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 .
Status
Claims 2, 4, 10, 60, 61, and 63-66 are pending, wherein Claims 65 and 66 are newly added. The independent claims were amended to require wherein the subject is identified as being infected with a biofilm having a polyamine component in the biofilm.
Therefore, Claims 2, 4, 10, 60, 61, and 63-66 are presented for examination.
Election/Restrictions
Applicant elected without traverse of Group II and chloroquine as the agent in the reply filed on 4/30/2024.
Withdrawn Claim Objections
Claims 2 and 10 were objected to because of informalities that were corrected by amendment. Therefore, the objection is hereby withdrawn.
Response to arguments against prior art
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant primarily argues that the cited references fail to teach or suggest a method requiring identification of a subject as being infected with a biofilm having a polyamine component prior to treatment, and asserts that this diagnostic feature distinguishes the claimed invention from the applied prior art. This argument is not persuasive because the claims do not recite a specific diagnostic step or require any particular method of detection. Rather, the claims merely recite a subject “identified as being infected,” which constitutes a statement of the condition of the subject being treated rather than an affirmative diagnostic step. Such language does not impose a structural or procedural limitation on the claimed method beyond the treatment of a subject having the recited condition. The prior art teaches treatment of subjects known to suffer from infections associated with biofilm-forming organisms, and a person of ordinary skill in the art would have reasonably understood that such subjects are “identified” as having such infections prior to treatment.
Applicant further argues that the prior art improperly assumes the presence of biofilms and polyamines, and that not all infections involve biofilms or polyamine components. However, the claims are not directed to all infections, but rather to treatment of a subject having an established biofilm with a polyamine component. As set forth in the rejection, the applied references collectively teach that (i) Staphylococcus aureus is a common and recurrent pathogen in SLE patients (Al-Rayes; Eichenseher), (ii) such organisms are capable of forming biofilms (Eichenseher), and (iii) polyamines play an essential role in biofilm formation and that biofilms contain DNA (Karatan). In view of these teachings, a person of ordinary skill in the art would have reasonably expected that at least a subset of infections in such patients would involve biofilm-associated bacteria in which polyamines contribute to biofilm integrity. The fact that not all infections or biofilms exhibit identical characteristics does not negate a reasonable expectation of success in applying the combined teachings to those cases that do.
Applicant also contends that the references fail to teach a connection between polyamine biology and a therapeutic decision based on detection of a polyamine-containing biofilm. However, the claims do not require and rejection does not rely on an explicit teaching of such a diagnostic-therapeutic linkage in a single reference. Rather, the rejection is based on the combined teachings of the references, which collectively establish that chloroquine is used to treat SLE (Kastan), that SLE patients frequently suffer from bacterial infections including S. aureus (Al-Rayes), that chloroquine exhibits antibacterial activity alone or in combination with antibiotics against such organisms (Eichenseher), and that polyamines are key contributors to biofilm formation and stability (Karatan), with inhibition of polyamine pathways shown to improve disease outcomes (Thomas). From these teachings, a person of ordinary skill in the art would have been motivated to combine chloroquine with an agent that interferes with polyamine function in order to weaken biofilm integrity and improve treatment outcomes in infected patients, with a reasonable expectation of success. Applicant’s argument that the claimed invention represents a “diagnostic-therapeutic integration” is also not persuasive, as the claims do not require performing any diagnostic assay or confirming the presence of a polyamine-containing biofilm using a specific technique as the driving factor for treatment. To the extent Applicant relies on newly added dependent claims (e.g., claims 65–66) reciting particular detection methods, such limitations do not link a treatment decision to the detection of polyamine-containing biofilm.
Applicant further argues that the cited references address different problems and therefore lack a motivation to combine. This argument is not persuasive because the references are all directed to related aspects of treating infections and immune-related conditions, including SLE, bacterial infection, biofilm formation, and polyamine biology. A person of ordinary skill in the art would have recognized that these teachings are complementary, and would have been motivated to combine them to address the known challenge of treating persistent or recurrent infections associated with biofilm-forming organisms in SLE patients.
Applicant’s assertion that the results of interfering with polyamine-DNA binding in biofilms would have been surprising is also not persuasive. Karatan teaches that polyamines play an essential role in biofilm formation across diverse bacterial systems. In view of this teaching, it would have been expected that interfering with polyamine function or interactions within biofilms would disrupt biofilm integrity. Therefore, the alleged effect is consistent with, and suggested by, the prior art.
Finally, Applicant argues that not all SLE patients have infections and not all infections involve biofilms. However, the claims are directed to treatment of a subject having an established polyamine-containing biofilm, and the prior art teaches that SLE patients frequently suffer from infections caused by organisms capable of forming such biofilms. A person of ordinary skill in the art would have found it obvious to treat such patients when presenting with biofilm-associated infection using the combination of agents taught by the prior art.
Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
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.
A. Rejection maintained - Claims 2, 4, 10, 60, 61, 63, and 64 are rejected under 35 U.S.C. 103 as being unpatentable over
Kastan (US PG-PUB 2008/0319010) in view of
Al-Rayes et al. (“Systemic lupus erythematosus and infections: a retrospective study in Saudis.” Lupus (2007) 16, 755–763),
Eichenseher, F. (US PG-PUB 2018/0271952 A1),
Thomas et al. (Clin. exp. Immunol. (1989) 78, 239-244), and
Karatan et al. (Biotechnol. Lett (2013) 35:1715–1717. DOI 10.1007/s10529-013-1286-3).
Claimed invention
Independent Claim 2 is drawn to treating a subject identified as being infected with a biofilm having a polyamine component in the biofilm, comprising administering to the subject an effective amount of chloroquine (CQ) and one or more agents that interfere with the binding of a polyamine to the DNA in the biofilm, wherein the one or more agents is not HMGB1 protein, a fragment thereof or an equivalent of each thereof.
Prior art
Kastan teaches that chloroquine (CQ) is effective for treating systemic lupus erythematosus (SLE) and can be administered at effective amounts including 80 mg/day. See 0015-0016; Claims 18 and 28.
Kastan does not teach 1) CQ is treating a biofilm and 2) identifying the patient as being infected with a biofilm having a polyamine component and further administration of an agent that interferes with polyamine binding to DNA in a biofilm.
Regarding 1) that CQ is treating an established biofilm:
Kastan further teaches administration of amounts of CQ (80 mg/day) that are effective for the claimed inhibition of established biofilm as evidenced by the instant specification. The instant specification states that amounts effective for the invention includes the active agent at effective amounts of at least 1 mg/day. See Specification, 0219. Additionally, subjects with SLE are known to have issues with bacterial infections. For example, Al-Rayes teaches that “[i]nfection was the major complication with 58.79% of SLE patient having suffered from various infections” (Al-Rayes, abstract) and the most common microorganism infecting SLE patients was Staphylococcus aureus (Al-Rayes, p. 756 , 2nd column and p. 759, 2nd column; see also Table 3 at p. 758). It is also known that Staphylococcus aureus was a prevalent pathogen colonizing a large portion of the human population causing long-term and recurrent infections but the organism can be inhibited by CQ. For example, Eichenseher teaches Staphylococcus aureus is a pathogen that colonizes approximately a third of all humans and cause and is one of the leading causes of bacteremia and infective endocarditis in the industrialized world. See Eichenseher, 0002. “In addition to emerging antibiotic resistance, persisting and recurrent infections substantially add to morbidity and mortality. Recurrence rates, in particular after osteomyelitis or endocarditis, are high and infections may relapse even years after apparent cure. Infection recurrence is associated with SCVs (small colony variants) and/or non-replicating persisters for several reasons. Their arrested or slow growth and reduced metabolism renders antibiotics inefficient.” See Eichenseher, 0002. However, Eichenseher demonstrated that CQ alone and in combination with the known antibiotic, flucloxacillin, provide antibacterial effects against S. aureus. See Eichenseher, fig. 3, fig. 4A-C, fig. 5; 0083-0085; See also Claims 1, 2 and 4.
A person of ordinary skill in the art (POSA) would have found it obvious to treat or decrease S. aureus infection in a subject with SLE by administering 80 mg/day CQ alone or in combination with flucloxacillin to the subject because patients with SLE were known to receive treatment by administering 80 mg/day of CQ (Kastan) and CQ was taught to be effective alone or in combination with flucloxacillin for providing antibacterial effect against S. aureus (Eichenseher), which was known to cause infection in SLE patients (Al-Rayes). The artisan would have reasonably expected that 80 mg/day would still be effective at treating the SLE patient while simultaneously providing any antibacterial effec1ts against bacteria that is known to commonly cause infections in SLE patients such as S. aureus. Given that the prior art suggests administration of amounts of CQ (80 mg/day) that are effective at inhibiting or preventing established biofilm as evidenced by the specification that teaches that effective amounts of at least 1 mg/day (see Specification, 0219), the method suggested by the prior art of treating the SLE patient with S. aureus with 80 mg/day of CQ, a known anti-S. aureus agent, would provide the effective amount for inhibiting biofilm as claimed.
Regarding 2) identifying the patient as being infected with a biofilm having a polyamine component and further administration of an agent that interferes with polyamine binding to DNA in a biofilm:
Thomas presented a study using inhibition of polyamine biosynthesis (via DMFO) to successfully prolong survival (see Fig. 1), delay lymphedema (see Fig. 2), and reduce anti-Z-DNA antibodies (see Fig. 3) in the MRL-lpr mice, a well-established in vivo model for SLE. (See ‘Results’ section spanning pp. 240-242. See also ‘Discussion’ section at p. 242.) The results presented in the Thomas study provides evidence for a beneficial effect of polyamine biosynthesis inhibition in downregulating the immunological abnormalities of murine lupus and suggest the possibility of developing a new class of drugs for the treatment of murine and perhaps human disease. See p. 243, left column.
Karatan teaches polyamines play an essential role in biofilm formation of diverse Gram-negative and Gram-positive bacteria. Biosynthetic pathways and transport systems for diverse polyamines have been identified as key components of bacterial biofilm formation. See abstract. Karatan further teaches DNA can be found in biofilm (see p. 1715) and polyamines have been shown to be required for or influence biofilm formation in both Gram-negative and Gram-positive bacteria. See p. 1716.
A person of ordinary skill in the art (POSA) would have further found it obvious identify whether the SLE patient is infected with a biofilm having a polyamine component in the treatment of SLE in a subject by administering CQ in combination with a polyamine-inhibiting agent because Kastan teaches CQ is a known therapy for SLE and Thomas teaches polyamine inhibition was shown to ameliorate lupus manifestation in the SLE mouse model. The POSA would have combined the two agents together in therapy for SLE to achieve at least an additive benefit in reducing lupus disease activity with a reasonable expectation of success. The POSA would have further sought to use the combine the polyamine-inhibiting agent to CQ to inhibit the polyamine’s known essential role in biofilm formation.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 4 recite that the agent is in combination with an agent that inhibits replication of the organism. As outlined above, the prior art suggests that both chloroquine (CQ) and flucloxacillin can be used effectively in SLE patients with Staph infection, which is killed by flucloxacillin. Thus, flucloxacillin is an agent that inhibits replication of the bacteria.
Claim 10 claims the option wherein the method is performed in the presence of or absence of administration of a DNAse enzyme. There is no requirement for the presence of a DNAse enzyme.
Claims 60 and 61 limit Claims 2 and 4, respectively, wherein the subject is suffering from a chronic or recurrent infection. While Kastan does not mention recurrent infection, Al-Rayes teaches recurrent infection is a common issue in SLE patients. See p. 760, 2nd column. Thus, the POSA would have found it obvious to provide CQ and flucloxacillin to treat SLE patients with S. aureus infection including recurrent infections.
Claim 63 limits Claim 4, wherein treatment excludes prophylaxis. The method of treating SLE patients with S. aureus suggested by the prior art does not require and is not limited to prophylaxis.
Claim 64 limits claim 2 or 4, wherein the subject is suffering from SLE or cystic fibrosis. Kastan teaches treatment of subjects with SLE.
B. New rejection necessitated by amendment - Claims 65 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over
Kastan in view of Al-Rayes, Eichenseher, Thomas and Karatan, as applied to Claims 2, 4, 10, 60, 61, 63, and 64 above, taken further in view of
Decho et al. (“Confocal imaging of in situ natural microbial communities and their extracellular polymeric secretions using Nanoplast resin.” Biotechniques. 1999 Dec;27(6):1246-52. PMID: 10631505.)
Claimed invention
Claim 65 limits claim 2 or 4, wherein the biofilm having the polyamine component is detected in a sample isolated from the subject by a method comprising immunofluorescent staining with an antibody specific for the polyamine or imaging via confocal laser scanning microscopy.
Claim 66 limits claim 65, wherein the sample is selected from sputum, bronchoalveolar lavage fluid, a wound swab, a tissue biopsy, or a middle ear effusion.
Prior art
The disclosures for Kastan, Al-Rayes, Eichenseher, Thomas and Karatan apply to the base claim as indicated above. Although Thomas further teaches the diagnostic step of detecting polyamine concentration in SLE tissue cells (e.g., spleen) using HPLC (high-pressure liquid chromatography) (see Thomas, p. 242, paragraph bridging columns), the above reference combination does not expressly teach the specific diagnostic steps of detecting the biofilm having the polyamine component in a sample isolated from the subject by a method comprising imaging via confocal laser scanning microscopy.
However, Decho teaches the use of confocal laser scanning microscopy (CLSM) for imaging microbial biofilms and their extracellular polymeric substances (EPS) in situ. Specifically Decho teaches:
excision and fixation in Nanoplast, a hydrophilic embedding resin, allows confocal imaging of natural microbial communities;
optical sectioning using CLSM to obtain high-resolution imaging of biofilm structures;
use of fluorescent probes (e.g., FITC-labeled lectin) to visualize extracellular components of biofilm; and
allowed concurrent imaging of multiple labeled components within biofilms.
Deco further teaches that such imaging techniques are “ easily adapted for examinations of other microbial systems.” See Decho abstract.
A person of ordinary skill in the art (POSA) would have found it obvious to incorporate the CLSM-based detection methods of Decho into the combined teachings of for Kastan, Al-Rayes, Eichenseher, Thomas and Karatan. Karatan teaches polyamines are structural components of biofilm and Thomas teaches tissue samples can be isolated and analyzed to determine polyamine amount. Decho teaches that CSLM, in combination with fluorescent labeling, is a standard and adaptable technique for visualizing biofilm structure and extracellular components. In view of these teachings, a POSA would have recognized CSLM as a useful tool to detect and visualize biofilms and their constituents in isolated tissue samples. The artisan would have sought to use CLSM due to obtaining high-resolution imaging of biofilm structures, visualization of extracellular components of the biofilm; or for concurrent imaging of multiple labeled components within biofilms as taught by Decho.
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 CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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