) (Pg. 14); contacting the cells with a nucleic acid stain; and determining the ratio of cells positively labelled for nucleic acid with the number of labelled cells (Abstract). Teng teaches that In order to quantify ETosis or the number of ET-like structures, the percentage area of positive nucleic acid staining may be divided by the percentage area of positive cell staining. In addition to facilitating ETosis quantification, this corrects the level of ETosis for the number of cell counted. Teng teaches one of skill will appreciate that images with a higher ratio are indicative of a greater amount of extracellular DNA present. This in turn is a marker of ETosis (Pg. 10). In view of this information, one of ordinary skill could easily determine the ratio of immunoglobulin to neutrophils required to induce maximal ET formation (as in claim 13).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Behnen et al., wherein Behnen teaches surface-bound immobilized immune complexes (iICs) comprising IgG induced NETosis in neutrophils with the teachings of Teng et al., wherein Teng teaches a method of quantifying ET formation of neutrophils by exposure to the inducer IVIG. That is, the skilled artisan would have found it prima facie obvious to compare the ET formation of IVIG and the ET formation of IgG in order to assess which inducer would contribute most to pathogen containment.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 2
Claim(s) 10 and 14-17 remain rejected under 35 U.S.C. 103 as being unpatentable over Behnen et al. (J Immunol. 2014 Aug 15;193(4):1954-65.) in view of Teng et al. (WO2017055604A1, Published 4/6/2017) as applied to claims 1-9 and 12 above, and further in view of Anders et al. (EP3017825A1, Published 5/11/2016).
The teachings of Behnen et al. and Teng et al. are relied upon as detailed above. And although the combination of Behnen et al. and Teng et al. teach inducing ET formation by contacting the immune cells in in vitro culture or within a biological sample with human polyvalent immunoglobulins immobilized on a solid support, said combination fails to teach
assessing the effect of a drug on ET formation in the in vitro culture of immune cells or in the biological sample (as in claim 10) or assessing the effect of a ET modulator on ET formation in the in vitro culture of immune cells or in the biological sample (as in claim 14).
Before the effective filing date of the claimed invention, Anders et al. taught use of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and/or of mixed lineage kinase domain-like protein in a screening method for identifying a compound useful for the treatment of a neutrophil extracellular trap (NET)-formation-associated disease (as further in claim 10 and as further in claim 14) (Pg. 6, para. 57), such as the inflammatory disease gout (as in claim 16) (Pg. 2, para. 2). To provide functional data also on RIPK3, Anders teaches neutrophils from wild-type and Ripk3-deficient mice on identical genetic backgrounds were isolated and exposed to PMA or MSU to induce NET formation. Ripk3-deficient neutrophils completely lacked nuclear DNA dye uptake, chromatin decondensation, NET formation (as in claim 15), and DNA release as compared to Ripk3+/+ wild type cells (Figure 14A-C; Pg. 15). These data confirm the role of RIPK3 in NET formation. Activated neutrophils release TNF-alpha, which could trigger necroptosis in an autocrine manner. In fact, neutrophils from Tnfr1/Tnfr2-double-deficient mice were partially protected from PMA-induced cell death and NET formation imposing a role for this autocrine pathway (figure 18). To validate these in vitro results Anders teaches 2.5 mg MSU crystals were injected into subcutaneous air pouches at the back of Balb/c mice and the effects of RIPK1 inhibition with 1.65 mg/kg Nec-1 on MSU-induced crystal-NET conglomerates, i.e. tophus formation, were analyzed. Nec-1 had no effect on neutrophil recruitment into the air pouch per se but significantly reduced tophus mass along the pouch membrane as determined by visual inspection (Figure 14D). In addition, Nec-1 significantly reduced NET-related DNA release into the lavage fluid (Figure 14E; Pg. 15). Anders teaches their data shows that NET formation is a consequence of RIPK1/RIPK3, and MLKL-dependent neutrophil necroptosis, and that RIPK1, RIPK3 or MLKL represent molecular targets to prevent NET-related tissue injury (Pg. 17,para. 94).
When taken with the teachings of Behnen et al. and Teng et al., wherein the combination teaches a method inducing NET formation by contacting neutrophils with an immobilized immune complex (iICs) comprising IVIG, one of ordinary skill in the art would have found it prima facie obvious to use the iICs screen a modulator of ET formation. The skilled artisan would have found it prima facie obvious to do in order to find a therapeutic for inflammatory diseases characterized by ET formation such as gout.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 3
Claim(s) 17-19 remain rejected under 35 U.S.C. 103 as being unpatentable over Behnen et al. (J Immunol. 2014 Aug 15;193(4):1954-65.) in view of Teng et al. (WO2017055604A1, Published 4/6/2017) as applied to claims 1-9 and 12 above, and further in view of Ruiz-Opazo et al. (PgPub US20190083595A1, Published 3/21/2019).
The teachings of Behnen et al. and Teng et al. are relied upon as detailed above. And although the combination of Behnen et al. and Teng et al. teach inducing ET formation by contacting the immune cells in in vitro culture or within a biological sample with human polyvalent immunoglobulins immobilized on a solid support, said combination fails to teach
quantifying ET formation induced in the biological sample or in the in vitro culture of immune cells; and c) comparing the ET formation induced in the biological sample or in the in vitro
culture of immune cells to a reference value, thereby monitoring the response
of the subject to the therapeutic or prophylactic agent (as further in claim 17(b) and 17(c)).
Before the effective filing date of the claimed invention, Ruiz-Opazo et al. teach a method of preventing or decreasing neutrophil extracellular trap (NET) release or actPMN NETosis or vital NETosis, the method comprising administering a therapeutically effective amount of a DEspR inhibitor to the subject (Pg. 1,para. 12). Ruiz-Opazo teaches hu-6g8 (anti-DEspR mAb (Pg. 3, para. 29)) reduces survival and increases apoptosis of DEspR-positive (+) activated neutrophils from acute lung injury (as in claim 19) patients, and that elimination of DEspR+ neutrophils significantly decreases NETosis since most NET+ neutrophils are DEspR+. Ruiz-Opazo notes that the % decrease in NETosis in hu-6g8 treated, LPS-activated NHV neutrophils compared to vehicle-treated person-matched controls can be performed via validated FACS measurement of NETs in whole blood (as further in claim 17 b, claim 17 c and as in claim 18) (Pg. 47, para. 697; Pg. 48, para. 703).
When taken with the teachings of Behnen et al. and Teng et al., wherein the combination teaches a method inducing NET formation by contacting neutrophils with an immobilized immune complex (iICs) comprising IVIG, one of ordinary skill in the art would have found it prima facie obvious to monitor the effect of a DEspR inhibitor on ET formation. The skilled artisan would have found it prima facie obvious to do in order to find a therapeutic for diseases characterized by ET formation.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious
Applicant’s Arguments/Response to Arguments
Applicant argues: Applicant first submits that the claimed invention features pooled human polyvalent IgG (IVIg) directly immobilized on a solid support, in the absence of any antigen or immune complex formation, robustly induces extracellular trap (ET) formation, whereas soluble IVig-tested up to 300 μg/mL under otherwise identical conditions-does not induce ETs. (Examiner’s emphasis).
In Response: Applicant’s arguments have been fully considered, but they are not found persuasive. Claim 1 is copied below. Note that all other independent claims require the limitations of claim 1.
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As clearly shown above, claim 1 does not recite “the absence of any antigen or immune complex formation.” Thus, Applicant’s arguments here are misplaced.
Applicant argues: The claims require antigen-free immobilized IVIg as the inducer (para.
[0079], [0081], and [0162] of the specification as filed). Under otherwise identical conditions, immobilized IVIg induces NETs; soluble IVIg does not (para. [0174]-[0l 75] and Figs. 5A-5B of the specification as filed). The immobilized-IVIg response is SYK-dependent (para. [0184]-[0187] and Fig. 7 of the specification as filed) and exhibits density/ratio dependence (para. [0181]-[0183] and Figs. 6A-6E of the specification as filed).
In Response: Applicant’s arguments have been fully considered, but they are not found persuasive. As noted above, claim 1 does not recite “the absence of any antigen“. Per MPEP 2111.03, the transitional term "comprising", as recited in claim - is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. (Examiner’s emphasis).
Applicant argues: Applicant further submits that the claimed immobilization of IVIG yields unexpected and technically significant results.
In Response: Per MPEP 716.01 (c) (II), arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
Applicant argues: Replacing Behnen' s antigen specific ii Cs with pooled human IVIg would not produce Applicant's antigen free immobilized IVIg film, so that one of ordinary skill would still expect to employ antigen plus antibody to prepare iICs per Behnen (pg. 1955, col. 1). Teng's framework reinforces use of soluble immunoglobulins as inducers (Abstract; p. 10, 14). Thus, the prior art points in a different direction than the claimed antigen free immobilized IVIg regime
In Response: Applicant’s arguments have been fully considered, but they are not found persuasive. As noted above, claim 1 does not recite “the absence of any antigen“. Per MPEP 2111.03, the transitional term "comprising", as recited in claim - is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. (Examiner’s emphasis).
Because Applicant’s arguments were not found persuasive, the rejections are maintained.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632