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 .
Information Disclosure Statement
The submitted information disclosure statements (IDS) were filed on 06/13/2024 and 07/12/2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 16 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 16 is indefinite because claim 16 is recited, “A dosage form comprising one or more compounds selected from the group consisting of: ranitidine bismuth citrate (RBC), Bi(TPP) (TPP: tetraphenylporphyrinate), Bi(TPyP) (TPyP: tetra(4-pyridyl)porphyrin), in an effective amount to inhibit Sars-CoV-2 helicase protein, in a subject, following administration, alone or in combination with 3 or 10 mol eq.” What are 3 or 10 mols equivalent to? The applicants do not specify what active agent that mols of one or several of 3 or 10 of Bismuth compounds to be equivalent to.
For further examining purpose, the statement: “with 3 or 10 mol eq.” is not included in claim 16.
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)(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.
(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, 3, 4, 6, 10, 11, 13, 14, 16, 18-22 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ghobadi et al. (US 20230181759 A1).
Claims 1, 3, 4, 6, 10, 11, 13,
Ghobadi et al. teach compositions and methods for treatment of viral respiratory infections, for example a coronavirus infection. A nanoparticle composition of the present disclosure may comprise a targeting moiety and/or anti-viral agent and reduces the infectivity of a virus for a host cell. A method of treating a viral infection may comprise administering a composition comprising a nanoparticle to a subject and reducing the infectivity of the virus for a host cell of the subject. The compositions may be administered via intranasal or systemic administration to treat or prevent a viral infection, for example a coronavirus infection, (Abs), comprising an effective amount of a nanoparticle composition. (0004). The disclosure provides pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient and a nanoparticle. (0006). The pharmaceutical compositions comprising compounds to facilitate administration and promote stability of the active agent, which may be admixed with at least one pharmaceutically acceptable carrier or excipient resulting in a pharmaceutical composition which is capably and effectively administered (given) to a living subject, such as to a suitable subject, a subject in need of treatment. The subject may be a human or any other animal. (0098). A composition of the present disclosure may be formulated for locally, for example intra-nasally (e.g., as a nasal spray, or inhalation), or systemically (e.g., intravenous or intraperitoneal) and administered for treating or preventing a respiratory viral infection (e.g., a coronavirus infection such as SARS-CoV-2). The compositions of the present disclosure (e.g., compositions formulated for nasal delivery or inhalation) may be administered to a subject who may be at risk of contracting a viral infection (e.g., SARS-CoV-2). For example, the compositions of the present disclosure may be administered to individuals in high-risk environments (e.g., healthcare workers), individuals who have been or who are suspected to have been exposed to a virus (e.g., SARS-CoV-2), or individuals who have tested positive for a viral infection. A composition of the present disclosure may be administered to an individual who is displaying symptoms of a respiratory infection (e.g., a SARS-CoV-2 infection) or who is asymptomatic at the time of administration. (0017).
With regard to claims 11 and 16, the method and the composition of claim 1 contains an anti-viral agent (e.g., remdesivir, chloroquine, hydroxychloroquine, lopinavir, ranitidine bismuth citrate, and ritonavir). (0020).
With regard to claims 14 and 18, for parenteral administration (including subcutaneous, intraocular, intradermal, intravenous, intramuscular, intra-articular and intraperitoneal. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. The formulation may be an aqueous or an oil-based solution, (0089), or the nanoparticle formulation can be liposome. (0027).
With regard to claims 19-20, 22, a composition may contain stabilizing agents, (0023), and additional mucolytic agents for use and compositions of the invention include N-acetyl-L-cysteine (ACS) (0084). These and other mucolytic or mucus-clearing agents are contacted with the nasal mucosa, typically in a concentration range of about 0.2 to 20 mM, coordinately with administration of the biologically active agent, to reduce the polar viscosity and/or elasticity of intranasal mucus. (0084). Coordinately with administration suggests administration tasks happening concurrently. In addition, drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts, (0095), treatment in accord with the methods described herein can be performed prior to, concurrent with, or after conventional treatment modalities for a respiratory virus. (0096). The pharmaceutical compositions comprising compounds as disclosed above, so as to facilitate administration and promote stability of the active agent. A compound of this disclosure may be admixed with at least one pharmaceutically acceptable carrier or excipient resulting in a pharmaceutical composition which is capably and effectively administered (given) to a living subject, such as to a suitable subject (i.e. "a subject in need of treatment" or "a subject in need thereof'). For the purposes of the aspects and embodiments of the invention, the subject may be a human or any other animal. (0098).
With regard to claims 21, a formulation comprising a composition for intranasal
deliver may have a pH corresponding to a physiologically acidic nasal pH. The physiologically acidic nasal pH may depend on intact nasal mucosa! function. A composition may comprise a pH of about be 6.5±0.5 (5.9 to 7.3) or about 6.7±0.6 (5.3 to 7.6). A composition may comprise a pH of about 3.8-7.7 (mean±SD 5.7±0.9). A composition for nasal deliver may be in the slightly acidic range. The average pH may have an acidity of pH 5.7. (0079).
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.
Claim(s) 1, 16 and 2, 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ghobadi et al. (US 20230181759 A1) as applied to claims 1 and 16 above, in view of Yang and Huang et al. (Yang and Huang et al., Bismuth Complexes Inhibit the SARS Coronavirus. Angew. Chem. Int. Ed. 2007, 46, 6464 –6468) and Yang and Sun et al. (Yang and Sun et al. Inhibition of SARS coronavirus helicase by bismuth complexes. Chem. Commun., 2007, 4413–4415).
The teachings of Ghobadi et al. are described in claims 1 and 16 above.
Claim 2,
Ghobadi et al. do not teach wherein (a) the effective amount of one or more Bismuth (III)-containing compounds is effective to inhibit the helicase protein of SARS-CoV-2, in the subject (b) wherein the composition is administered in an effective amount to reduce viral replication; and/or (c) wherein the subject is presently suffering from an infection of the SARS-CoV-2.
Yang/Huang et al. teach Bismuth Complexes Inhibit the SARS Coronavirus. (Title). The SARS coronavirus (SCV) having the SCVS protein, main proteinase, cysteine proteinases, nucleoside triphosphate hydrolase (NTPase)/helicase and RNA polymerase proteins, which have been identified as potential targets for antiviral therapy. (pg. 6464, left col., 1st par.). The SCV NTPase/helicase has RNA capping activity and is able to unwind both RNA and DNA duplexes. Helicases have previously been identified as attractive targets for antiviral drug design. (pg. 6464, right col., 1st par.). There is an unusually strong cysteine–bismuth interaction
in metallothioneins and so bismuth ions might bind within the MBD, thereby affecting the enzymatic activities of the helicase. (pg. 6464, right col., 2nd par.). Ranitidine bismuth citrate (RBC) a) significantly inhibited SCV reproduction with the viral titer reduced by approximately 80% at 25 mm, b) and concentrations of 500 mm RBC almost completely inhibited SCV infection, replication, and/or release. (pg. 6466, right col., 1st par.).
Yang/Sun et al. (Inhibition of SARS coronavirus helicase by bismuth complexes), teach bismuth complexes inhibition against the SARS coronavirus helicase ATPase and duplex-unwinding activities at micromolar concentrations. (pg. 4413, left col. 1st par.).
Ghobadi et al. teach a composition of the present disclosure may be administered to an individual c) who is displaying symptoms of a respiratory infection (e.g., a SARS-CoV-2 infection) or who is asymptomatic at the time of administration.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to prepare compositions for treatment of viral respiratory infections, specifically for SARS-CoV-2 infection, with an effective amount of a composition with Rantidine bismuth citrate, to be administered to an individual who is displaying symptoms of a respiratory infection (e.g., a SARS-CoV-2 infection), taught by Ghobadi, and the rantidine bismuth citrate complex effectively inhibits SARS coronavirus replication, and helicase ATPase taught by Yang and Huang et al., and rantidine bismuth citrate complex effectively inhibit the SARS coronavirus helicase ATPase, taught by Yang and Sun et al., since they have proven rantidine bismuth citrate complex can be effectively treat a subject for a SARS-CoV-2 infection.
With regard to Claim 9, Ghobadi et al. teach severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) that was responsible for SARS epidemic in 2002-2004, Middle East respiratory syndrome coronavirus (MERS-CoV) that caused MERS first reported in 2012, and SARS-CoV-2 that has been responsible for the more recent coronavirus disease 2019 (Covid-19) pandemic all bind to angiotensin converting enzyme 2 (ACE2) on the surface of the cells in order to infect the cells. Basically ACE-2 is the functional receptor for SARS-CoV-1, SARS-CoV-2, and MERS-COV and most likely future SARS-COV variants. (0014).
Claims 16 and 17, is/are rejected under 35 U.S.C. 103 as being unpatentable over Ghobadi et al. (US 20230181759 A1) as applied to claims 1 and 16 above, in view of Yang and Huang et al. (Yang and Huang et al., Bismuth Complexes Inhibit the SARS Coronavirus. Angew. Chem. Int. Ed. 2007, 46, 6464 –6468) and Yang and Sun et al. (Yang and Sun et al. Inhibition of SARS coronavirus helicase by bismuth complexes. Chem. Commun., 2007, 4413–4415) and further in view of in view of Snow (US 20210346453 A1).
The teachings of Ghobadi et al. are described in claims 1 and 16 above.
Ghobadi et al. teach oral delivery, but do not recite clearly tablets or capsules.
Snow teaches the composition may be formulated as a pill, tablet, soft or hard gelatin capsule. (0006).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to prepare compositions for treatment of viral respiratory infections, specifically for SARS-CoV-2 infection, with an effective amount of a composition with Rantidine bismuth citrate, to be administered to an individual who is displaying symptoms of a respiratory infection (e.g., a SARS-CoV-2 infection), taught by Ghobadi, and the dosage can be tablet or capsule taught by Snow, since they have proven that Rantidine bismuth citrate can be formulated in tablets or capsules.
Claim(s) 1, 6 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ghobadi et al. (US 20230181759 A1) as applied to claim 1 above, in view of Snow (US 20210346453 A1).
The teachings of Ghobadi et al. are described in claims 1 and 6 above.
Claim 7,
Ghobadi et al. do not teach the symptoms include fever, congestion in the nasal sinuses and/or lungs, runny or stuffy nose, cough, sneezing, sore throat, body aches, fatigue, shortness of breath, chest tightness, wheezing when exhaling, chills, muscle aches, headache, diarrhea, tiredness, nausea, vomiting, and combinations thereof.
Snow teaches symptoms of SARS-CoV-2 infection (e.g., COVID-19) include fever, dizziness, cough, shortness of breath, fatigue, headache, nasal congestion, sore throat, coughing up sputum, pain in muscles or joints, chills, nausea, vomiting, and diarrhea. (0028).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to prepare compositions for treatment of viral respiratory infections, specifically for SARS-CoV-2 infection, with an effective amount of a composition with Rantidine bismuth citrate, to be administered to an individual who is displaying symptoms of a respiratory infection (e.g., a SARS-CoV-2 infection), taught by Ghobadi, and to have the SARS-CoV-2 infection (e.g., COVID-19) symptoms taught by Snow, since knowing these symptoms would help to prepare the test and the treatment steps.
Claim(s) 1 and 12, and 20 and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ghobadi et al. (US 20230181759 A1) as applied to claim 1 above, in view of in view of Wang et al. (Wang et al., Bismuth antimicrobial drugs serve as broad spectrum metallo-β-lactamase inhibitors. Nature Connunications | (2018) 9:439).
The teachings of Ghobadi et al. are described in claims 1 and 20 above.
Claims 1 and 12,
Ghobadi et al. do not teach composition comprises colloidal bismuth subcitrate (CBS).
Wang et al. teach colloidal bismuth subcitrate (CBS) and related Bi(III) compounds. (Abs)
Claims 20 and 23,
Ghobadi et al. do not teach the thiol containing small molecule is used at a 3 or 10 mol eq. to the bismuth (III) compounds or pharmaceutically acceptable salts thereof.
Wang et al. teach Cysteine (Cys208) at the active site is shown to play a pivotal role for the activity of Bi(III) compounds. (pg. 2nd, right col., 2nd par.). Four typical Bi(III) compounds were shown in Table 1 to exemplify their potent synergy with MER against different MBL producers. In particular, a complex of bismuth with N-acetyl-cysteine (Bi(NAC)3) exhibited the most potent inhibitory activity against different MBL-positive strains with a 32-fold, 64-fold, and 16-fold decrease in the MIC of MER against NDM-1-positive, VIM-2-positive, and IMP-4-positive E. coli, respectively, and the FICI values ranged from 0.063 to 0.188 (Supplementary Fig. 3b). The combination of MER and Bi(NAC)3 was able to eradicate the bacterium
completely within 6 h (Supplementary Fig. 4a). Such an excellent inhibitory activity may arise from cooperative inhibition of Bi(III) ions and NAC ligand dissociated from Bi(NAC) 3, as well as elevated cellular uptake of Bi(III) (Supplementary Fig. 4b). (pg. 4, left col., 2nd last par.). N-acetyl-cysteine (NAC), a thiol compound, with 3 mol eq to the bismuth (III) compound increases bismuth (III) activity.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to prepare compositions for treatment of viral respiratory infections, specifically for SARS-CoV-2 infection, with an effective amount of a composition with Rantidine bismuth citrate, to be administered to an individual who is displaying symptoms of a respiratory infection (e.g., a SARS-CoV-2 infection), taught by Ghobadi, and the thiol compound, N-acetyl-cysteine (NAC) with 3 mol eq. to bismuth (III) increased bismuth(III), including colloidal bismuth subcitrate and related Bi(III) compounds activity, taught by Yang, since they have proven bismuth can inhibit SARS-CoV-2 replication and NAC with 3 mol eq can increase the activity of bismuth (III) compounds.
Conclusion
No claim is allowed at this time.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615