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
This office action is in reply to the Applicant’s Remarks/Arguments filed 09 June 2026 for application 18/602,132 filed 12 March 2024. Claims 1 and 5 are amended. Claims 2, 9 and 11 are canceled. Currently, claims 1, 3-8, 10 and 12-15 are pending.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection the previous office action is set out below.
35 U.S.C. 102, 103, and Double Patenting
Applicant’s amendments to claim 1, attenuating macrophage polarization toward M1 phenotype, thereby, was sufficient to overcome the 103 rejections.
REJECTIONS – MAINTAINED & NEW
Applicant’s amendments to independent claim 1 have resulted in the below new prior art rejections.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(New) Claims 1, 4, 7, 10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over García-Patiño et al. (The immune response against Acinetobacter baumannii, an emerging pathogen in nosocomial infections, Front. Immunol. 2017, 8, 441) in view of Wu et al. (The protective effects of naproxen against interleukin-16 (IL-16)- induced damage in human umbilical vein endothelial cells (HUVECs), Bioengineered 2021, 12, 1, 5361-5372), modified by Liu et al. (Neutrophil and macrophage response in Acinetobacter Baumannii infection and their relationship to lung injury, Front. Cell. Infect. Microbiol. 2022, 12, 890511) and Mishra et al. (Role of plant-derived natural compounds in macrophage polarization, J. Vaccines Immunol. 2022, 8, 1, 14-22).
García-Patiño discloses that A. baumannii is a gram-negative coccobacillus that is known to cause nosocomial infections with a wide range of clinical manifestations. García-Patiño also discloses that the immune activation response to A. baumannii centers around toll-like receptors (TLRs), primarily TLR-4 and some evidence regarding TLR-2, some discussion about possible NOD receptors activation, CD14, and MD2, resulting in a broad range of signaling pathways from cytokines such as IL-1ß IL-8, THF-α, NF-kB, IL-6, IL-12, amongst other.
García-Patiño does not, however, disclose the use of naproxen, acetylsalicylic acid (ASA), dexamethasone (DXMS), or azathioprine (AzA) in the treatment of the cytokine release caused by an A. baumannii infection.
Wu rectifies this by teaching the use of naproxen for protection against atherosclerosis, a type of auto-immune disease, utilizing HUVEC exposure to IL-1B with and without treatment by the nonsteroidal anti-inflammatory drug (NSAID) naproxen. Wu finds that not only did naproxen protect against IL-1ß-induced damage by improving cell viability and preventing cell death, but also suppressed the expression of cytokines IL-6, IL-12 and TNF-α, and further downregulated the expression of vascular endothelial growth factor (VEGF) and tissue factor (TF) (abstract).
Regarding the limitations introduced by amendment in claim 1 “attenuating macrophage polarization toward M1 phenotype, thereby”, are inherently met as Liu teaches that early-stage A. Baumannii infection introduce LPS from the bacteria and TNF-α from the infected tissues to induce M1 macrophages to activate from resting M1 macrophages. LPS activates the innate immunity by interacting with macrophage TLR4, resulting in M1 macrophages producing a large number of proinflammatory cytokines and chemokines, which induce recruitment of macrophages and neutrophils from bloodstream and nearby tissues to the infection site (pg. 2, col. 2). The introduced limitation fails to further limit the claim as the limitation is merely a consequence of an A. Baumannii infection. Mishra further teaches the use of plant-derived natural compounds, in a similarly suggested manner, to polarize macrophages to toward M2 phenotypes, away from M1 (abstract).
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the use of NSAIDs in the suppression of cytokine signaling arising from A. baumannii infection as many of the observed hallmark cytokine signaling pathways overlap with the inflammatory signals resulting from atherosclerosis, an auto- immune disease. This is further refined as Liu teaches that macrophage polarization toward M1 is a direct consequence of bacterial infections while Mishra teaches the use of plant derived natural compounds to polarize macrophages away from M1 toward the M2 phenotype.
(New) Regarding the limitations of claim 4, wherein the subject overexpresses one or more pro-inflammatory factors selected from the group consisting of IL-1ß, IL-6, IL-10, IL-12, IL-17a, IL-23, IL-27, IFN-y, and TNF-α, are met as García-Patiño describes the inflammatory cascade that occurs during an A. baumannii infection includes many of the same signaling factors (pg. 7).
(New) With respect to the limitations of claim 7, wherein the A. baumannii infection is the result of antibiotic-resistant A. baumannii, are met as García-Patiño teaches that A. baumannii belongs to a group of bacteria termed ESKAPE, pathogens that escape the effect of many antibacterial drugs and are the major antibiotic-resistant microorganisms responsible for nosocomial infections (pg. 2).
(New) Concerning the limitations of claim 10, wherein the A. baumannii infection results from an A. baumannii strain selected from the group consisting of ATCC 17978, ATCC 19606, AB5075, ATC 9955, ATCC 17904, R 477, and R 0211019, are met as García-Patiño lists several research models used to study host responses against A. baumannii including ATCC 17978, ATCC 19606, and AB5075 (table 1, pg. 3).
(New) Regarding the limitations of claim 12, wherein the A. baumannii infection is present in one or more of a wound, a surgical site, a catheter site, blood, urinary tract, skin, lungs, or respiratory tract, are met as García-Patiño teaches that A. baumannii infections has several clinical manifestations including urinary tract, skin, soft tissue infections (introduction, pg. 1), wound infection, blood and lung cells (table 1, pg. 4).
(New) Claims 3 and 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over García-Patiño, Wu, Liu and Mishra as applied to claims 1, 4, 7, 10 and 12 above, and further in view of Takeuchi et al. (Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components, Immunity 1999, 11, 443-451).
García-Patiño taught the cytokine signals that are a result from A. baumannii infection, Wu taught the anti-inflammatory effect of naproxen in the case of atherosclerosis, Liu teaches macrophage polarization toward M1 phenotype during bacterial infection while Mishra teaches that plant derived natural products can be used to polarize macrophages toward the M2 phenotype.
They did not, however, specifically teach the activation of NF-kB through TLR2.
Takeuchi addresses this by investigating NF-kB activation through TLR family members via an adaptor protein MyD88 in response to lipopolysaccharide (LPS) and peptidoglycan (PGN). TLR2-deficient cells demonstrated no NF-kB activation in response to stimulation by PGN whereas TLR4-deficient cells demonstrated no NF-kB activation in response to stimulation by LPS (IRAK and NF-kß activation in response to LPS and PGN, pg. 447). As A. baumannii infection is associated with both TLR2 and TLR4 in mammalian antimicrobial responses, as disclosed by García-Patiño, activation of the TLR2/MyD88/NF-kB signaling pathway in response to infection is inherent.
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider that the TLR2/MyD88/NF-kB signaling pathway would be activated during an A. baumannii infection in a subject.
(New) With regards to the limitations of claim 5, wherein the A. baumannii infection activates a TLR2/MyD88/NF-kB signaling pathway in the subject; the therapeutic is naproxen or a pharmaceutically acceptable salt thereof; and administration of naproxen results in a reduction in the relative expression of TLR2/MyD88/NF-kB signaling pathway-related genes, are met as Takeuchi demonstrates NF-kB activation by LPS and PGN specifically by introducing mutations into the TLR2 to produce TLR2 deficient mice (pg. 444 - results). As such, translation/transcription of related genes are necessarily part of the signaling expression cascade and a reduction, pharmacologically induced or otherwise, in signaling, necessarily results from the reduction in expression of these proteins.
(New) Concerning the limitation of claim 6, wherein the TLR2/MyD88/NF-kB signaling pathway- related genes are selected from the group consisting of toll-like receptor 2 (TLR2), myeloid differentiation primary response 88 (Myd88), nuclear factor kappa B subunit 1 (Nfkb1), nuclear factor kappa B subunit 2 (Nfkb2), Interleukin 1 beta (ll1b), interleukin 6 (116), and tumor necrosis factor (Tnf), are met as the TLR2/MyD88/NF-kB signaling pathway activation necessarily requires the translation/transcription of genes in the signaling pathway for protein expression and therefore all associated proteins and genes are inherently involved
(New) Claims 8 and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over García-Patiño, Wu, Liu and Mishra as applied to claims 1, 4, 7, 10 and 12 above, and further in view of Lee et al. (Treatment of pan-drug resistant Acinetobacter baumannii, Scandinavian J. Infect. Diseases 2005, 37, 3, 195-199).
García-Patiño taught the cytokine signals that are a result from A. baumannii infection, Wu taught the anti-inflammatory effect of naproxen in the case of atherosclerosis, Liu teaches macrophage polarization toward M1 phenotype during bacterial infection while Mishra teaches that plant derived natural products can be used to polarize macrophages toward the M2 phenotype.
They did not, however, teach where the antibiotic-resistant A. baumannii is resistant to one or more antibacterials selected from the group consisting of aminoglycosides, fluoroquinolones, and carbapenems.
Lee expands on antibiotic-resistant A. baumannii by teaching a study that investigated the role of sulbactam in the treatment of pan-drug resistant A. baumannii with two groups of 89 patients, group A treated with carbapenem and sulbactam, and group B with cephalosporins, antipseudomonas penicillins, or fluoroquinolones with aminoglycosides. Lee finds that the clinical outcomes of the two groups didn't differ significantly in terms of resolution of infection or survival (abstract).
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider antibiotic-resistant A. baumannii when investigating the effects of naproxen on cytokine reduction resulting from A. baumannii infection as García-Patiño and Lee illustrates a ubiquitous awareness of pan-drug resistant A. baumannii while Lee actively investigates combinatorial drug efficacy on patients infected with such.
(New) Regarding the limitations of claim 13, diagnosing the subject with an A. baumannii infection prior to administering the therapeutically effective amount of naproxen, are met as Lee teaches a clinical study consisting of patients infected with nosocomial, an infection not existent at the point of admission, pan-drug resistant A. baumannii, which must necessarily be diagnosed while being treated in the hospital as it is acquired after entering the clinical setting, being acquired from several sources including sputum, wounds, urine, blood, and cerebrospinal fluid (patients and methods, pg. 2).
(New) Concerning the limitations of claim 14, co-administering a therapeutically effective amount of an antibacterial agent to the subject, are met as Lee teaches a combinatorial approach with antibiotics to assess efficacy over mono-antibiotic therapy (table 1, clinical outcomes).
(New) With respect to the limitations of claim 15, wherein the antibacterial agent is selected from the group consisting of meropenem, polymyxin E, polymyxin B, sulbactam, piperacillin/tazobactam, minocycline, tigecycline and aminoglycosides, are met as Lee teaches the use of sulbactam, meropenem, carbapenem, and aminoglycosides amikacin (abstract, pg. 2).
Response to Arguments
The office kindly thanks the Applicant for their consideration and arguments to the previous office action. Responses are detailed below.
Applicant's arguments filed 09 June 2026 have been fully considered but they are not persuasive.
Applicant’s arguments, see pg. 4, Claims Rejections – 35 USC § 103, claims 1-2, 4, 7 and 10-12, filed 09 June 2026, with respect to the rejection(s) of claims 1-2, 4, 7 and 10-12 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Liu et al. (Neutrophil and macrophage response in Acinetobacter Baumannii infection and their relationship to lung injury, Front. Cell. Infect. Microbiol. 2022, 12, 890511) and Mishra et al. (Role of plant-derived natural compounds in macrophage polarization, J. Vaccines Immunol. 2022, 8, 1, 14-22) where Liu teaches macrophage polarization toward M1 phenotype during bacterial infection while Mishra teaches that plant derived natural products can be used to polarize macrophages toward the M2 phenotype.
On pg. 6, Claims Rejections – 35 USC § 103, claims 3 and 5-6, filed 09 June 2026, the Applicant argues:
…Takeuchi does not disclose or teach at the least the specific method of attenuating macrophage polarization toward M1 phenotype… also does not disclose or teach at least the naproxen-induced reduction in relative expression of TLR2/MyD88/NF-κΒ signaling pathway-related genes in an A. baumannii-associated cytokine storm treatment method…
The first section is addressed in paragraph 33 above. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
On pg. 6, Claims Rejections – 35 USC § 103, claims 8-9 and 13-15, filed 09 June 2026, the Applicant argues:
… Lee does not disclose or teach at least the specific method of attenuating macrophage polarization toward M1 phenotype…
In response, this is addressed in paragraph 33 above.
On pg. 7, filed 09 June 2026, the Applicant argues:
… the method of the present application produced an unexpectedly superior effect compared to methods using other immunosuppressants… naproxen outperformed the other therapeutics, including ASA, AzA, and DXMS in protecting ATCC17978-infected mice… NPXS effectively attenuated CD86 MFI levels, thereby inhibiting the macrophage polarization… naproxen unexpectedly provided superior protection relative to the other therapeutics such ASA, AzA and DXMS in the A baumannii infection model…
The Examiner acknowledges the effect Naproxen has on the disease model of interest. However, these are merely properties inherently possessed by Naproxen since the discovery and commercialization of the drug, existing before the identification of its efficacy in this model. Indeed, for the purposes of responding to this argument, Kuchar et al. (Anti-inflammatory therapy of infections, Encyclopedia of Infection and Immunity 2022, 791-797), teaches that non-steroidal anti-inflammatory drugs (NSAIDs), which includes Naproxen, as a family of drugs are prolific and ubiquitously used to reduce inflammation, fever and pain (pg. 791 – Non-steroidal anti-inflammatory drugs). Similarly, the instant invention, as the Examiner interprets the claims, utilizes Naproxen to treat the inflammation, i.e. cytokine storm, arising from A. baumannii infection using Naproxen and its known anti-inflammatory properties.
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.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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