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 .
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Response to Arguments
Applicant's arguments filed 9/11/2025 regarding the claims rejected under 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant’s position is that 1) Lohan does not teach or suggest the use of shorter (C9-C13) aliphatic chain peptides as adjuvants nor that such compounds would have a synergistic effect when co-administered with an antibiotic of interest (see summary at Pg 17, third paragraph); moreover, 2) the synergy demonstrated by the combination of the peptide 12C-PRP and minocycline or rifampicin is an unexpected result.
Regarding 1), 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).
As stated in the prior Office Action and reiterated herein, the teachings of Fraser, Runti, and Lohan collectively render the instant claims obvious. Fraser teaches the method of permeabilizing or sensitizing gram negative bacterial cells to an antibiotic by administering a combination of an antibiotic and an antimicrobial peptide, such as one comprising the instant SEQ ID NO: 3. Runti demonstrates that the peptide comprising the instant SEQ ID NO: 3 permeabilizes bacterial cell membranes. Finally, Lohan teaches compounds with shorter C10-C12 aliphatic chain peptides that demonstrate improved antimicrobial activity; see, for instance, compounds LP19 (C8 aliphatic chain); LP14, LP20, and LP26 (C10 aliphatic chain); and LP9, LP15, LP21, and LP26 (C12 aliphatic chain) in Table 2. See maintained/modified art rejections below.
Regarding 2), unexpected results must be compared to the closest prior art, which is Fraser (WO 98/40401, published 9/17/1998), cited in the prior Office Action and reiterated herein below. Fraser teaches a peptide comprising the instant SEQ ID NO: 3, in combination with an antibiotic, can effectively treat gram negative bacterial infections by enhancing the activity of the antibiotic agent. In other words, Fraser teaches that the combination SEQ ID NO: 3 and an antibiotic is synergistic. Consequently, based on these teachings, the results are not unexpected. See art rejections below.
Claim Status
Claims 1-19 are pending under examination. Claim 13 is currently amended. Claims 18 and 19 are new.
Priority
The application is a divisional of application 16/975,791, now abandoned, which was the 371 national stage entry of PCT/CA2019/050285, filed 3/8/2019, which claims priority to the provisional application 62/640,318, filed on 3/8/2018. The priority date of 3/8/2018 is acknowledged.
New - Drawings
The drawings are objected to because Figure 1 includes the tradename Adriamycin® without the generic name (also see Specification objections, below). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
New - Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
There is a sequence on Pg 10, line 14 without a SEQ ID NO.
New - Specification
The use of the terms Adriamycin® (see, Pg 4, line 24; Pg 17, lines 24 and 29; Pg 18, line 1; Pg 22, line 26; Pg 23, line 6); Bruker (Pg 20, lines 17 and 20); Emax (Pg 21, line 8; Pg 22, lines 1 and 13); Triton X-100 (Pg 21, line 20); CyQuant (Pg 22, lines 21, 28, and 20); SpectraMax (Pg 22, line 29), which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
New - Claim Interpretation
Claim 18 recites that the non-hemolytic compound requires a concentration of greater than 512ug/ml for 5% red blood cell lysis. This claim recites functional limitations resulting from the structure of the non-hemolytic compound as set forth in claim 1. As such, the claim is being interpreted based upon the structural limitations (a compound comprising the peptide set forth in SEQ ID NO: 3 or SEQ ID NO: 4 connected to a C9-C13 aliphatic chain) where the functional limitation of claim 18 is a property endowed by the structure.
Modified/Maintained - 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.
Claims 1-19 are 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 1 recites that the claimed compound is “non-hemolytic”. The instant specification does not define “non-hemolytic,” making it unclear to what extent or under what conditions the compound transitions from being non-hemolytic to hemolytic. Consequently, this limitation renders the scope of the claim indefinite. Further, by virtue of their dependency on claim 1, claims 2-19 are hereby rejected for this same reasoning.
Modified/Maintained - Claim Rejections - 35 USC § 103
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.
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 nonobviousness.
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.
First rejection – SEQ ID NO: 3
Claim(s) 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Fraser et al. (WO 98/40401, published 9/17/1998) in view of Runti et al. (Runti et al., 2017. The Mechanism of Killing by the Proline-Rich Peptide Bac7(1–35) against Clinical Strains of Pseudomonas aeruginosa Differs from That against Other Gram-Negative Bacteria. Antimicrob Agents Chemother 61:10.1128/aac.01660-16.) and Lohan et al. (Lohan S, Cameotra SS, Bisht GS. Systematic study of non-natural short cationic lipopeptides as novel broad-spectrum antimicrobial agents. Chem Biol Drug Des. 2013 Nov;82(5):557-66.).
Fraser teaches compositions and methods for treating infections, especially bacterial infections, by using cationic peptides in combination with an antibiotic agent. The combination can be administered to a patient to enhance the activity of the antibiotic agent, overcome tolerance, overcome acquired resistance, or overcome inherent resistance (Abstract).
One of the cationic peptides taught by Fraser is Bac7, derived from the cytoplasmic granules of bovine neutrophils, which comprises the instant SEQ ID NO: 3 (Table 1, Pg 7). The cationic peptides taught, such as the instant SEQ ID NO: 3, can be used in combination with antibiotics to treat bacterial infections.
Fraser assesses potential cationic peptides either alone or in combination with an antibiotic agent or another using a series of assays (Pg 17, immediately under “Testing”). In vitro assays such as agarose dilution minimum inhibitory concentration (MIC) can be performed to assess the antibiotic activity of the cationic peptide alone or in combination (Pg 17, “A. In vitro assays” first paragraph – Pg 18, first paragraph). Candidate cationic peptides can also be tested for their toxicity to normal mammalian cells, such as through a red blood cell (erythrocyte) hemolysis assay (Pg 18, third paragraph).
Fraser further teaches that the enhanced activity of the combination of cationic peptide and an antibiotic agent is especially desirable in situations where it allows for administration of lower dosages of antibiotic agent or cationic peptide, restores a cytocidal effect, overcomes inherent resistance, and overcomes acquired resistance (Pg 25, final paragraph). Fraser demonstrates many different combinations of cationic peptides and antibiotic agents administered together that effectively reduce the MIC as compared to the MIC of the antibiotic alone; this was tested in several species of Gram-negative bacteria, including P. aeruginosa, A. baumannii, and E. coli (Example 4, Tables 10-12, Pg 53-67; Example 6, Tables 14-17, Pg 69-71; Example 7, Tables 18020, Pg 72-82).
Fraser does not explicitly teach that the compound comprising the instant SEQ ID NO: 3 administered with the antibiotic of interest results in the permeabilization of a Gram-negative bacterial membrane, nor does Fraser teach that the cationic peptides such as the instant SEQ ID NO: 3 are connected to a C9-C13 aliphatic chain.
Runti teaches that the mammalian proline-rich antimicrobial peptide Bac7 (1-35), which encompasses the instant SEQ ID NO: 3, is active against some multidrug-resistant cystic fibrosis isolates of P. aeruginosa and determines that, mechanistically, Bac7(1-35) exerts its antimicrobial impacts by inactivating target cell membranes (Abstract). Specifically, Runti teaches that Bac7(1-35) acts on clinical isolates of P. aeruginosa such as PAO1, PA21, PA05, PA35 by permeabilizing their cell membranes (Pg 2-3, “Mechanism of action of Bac7(1-35) on P. aeruginosa PAO1”). Moreover, Runti demonstrates that the addition of the nonlytic, protein synthesis inhibitor antibiotic tobramycin in addition to Bac7(1-35) resulted in a decrease in cell viability, indicating that the observed membrane permeabilization was not a result of cell death (Pg 2-3, “Mechanism of action of Bac7(1-35) on P. aeruginosa PAO1”; Figure 1C and D compared to A and B).
Lohan teaches a series of non-natural short cationic lipopeptides used as antimicrobial agents against a range of microbes including Gram-negative and -positive bacteria, fungi including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) (Abstract). Lipopeptides are a class of native antimicrobial agents produced non-ribosomally in bacteria and fungi during cultivation on various carbon sources composed of an aliphatic acid attached to the N-terminus of short cationic or anionic peptidic moiety of 6-7 amino acids. Further, the modes of action of AMPs and some of the lipopeptides are similar; both of them act via perturbation of the bacterial cell membranes. The initial step of bactericidal activity of lipopeptide is governed by the electrostatic interaction between positively charged side chain residues and negatively charged lipopolysaccharide (LPS) of Gram-negative bacteria or lipoteichoic acid of Gram-positive. Lipopeptides further traverse into the inner core and destabilize the membrane architecture bacteria (Pg 557, second column, second paragraph).
Lohan further teaches that it is known in the art that conjugation of a fatty acid to the N-terminus of linear AMPs results in improved antimicrobial activity, aliphatic acid conjugation to inactive cationic peptides endows them with antimicrobial activity, and conjugation of a fatty acid can reduce the length of the peptidic chain by compensating for hydrophobic bulk (Pg 558, first column, second paragraph).
The peptides taught by Lohan range from 1-5 amino acids of ornithine conjugated at the N-terminus to hydrophobic chains consisting of C8-C18 carbons and are non-hemolytic (Pg 559, second column, last paragraph; Scheme 1; Table 1).
Thus, regarding claim 1, Fraser teaches a method of treating Gram-negative bacterial infections through administering an effective amount of Bac7, which comprises the instant SEQ ID NO: 3, and an antibiotic agent, such that the antibiotic can be administered at a decreased MIC as compared to its administration alone; Runti teaches Bac7(1-35), comprising the instant SEQ ID NO: 3, can permeabilize the membrane of P. aeruginosa species; and Lohan teaches cationic peptides conjugated to fatty acids ranging from C8-C18 carbons that are non-hemolytic.
Thus the instant invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention because:
Fraser taught that by administering a cationic, antimicrobial peptide in combination with an antibiotic, one could effectively treat a Gram-negative bacterial infection with a reduced MIC. One skilled in the art would have been drawn to the teachings of Fraser as a starting point in order to identity an antimicrobial peptide suitable for co-administration with an antibiotic that could effectively reduce the MIC of the antibiotic as compared to administration of the antibiotic alone; further, one would have recognized that the advantage of reducing the MIC of the co-administered antibiotic would be a reduced likelihood of the bacterial strain developing antibiotic resistance.
Runti taught that the antimicrobial peptide Bac7(1-35) could treat species of P. aeruginosa, including multidrug resistant ones, through permeabilization of the cellular membrane and co-administration of the nonlytic antibiotic tobramycin further lowered the viability of P. aeruginosa cells. In light of the teachings of Fraser, one skilled in the art would have recognized the utility of Bac7(1-35) based on its ability to permeabilize bacterial cell membranes, which would sensitize bacterial cells and, thereby, make them more susceptible to antibiotics and allow them to be treated with reduced dosages.
Lohan taught that it is advantageous to conjugate fatty acids to antimicrobial peptides, in particular those with 8-18 carbons, as it results in improved antimicrobial activity but does not cause hemolytic activity. In light of the teachings of Fraser and Runti, one skilled in the art would have chosen to modify Bac7(1-35) by attaching a fatty acid molecule with 8-18 carbons to because it was known that the antimicrobial peptide Bac7(1-35) could treat Gram-negative bacteria, including some multidrug resistant strains. Additionally, one would have been motivated to add the fatty acid chain to Bac7(1-35) in order to further improve its potency and prevent potential hemolysis of non-bacterial cells.
One skilled in the art would have had a reasonable expectation of success in combining
the above teachings because each of the individual components taught above improves upon the method of treating a Gram-negative bacterial infection and each of these features is maintained within the instant invention.
Regarding claims 2 and 3, Lohan teaches the addition of fatty acid chains consisting of C8-C18 carbons to the N-terminus of an antimicrobial peptide (Pg 559, second column, last paragraph; Scheme 1; Table 1).
Regarding claims 4 and 5, Lohan teaches antimicrobial peptides with lauric acid (dodecanoic acid) attached at the N-terminus of the antimicrobial peptide (Table 1; also see Pg 558, Materials paragraph).
Regarding claim 6, Runti demonstrates that the addition of the nonlytic, protein synthesis inhibitor antibiotic tobramycin in addition to Bac7(1-35) resulted in a decrease in cell viability, indicating that the observed membrane permeabilization was not a result of cell death (Pg 2-3, “Mechanism of action of Bac7(1-35) on P. aeruginosa PAO1”; Figure 1C and D compared to A and B).
Regarding claims 7-10, Fraser teaches methods for treating and preventing infections by administering to a patient a therapeutically effective amount of a cationic peptide as described. Patients suitable for such treatment may be identified by well-established hallmarks of an infection, such as fever, pus, culture of organisms, and the like. Infections that may be treated with peptide analogues include those caused by or due to microorganisms, such as bacteria, including Gram-positive and -negative bacteria, fungi, parasites, viruses, and prions (Pg 33 last paragraph – 34 first paragraph). Further clinical indications are listed Pgs 34-38; in the clinical indications for nosocomial pneumonia, Fraser states that in severely compromised patients, multiantibiotic-resistant nosocomial pathogens are likely to be the cause of pneumonia, and one of the main organisms responsible is P. aeruginosa (Pg 36, final paragraph – Pg 37, first paragraph). Fraser further demonstrates the ability of cationic peptides in combination with antibiotic agents to effectively treat P. aeruginosa, as shown in Table 18 (Pg 72 – 74). Table 18 demonstrates that in all cases where P. aeruginosa is treated with a cationic peptide and antibiotic agent combination the MIC is reduced as compared to administration of antibiotic agent alone.
Regarding claim 11, Runti teaches that Bac7(1-35) exerts its antimicrobial impacts by inactivating target cell membranes (Abstract). Specifically, Runti teaches that Bac7(1-35) acts on clinical isolates of P. aeruginosa such as PAO1, PA21, PA05, PA35 by permeabilizing their cell membranes (Pg 2-3, “Mechanism of action of Bac7(1-35) on P. aeruginosa PAO1”).
Regarding claim 12, Fraser teaches that anti-bacterial antibiotic agents can include, but are not limited to penicillins, cephalosporins, monobactams, quinolones, or tetracycline among others (Pg 20-22; Table 2, Pg 23-24).
Regarding claim 13, Runti teaches that Bac7(1-35) exerts its antimicrobial impacts by inactivating target cell membranes (Abstract). Specifically, Runti teaches that Bac7(1-35) acts on clinical isolates of P. aeruginosa such as PAO1, PA21, PA05, PA35 by permeabilizing their cell membranes (Pg 2-3, “Mechanism of action of Bac7(1-35) on P. aeruginosa PAO1”). Although not explicitly disclosed by Runti, one skilled in the art would recognize that an untreated control wherein no Bac7(1-35) is provided to P. aeruginosa or any other bacterial cells would necessarily result in those cells retaining intact membranes.
Regarding claims 14 and 16, Fraser teaches that pharmaceutical compositions of the invention may be administered in various manners; for example, cationic peptides with or without antibiotic agents may be administered by intravenous injection, intraperitoneal injection or implantation, subcutaneous injection or implantation, intradermal injection, lavage, inhalation, implantation, intramuscular injection or implantation, intrathecal injection, bladder wash-out, suppositories, pessaries, topical application (creams, ointments, skin patches, eye drops, ear drops, shampoos), enteric, oral or nasal route (Pg 40, second paragraph).
Regarding claims 15 and 17, Fraser teaches that the peptides and antibiotic agents of the invention are preferably administered as a pharmaceutical composition, comprised of one or more of the peptide analogues described in combination one or more physiologically acceptable carriers, diluents, or excipients (Pg 39, second paragraph).
Regarding claim 18, as described above, Fraser, Ranti, and Lohan teach a non-hemolytic compound comprising the peptide as set forth in SEQ ID NO: 3 connected to a C9-C13 aliphatic chain; therefore, the structure of the compound disclosed by Fraser, Ranti, and Lohan renders claim 18 obvious.
Second rejection – SEQ ID NO: 4
Claim(s) 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Fraser et al. (WO 98/40401, published 9/17/1998), Runti et al. (Runti et al., 2017. The Mechanism of Killing by the Proline-Rich Peptide Bac7(1–35) against Clinical Strains of Pseudomonas aeruginosa Differs from That against Other Gram-Negative Bacteria. Antimicrob Agents Chemother 61:10.1128/aac.01660-16.), and Lohan et al. (Lohan S, Cameotra SS, Bisht GS. Systematic study of non-natural short cationic lipopeptides as novel broad-spectrum antimicrobial agents. Chem Biol Drug Des. 2013 Nov;82(5):557-66.) in view of Podda et al. (Dual mode of action of Bac7, a proline-rich antibacterial peptide. Biochim Biophys Acta. 2006 Nov;1760(11):1732-40.).
The teachings of Fraser, Runti, and Lohan have been set forth above. Fraser, Runti, and Lohan do not teach the instant SEQ ID NO: 4.
Podda teaches treating E. coli and S. enterica species with an all D enantiomer version of Bac7(1-35), which encompasses the instant SEQ ID NO: 4 (Table 1 for sequence; Figures 1 and 2; Pg 1734, “3.1 Antibacterial activity of the Bac7(1-35) enantiomers”).
Thus, regarding claim 1, Fraser, Runti, and Lohan teach a method of treating Gram-negative bacterial infections through administering an effective amount a non-hemolytic peptide comprising the instant SEQ ID NO: 3, connected to a C8-C18 aliphatic tail, and an antibiotic agent, such that the antibiotic can be administered at a decreased MIC as compared to its administration alone. Podda teaches a peptide comprising the instant SEQ ID NO: 4 can also be used to treat Gram Negative bacteria such as E. coli and S. enterica. Based on these teachings, it would have been prima facie obvious to incorporate the peptide taught by Podda into the method taught by Fraser, Runti, and Lohan. One skilled in the art would have been motivated to do so because Fraser, Runti, and Lohan demonstrated that peptides comprising SEQ ID NO: 3 could permeabilize/sensitize bacterial cells to antibiotics, thereby allowing a lower dosages of antibiotics to be administered in combination that could still effectively treat bacteria. One would have a reasonable expectation of success as Podda similarly demonstrated that a peptide comprising the instant SEQ ID NO: 4 could permeabilize bacterial cell membranes to similar extents as SEQ ID NO: 3 (L-Bac7(1-35); see, for example, Figure 3).
Regarding claims 2 and 3, Lohan teaches the addition of fatty acid chains consisting of C8-C18 carbons to the N-terminus of an antimicrobial peptide (Pg 559, second column, last paragraph; Scheme 1; Table 1).
Regarding claims 4 and 5, Lohan teaches antimicrobial peptides with lauric acid (dodecanoic acid) attached at the N-terminus of the antimicrobial peptide (Table 1; also see Pg 558, Materials paragraph).
Regarding claim 6, Runti demonstrates that the addition of the nonlytic, protein synthesis inhibitor antibiotic tobramycin in addition to Bac7(1-35) resulted in a decrease in cell viability, indicating that the observed membrane permeabilization was not a result of cell death (Pg 2-3, “Mechanism of action of Bac7(1-35) on P. aeruginosa PAO1”; Figure 1C and D compared to A and B).
Regarding claims 7-10, Fraser teaches methods for treating and preventing infections by administering to a patient a therapeutically effective amount of a cationic peptide as described. Patients suitable for such treatment may be identified by well-established hallmarks of an infection, such as fever, pus, culture of organisms, and the like. Infections that may be treated with peptide analogues include those caused by or due to microorganisms, such as bacteria, including Gram-positive and -negative bacteria, fungi, parasites, viruses, and prions (Pg 33 last paragraph – 34 first paragraph). Further clinical indications are listed Pgs 34-38; in the clinical indications for nosocomial pneumonia, Fraser states that in severely compromised patients, multiantibiotic-resistant nosocomial pathogens are likely to be the cause of pneumonia, and one of the main organisms responsible is P. aeruginosa (Pg 36, final paragraph – Pg 37, first paragraph). Fraser further demonstrates the ability of cationic peptides in combination with antibiotic agents to effectively treat P. aeruginosa, as shown in Table 18 (Pg 72 – 74). Table 18 demonstrates that in all cases where P. aeruginosa is treated with a cationic peptide and antibiotic agent combination the MIC is reduced as compared to administration of antibiotic agent alone.
Regarding claim 11, Runti teaches that Bac7(1-35) exerts its antimicrobial impacts by inactivating target cell membranes (Abstract). Specifically, Runti teaches that Bac7(1-35) acts on clinical isolates of P. aeruginosa such as PAO1, PA21, PA05, PA35 by permeabilizing their cell membranes (Pg 2-3, “Mechanism of action of Bac7(1-35) on P. aeruginosa PAO1”).
Regarding claim 12, Fraser teaches that anti-bacterial antibiotic agents can include, but are not limited to penicillins, cephalosporins, monobactams, quinolones, or tetracycline among others (Pg 20-22; Table 2, Pg 23-24).
Regarding claim 13, Runti teaches that Bac7(1-35) exerts its antimicrobial impacts by inactivating target cell membranes (Abstract). Specifically, Runti teaches that Bac7(1-35) acts on clinical isolates of P. aeruginosa such as PAO1, PA21, PA05, PA35 by permeabilizing their cell membranes (Pg 2-3, “Mechanism of action of Bac7(1-35) on P. aeruginosa PAO1”). Although not explicitly disclosed by Runti, one skilled in the art would recognize that an untreated control wherein no Bac7(1-35) is provided to P. aeruginosa or any other bacterial cells would necessarily result in those cells retaining intact membranes.
Regarding claims 14 and 16, Fraser teaches that pharmaceutical compositions of the invention may be administered in various manners; for example, cationic peptides with or without antibiotic agents may be administered by intravenous injection, intraperitoneal injection or implantation, subcutaneous injection or implantation, intradermal injection, lavage, inhalation, implantation, intramuscular injection or implantation, intrathecal injection, bladder wash-out, suppositories, pessaries, topical application (creams, ointments, skin patches, eye drops, ear drops, shampoos), enteric, oral or nasal route (Pg 40, second paragraph).
Regarding claims 15 and 17, Fraser teaches that the peptides and antibiotic agents of the invention are preferably administered as a pharmaceutical composition, comprised of one or more of the peptide analogues described in combination one or more physiologically acceptable carriers, diluents, or excipients (Pg 39, second paragraph).
Regarding claim 18, as described above, Fraser, Ranti, Lohan, and Podda teach a non-hemolytic compound comprising the peptide as set forth in SEQ ID NO: 4 connected to a C9-C13 aliphatic chain; therefore, the structure of the compound disclosed by Fraser, Ranti, Lohan, and Podda renders claim 18 obvious.
Allowable Subject Matter
A compound consisting of SEQ ID NO: 3 or SEQ ID NO: 4 connected to a C9-C13 aliphatic chain is free of the art.
The closest art is Nishi et al. (The soybean beta-conglycinin beta 51-63 fragment suppresses appetite by stimulating cholecystokinin release in rats. J Nutr. 2003 Aug;133(8):2537-42.) which teaches the instant SEQ ID NO: 3 (Table 2). Nishi teaches the peptide equivalent to SEQ ID NO: 3 is a fragment derived from soybean β-conglycinin peptone, which is known to suppress food intake and gastric emptying to stimulate cholecystokinin (CCK) release (Abstract). Nishi does not teach administering SEQ ID NO: 3 as part of a method for permeabilizing Gram Negative bacteria nor modification of SEQ ID NO: 3 through the addition of an aliphatic chain. Additionally, because SEQ ID NO: 4 is equivalent to SEQ ID NO: 3 but in D-amino acids, SEQ ID NO: 4 is also free of the art for the same reasons.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sara E Konopelski Snavely whose telephone number is (571)272-1841. The examiner can normally be reached Monday - Friday 9-6pm EST.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658