DETAILED ACTION
All rejections and objections not mentioned below are withdrawn.
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
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. EP21305619.5, filed on 5/12/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/07/2023 and 04/10/2026 are being considered by the examiner.
Claim Rejections - 35 USC § 102- Modified due to Amendments
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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(s) 1, 13 and 18 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by D'ANGELO (D'ANGELO ET AL: "Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 62, no. 11, 2018-11-01, IDS).
The reference D'ANGELO teaches “Here, we describe the identification of new inhibitors of the pqs QS system of the human pathogen Pseudomonas aeruginosa by screening a library of 1,600 U.S. Food and Drug Administration-approved drugs. Phenotypic characterization of ad hoc engineered strains and in silico molecular docking demonstrated that the antifungal drugs clotrimazole and miconazole, as well as an antibacterial compound active against Gram-positive pathogens, clofoctol, inhibit the pqs system, probably by targeting the transcriptional regulator PqsR. The most active inhibitor, clofoctol, specifically inhibited the expression of pqs-controlled virulence traits in P. aeruginosa, such as pyocyanin production, swarming motility, biofilm formation, and expression of genes involved in siderophore production. Moreover, clofoctol protected Galleria mellonella larvae from P. aeruginosa infection and inhibited the pqs QS system in P. aeruginosa isolates from cystic fibrosis patients. Notably, clofoctol is already approved for clinical treatment of pulmonary infections caused by Gram-positive bacterial pathogens; hence, this drug has considerable clinical potential as an antivirulence agent for the treatment of P. aeruginosa lung infections”(abstract). This anticipates claims 1, 13 and 18.
The instant specification defines inflammation as: “As used herein, the term "inflammation" is used to describe the fundamental pathological process consisting of a dynamic complex of cytologic and histologic reactions that occur in tissues in response to an injury or abnormal stimulation caused by a physical, chemical or biologic agent (e.g. bacterium, virus...) including the local reactions and resulting morphologic changes, the destruction or removal of the injurious material, and the responses that lead to repair and healing”(page 2) and “The method of the present invention is thus particularly suitable for the treatment of 5 inflammatory diseases. As used herein, "inflammatory disease" means a clinical disorder in which inflammation is a prominent contributor to the clinical condition. Typically, the inflammatory disease is selected from the group consisting of asthma, chronic obstructive lung disease, pulmonary fibrosis, pneumonitis (including hypersensitivity pneumonitis and radiation pneumonitis), pneumonia, cystic fibrosis... bacterial-induced inflammation, and viral induced inflammation”(page 3). Clofoctol is commonly known as an antibiotic (D'ANGELO) and has been used in the treatment of infectious respiratory diseases(D'ANGELO). Respiratory diseases are inflammatory diseases (instant specification). Additionally, as defined by the instant specification (pages 2-3), inflammation can be defined as a fundamental pathological processes that occur in tissues in response biologic agent (e.g. bacterium, virus...). Thus treating a bacterial infection or virus would reduce these processes and thus reduce inflammation as defined herein. Thus, any prior art relating to the antimicrobial activities of clofoctol regarding microbiota causing diseases in the respiratory tract renders the subject-matter of at least present claims 1, 13 and 18 are anticipated.
Claim(s) 1, 9-10 and 13-14 and 20-21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by BAILLY (BAILLY ET AL: "A new horizon for the old antibacterial drug clofoctol", DRUG DISCOVERY TODAY, vol. 26, no. 5, p. 1302-1310, 2021-02-10, IDS).
The reference BAILLY teaches “The synthetic antibacterial drug clofoctol (CFT) has long been used to treat respiratory tract infections in Europe. In recent years, the drug was found to target two biologically important proteins, the Cdc7/Dbf4 protein kinase complex and the mRNA-binding protein cold shock domain containing E1 (CSDE1), also known as upstream-of-N-Ras protein (UNR). These interactions are at the origin of the antitumor activity of CFT, recently evidenced in prostate cancer and neuroglioma. Drug–protein binding models provide a structural basis to guide the design of more potent anticancer compounds. A renewed interest in CFT can be anticipated for the treatment of cancers, and possibly Coronavirus 2019 (COVID-19)”(abstract) and “CFT (Fig. 1) is an old antibacterial drug, active essentially on Gram-positive bacteria, such as Streptococcus pyogenes and Streptococcus pneumoniae, common pathogens of upper and lower respiratory tract infections. CFT was developed during the late 1970s and marketed in France (trade name Octofene1) until January 2005 and in Italy (Gramplus1), where it is still prescribed. CFT inhibits cell wall synthesis in bacteria and induces membrane permeabilization, which is at the origin of the bactericidal activity [1–3]. The drug is active against clinical isolates of penicillin-susceptible and penicillin-resistant S. pneumoniae, and against methicillin-susceptible and methicillin-resistant Staphylococcus aureus [4]. It was a useful antibacterial drug to treat ear, nose, and throat infections, providing an alternative to antibiotic therapy for the treatment of bronchopulmonary diseases [5,6]. The drug does not induce antibacterial drug resistance, thus permitting complete eradication of the pathogen [7]. CFT can be administered by the oral or rectal route, the latter producing a more rapid absorption and elimination compared with oral treatment. By both routes, the drug circulates well in the body and can easily accumulate in tissues, reaching concentrations higher than in the plasma [8]. Interestingly, the drug accumulates in the lung. Ninety minutes after injection of a rectal suppository containing 1.5 g CFT, the lung tissue: plasma ratio was 6.2, illustrating the rapid and time-dependent delivery of the drug into the lung and its storage in this compartment. This property might explain its efficacy against bacterial respiratory infections [9,10] and could be useful to combat other lung diseases (see later)”(page 1302). This anticipates claims 1, 9-10 and 13-14.
The instant specification defines inflammation as: “As used herein, the term "inflammation" is used to describe the fundamental pathological process consisting of a dynamic complex of cytologic and histologic reactions that occur in tissues in response to an injury or abnormal stimulation caused by a physical, chemical or biologic agent (e.g. bacterium, virus...) including the local reactions and resulting morphologic changes, the destruction or removal of the injurious material, and the responses that lead to repair and healing”(page 2) and “The method of the present invention is thus particularly suitable for the treatment of 5 inflammatory diseases. As used herein, "inflammatory disease" means a clinical disorder in which inflammation is a prominent contributor to the clinical condition. Typically, the inflammatory disease is selected from the group consisting of asthma, chronic obstructive lung disease, pulmonary fibrosis, pneumonitis (including hypersensitivity pneumonitis and radiation pneumonitis), pneumonia, cystic fibrosis... bacterial-induced inflammation, and viral induced inflammation”(page 3). Clofoctol is commonly known as an antibiotic (BAILLY) and has been used in the treatment of infectious respiratory diseases(BAILLY). Respiratory diseases are inflammatory diseases (instant specification). Additionally, as defined by the instant specification (pages 2-3), inflammation can be defined as a fundamental pathological processes that occur in tissues in response biologic agent (e.g. bacterium, virus...). Thus treating a bacterial infection or virus would reduce these processes and thus reduce inflammation as defined herein. Thus, any prior art relating to the antimicrobial activities of clofoctol regarding microbiota causing diseases in the respiratory tract renders the subject-matter of at least present claims 1, 9-10 and 13-14 are anticipated.
The reference BAILLY teaches “As a regulator of UPR, different applications beyond cancer can be envisioned for CFT. Recently, the hypothesis was formulated that a mild UPR induction is associated with protective effects in the vascular endothelium against inflammation [64]. In particular, UPR is triggered in the airway of patients with different respiratory diseases, including obstructive lung diseases (such as asthma), lung cancer and some pulmonary viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [65–68]. Therefore, the use of small molecules targeting the UPR, or distinct components of this complex machinery, is envisioned for the treatment of various human diseases [69]. In particular, the pharmacological modulation of the UPR is viewed as a new strategy to control respiratory virus replication, notably rhinovirus infections [70]” (page 1308). This anticipated claims 1, 9-10 and 13-14 and 20-21.
Claim Rejections - 35 USC § 103- Modified due to Amendments
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1 and 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over D'ANGELO (D'ANGELO ET AL: "Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 62, no. 11, 2018-11-01, IDS) in view of Sriskandan (Sriskandan et al., GRAM-POSITIVE SEPSIS: Mechanisms and Differences from Gram-Negative Sepsis, Infectious Disease Clinics of North America Volume 13, Issue 2, 1 June 1999, Pages 397-412, previously provided).
The D'ANGELO has been discussed supra and does not disclose sepsis (claims 11).
The reference Sriskandan teaches “In modern intensive care settings, gram-positive bacteria account for up to 50% of severe sepsis or septic shock cases, yet the pathogenesis of gram-positive shock is poorly understood”(abstract). This helps to teach claim 11.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified D'ANGELO with Sriskandan because D'ANGELO teaches an antibacterial compound active against Gram-positive pathogens, clofoctol, and Sriskandan teaches Gram-positive pathogens may trigger sepsis. One would be motivated to combine the references to treat sepsis and one would have a reasonable expectation of success because clofoctol is a well-known antibacterial.
Claim(s) 1 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over D'ANGELO (D'ANGELO ET AL: "Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 62, no. 11, 2018-11-01, IDS) in view of Martin (Martin et al., Gram-Negative Sepsis and the Adult Respiratory Distress Syndrome, Clinical Infectious Diseases 1992;14:1213-28, previously provided).
The D'ANGELO has been discussed supra and does not disclose respiratory distress syndrome (claims 15).
The reference Martin teaches “Gram-negative sepsis has dramatically increased in frequency throughout the twentieth century in the United States. Currently, —200,000 patients develop gram-negative sepsis each year in this country. Of these, about one-quarter develop the adult respiratory distress syndrome (ARDS). Among these critically ill patients, mortality is estimated at 60%-90%. In the complex series of events leading to acute lung injury in gram-negative sepsis, endotoxin is the proximal mediator. Although endotoxin may be capable of causing direct injury to the pulmonary endothelium, its primary role is as a trigger activating inflammatory agents, including complement, neutrophils, and platelets, and inducing the production of cytokines and arachidonic acid metabolites. The end results are impairment of the endothelial barrier, diffusely increased capillary permeability, and adherence of neutrophils to the endothelium with subsequent migration into the tissues. The consequent clinical syndrome is one of acute respiratory distress with pulmonary edema, poorly compliant lungs, and refractory hypoxemia”(abstract) and “Although our review focuses on acute lung injury occurring during the course of gram-negative sepsis, ARDS can also develop as a consequence of sepsis caused by gram-positive bacteria or even fungi”(page 1214).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified D'ANGELO with Martin because D'ANGELO teaches an antibacterial compound active against Gram-positive pathogens, clofoctol, and Martin teaches Gram-positive pathogens may trigger ARDS. One would be motivated to combine the references to treat ARDS and one would have a reasonable expectation of success because clofoctol is a well-known antibacterial.
Claim(s) 1, and 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over BAILLY (BAILLY ET AL: "A new horizon for the old antibacterial drug clofoctol", DRUG DISCOVERY TODAY, vol. 26, no. 5, p. 1302-1310, 2021-02-10, IDS) in view of Grimaud (Grimaud et al., Acute myocarditis and multisystem inflammatory emerging disease following SARS‑CoV‑2 infection in critically ill children, Ann. Intensive Care (2020) 10:69, previously provided).
The BAILLY has been discussed supra and does not disclose multisystem inflammatory syndrome(claim 16) or multisystem inflammatory syndrome (MIS-C) with severe myocarditis (claim 17).
The reference Grimaud teaches “Acute myocarditis and multisystem inflammatory emerging disease following SARS‑CoV‑2 infection in critically ill children” (title). This helps to teach claims 16-17.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified BAILLY with Grimaud because BAILLY teaches clofoctol for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) , and Grimaud teaches acute myocarditis and multisystem inflammatory maybe caused by SARS‑CoV‑2 infection. One would be motivated to combine the references to treat acute myocarditis and multisystem inflammatory caused by SARS‑CoV‑2 infection and one would have a reasonable expectation of success because clofoctol is proposed to treat SARS‑CoV‑2 infection.
Response to Arguments
Applicant's arguments filed 04/10/2026 have been fully considered but they are not persuasive.
102/103 Rejections
The applicant argues:
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This argument is not considered persuasive because the reference D’Angelo teaches “Moreover, clofoctol protected Galleria mellonella larvae from P. aeruginosa infection and inhibited the pqs QS system in P. aeruginosa isolates from cystic fibrosis patients. Notably, clofoctol is already approved for clinical treatment of pulmonary infections caused by Gram-positive bacterial pathogens; hence, this drug has considerable clinical potential as an antivirulence agent for the treatment of P. aeruginosa lung infections”(abstract). This clearly anticipate clofoctol for treatment of P. aeruginosa lung infections from patients. The applicant argues that the reference is silent on viral infections but the claim states viral or bacterial infections so the viral part is optional. The applicant also argues lack of mentioning any effect on lung inflammation this is not persuasive because the applicants have defined inflammation in the specification as “As used herein, the term "inflammation" is used to describe the fundamental pathological process consisting of a dynamic complex of cytologic and histologic reactions that occur in tissues in response to an injury or abnormal stimulation caused by a physical, chemical or biologic agent (e.g. bacterium, virus...) including the local reactions and resulting morphologic changes, the destruction or removal of the injurious material, and the responses that lead to repair and healing”(page 2). Thus by this definition of inflammation, which includes any fundamental pathological process that occur in tissues in response abnormal stimulation caused by a bacterium, the treatment or inhibition of infection would lower any response to such infection because there is less to respond too. Since the art anticipates the treatment or inhibition of such bacterial infection in the lung thus one would anticipate a reduced level of lung inflammation/response abnormal stimulation caused by a bacterium in the lung.
The applicant argues:
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This argument is not considered persuasive because the reference Bailly teaches “A renewed interest in CFT can be anticipated for the treatment of cancers, and possibly Coronavirus 2019 (COVID-19)”(abstract). The applicant also argues lack of mentioning any effect on lung inflammation this is not persuasive because the applicants have defined inflammation in the specification as “As used herein, the term "inflammation" is used to describe the fundamental pathological process consisting of a dynamic complex of cytologic and histologic reactions that occur in tissues in response to an injury or abnormal stimulation caused by a physical, chemical or biologic agent (e.g. bacterium, virus...) including the local reactions and resulting morphologic changes, the destruction or removal of the injurious material, and the responses that lead to repair and healing”(page 2). Thus by this definition of inflammation, which includes any fundamental pathological process that occur in tissues in response abnormal stimulation caused by a virus, the treatment of the infection would lower any response to such infection because there is less to respond too. Since the art anticipates the treatment of such viral infection in the lung thus one would anticipate a reduced level of lung inflammation/response abnormal stimulation caused by a virus.
Conclusion
Claims 1, 9-11, 13-18 and 20-21 are rejected.
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.
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/A.A.H./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627
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