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 .
Response to Amendment
The Amendment filed 07/06/2026 in which claims 1 and 21 were amended has been entered. Claim 20 has been cancelled.
Claims 1-2, 4-5, 7, 10, and 21 are under examination on the merits.
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.
(Previous rejection, withdrawn) Claim 1 - 2, 7, and 20-21 was rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling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.
Applicant has amended the claims. Applicant has also cancelled claim 20.
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.
(Previous rejection, withdrawn) Claims 1 – 2, 4 – 5, 7, 10, and 20-21 were rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly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
Applicant has amended the claims. Applicant has also cancelled claim 20.
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.
(Previous rejection, withdrawn) Claim(s) 1 was rejected under 35 U.S.C. 102(a)(2) as being anticipated by Bottazzi et al (US20230251274A1, hereinafter, “Bottazzi”).
Applicant has amended the claim.
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.
(Previous rejection, maintained and modified as necessitated by amendments) Claims 1, 2, 5, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Bottazzi et al (US20230251274A1, hereinafter, “Bottazzi”), and further in view of Lopez-Collazo et al (Int J Biol Sci, July 2020, hereinafter, “Lopez-Collazo”), Shirey et al (Mucosal Immunol, 2016, hereinafter, “Shirey”).
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, Bottazzi 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).
Bottazi 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, 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).
Furthermore, Shirey teaches 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). 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). 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).
Claims 2 and 5 are drawn to zonulin as a biomarker. Claim 21 is drawn to a treatment of larazotide acetate. As discussed above, Bottazzi, Lopez-Collazo, and Shirey teach zonulin as a biomarker and larazotide acetate as a treatment.
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, including established a baseline of severity, 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 biomarkers and larazotide as a treatment for SARS-CoV-2 infections given that targeting zonulin with larazotide treatment for ARDS is well known, has been successfully demonstrated, and is commonly used in the prior art.
(Previous rejection, maintained and modified as necessitated by amendments) Claims 4 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Bottazzi, Lopez-Collazo, and Shirey, as applied to claims 1, 2, 5, and 21 above, and further in view of Saljoughian (US Pharm, 2008, hereinafter, “Saljoughian”).
As discussed above, claims 1, 2, 5, and 21 were rendered prima facie obvious by Bottazzi, Lopez-Collazo, and Shirey. The references fail to teach a secondary biomarker of inflammation such as CRP.
However, regarding claims 4 and 7, as discussed above, Lopez-Collazo teaches clinical characteristics of COVID-19, highlighting the increased cytokine levels after SARS-CoV-2 infection (Abstract). 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, Lopez-Collazo, Shirey, 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). Shirey teaches the use of larazotide to treat influenza (Section: A PAR2 antagonist blocks influenza-induced lethality and lung leak). 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.
(Previous rejection, maintained and modified as necessitated by amendments) Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Bottazzi, Lopez-Collazo, and Shirey as applied to claims 1, 2, 5, and 21 above, and further in view of Martin et al (American Journal of Respiratory and Critical Care Medicine, 1997, hereinafter, “Martin”).
As discussed above, claims 1, 2, 5, and 21 were rendered prima facie obvious Bottazzi, Lopez-Collazo, and Shirey. The references 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 are highly correlated with major markers of lung inflammation (Abstract). Martin further teaches that LBP and sCD14 amplify the effects of LPS.
Bottazzi, Lopez-Collazo, Shirey, and Martin are considered to be analogous to the claim invention because they aim to treat or lessen respiratory viral infections. 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 biomarkers 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 biomarkers given that LBP and sCD14 as biomarkers 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.
Response to Arguments
1) Applicant states amendments made to claim 1 overcomes the U.S.C. § 112 – Scope of Enablement
Applicant has amended claim 1. Examiner has withdrawn the rejection.
2) Applicant states amendments made to claim 1 overcomes the U.S.C. § 101
Applicant has amended claim 1. Examiner has withdrawn the rejection.
3) Applicant states amendments made to claim 1 overcomes the U.S.C. § 102
Applicant has amended claim 1. Examiner has withdrawn the rejection.
4) Applicant states that the amendments made to claim 1 and cancellation of claim 20 overcome the U.S.C. § 103 rejection
Applicant’s arguments are not persuasive.
Applicant states that although larazotide “targets a specific pathway, it would not motivate a skilled artisan to utilize a component of that pathway as a diagnostic biomarker.”
As discussed previously and above, the cited art establishes that one of ordinary skill in the art would have had a reasonable expectation of success in using zonulin as a biomarker 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.
Bottazi teaches a method of using biomarkers to detect the severity of COVID-19. Shirley teaches the use of larazotide to treat virus induced damages to the lung. Lopez-Collazo teaches that both CRP and haptoglobin, a mature form of zonulin, are elevated in cases of severe COVID-19. The prior art establishes a nexus between zonulin, ARDS, COVID-19, and subsequently larazotide treatment. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have identified an increased risk of severity of a COVID-19 illness by measuring levels of zonulin in a patient because it is well known that high levels of haptoglobin, a mature form of zonulin, are associated with severe COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). One such COVID-19 associated illness is acute respiratory distress syndrome (ARDS) has been treated with larazotide, a direct zonulin receptor antagonist. One of ordinary skill in the art would have been motivated to measure zonulin levels before administering larazotide as this would have established a baseline for providers to measure drug response.
Applicant states utilizing zonulin as a "readout of larazotide treatment", as suggested by the Examiner, is fundamentally different from using zonulin as an independent diagnostic for identifying COVID-19 severity and that the use of zonlulin as a diagnostic step requires the patient to already be undergoing larazotide treatment for ARDS to justify tracking zonulin.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
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Soley to rebut the applicant’s argument, Zhang et al (Adv Biomark Sci Technol, August 2020, 10.1016/j.abst.2020.08.001) evidences “[b]iomarkers can be applied to describe observable characteristics of a certain disease and to determine optimal treatments based on these phenotypes, as well as genotypes.” Moreover, as discussed above, Lopez-Collazo teaches that both CRP and haptoglobin, a mature form of zonulin, are elevated in cases of severe COVID-19. Lopez-Collazo also teaches a simplified time course of what immune response would look like in patients infected with SARS-CoV-2 (Figure 1, reproduced below).
Importantly, Lopez-Collazo teaches tracking severity biomarkers across time points to identify severe cases, which as discussed previously and above, include haptoglobin (Figure 1, Section: Coagulation abnormalities: another effect of dysregulation of the innate immune response with a mirror image in sepsis, ¶2). Shirey teaches 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). Shirey also 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). Therefore, it would have been routine for medical care providers to establish a patient’s zonulin levels to determine the best course of action based on a patients phenotype as well as continue monitoring of zonulin to determine the severity of the SARS-CoV-2 infection.
Applicant states that there is nothing in the cited art that suggests that an ARDS
treatment would be effective for identifying severe COVID-19, that ARDS is a severe lung injury that can be caused in various ways, and that the cited art does not suggest that zonulin would be a specific or effective biomarker for predicting COVID-19 severity.
As discussed previously and above, Lopez-Collazo teaches that both CRP and haptoglobin, a mature form of zonulin, are elevated in cases of severe COVID-19. Paterson teaches the use of larazotide, a zonulin receptor agonist, to treat acute respiratory distress syndrome (ARDS) caused by viral infection. The prior art has established that zonulin is involved in COVID-19 and that disrupting zonulin activity is an effective treatment for ARDS caused by viral infections. Furthermore, the art has also established that haptoglobin, a mature form of zonulin, are elevated in cases of severe COVID-19. One of ordinary skill in the art would have reasonable expectations of success in using zonulin as a biomarker for an increased risk of severe COVID-19 given that zonulin’s role in ARDS was well established and haptoglobin was known to be a marker for severe COVID-19.
Conclusion
NO CLAIMS ARE ALLOWED
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Danyal H Alam whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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/DANYAL HASSAN ALAM/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
