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 This is a National Stage Entry under 35 U.S.C. 371 of International Patent Application No. PCT/ US2021/058994 , filed November 1 1 , 2021. This application also claims priority to US Provisional Application No. 63112547 , filed on November 1 1 , 2020. Election/Restrictions Applicant's election without traverse of Claims 1-2,4-5,7,10 and 20-21 in the reply filed on 01/30/2026 is acknowledged. The elected species are as follows: Zonulin Zonulin receptor antagonist Claims 3,6,8-9,11,13-14,18 and 25-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/30/2026. Claims 1-2,4-5,7,10 and 20-21 are under consideration. Claim Rejections - 35 USC § 112 The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claim 1 - 2, 7 , and 20-21 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for the detection of zonulin , LPS binding protein, B-Glucan, soluble CD14, MPO , galectin-3, galectin-9, C3, GDF-15, and /or succinic acid and correlating the level of these biomarkers with a control level to detect an increased risk of moderate or severe COVID-19 , does not reasonably provide enablement for detecting the level of any biomarker ( s ) and correlating the level of the biomarker ( s ) with a control level to detect an increased risk of moderate or severe COVID-19 . Regarding claims 2 and 7, while several of the biomarkers are enabled, other biomarkers are not enabled. For example, REG3a in claim 2 is not enabled by the specification. Similarly, claim 7 includes IL-1, IL-10 , MCP-2, fractalkine, Mip-1a and IL-21 among other biomarkers that are not enabled by the specification. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to: • (A) The breadth of the claims; • (B) The nature of the invention; • (C) The state of the prior art; • (D) The level of one of ordinary skill; • (E) The level of predictability in the art; • (F) The amount of direction provided by the inventor; • (G) The existence of working examples; and • (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Here, the instant claims are broadly drawn to a method for detecting an increased risk of moderate or severe COVID-19 illness within a subject , comparing the level of the subject’s biomarker to a control level, diagnosing the subject with an increased risk of moderate or severe COVID-19 related, and treating the subject for moderate or severe illness when increased risk is detected. The level of skill in the art is high and would include, e.g ., Ph.D. level scientists . Moreno-Perez et al. ( Int Journal of Inf Diseases , September 2020 , hereinafter, “Moreno-Perez” ) teaches biomarkers that are predictive of disease severity during SARS-CoV-2 infection. Moreno-Perez teaches the identification of blood composition in SARS-CoV-2 patients and identifying biomarkers that are or are not correlated with disease severity during SARS-CoV-2 infection (Abstract). Furthermore, Moreno-Perez teaches that potassium levels are predictive of disease severity while lactate dehydrogenase is not predictive of moderate or severe COVID 19 ( Table 1 ). Shen et al. (Cell, July 2020 , hereinafter, “Shen” ) teaches a proteomic and metabolic screen of COVID-19 patient sera, identifying differentially expressed factors that correlate with disease severity (Section: In Brief). Shen teaches by analyzing the serum samples of patients infected with SARS-CoV-2, they are able to identify multiple biomarkers that are and are not predictive of disease severity (Section: Classification of Severe COVID-19 Patients ) . Importantly, Shen teaches that sever biomarkers such as Alanine aminotransferase, glutatransferase , bilirubin, and creatinine are not predictive of moderate or severe COVID-19 (Figure S1) . As such, the art offers no predictability for the use of any biomarker to detect the severity of COVID-19 in any subject. The Specification only exemplifies and reduces to detecting the level of zonulin , LPS binding protein, B-Glucan, soluble CD14, MPO , galectin-3, galectin-9, C3, GDF-15, and succinic acid and correlating the level of these biomarkers with a control level to detect an increased risk of moderate or severe COVID-19 . However, the Specification offers no reasonable direction or working example for the detection of any biomarker , e.g., testosterone, FoxP2, or SLox 1, in virtually any subject suspected of having an illness associated with any coronavirus infection . In view of the foregoing, a vast quantity of experimentation, including expansive clinical trials, would be needed to use the invention based on the content of the disclosure. Taken together, the Specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. Claim Rejections - 35 USC § 101 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims FILLIN "Pluralize the word 'Claim' if necessary and then identify the claim(s) being rejected." 1 – 2, 4 – 5, 7, 10, and 20 -21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to FILLIN "Identify whether the claim(s) are directed to a law of nature; a natural phenomenon; or an abstract idea." \* MERGEFORMAT judicial exception without significantly more. This judicial exception is not integrated into a practical application and the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because FILLIN "Identify the additional elements and explain why--when considered separately and in combination--they do not add significantly more to the exception. See examiner note 6." \* MERGEFORMAT for the reasons set forth below. See MPEP § 2106 for analysis parameters. The instant claims are drawn to a method of diagnosing an increased risk of moderate or severe COVID-19 in a subject and in some embodiments treating subjects diagnosed with an increased risk of moderate or severe COVID-19 with a treatment , which is a statutory category of invention (Step 1: YES). The instant claims are directed to the natural correlation between specific biomarker levels and increased risk of moderate or severe COVID-19 illness in a subject . The claims are further directed to a diagnosing step, which reasonably encompasses the mental step of appreciating the natural correlation and deciding whether to treat or not based on that appreciation. If the outcome is the decision not to treat, then the claimed method is limited to only gathering data, mentally analyzing data, and making a decision based on that analysis. As such the instant claims recite judicial exceptions (JE) in the form of a law of nature and abstract idea (STEP 2A, Prong One: YES). While in some embodiments, a zonlulin receptor antagonist treatment is administered to a subject who is identified as a positive amount of zonulin , in other embodiment the subject is identified as negative for zonulin and no treatment is given. In such embodiments, the claimed method is limited to appreciation of the natural correlation to make a decision, i.e ., do not administer a zonulin receptor antagonist to a subject, based on gathered biomarker data. As such, these embodiments do not integrate the JE into a practical application (STEP 2A, Prong Two: NO). Furthermore, in some embodiments a n ill-defined treatment is applied to a subject who is identified as a positive amount of zonulin , in other embodiments “blocking the zonulin pathway” is given as a treatment. In such embodiments, the claims account to little more than a gen er ic instruction to treat. As such, these embodiments do not integrate the JE into a practical application (STEP 2A, Prong Two: NO). As discussed in detail below, it was well-understood, routine, and conventional ( WURC ) at the time of filing to identify an altered protein profile in a subject’s biological sample and correlate the expression profiles to diagnose increased risk of moderate to severe COVID-19 in a subject . In the instan t claims where no treatment is given after identifying a subject’s negative biomarker status, or are limited to a generic instruction to treat, the claims are limited to only recite WURC data-gathering steps, which does not reasonably provide an inventive concept. As such the instant claims do not recite significantly more than JE (STEP2B: NO ). . As such the instant claims do not recite significantly more than JE (STEP2B: NO). In view of the foregoing, the instant claims do not constitute patent eligible subject matter under 35 U.S.C 101. 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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claim(s) 1 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Bottazzi et al (US20230251274A1, hereinafter, “Bottazzi”). Bottazzi teaches a method of diagnosing SARS-CoV-2 infection in subjects using the protein PTX3, a key component of humoral innate immunity, to evaluate the prognosis of COVID-19 (Claim 1, ¶0004). Regarding claim 1, teaches detecting an increased risk of moderate or severe COVID-19 by detecting the level of a biomarker within a subject, in this case PTX3 (Claim 1), comparing the level of PTX3 to a control level (Claim 1) , diagnosing the subject with an increased risk of moderate or severe illness when an increase in the level of PTX3 is detected (Claim 6), and then treating the subject for moderate or severe illness when the increased risk is detected ( Claim 1: “monitoring of the efficacy of a therapeutic treatment”, ¶0084 ). Accordingly, the claimed invention was anticipated by Bottazzi. Claim Rejections - 35 USC § 103 The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. Claim s 2, 5, and 20 – 21 are rejected under 35 U.S.C. 103 as being unpatentable over Bottazzi as applied to claim 1 above, and further in view o f Paterson et al (US10723763B2, hereinafter, “Paterson”) Shirey et al (Mucosal Immunol, 2016, hereinafter, “Shirey”) , and Gibson et al (Med J Aust, June 2020, hereinafter, “Gibson”) . As discussed above, claim 1 was anticipated by Bottazi . The reference fails to teach zonulin as a biomarker used to detect severity risk or the use of larazotide to treat a subject with COVID-19 . However, r egarding claim 2 , 5, 20, and 21 , Paterson teaches the use of larazotide to treat a cute r espiratory d istress s yndrome ( ARDS ) caused by viral infection (Claim 1, Background ¶2). Paterson teaches compositions and methods to treat acute lung injury and acute respiratory distress syndrome by administering larazotide (Abstract, Claim 1, Claim 9). Paterson teaches larazotide, a peptide with the sequence GGVLVQPG , can be used for lung disease caused by viruses (Background ¶2). As taught by Gibson, ARDS is a disease caused by SARS-CoV-2 (“COVID‐19 ARDS is a predictable serious complication of COVID‐19 that requires early recognition and comprehensive management”). Furthermore, Shirey teaches the use of larazotide acetate to treat lung disease caused by influenza and that larazotide is a zonulin receptor antagonist peptide antagonist, (Section: A PAR2 antagonist blocks influenza-induced lethality and lung leak). Shirey teaches different strategies to target innate immune responses to influenza (Title, Abstract). One of the methods Shirey discusses is the targeting of zonulin which increases permeability of the intestines (Section: A PAR2 antagonist blocks influenza-induced lethality and lung leak). Shirey teaches the targeting of zonulin using AT-1001, which is also known as larazotide acetate (Section: A PAR2 antagonist blocks influenza-induced lethality and lung leak). The use of AT-1001 during a lethal influenza challenge in mice resulted in protection and lowered clinical scores compared to other treatment with a notable reduction in pulmonary edema associated with lipopolysaccharide, also known as LPS (Section: A PAR2 antagonist blocks influenza-induced lethality and lung leak). Bottazzi, Paterson , Shirey , and Gibson are considered to be analogous to the claim invention because they both aim to treat or lessen viral infections. Bottazi teaches a method of using biomarkers to detect the severity of COVID-19 (Claim 1). Paterson teaches the use of larazotide to treat ARDS (Abstract, Claim 1, Claim 9) . Gibson teaches that “ARDS is a predictable serious complication of COVID‐19 that requires early recognition and comprehensive management.” Shirey teaches the use of larazotide to treat viral caused lung disease (Section: A PAR2 antagonist blocks influenza-induced lethality and lung leak) . Together the prior art teaches that ARDS is a predictable complication of COVID-19 and that larazotide, a zonulin receptor antagonist, is an effective treatment for ARDS. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to use larazotide to treat COVID-19 within a patient because doing so would advantageously allow one to target and treat ARDS caused by SARS-CoV-2. Furthermore, it would have been prima facie obvious before the effective filing date of the claimed invention to use zonulin as a biomarker in addition to PXT3 for detecting an increased risk of moderate or severe COVID-19 illness because by tracking zonulin and PXT3 because one of ordinary skill in the art would have the benefit of tracking lung disease progress using zonulin as a readout of larazotide treatment while also tracking the increased risk of moderate or severe COVID-19 through PXT3 . One of ordinary skill in the art would have had a reasonable expectation of success in using zonulin and PXT3 as biomarker s and larazotide as a treatment for SARS-CoV-2 infections given that targeting of zonulin with larazotide treatment for ARDS is well known, has been successfully demonstrated, and is commonly used in the prior art. Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary. Claims 4 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Bottazzi , Paterson, Shirey, and Gibson as applied to claim s 2, 5, and 20 – 21 above, and further in view of Lopez-Collazo et al ( Int J Biol Sci , July 2020, hereinafter, “ Lopez-Collazo ”) and Saljoughian ( US Pharm , 2008 , hereinafter, “ Saljoughian ”). As discussed above, c laims 2, 5, 20 , and 21 were rendered prima facie obvious by Bottazi , Paterson, Shirey, and Gibson (see also rejection of claim 1 as anticipated by Bottazzi ) . The reference s fail to teach a secondary biomarker of inflammation such as CRP . However, regarding claims 4 and 7, Lopez-Collazo teaches clinical characteristics of COVID-19, highlighting the increased cytokine levels after SARS-CoV-2 infection (Abstract). Lopez-Collazo teaches that proinflammatory cytokines induce the production of CRP and haptoglobin by hepatocytes and that high CRP and haptoglobin levels in patients with COVID-19 are associated with a severe condition (Section: Coagulation abnormalities: another effect of dysregulation of the innate immune response with a mirror image in sepsis). It is important to note, as taught by Shirey and discussed above, that zonulin is the precursor to haptoglobin-2 and therefore correlates with haptoglobin-2 levels (Shirey: Section: A PAR2 antagonist blocks influenza-induced lethality and lung leak). Lopez-Collazo further teaches that D-dimer serves as a biomarker of pulmonary embolism and that higher D-dimer levels are associated with increased rates of COVID-19 mortality (Section: Coagulation abnormalities: another effect of dysregulation of the innate immune response with a mirror image in sepsis). Saljoughian teaches the role of CRP and explicitly states “CRP is used mainly as a marker of inflammation.” Bottazzi , Paterson, Shirey, Gibson, Lopez-Collazo , and Saljoughian are considered to be analogous to the claim invention because they aim to treat or lessen respiratory viral infections . Bottazi teaches a method of using biomarkers , such as PXT3, to detect the severity of COVID-19 (Claim 1). Paterson teaches the use of larazotide to treat ARDS (Abstract, Claim 1, Claim 9). Shirey teaches the use of larazotide to treat influenza (Section: A PAR2 antagonist blocks influenza-induced lethality and lung leak). Gibson teaches that “ARDS is a predictable serious complication of COVID‐19 that requires early recognition and comprehensive management.” Lopez-Collazo teaches that both CRP and haptoglobin, a mature form of zonulin , are elevated in cases of severe COVID-19 Section: Coagulation abnormalities: another effect of dysregulation of the innate immune response with a mirror image in sepsis). Saljoughian teaches that CRP is used “as a marker of inflammation.” Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize CRP in addition to zonulin and PXT3 as a biomarker to detect the severity of COVID-19 because the use of additional markers would reduce false positives and lead to better subject outcomes . One of ordinary skill in the art would have had a reasonable expectation of success in using CRP along with zonulin and PXT3 as a biomarker given that CRP as a biomarker for COVID-19 is well known, has been successfully demonstrated, and commonly used in the prior art. Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary. Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Bottazzi, Paterson, Shirey, and Gibson as applied to claim s 2, 5, and 20 – 21 above, and further in view of Martin et al ( American Journal of Respiratory and Critical Care Medicine , 1997 , hereinafter, “ Martin”). As discussed above, c laims 2, 5, 20, and 21 were rendered prima facie obvious by Bottazi , Paterson, Shirey, and Gibson (see also rejection of claim 1 as anticipated by Bottazzi ) . The reference s fail to teach a combination of zonulin , LBP, and sCD14 as biomarkers . However, regarding claim 10 , Martin teaches clinical characteristics of ARDS , highlighting role of LBP and sCD14 in disease severity (Abstract). In a study exploring the inflammatory response of patients diagnosed with ARDS, Martin teaches that LBP and sCD14 is highly correlated with major markers of lung inflammation (Abstract). Martin further teaches that LBP and sCD14 amplifies the effects of LPS. Bottazzi, Paterson, Shirey, Gibson, and Martin are considered to be analogous to the claim invention because they aim to treat or lessen respiratory viral infections. Bottazi teaches a method of using biomarkers , such as PXT3, to detect the severity of COVID-19 (Claim 1). Paterson teaches the use of larazotide to treat ARDS (Abstract, Claim 1, Claim 9). Shirey teaches the use of larazotide to treat influenza (Section: A PAR2 antagonist blocks influenza-induced lethality and lung leak). Gibson teaches that “ARDS is a predictable serious complication of COVID‐19 that requires early recognition and comprehensive management.” Martin teaches that both LBP and sCD14 , are elevated in cases of severe of ARDS (Abstract). Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize LBP and sCD14 in addition to zonulin and PXT3 as biomarker s to detect the severity of ARDS and COVID-19 because the use of additional markers would reduce false positives and lead to better subject outcomes. One of ordinary skill in the art would have had a reasonable expectation of success in using LBP and sCD14 along with zonulin and PXT3 as biomarker s given that LBP and sCD14 as biomarker s for ARDS, a prominent symptom of COVID-19, is well known, has been successfully demonstrated, and commonly used in the prior art. Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary. Conclusion NO CLAIMS ARE ALLOWED Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT Danyal H Alam whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-1102 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT M - F 9am - 5pm . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Thomas J. Visone can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 571-270-0684 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center ( EBC ) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /DANYAL HASSAN ALAM/ Examiner, Art Unit 1672 /THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672