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
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2020/022557, filed 11/21/2024, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/818,814, filed 03/15/2019.
Status of the Claims
Claims 1, 4-5, 7, 9-10, 12, 15 and 17-20 are pending; claims 1 and 12 are amended, claims 2-3, 6, 8, 11, 13-14 and 16 are canceled; claims 4-5, 9-10 and 18-20 are withdrawn. Claims 1, 7, 12, 15 and 17 are examined below.
Claim Objections
Claim 12 is objected to because of the following informalities:
In claim 12 line 9, “and the post-treatment, peritoneal fluid sample” should read “and a post-treatment, peritoneal fluid sample”.
Appropriate correction is required.
Maintained Rejection
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 12, 15 and 17 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 12 recites “[a] method of diagnosing and treating an infection in a patient, comprising: measuring the level of at least one antimicrobial peptide in a pre-treatment, peritoneal fluid sample taken from a patient by contacting the pre-treatment, peritoneal fluid sample with an anti-antimicrobial peptide antibody, wherein the at least one antimicrobial peptide is RNase 3; placing the patient on a treatment of a predetermined type; measuring the levels of the at least one antimicrobial peptide in the pre-treatment peritoneal fluid sample and the post-treatment, peritoneal fluid sample; diagnosing the patient with an infection when the amount of the at least one antimicrobial peptide in the post-treatment, peritoneal fluid sample exceeds the amount of at least one antimicrobial peptide in the pre-treatment, peritoneal fluid sample by a predetermined amount; and administering an effective amount of antibiotic treatment to the patient for treating the infection”. Therefore, the claims require, measuring the level of antimicrobial peptide in a pre-treatment sample, placing the patient on a treatment, measuring the level of antimicrobial peptide in the pre-treatment sample and the post-treatment sample, diagnosing the patient based on the levels measured in the post-treatment sample and pre-treatment sample, and administrating antibiotic treatment. However, it is unclear how one would measure the level of antimicrobial peptide from the pre-treatment sample after placing the patient on a treatment because the levels of antimicrobial peptide were already measured in the pre-treatment sample. Furthermore, it is unclear whether the diagnosis of infection relies on the level of antimicrobial peptides in the first measurement of the pre-treatment sample, or the second measurement of the pre-treatment sample.
Claims 15 and 17 are included in this rejection as it depends from rejected claim 12 but does not clarify the scope of patent protection sought.
Maintained Rejections
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hellman et al. Peritoneal Dialysis International, Vol. 20, pp. 295-300 https://doi.org/10.1177/089686080002000305 (May 2000) (“Hellman”) as evidenced by Beaumont et al. (WO 2013/067051 A1) (Cited in OA filed 1/3/2025) (hereinafter Beaumont), as evidenced by Li et al. Peritoneal Dialysis International Volume 36, Issue 5, September 2016, Pages 481-508 https://doi.org/10.3747/pdi.2016.00078 (“ISDP”), as evidenced by Ejaz et al. Nephron 1999; 81:121-130 (“Ejaz”) and as evidenced by Tas et al. Asian Pac J Allergy Immunol 2012;31:67-72 (“Tas”).
Regarding claim 1, Hellman teaches a method of diagnosing peritonitis in a patient undergoing peritoneal dialysis (“Objective: To characterize eosinophils and soluble factors in effluent from continuous ambulatory peritoneal dialysis (CAPO) patients and connect these findings to related conditions with eosinophilic accumulation… Increased levels of …eosinophil cationic protein…were found in effluent from the PFE [peritoneal fluid eosinophilia] patients compared to the patient with neutrophilia….The finding of activated eosinophils in … PFE indicates existing similarities between PFE and conditions found during recruitment of eosinophils in allergic inflammatory responses” Abstract). Note that eosinophil cationic protein (ECP) is RNase 3 as evidenced by Beaumont (“RNASE3 (ECP; eosinophil cationic protein)” paragraph 61). Note also that peritoneal fluid eosinophilia (PFE) is also “termed ‘eosinophilic peritonitis’” as evidenced by Ejaz (page 125 column 2 paragraph 2). Therefore, although Hellman fails to use the language “a method of diagnosing peritonitis”, the teachings of characterizing eosinophil soluble factors, i.e. ECP, in patients with peritoneal fluid eosinophilia, inherently provides a method of diagnosing peritonitis. Hellman further teaches establishing a baseline level of an RNase 3 antimicrobial peptide in a specific patient or in a patient population undergoing peritoneal dialysis (“[l]evels of eosinophil cationic protein (ECP) (b)” See Fig. 1). Hellman further teaches wherein the peritoneal dialysis involves accessing fluid from the patient’s peritoneal cavity prior to the patient presenting with suspected infectious peritonitis (“Effluents from the night bags (standard double bag system)…were collected from… 3 patients with cloudy PF [peritoneal dialysis fluid] (Patients D , E, and F in Table 1)” page 295 column 2 last paragraph, “Cell Counts and Soluble Factors in Dialysis Fluids from CAPD Patients” page 297, Table 3, see the high leukocyte counts (> 100/μL) of patients D, E and F in Table 3). Note that the specification discloses that “[c]linical diagnosis of acute peritonitis was based on the International Society of Peritoneal Dialysis (ISPD) Consensus Guidelines [48]” (paragraph 36). As evidenced by the ISDP “[w]e recommend that peritonitis always be diagnosed when at least 2 of the following are present: (1)… cloudy dialysis effluent; (2) dialysis effluent white cell count > 100/μL …[w]e recommend that PD patients presenting with cloudy effluent be presumed to have peritonitis and treated as such until the diagnosis can be confirmed or excluded (1C)…. Some patients present with cloudy effluent but no or minimal abdominal pain” (page 486 column 2 paragraphs 3-4). Hellman further teaches by way of quantitative antibody-based immunoassays that include anti-antimicrobial peptide antibodies, measuring the level of the RNase 3 antimicrobial peptide in a peritoneal fluid sample taken from the patient after the patient presents with suspected infectious peritonitis; detecting binding between the RNase 3 antimicrobial peptide and the anti-antimicrobial peptide antibodies (“Levels of ECP were measured using the Pharmacia ECP CAP FEIA System (Pharmacia & Upjohn)” page 296 column 2 paragraph 2, see Fig. 1 showing quantitative “Levels of eosinophil cationic protein (ECP) (b)” page 298). Note that the “ECP CAP FEIA System (Pharmacia & Upjohn)” is an antibody-based immunoassay as evidenced by Tas, “ECP flourescein enzyme immunoassay (FEIA) kits (Pharmacia & Upjohn Diagnostics AB Uppsala, Sweden) by CAP System” (page 69 column 1 paragraph 2). Hellman teaches comparing the baseline level of the RNase 3 antimicrobial peptide to the measured level of the RNase 3 antimicrobial peptide; and diagnosing the patient with peritonitis if the baseline level of the RNase 3 antimicrobial peptide exceeds the measured level of the RNase 3 antimicrobial peptide by a predetermined amount (“[o]nce recruited, eosinophils might degranulate and release basic proteins, ECP for example…We found ECP in PF at all visits; concentration was markedly increased before medication at V4, and decreased thereafter. Collectively, our findings imply that recruited eosinophils are in an activated state (5- 7). This is in line with previous studies reporting on the increased proportion of hypodense, that is, activated eosinophils in PF from patients with PFE (11).” page 298 column 2 paragraph 1).
Maintained Rejections
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 7 is rejected under 35 U.S.C. 103 as being unpatentable over Hellman as evidenced by Beaumont, ISDP, Ejaz, and Tas as applied to claim 1 above, and further in view of Beaumont.
Regarding claim 7, Hellman teaches the method of claim 1 as discussed above.
Hellman fails to teach wherein the quantitative antibody-based immunoassays include enzyme-linked immunosorbent assays and lateral flow assays.
Beaumont teaches measuring RNase3, a biomarker of TSLP blockade (“measuring…RNase3…wherein decreased expression [of] the marker compared to a control is indicative of TSLP blockade” paragraph 7). Beaumont further teaches that “it would be within the skill in the art for medical practitioners to determine the levels of the biomarkers of the invention in a number of human subjects, both with and without allergic disease…[t]hese baseline data would also be analyzed for variability using standard statistical approaches to determine the precision of the assay(s) in question” (paragraph 90). Beaumont further teaches that “[a] "subject" may be a human subject who is diagnosed with, or suspected of having, a disease or disorder” (paragraph 38). Beaumont further teaches that “[t]he biomarkers of the invention are well known in the art, and their sequences can be found in GenBank. For example, the GenBank Accession Numbers for the biomarkers of the invention are as follows…Gene: EAR11, Human Ortholog: RNASE3 (ECP; eosinophil cationic protein), Genebank Accession No. (human ortholog): NM 002935.2” (paragraph 61). Beaumont further teaches that “[b]iomarker levels can be quantitated by any method known in the art, including…ELISA” (paragraph 74). Beaumont teaches lateral flow assays (“[l]ateral flow format immunoassays (immunochromatographic assay) may also be used… The level of analyte (biomarker) may then be assessed qualitatively or quantitatively by the intensity of the signal at the second zone” paragraph 78).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Hellman to rely on the enzyme-linked immunosorbent assay and lateral flow assay taught by Beaumont because Beaumont suggests that this enables statistical comparisons of the level of RNase 3 between measurements. A person having ordinary skill in the art would have had a reasonable expectation of success because Beaumont teaches that RNase 3 is well known in the art and both Hellman and Beaumont teach quantitative antibody-based immunoassays for measuring levels of RNase 3.
Claims 12 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Eberl et al. (United States Patent No. US 10,209,255 B2) ("Eberl") (Cited in OA filed 1/3/2025), Hellman and Ejaz as evidenced by Beaumont, Ejaz and Tas.
Regarding claim 12, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the second measuring the level of at least one antimicrobial peptide in the pre-treatment peritoneal fluid sample (lines 8-9) is interpreted to be drawn to the same measurement of antimicrobial peptide recited in lines 3-4, i.e. the claim is interpreted to recite only one measurement of antimicrobial peptide in a pre-treatment sample (the measurement recited in lines 3-4).
Eberl teaches a method of diagnosing (“a method for identifying a Gram-negative bacterial infection in a peritoneal sample” column 3 lines 22-23) and treating an infection in a patient (“[a] method for treating an individual suffering from a peritoneal Gram-negative bacterial infection comprising:(a) obtaining a peritoneal sample” claim 1), comprising: measuring the level of “(c)Vγ2+ T cells expressing HLA-DR; (d) TNF-α; (e) IL-1β; and/or (f) monocytes within the peritoneal leukocyte population expressing CD86” (claim 5) in a pre-treatment, peritoneal fluid sample taken from a patient by contacting the pre-treatment, peritoneal fluid sample with an antibody (“The method according to claim 1 wherein at least one additional study is undertaken prior to the step of administering to determine an amount of any one or more of the following in the peritoneal sample relative to said control sample:(c)Vγ2+ T cells expressing HLA-DR; (d) TNF-α; (e) IL-1β; and/or (f) monocytes within the peritoneal leukocyte population expressing CD86” claim 5, “cell-free peritoneal effluents were analyzed for TNF-a… using conventional ELISA kits” column 9 lines 61-67); placing the patient on a treatment of a predetermined type (“administering to the individual a therapeutic for treating the peritoneal Gram-negative bacterial infection” claim 1); measuring the level of “(c)Vγ2+ T cells expressing HLA-DR; (d) TNF-α; (e) IL-1β; and/or (f) monocytes within the peritoneal leukocyte population expressing CD86” (claim 5) in a post-treatment, peritoneal fluid sample taken from the patient (“[t]he method according to claim 5 wherein said method is performed using steps a-b and any one or more of steps (c)-(f) including any combination thereof” claim 6, “using conventional ELISA kits” column 9 lines 66-67); diagnosing the patient with an infection when the amount in the post-treatment, peritoneal fluid sample exceeds the amount in the pre-treatment, peritoneal fluid sample by a predetermined amount; and administering an effective amount of antibiotic treatment to the patient for treating the infection (“[t]he method of claim 1, further including…where it is concluded that said individual is still suffering from the peritoneal Gram-negative bacterial infection, continuing to administer to said individual the therapeutic for treating the peritoneal Gram-negative bacterial infection” claim 2, “[t]he method according to claim 2 wherein said therapeutic is selected from the group consisting of: penicillins… and all antibiotics not covered by generic classes such as chloramphenicol, rifampicin… as well as structural analogues and derivatives thereof” claim 3). Note that although Eberl does not explicitly recite that the diagnosis of the infection involving an amount in the post-treatment, peritoneal fluid sample exceeding the amount in the pre-treatment, peritoneal fluid sample, the recitation of “[t]he method of claim 1, further including periodically repeating the step of identifying the Gram-negative infection, and where it is concluded that said individual is still suffering from the peritoneal Gram-negative infection” (claim 2) addresses the claim because the method of claims 1 and 5 involves concluding that the individual has an infection based on an “increased” amount.
Eberl fails to teach at least one antimicrobial peptides, wherein the at least one antimicrobial peptide is RNase 3 and an anti-antimicrobial peptide antibody.
Hellman teaches measuring at least one antimicrobial peptides, wherein the at least one antimicrobial peptide is RNase 3 (Table 3, Fig. 1). Note that eosinophil cationic protein (ECP) is RNase 3 as evidenced by Beaumont (paragraph 61). Hellman further teaches an anti-antimicrobial peptide antibody, and detecting binding between the antimicrobial peptide and the anti-antimicrobial peptide antibody (page 296 column 2 paragraph 2). Note that the “ECP CAP FEIA System (Pharmacia & Upjohn)” used by Hellman is an antibody-based immunoassay as evidenced by Tas, (page 69 column 1 paragraph 2). Hellman further suggests that RNase 3 is a biomarker of peritoneal fluid eosinophilia and peritonitis (Table 3, Abstract) given that peritoneal fluid eosinophilia (PFE) taught by Hellman is also “termed ‘eosinophilic peritonitis’” as evidenced by Ejaz (page 125 column 2 paragraph 2).
Ejaz teaches “pathophysiology of peritoneal fluid eosinophilia in peritoneal dialysis patients” (Title). Ejaz further teaches that peritoneal fluid eosinophilia may be caused by an infection (“Uremia per se [26], viral infection [27], Paecilomyces variotti infection [28], and Aspergillus niger infection [29] can cause peritoneal fluid eosinophilia” page 127 column 2 paragraph 2). Ejaz further teaches that “peritoneal fluid eosinophilia is a rather common event that occurs irregularly and intermittently during the course of peritoneal dialysis” (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Eberl to rely on measuring RNase 3 as taught by Hellman because Hellman suggests that RNase 3 is a marker of peritoneal fluid eosinophilia and Ejaz teaches that peritoneal fluid eosinophilia may be caused by an infection. Therefore one would be motivated to measure RNase 3 because the art teaches RNase 3 is a marker of infection. A person having ordinary skill in the art would have had a reasonable expectation of success because Ejaz teaches that peritoneal fluid eosinophilia is common in patients undergoing peritoneal dialysis and Eberl teaches that the patient is undergoing peritoneal dialysis. Furthermore, Hellman teaches the use of a commercially acquired immunoassay to measure the levels of RNase 3.
Regarding claim 17, Eberl in view of Hellman and Ejaz teach the method of claim 12 as discussed above.
Eberl further teaches wherein the treatment is peritoneal dialysis (“[t]he method according to claim 1 wherein said peritoneal sample is fluid from the peritoneal space…of an individual undergoing peritoneal dialysis treatment” claim 4) and the infection is acute infectious peritonitis (“[w]e recruited 52 adult patients who were receiving PD at the University Hospital of Wales, Cardiff, UK, and were admitted on day 1 of acute peritonitis” column 9 lines 29-31).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Eberl in view of Hellman and Ejaz as evidenced by Beaumont, Ejaz, and Tas as applied to claim 12 above, and further in view of Beaumont.
Regarding claim 15, Eberl in view of Hellman and Ejaz as evidenced by Beaumont, Ejaz and Tas address the method of claim 12 as discussed above.
Eberl further teaches quantitative antibody-based immunoassays (claim 6, “using conventional ELISA kits” column 9 lines 66-67).
Hellman teaches wherein the levels of antimicrobial peptides are measured using quantitative antibody-based immunoassays (page 296 column 2 paragraph 2).
Eberl in view of Hellman and Ejaz as evidenced by Beaumont, Ejaz and Tas fail to teach wherein the quantitative antibody-based immunoassays include enzyme-linked immunosorbent assays and lateral flow assays
Beaumont teaches measuring RNase3, a biomarker of TSLP blockade (paragraph 7). Beaumont further teaches that “it would be within the skill in the art for medical practitioners to determine the levels of the biomarkers of the invention in a number of human subjects, both with and without allergic disease…[t]hese baseline data would also be analyzed for variability using standard statistical approaches to determine the precision of the assay(s) in question” (paragraph 90). Beaumont further teaches that “[a] "subject" may be a human subject who is diagnosed with, or suspected of having, a disease or disorder” (paragraph 38). Beaumont further teaches that “[t]he biomarkers of the invention are well known in the art, and their sequences can be found in GenBank. For example, the GenBank Accession Numbers for the biomarkers of the invention are as follows…Gene: EAR11, Human Ortholog: RNASE3 (ECP; eosinophil cationic protein), Genebank Accession No. (human ortholog): NM 002935.2” (paragraph 61). Beaumont further teaches that “[b]iomarker levels can be quantitated by any method known in the art, including…ELISA” (paragraph 74). Beaumont further teaches lateral flow assays (“[l]ateral flow format immunoassays (immunochromatographic assay) may also be used… The level of analyte (biomarker) may then be assessed qualitatively or quantitatively by the intensity of the signal at the second zone” paragraph 78).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Eberl in view of Hellman and Ejaz to rely on the enzyme-linked immunosorbent assay and lateral flow assay taught by Beaumont because Beaumont suggests that this enables statistical comparisons of the level of RNase 3 between measurements. A person having ordinary skill in the art would have had a reasonable expectation of success because Beaumont teaches that RNase 3 is well known in the art and both Eberl, Hellman and Beaumont teach quantitative antibody-based immunoassays.
Maintained Rejections
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10,209,255 B2 (which also qualifies as prior art, i.e., “Eberl”) in view of Hellman as evidenced by Beaumont, ISDP, Ejaz and Tas.
Regarding claim 1, U.S. Patent No. 10,209,255 B2 recites a method of diagnosing peritonitis (“a method for treating an individual suffering from a peritoneal Gram-negative bacterial infection…concluding that the individual from whom the peritoneal sample has been taken has a Gram-negative bacterial infection” claims 1 and 5) in a patient undergoing peritoneal dialysis (“an individual undergoing peritoneal dialysis treatment” claim 4), comprising: measuring the level of “(c)Vγ2+ T cells expressing HLA-DR; (d) TNF-α; (e) IL-1β; and/or (f) monocytes within the peritoneal leukocyte population expressing CD86” (claim 5) in a peritoneal fluid sample taken from the patient after the patient presents with suspected infectious peritonitis (“[t]he method of claim 1, further including periodically repeating the step of identifying the Gram-negative infection and, where it is concluded that said individual is still suffering from the peritoneal Gram-negative bacterial infection, continuing to administer to said individual the therapeutic for treating the peritoneal Gram-negative bacterial infection” claim 2); note that although U.S. Patent No. 10,209,255 B2 fails to use the language “after the patient presents with suspected infectious peritonitis”, the recitation of “further including periodically repeating the step of identifying the Gram-negative infection, and where it is concluded that said individual is still suffering from the peritoneal Gram-negative bacterial infection, continuing to administer to said individual the therapeutic” implicitly recites that the measuring step happens after the patient presents with suspected infectious peritonitis.
U.S. Patent No. 10,209,255 B2 further recites comparing the baseline level of “(c)Vγ2+ T cells expressing HLA-DR; (d) TNF-α; (e) IL-1β; and/or (f) monocytes within the peritoneal leukocyte population expressing CD86” (claim 5) to the measured level of “(c)Vγ2+ T cells expressing HLA-DR; (d) TNF-α; (e) IL-1β; and/or (f) monocytes within the peritoneal leukocyte population expressing CD86” (claim 5) (“[t]he method of claim 1, further including periodically repeating the step of identifying the Gram-negative infection, and where it is concluded that said individual is still suffering from the peritoneal Gram-negative bacterial infection” claim 2 “[t]he method according to claim 5 wherein said method is performed using steps a-b and any one or more of steps (c)-(f) including any combination thereof” claim 6); note here that again even though U.S. Patent No. 10,209,255 B2 fails to use the language “comparing the baseline level to the measured level” U.S. Patent No. 10,209,255 B2 implicitly recites this limitation when reciting “periodically” and “including any combination thereof” because this implies that the comparison of claims 1 and 5 between the measurement and control happens after the suspected infection.
U.S. Patent No. 10,209,255 B2 further recites and diagnosing the patient with peritonitis if the baseline level of “(c)Vγ2+ T cells expressing HLA-DR; (d) TNF-α; (e) IL-1β; and/or (f) monocytes within the peritoneal leukocyte population expressing CD86” (claim 5) exceeds the measured level of “(c)Vγ2+ T cells expressing HLA-DR; (d) TNF-α; (e) IL-1β; and/or (f) monocytes within the peritoneal leukocyte population expressing CD86” (claim 5) by a predetermined amount (“where the amount of any one or more of ( c )-( e) is increased relative to the amount of same in said control or in the case of (f) is decreased relative to the amount of same in said control, concluding that the individual from whom the peritoneal sample has been taken has a Gram-negative bacterial infection” claim 5).
U.S. Patent No. 10,209,255 B2 fails to teach RNase 3 and establishing a baseline level in a specific patient or in a patient population undergoing peritoneal dialysis, wherein the peritoneal dialysis involves accessing fluid from the patient's peritoneal cavity prior to the patient presenting with suspected infectious peritonitis. U.S. Patent No. 10,209,255 B2 fails to teach by way of quantitative antibody-based immunoassays that include anti-microbial peptide antibodies, and detecting binding between the RNase 3 antimicrobial peptide and the anti-antimicrobial peptide antibodies.
Hellman suggests a method of diagnosing peritonitis in a patient undergoing peritoneal dialysis (Abstract). Note that eosinophil cationic protein (ECP) is RNase 3 as evidenced by Beaumont (paragraph 61). Note also that although Hellman fails to use the language “a method of diagnosing peritonitis”, the teachings of characterizing eosinophil soluble factors, i.e. ECP, in patients with peritoneal fluid eosinophilia, inherently suggests a method of diagnosing peritonitis. Note also that peritoneal fluid eosinophilia (PFE) is also “termed ‘eosinophilic peritonitis’” as evidenced by Ejaz (page 125 column 2 paragraph 2). Hellman further teaches establishing a baseline level of an RNase 3 antimicrobial peptide in a specific patient or in a patient population undergoing peritoneal dialysis (See Fig. 1). Hellman further suggests wherein the peritoneal dialysis involves accessing fluid from the patient’s peritoneal cavity prior to the patient presenting with suspected infectious peritonitis (page 295 column 2 last paragraph, page 297, Table 3, see the high leukocyte counts (> 100/μL) of patients D, E and F in Table 3). Note that the specification discloses that “[c]linical diagnosis of acute peritonitis was based on the International Society of Peritoneal Dialysis (ISPD) Consensus Guidelines [48]” (paragraph 36). As evidenced by the ISDP “[w]e recommend that peritonitis always be diagnosed when at least 2 of the following are present: (1)… cloudy dialysis effluent; (2) dialysis effluent white cell count > 100/μL …[w]e recommend that PD patients presenting with cloudy effluent be presumed to have peritonitis and treated as such until the diagnosis can be confirmed or excluded (1C)…. Some patients present with cloudy effluent but no or minimal abdominal pain” (page 486 column 2 paragraphs 3-4). Hellman further teaches by way of quantitative antibody-based immunoassays that include anti-antimicrobial peptide antibodies, measuring the level of the RNase 3 antimicrobial peptide in a peritoneal fluid sample taken from the patient after the patient presents with suspected infectious peritonitis; detecting binding between the RNase 3 antimicrobial peptide and the anti-antimicrobial peptide antibodies (page 296 column 2 paragraph 2, see Fig. 1 page 298). Note that the “ECP CAP FEIA System (Pharmacia & Upjohn)” is an antibody-based immunoassay as evidenced by Tas, “ECP flourescein enzyme immunoassay (FEIA) kits (Pharmacia & Upjohn Diagnostics AB Uppsala, Sweden) by CAP System” (page 69 column 1 paragraph 2). Hellman suggests comparing the baseline level of the RNase 3 antimicrobial peptide to the measured level of the RNase 3 antimicrobial peptide; and diagnosing the patient with peritonitis if the baseline level of the RNase 3 antimicrobial peptide exceeds the measured level of the RNase 3 antimicrobial peptide by a predetermined amount (page 298 column 2 paragraph 1). Furthermore, Hellman shows that the quantitative antibody-based immunoassays that include anti-microbial peptide antibodies, and detecting binding between the RNase 3 antimicrobial peptide and the anti-antimicrobial peptide antibodies enables statistical comparisons (page 296 column 2 last paragraph and page 297 column 1 paragraph 1 and column 2 last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of U.S. Patent No. 10,209,255 B2 to rely on RNase 3, establishing a baseline level in a specific patient or in a patient population undergoing peritoneal dialysis, wherein the peritoneal dialysis involves accessing fluid from the patient's peritoneal cavity prior to the patient presenting with a suspected infection, quantitative antibody-based immunoassays that include anti-microbial peptide antibodies, and detecting binding between the RNase 3 antimicrobial peptide and the anti-antimicrobial peptide antibodies as taught by Hellman because Hellman teaches that RNase 3 levels markedly increased before medication and decreased thereafter, thereby suggesting that RNase 3 is a biomarker of peritonitis and motivating a person having ordinary skill in the art to use RNase 3 to diagnose peritonitis. Furthermore, Hellman shows that the quantitative antibody-based immunoassays that include anti-microbial peptide antibodies, and detecting binding between the RNase 3 antimicrobial peptide and the anti-antimicrobial peptide antibodies enables statistical comparisons. A person having ordinary skill in the art would have had a reasonable expectation of success because both Hellman and U.S. Patent No. 10,209,255 B2 teach methods involving diagnosing an peritonitis by measuring the level of a peptide in a sample.
Regarding claim 12, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the second measuring the level of at least one antimicrobial peptide in the pre-treatment peritoneal fluid sample (lines 8-9) is interpreted to be drawn to the same measurement of antimicrobial peptide recited in lines 3-4, i.e. the claim is interpreted to recite only one measurement of antimicrobial peptide in a pre-treatment sample (the measurement recited in lines 3-4).
U.S. Patent No. 10,209,255 B2 recites a method of diagnosing (claim 5) and treating an infection in a patient (claim1) , comprising: measuring the level of “(c)Vγ2+ T cells expressing HLA-DR; (d) TNF-α; (e) IL-1β; and/or (f) monocytes within the peritoneal leukocyte population expressing CD86” (claim 5) in a pre-treatment, peritoneal fluid sample taken from a patient (claim 4, claim 5); placing the patient on a treatment of a predetermined type (claim 1); measuring the level of “(c)Vγ2+ T cells expressing HLA-DR; (d) TNF-α; (e) IL-1β; and/or (f) monocytes within the peritoneal leukocyte population expressing CD86” (claim 5) in a post-treatment, peritoneal fluid sample taken from the patient (claim 6); diagnosing the patient with an infection when the amount in the post-treatment, peritoneal fluid sample exceeds the amount in the pre-treatment, peritoneal fluid sample by a predetermined amount; and administering an effective amount of antibiotic treatment to the patient for treating the infection (claim 2, claim 3). Note that although U.S. Patent No. 10,209,255 B2 does not explicitly recite that the diagnosis of the infection involving an amount in the post-treatment, peritoneal fluid sample exceeding the amount in the pre-treatment, peritoneal fluid sample, the recitation of “[t]he method of claim 1, further including periodically repeating the step of identifying the Gram-negative infection, and where it is concluded that said individual is still suffering from the peritoneal Gram-negative infection” (claim 2) addresses the claim because the method of claims 1 and 5 involves concluding that the individual has an infection based on an “increased” amount.
U.S. Patent No. 10,209,255 B2 fails to recite antimicrobial peptides, wherein the at least one antimicrobial peptide is RNase 3, and an anti-antimicrobial peptide antibody.
Hellman suggests antimicrobial peptides, wherein the at least one antimicrobial peptide is RNase 3, and an anti-antimicrobial peptide antibody (see citations above).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of U.S. Patent No. 10,209,255 B2 to rely on RNase 3, anti-microbial peptide antibodies, and detecting binding between the RNase 3 antimicrobial peptide and the anti-antimicrobial peptide antibodies as taught by Hellman for the same reasons as discussed above in claim 1 (see analysis above). A person having ordinary skill in the art would have had a reasonable expectation of success because both Hellman and U.S. Patent No. 10,209,255 B2 teach methods involving diagnosing an peritonitis by measuring the level of a peptide in a sample.
Claims 7 and 15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10,209,255 B2 (which also qualifies as prior art, i.e., “Eberl”) in view of Hellman as evidenced by Beaumont, ISDP, Ejaz and Tas as applied to claims 1 and 12 above, and further in view of Beaumont.
Regarding claims 7 and 15, U.S. Patent No. 10,209,255 B2 in view of Hellman as evidenced by Beaumont, ISDP, Ejaz and Tas address the method of claim 1 and 12 as discussed above.
Hellman further teaches wherein the levels of antimicrobial peptides are measured using quantitative antibody-based immunoassays (page 296 column 2 paragraph 2, see Fig. 1 page 298).
U.S. Patent No. 10,209,255 B2 in view of Hellman as evidenced by Beaumont, ISDP, Ejaz and Tas fail to address and wherein the quantitative antibody-based immunoassays include enzyme-linked immunosorbent assays and lateral flow assays.
Beaumont teaches measuring RNase3, a biomarker of TSLP blockade (paragraph 7). Beaumont further teaches that “it would be within the skill in the art for medical practitioners to determine the levels of the biomarkers of the invention in a number of human subjects, both with and without allergic disease…[t]hese baseline data would also be analyzed for variability using standard statistical approaches to determine the precision of the assay(s) in question” (paragraph 90). Beaumont further teaches that “[a] "subject" may be a human subject who is diagnosed with, or suspected of having, a disease or disorder” (paragraph 38). Beaumont further teaches that “[t]he biomarkers of the invention are well known in the art, and their sequences can be found in GenBank. For example, the GenBank Accession Numbers for the biomarkers of the invention are as follows…Gene: EAR11, Human Ortholog: RNASE3 (ECP; eosinophil cationic protein), Genebank Accession No. (human ortholog): NM 002935.2” (paragraph 61). Beaumont further teaches that “[b]iomarker levels can be quantitated by any method known in the art, including…ELISA” (paragraph 74). Beaumont further teaches lateral flow assays (paragraph 78).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of U.S. Patent No. 10,209,255 B2 in view of Hellman as evidenced by Beaumont, ISDP, Ejaz and Tas to rely on the enzyme-linked immunosorbent assay and lateral flow assay taught by Beaumont because Beaumont suggests that this enables statistical comparisons of the level of RNase 3 between measurements. A person having ordinary skill in the art would have had a reasonable expectation of success because Beaumont teaches that RNase 3 is well known in the art and both Hellman and Beaumont teach quantitative antibody-based immunoassays for measuring levels of RNase 3.
Claim 17 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10,209,255 B2 (and as prior art “Eberl”) in view of Hellman as evidenced by Beaumont, ISDP, Ejaz and Tas as applied to claim 12 above, and further in view of Eberl.
Regarding claim 17, U.S. Patent No. 10,209,255 B2 in view of Hellman address the method of claim 12.
U.S. Patent No. 10,209,255 B2 recites wherein the treatment is peritoneal dialysis (“an individual undergoing peritoneal dialysis treatment” claim 4). U.S. Patent No. 10,209,255 B2 further recites that certain peptides are biomarkers of a gram-negative infection, such as Vγ2+ T cells expressing HLA-DR; TNF-α; IL-1β; and/or monocytes within the peritoneal leukocyte population expressing CD86 (claim 5).
U.S. Patent No. 10,209,255 B2 in view of Hellman fails to recite wherein the infection is acute infectious peritonitis.
Eberl teaches wherein the infection is acute infectious peritonitis (column 9 lines 29-32). Eberl suggests that rapid diagnosis of acute peritonitis improves targeting of a therapy and its ultimate efficacy (“The present disclosure relates to methods of rapid diagnosis of infection in peritoneal disease. In the present study we performed a detailed immunological and microbiological analysis in PD patients on the first day of presentation with acute peritonitis... As such, these results have far-reaching implications for differential diagnosis of patients with suspected infections and may help guide patient management through faster biomarker-based diagnostics, better predictive risk modelling and improved targeting of a therapy and its ultimate efficacy” column 3 lines 1-17). Eberl further suggests that Vγ2+ T cells expressing HLA-DR; TNF-α; IL-1β; and/or monocytes within the peritoneal leukocyte population expressing CD86 are markers for acute peritonitis characterized by a gram-negative infection (“Within the T cell population, Vγ2+ T cells were significantly increased and expressed higher levels of the activation marker HLA-DR in Gram-negative infections. In turn, peritoneal monocytes/macrophages expressed lower levels of CD86 in Gram-negative infections, compared to the rest of the patients. Inflammatory markers significantly increased in Gram-negative infections included IL-1~, IL-10 and TNF-a” column 11 lines 3-9).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of U.S. Patent No. 10,209,255 B2 in view of Eberl and Hellman to diagnose acute infectious peritonitis taught by Eberl instead of a broader gram-negative infection recited by U.S. Patent No. 10,209,255 B2 because Eberl suggests that this would enable improved targeting of a therapy and its ultimate efficacy. A person having ordinary skill in the art would have had a reasonable expectation of success because Eberl teaches that acute peritonitis is a specific form of infection encompassed by gram-negative infections and is associated with the markers recited by U.S. Patent No. 10,209,255 B2 (Vγ2+ T cells expressing HLA-DR; TNF-α; IL-1β; and/or monocytes within the peritoneal leukocyte population expressing CD86).
Response to Arguments
Applicant's arguments filed 11/7/2025 have been fully considered but they are not persuasive.
Regarding the claim objections,
Applicant remarks that “Applicants have amended claims 1 and 12 to address the concerns identified by the Examiner”. (page 5 para. 3).
However, claim 12 stands objected because the amendments fail to address the objection, namely that “the post-treatment, peritoneal fluid sample” should read as “a post-treatment, peritoneal fluid sample” (emphasis added).
Regarding the 102 rejections,
Applicant argues that “Hellman does not teach diagnosis of a subject with infectious peritonitis, but instead characterizes the leukocytes and other soluble mediators in peritoneal fluid eosinophilia, which is a different disease…Eosinophilia is diagnosed by the presence of more than 100 eosinophils/mm3 or over 10% eosinophils in the total white blood cell count of the peritoneal fluid, and is non-infectious complication (e.g., an allergic reaction) to items like peritoneal dialysis and a catheter. …Infectious peritonitis, on the other hand, is a microbial infection diagnosed by a positive culture for bacteria or fungi from the peritoneal fluid and a high white blood cell count, composed primarily of neutrophils, not eosinophils” (page 5 last paragraph and page 6 paragraph 1).
However, although Hellman does teach eosinophilic peritonitis and not infectious peritonitis, the claims are not limited to the diagnosis of infectious peritonitis. The claims, as currently amended, recite “diagnosing peritonitis in a patient undergoing peritoneal dialysis, comprising:
establishing a baseline level of an RNase 3 antimicrobial peptide in a specific patient population undergoing peritoneal dialysis, wherein the peritoneal dialysis involves accessing fluid from the patient's peritoneal cavity prior to the patient presenting with suspected infectious peritonitis; by way of quantitative antibody-based immunoassays that include anti-antimicrobial peptide antibodies, measuring the level of the RNase antimicrobial peptide in a peritoneal fluid sample taken from the patent after the patient presents with suspected infectious peritonitis…” (emphasis added). Therefore, Hellman does anticipate the claim.
Declaration under 37 C.F.R. § 1.132
The declaration under 37 C.F.R. § 1.132 filed 11/07/2025, i.e. the Becknell declaration, is insufficient to overcome the outstanding rejections under 102. Applicant asserts that “The
International Society of Peritoneal Dialysis guidelines define infectious peritonitis in peritoneal
dialysis patients based on a dialysis effluent white cell count> 100/μL or> 0.1 x 109/L (after a dwell time of at least 2 hours), with> 50% neutrophils. We identified RNase3, also known as eosinophil cationic protein (ECP) as an elevated protein in the effluent of patients receiving PD who experienced infectious peritonitis. This is the basis of the invention and is distinct from observations by Hellman…” (page 1 para. 4 of Becknell Declaration 11/7/2025). However, Hellman teaches measuring RNase 3 to diagnose eosinophilic peritonitis in a patient presenting with a suspected infectious peritonitis (cloudy effluent bag). Given that the International Society for Peritoneal Dialysis (ISPD) (Cite No. V of PTO 892 5/16/2025), which was cited by inventor Becknell in his Declaration filed 11/7/2025, teaches that “Cloudy effluent almost always represents infectious peritonitis” (page 486 col. 2 para. 4), the cloudy effluent bags of the dialysis patients taught by Hellman inherently provides the patient presenting with a suspected infectious peritonitis claimed. Therefore, the rejection is maintained.
Regarding the 103 rejections,
Applicant argues that “Eberl teaches a method of determining whether a subject has a Gram-negative or Gram-positive peritoneal infection by evaluating one or more cellular and/or humoral markers in the sample. Eberl makes no reference to eosinophils. Hellman et al. is directed towards determining phenotypical alterations of eosinophils in peritoneal fluid in peritoneal dialysis patients (i.e., Peritoneal fluid eosinophilia), while Eberl evaluates cellular and humoral markers, but not RNase 3 for diagnosis of infectious peritonitis. Since these references teach diagnosis of different diseases using different markers, it would not be obvious to combine these references” (page 7 paras. 2-3).
However, contrary to Applicant’s argument, it would have been obvious to combine the references because Ejaz (Cite No. W of PTO 892 5/15/2025) teaches that peritoneal fluid eosinophilia is a common event during peritoneal dialysis and can be caused by an infection and Eberl is interest in measuring biomarkers of infection in peritoneal dialysis patients (see rejection above). Furthermore, both Hellman and Eberl teach measuring biomarkers in peritoneal fluid of peritoneal dialysis patients. Therefore, there is a clear connection between the references (see rejection above).
Applicant further argues that “Beaumont's teachings… do nothing to overcome the deficiencies noted above… Applicants respectfully request that the rejection of claim 15 for obviousness be withdrawn” (page 7 para. 4).
However, there are no deficiencies in the 103 rejections.
Regarding the double patenting rejections,
Applicant remarks to “Please hold this rejection in abeyance until allowable subject matter has been identified” (page 8 para. 1).
However, no claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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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/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678