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 .
DETAILED ACTION
Status of the Claims
Claims 1-21 are pending and the subject of this FINAL Office Action.
Claim Interpretations
“Stoma” is broad. It means any opening. See e.g. Spec, para. 0005 (“an artificial opening (stoma)”); Wikipedia, Stoma (medicine), available at https://en.wikipedia.org/wiki/Stoma_(medicine), accessed 07/29/2026 (“In anatomy, a stoma (pl.: stomata /ˈstoʊ.mə.tə/ or stomas) is any opening in the body”).
“Effluent” is also broad.
The effluent may comprise, for example, fecal matter, mucus, urine, bile, blood, plasma, aggregated tissue, irrigation fluid, lymphatic fluid, lymphovascular fluid, interstitial fluid, cells, cellular debris, bacteria, protein, and nucleic acid, or a combination thereof. The fluid may further comprise sweat, semen, vaginal secretions, cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, amniotic fluid, or saliva depending on the location from which it is obtained
(Spec., para. 0007).
In contrast, the specific examples seem to be collecting surgical drain fluids. Applicants are encouraged to amend the claims accordingly.
In the interest of compact prosecution, the prior art applied below is directed to detecting biomarkers in surgical fluids.
Claim Rejections - 35 USC § 102 - Maintained
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 –
(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.
Claims 1-4, 7-9, 11-12, 15-17 and 19-21 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Lassig et al, Association of Oral Cavity and Oropharyngeal Cancer Biomarkers in Surgical Drain Fluid With Patient Outcomes, JAMA Otolaryngol Head Neck Surg. 2017 Apr 13;143(7):670–678. doi: 10.1001/jamaoto.2016.3595.
As to claim 1, Lassig teaches method for monitoring efficacy of a treatment, the method comprising the steps of: obtaining, as a first sample, effluent from a patient having undergone a surgical procedure, wherein the first sample is obtained at a first time point (“Surgical drain fluid samples were collected postoperatively every 8 hours until drains met clinical criteria for removal”; Figs. 1-2); obtaining, as a second sample, effluent from the patient, wherein the second sample is obtained at a second time point; identifying in the sample a difference in the first sample and the second sample in a biomarker indicative of disease (id.); and determining the efficacy of treatment based on the presence or absence of the biomarker in the sample (“Surgical drain fluid was evaluated for a panel of biomarkers present in the tumor environment and/or healing wound by an investigator blinded to clinical outcome end points”; Figs. 1-2; Abstract; Table 2).
As to claim 2, Lassig teaches the first sample is obtained at or near the time of the surgical procedure (“Wound fluid samples were collected from all patients undergoing surgery beginning on postoperative day 1 at a protocol-directed time from surgery. Once collected, the fluid samples were stored using a standard protocol in a −80°C freezer. Surgical drain fluid samples were collected postoperatively every 8 hours until drains met clinical criteria for removal.”; Figs. 1-2; Table 2).
As to claim 3, Lassig teaches the difference identified is the presence or absence of the biomarker indicative of disease, wherein the presence or absence of the biomarker is an indication of treatment efficacy (“This cohort study determines whether there is an association between biomarker levels in surgical drain fluid of patients with head and neck cancer and disease-free survival and cancer recurrence”; Abstract).
As to claim 4, Lassig teaches the second sample is obtained after the patient has undergone treatment (id.).
As to claim 7, Lassig teaches the first sample and/or the second sample is collected from a percutaneous catheter, peritoneal port, or intraperitoneal drain (“At the completion of the surgery, standard 10-mm flat silicone surgical drains (Jackson Pratt; Cardinal Health) were placed as clinically indicated. All patients had at least 1 drain placed running medial to lateral and superior to inferior in the lateral neck”).
As to claim 8, Lassig teaches the presence of the biomarker is indicative of minimal residual disease. This is an intended use that fails to distinguish the method steps of claim 1 from the prior art.
As to claim 9, Lassig teaches the biomarker is selected from a nucleic acid, a protein, a bacterium, a cell, and a virus (Figs. 1-2).
As to claim 11, Lassig teaches the biomarker comprises one or more of interleukin-1, interleukin-6, interleukin-10, a tumor necrosis factor, matrix metalloproteinase-1, matrix metalloproteinase-2, matrix metalloproteinase-9, matrix metalloproteinase-13, or a nucleic acid comprising a mutation (“Fluid samples were evaluated for MMP-1, MMP-3, and MMP-9 levels”; Figs. 1-2).
As to claim 12, Lassig teaches method for assessing surgical success, the method comprising the steps of: obtaining, as a sample, effluent from a patient having undergone a surgical procedure (Methods- “Surgical drain fluid samples were collected postoperatively every 8 hours until drains met clinical criteria for removal. Every 8-hour period of sequential wound fluid collection was deemed to be a shift throughout this report. Surgical drain fluid was evaluated for a panel of biomarkers present in the tumor environment and/or healing wound by an investigator blinded to clinical outcome end points”); identifying in the sample a biomarker indicative of disease (id.; Figs. 1-2 and Table 2); and determining the success of the surgery based on the presence or absence of the biomarker in the sample (measuring survival and recurrence; id.).
As to claim 15, Lassig teaches the sample is collected from a percutaneous catheter, peritoneal port, or intraperitoneal drain (“At the completion of the surgery, standard 10-mm flat silicone surgical drains (Jackson Pratt; Cardinal Health) were placed as clinically indicated. All patients had at least 1 drain placed running medial to lateral and superior to inferior in the lateral neck”).
As to claim 16, Lassig teaches the presence of the biomarker is indicative of minimal residual disease. This is an intended use that fails to distinguish the method steps of claim 1 from the prior art.
As to claim 17, Lassig teaches the biomarker is selected from a nucleic acid, a protein, a bacterium, a cell, and a virus (Figs. 1-2).
As to claim 19, Lassig teaches the biomarker comprises one or more of interleukin-1, interleukin-6, interleukin-10, a tumor necrosis factor, matrix metalloproteinase-1, matrix metalloproteinase-2, matrix metalloproteinase-9, matrix metalloproteinase-13, or a nucleic acid comprising a mutation (“Fluid samples were evaluated for MMP-1, MMP-3, and MMP-9 levels”; Figs. 1-2).
As to claim 20, Lassig teaches the step of obtaining a genomic profile from the sample (Figs. 1-2; Table 2).
Claims 1-4, 7-9, 12, 15-17 and 20-21 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by ZEVALLOS (WO2021127065, pub 06/24/2021).
As to claim 1, ZEVALLOS teaches method for monitoring efficacy of a treatment (“detecting minimal residual disease”; Abstract), the method comprising the steps of: obtaining, as a first sample, effluent from a patient having undergone a surgical procedure, wherein the first sample is obtained at a first time point (“A method for detecting minimal residual disease in a subject following a cancer surgery is disclosed. The method includes obtaining a sample from the subject. The sample includes a surgical drainage”; Abstract); obtaining, as a second sample, effluent from the patient, wherein the second sample is obtained at a second time point; identifying in the sample a difference in the first sample and the second sample in a biomarker indicative of disease (id.); and determining the efficacy of treatment based on the presence or absence of the biomarker in the sample (id.)
As to claim 2, ZEVALLOS teaches the first sample is obtained at or near the time of the surgical procedure (id.)
As to claim 3, ZEVALLOS teaches the difference identified is the presence or absence of the biomarker indicative of disease, wherein the presence or absence of the biomarker is an indication of treatment efficacy (paras. 0004-09, 0017 & 0056).
As to claim 4, ZEVALLOS teaches the second sample is obtained after the patient has undergone treatment (Abstract).
As to claim 7, ZEVALLOS teaches the first sample and/or the second sample is collected from a percutaneous catheter, peritoneal port, or intraperitoneal drain (Abstract).
As to claim 8, ZEVALLOS teaches the presence of the biomarker is indicative of minimal residual disease (Abstract). This is an intended use that fails to distinguish the method steps of claim 1 from the prior art.
As to claim 9, ZEVALLOS teaches the biomarker is selected from a nucleic acid, a protein, a bacterium, a cell, and a virus (paras. 0008-09).
As to claim 12, ZEVALLOS teaches method for assessing surgical success, the method comprising the steps of: obtaining, as a sample, effluent from a patient having undergone a surgical procedure (Abstract); identifying in the sample a biomarker indicative of disease (id.); and determining the success of the surgery based on the presence or absence of the biomarker in the sample (MRD; id.).
As to claim 15, ZEVALLOS teaches the sample is collected from a percutaneous catheter, peritoneal port, or intraperitoneal drain (Abstract).
As to claim 16, ZEVALLOS teaches the presence of the biomarker is indicative of minimal residual disease (Abstract). This is an intended use that fails to distinguish the method steps of claim 1 from the prior art.
As to claim 17, ZEVALLOS teaches the biomarker is selected from a nucleic acid, a protein, a bacterium, a cell, and a virus (paras. 0008-09).
As to claim 20, ZEVALLOS teaches the step of obtaining a genomic profile from the sample (para. 0055).
Response to Arguments
The rejections are maintained because both Lassig and ZEVALLOS teach stoma/openings. Lassig teaches “At the completion of the surgery, standard 10-mm fl at silicone surgical drains(Jackson Pratt; Cardinal Health) were placed as clinically indicated. All patients had at least 1 drain placedrunning medial to lateral and superior to inferior in the lateral neck” (Introduction; see also Abstract); and ZEVALLOS teaches samples from surgical drainages for drainage tube out of body, which require stoma/opening for tube (e.g. paras. 0008-09).
As to new claim 21, Lassig teaches nucleic acid biomarker (e.g. MMPs; Abstract); as does ZEVALLOS (e.g. paras. 0008-09).
Claim Rejections - 35 USC § 103 - Maintained
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) 5-6 and 13-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over ZEVALLOS or Lassig, in view of CHEN (US 20250040914) and LO (US20180149636).
The prior art as a whole demonstrates that it would have been obvious to a skilled artisan at the time of filing to substitute familiar techniques to collect post-operative fluids for the drains of ZEVALLOS or Lassig to achieve the same detection results with a reasonable expectation of success.
Neither ZEVALLOS nor Lassig explicitly teach the sample is collected from a colostomy, ileostomy, jejunostomy, duodostomy, gastrostomy, or urostomy bag; or sample is obtained from a bag or pouch system connected to a stoma created by an ostomy.
However, the prior art demonstrates that these techniques were standard operating procedures that would substitute as techniques for collecting post-operative fluids for the same purpose in ZEVALLOS and Lassig. For example, CHEN teaches
Pig whole blood (˜10 mL) was collected via percutaneous catheter within a peripheral vessel using BD Vacutainer K2 EDTA tubes (Becton Dickinson, Franklin Lakes, NJ, USA). Plasma aliquots were isolated and stored as described in Ex. 8. Circulating tumor DNA was extracted and quantified using ddPCR as described in Ex. 8
(para. 0232). Lo teaches collection of cfDNA from percutaneous nephrostomy (para. 0160) A skilled artisan would have been motivated to substitute these other well-known sources of post-operative fluids for the drains of ZEVALLOS and Lassig to achieve similar biomarker detection with a reasonable expectation of success.
Thus, the claims are obvious.
Claim(s) 10 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over ZEVALLOS or Lassig, in view of Ye Z, Wang C, Wan S, et al. Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA. Eur J Cancer 2019;106:133-43 and Bortolini Silveira A, Bidard FC, Tanguy ML, et al. Multimodal liquid biopsy for early monitoring and outcome prediction of chemotherapy in metastatic breast cancer. NPJ Breast Cancer 2021;7:115.
The prior art as a whole demonstrates that it would have been obvious to a skilled artisan at the time of filing to apply familiar techniques to detect residual disease to the residual disease analysis of ZEVALLOS or Lassig to achieve the same detection results with a reasonable expectation of success.
Neither ZEVALLOS nor Lassig explicitly teach the biomarker is a ratio of circulating tumor cells to cell-free DNA.
However, the prior art demonstrates that detection of CTC:ctDNA for the same purpose in ZEVALLOS and Lassig. For example, Ye teaches “CTC and ccfDNA levels had a joint effect on patient outcomes. Compared to patients with low levels of both CTC and ccfDNA, those with high levels of both markers exhibited a > 17-fold increased death risk (P < 0.001)” (Abstract). Figures 1-3 show that CTC:ctDNA ratios and their correlation to therapy outcomes and disease monitoring. Similarly, Silveira teaches “We prospectively evaluated the clinical validity of quantifying both CTCs (CellSearch) and ctDNA (targeted next-generation sequencing). Their combined value as prognostic and early monitoring markers was assessed in 198 HER2-negative metastatic breast cancer patients. . . . Both CTC and ctDNA levels at baseline and after four weeks of treatment were correlated with survival. For progression-free and overall survival, the best multivariate prognostic model included tumor subtype (triple negative vs other), grade (grade 3 vs other), ctDNA variant allele frequency (VAF) at baseline (per 10% increase), and CTC count at four weeks (≥5CTC/7.5 mL). Overall, this study demonstrates that CTCs and ctDNA have nonoverlapping detection profiles and complementary prognostic values in metastatic breast cancer patients. A comprehensive liquid-biopsy approach may involve simultaneous detection of ctDNA and CTCs” (Abstract). Figure 3 shows overall survival and progression-free survival according to the combination of CTC counts and ctDNA levels. A skilled artisan would have been motivated to apply these familiar CTC:ctDNA analyses to detect residual disease, monitor treatments and predict survival just like in ZEVALLOS and Lassig with a reasonable expectation of success.
Thus, the claims are obvious.
Response to Arguments
The rejections are maintained because both Lassig and ZEVALLOS teach stoma/openings. Lassig teaches “At the completion of the surgery, standard 10-mm fl at silicone surgical drains(Jackson Pratt; Cardinal Health) were placed as clinically indicated. All patients had at least 1 drain placedrunning medial to lateral and superior to inferior in the lateral neck” (Introduction; see also Abstract); and ZEVALLOS teaches samples from surgical drainages for drainage tube out of body, which require stoma/opening for tube (e.g. paras. 0008-09).
As to new claim 21, Lassig teaches nucleic acid biomarker (e.g. MMPs; Abstract); as does ZEVALLOS (e.g. paras. 0008-09).
Potential Double-Patenting
The following may form the basis of double patenting rejection in the future: US 12152280; 18/958592; 17/947881; 17/947861; 18/087185; 18/087165; 18/087148; US 12416626; 19/326348; 17/948760; 18/282933; 18/837265; 18/838078; 18/848363.
Prior Art
The following prior art teaches to evaluate biomarkers such as ctDNA in effluent such as blood, urine pleural fluid, peritoneal fluid, and cerebrospinal fluid: WO 2020112566; WO 2020127629; US 20210355222; US 20070248546; WO 2021202351; WO 2021222220; WO 2022204358; Pajek et al, Cell-free DNA in the Peritoneal Effluent of Peritoneal Dialysis Solutions, Therapeutic Apheresis and Dialysis, 14: 20-26. https://doi.org/10.1111/j.1744-9987.2009.00717.x, 12 February 2010; Mokanszki et al., Cell-free DNA From Pleural Effusion Samples: Is It Right for Molecular Testing in Lung Adenocarcinoma?, Pathol Oncol Res. 2021 Mar 30;27:613071. doi: 10.3389/pore.2021.613071; Peng et al, Non-blood circulating tumor DNA detection in cancer, Oncotarget. 2017 Aug 4;8(40):69162–69173. doi: 10.18632/oncotarget.19942.
Conclusion
No claims are allowed.
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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/AARON A PRIEST/Primary Examiner, Art Unit 1681
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