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 .
This is the First Office Action on the Merits of US Application 18/453,936 filed on 08/22/2023 which is a CON of 17/357,784 filed on 06/24/2021 which is a CON of 16/743,455 filed on 01/15/2020 which is a CON of 15/579,926 filed on 07/02/2018 (US Patent 10,543,250) which is a 371 of PCT/US2016/035896 filed on 06/03/2016 which claims US priority benefit of US Provisional 62/171,868 filed on 06/05/2015.
Status of the claims
Claims 1-12, and 16-20 are pending. There are no cancelled claims to account for the missing claims in the original listing. The claims have been renumbered by Examiner, with claims 16-20 renumbered 13-17; claims 18-20 have been cancelled. A compliant, follow up correction of the claims listing is requested. Claims 1-17 are now pending and are presented for examination on the merits.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-4 and 6-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims encompass pharmaceutical compositions with the intended use of treating an infection in a subject. Claims require the critically essential element of a functional, therapeutic peptide that is effective in treating an infection in a patient and where the infection is caused by multidrug-resistant Pseudomonas aeruginosa (MDRPA) or multidrug-resistant Acinetobacter baumannii (MDRAB), and wherein the infection is caused by a parasite and the patient suffers from malaria.
The specification shows possession of pharmaceutical compositions of the peptide of instant SEQ ID NO:1 (e.g., claim 5). However, it is considered that one of ordinary skill in the art would not be able to envision whether a given species of variant of SEQ ID NO: 1 as encompassed by the claims would possess the required properties of a therapeutic peptide that is effective in treating an infection in a patient and where the infection is caused by multidrug-resistant Pseudomonas aeruginosa (MDRPA) or multidrug-resistant Acinetobacter baumannii (MDRAB), and wherein the infection is caused by a parasite and the patient suffers from malaria. The specification does not contain a representative set of variants of SEQ ID NO: 1, having these required properties of the claims.
Further, the state of the art provides evidence that even a single amino acid change to a therapeutic peptide may significantly change the functional properties of the peptide. For example, Sengupta et al discloses that site-specific amino acid substitution in dodecameric peptides determine the function of the peptide in cancer cells (See Sengupta et al Nucleic Acids_Res 2018 Nov 2 Vol 46 No. 19 pages 9932-9950).
The Court of Appeals for the Federal Circuit has recently held that a "written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as be structure, formula [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." University of California v. Eli Lilly and Co., 1997 U.S. App. LEXlS 18221, at *23, quoting Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (bracketed material in original).
To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these.
While having written description of the claims drawn to the pharmaceutical comprising the peptide consisting SEQ ID NO: 1, the specification does not provide sufficient descriptive support for the myriad of embodiments embraced by the claims. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Given this lack of description of representative species encompassed by the genus of the claim, the specification does not sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the entire scope of the claimed invention.
For inventions in an unpredictable art, adequate written description of a genus, which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly. Description of a representative number of species does not require the description to be of such specificity that it would provide individual support for each species that the genus embraces. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, first paragraph. In the instant case, the unpredictability of the art is evidenced by the cited references, above. Adequate written description requires more than a mere statement that a compound is part of the invention and reference to a potential method of isolating a compound. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
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.
Claims 1, 3, 4, 6, 7, 8, 9, 10, 11, 12, and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Yeaman et al. ("Yeaman", US 7,820,619, IDS dated 08/22/2023) in view of Yount et al. (WO2007/149542, IDS dated 08/22/2023) and Yeaman et al. ("Yeaman Poster #72 MHSRS- 687", 2014, IDS dated 08/22/2023).
Regarding claims 1, 3, 4, 6, 7, 8, 9, 10, 11, 12, and 13, Yeaman discloses antimicrobial peptides and polynucleotides encoding such, the peptides comprising a 100% match to instant SEQ ID NO: 3 (ALYKKFKKKLLKSLKRLG) ("RP-1", a 18 residue antimicrobial peptide, SEQ ID NO:3 of Yeaman). Yeaman disclose that their disclosed peptides can be used as individual antimicrobial agents and antimicrobial agents in combination with other antimicrobial peptides (e.g., cols, 2-14, 42-48, ref claims). Yeaman discloses conjugates (combination/fusion examples, cols. 44- 48). The peptides exert potent, broad spectrum antimicrobial activities in vitro, and can be used to potentiate conventional antimicrobial agents, to potentiate other antimicrobial peptides, are active against many organisms that exhibit resistance to multiple antibiotics, and enhance the antimicrobial functions of leukocytes (e.g., col. 12). The peptides and metapeptides can be designed to overcome problems of toxicity, immunogenicity, and shortness of duration of effectiveness due to biodegradation, retaining activity in plasma and serum, since they are based upon natural antimicrobial peptides that have lower inherent mammalian cell toxicities than conventional antimicrobial peptides (e.g., col. 12.). The peptides are effective, e.g., against Staphylococcus aureus and Salmonella typhimurium (e.g., col. 49 and Figures 4-11).
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Regarding claim 7, Yeaman discloses conservative and non-conservative substitutions of one or more amino acids(e.g., in cols. 27 and 30).
Regarding claim 12, Yeaman also teaches that their peptides are amenable to chemical synthesis and recombinant DNA expression techniques. Recombinant DNA expression would necessarily require a polynucleotide encoding the peptide and/or fusion peptide, facilitating their production in quantities necessary for use and evaluation in vitro, and eventual therapeutic applications (e.g., col. 12).
However, Yeaman does not expressly teach combining/making a fusion peptide/polynucleotide with CPTAQLIATLKNGRKICLDLQ (SEQ ID NO: 2) or a sequence that is at least 85% sequence identical to SEQ ID NO: 2.
Regarding claims 1, 3, 4, 6, 7, 8, 9, 10, 11, 12, and 13-16, Yount teaches novel kinocidin peptides comprising a C-terminal protein of a kinocidin, including the core portion of PF-4 (Human) which is CPTAQLIATLKNGRKICLDLQAP which has 100% identity to instant SEQ ID NO:2. (See Figure 13, demonstrating the Y-core domain within kinocidins, including PF-4). Yount discloses novel kinocidin peptides comprising a C-terminal portion of a kinocidin, wherein the C-terminal portion encompasses an α-helical secondary structure and further displays antimicrobial activity. The kinocidin peptides of Yount are derived from and correspond to a C-terminal portion of a kinocidin that includes a Үкс core and that can be a CXC, CC, or C class chemokine (e.g., abstract).
Yount teaches that, in many contexts of infection or inflammation, pH of interstitial fluids, abscess exudates, and serum is significantly lower than that of plasma. Furthermore, recurring host-defense strategies include mild acidification of mucosal epithelia and the neutrophil phagolysosome. Thus, assessment of IL-8 and subdomain antimicrobial efficacy at pH 7.5 versus 5.5 was designed to reflect such microenvironments. The fact that kinocidins, including IL-8 and the 5 IL-8α antimicrobial domain, exert enhanced antimicrobial efficacy at pH 5.5 is consistent with these concepts. Thus, beyond providing a chemical barrier, such pH modulation may contribute to mucosal surfaces that are inhospitable to microbial colonization. A parallel line of reasoning also supports the concept that kinocidins mutually potentiate the antimicrobial mechanisms of leukocytes. Kinocidins are known to interact with leukocytes via chemokine 0 motifs, and with microorganisms via charge-mediated properties. Thus, pathogens pre-decorated with kinocidins or antimicrobial domains thereof are believed to be more efficiently killed when internalized into the acidic phagolysosome of professional phagocytes. Additional support for this concept is exemplified by studies demonstrating significant quantities of the kinocidin PBP in the 5 phagolysosomes of activated macrophages. In these ways, kinocidins are likely evolved to function in specific contexts to optimize antimicrobial defenses without concomitant host toxicity.
Especially regarding claims 13-14, according to Yount, a fungal infection that may be treated according to the invention may be caused by a variety of fungal species including Candida (including C. albicans, C. tropicalis, C. parapsilosis, C. stellatoidea, C. krusei, C. parakrusei, C. lusitanae, C. pseudotropicalis, C. guilliermondi, C. dubliniensis, C.famata or C. glabrata), Aspergillus (including A. fumigatus, A.flavus, A. niger, A. nidulans, A. terreus, A. sydowi, A. flavatus, or A. glaucus), Cryptococcus, Histoplasma, Coccidioides, Paracoccidioides, Blastomyces, Basidiobolus, Conidiobolus, Rhizopus, Rhizomucor, Mucor, Absidia, Mortierella, Cunninghamella, Saksenaea, Pseudallescheria, Paecilomyces, Fusarium, Trichophyton, Trichosporon, Microsporum, Epidermophyton, Scytalidium, Malassezia, Actinomycetes, Sporothrix, Penicillium, Saccharomyces or Pneumocystis.
Other infections that may be treated using a peptide construct according to Yount may be caused by gram-negative bacterial species that include Acidaminococcus, Acinetobacter, Aeromonas, Alcaligenes, Bacteroides, Bordetella, Bránhamella, Brucella, Burkholderia, Calymmatobacterium, Campylobacter, Cardiobaclerium, Chromobacterium, Citrobacter, Edwardsiella, Enterobacter, Escherichia, Flavobacterium, Francisella, Fusobacterium, Haemophilus, Klebsiella, Legionella, Moraxella, Morganella, Neisseria, Pasturella, Plesiomonas, Porphyromonas, Prevotella, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Shigella, Stentrophomonas, Streptobacillus, Treponema, Veillonella, Vibrio, or Yersinia species; Chlamydia; or gram-positive bacterial species that include Staphylococcus, Streptococcus, Micrococcus, Peptococcus, Peptostreptococcus, Enterococcus, Bacillus, Clostridium, Lactobacillus, Listeria, Erysipelothrix, Propionibacterium, Eubacterium, Nocardia, Actinomyces, or Corynebacterium species as well as Mycoplasma, Ureaplasma, or Mycobacteria.
Especially regarding claims 13-14, and 16, other infections include infections by protozoa including Plasmodia, Toxoplasma, Leishmania, Trypanosoma, Giardia, Entamoeba, Acanthamoeba, Nagleria, Hartmanella, Balantidium, Babesia, Cryptosporidium, Isospora, Microsporidium, Trichomonas or Pneumocystis species; or infections by other parasites include helminths (e.g., pages 28-29).
Compositions, including therapeutic compositions, of the peptide construct of Yount may be administered systemically or topically. Systemic routes of administration include oral, intravenous, intramuscular or subcutaneous injection (including into depots for long- term release), intraocular or retrobulbar, intrathecal, intraperitoneal (e.g. by intraperitoneal lavage), intrapulmonary (using powdered drug, or an aerosolized or nebulized drug solution), or transdermal. Topical routes include administration in the form of rinses, washes, salves, creams, jellies, drops or ointments (including opthalmic and otic preparations), suppositories, such as vaginal suppositories, or irrigation fluids (for, e.g., irrigation of wounds).
Known antibacterial agents which can be co-administered or combined with the peptide construct according to Yount include antibiotics, which are natural chemical substances of relatively low molecular weight produced by various species of microorganisms, such as bacteria (including Bacillus species), actinomycetes (including Streptomyces) or fungi, that inhibit growth of or destroy other microorganisms. Substances of similar structure and mode of action may be synthesized chemically, or natural compounds may be modified to produce semi-synthetic antibiotics. These biosynthetic and semisynthetic derivatives are also effective as antibiotics. The major classes of antibiotics include (1) the ß-lactams, including the penicillins, cephalosporins or monobactams, including those with ß-lactamase inhibitors; (2) the aminoglycosides, e.g., gentamicin, tobramycin, netilmycin, or amikacin; (3) the tetracyclines; (4) the sulfonamides and/or trimethoprim; (5) the quinolones or fluoroquinolones, e.g., ciprofloxacin, norfloxacin, ofloxacin, moxifloxacin, trovafloxacin, grepafloxacin, levofloxacin or gatifloxacin (6) vancomycin; (7) the macrolides, which include for example, erythromycin, azithromycin, or clarithromycin; or (8) other antibiotics, e.g., the polymyxins, chloramphenicol, rifampin, the lincosamides, or the oxazolidinones.
Furthermore, Yeaman Poster #72, MHSRS 687, 2014, describes a fusion peptide with antibacterial properties of the CLCX4 kinocidin Y-core motif-RP-1 construct (see Poster, Y-RP-1), therefore confirming that such fusion peptides were known to those of ordinary skill in the art.
Especially regarding claims 14-15, Yeaman Poster #72, MHSRS 687 discloses that increasing rates of life-threatening infection and antibiotic resistance urge development of novel anti-infectives versus multi-drug resistant Acinetobacter baumannii (MDRAB) and like Gram-negative pathogens. Yeaman Poster #72 goes on to teach that few compounds in the development pipeline have novel mechanisms of action against these pathogens, and even fewer have acceptable pharmacology and toxicity profiles (e.g., col. 1). Y-RP-1 is a synthetic metapeptide engineered on kinocidin CXCL4, with promising in vitro and ex vivo efficacies against MDRAB. Peptide efficacies were studied in vitro, ex vivo and in mouse neutropenic MDRAB pneumonia (e.g., cols. 1-2). Y-RP-1 has promising efficacy and favorably interacts with gold-standard antibiotics against MDRAB. Systemic peptide administration achieved robust efficacy vs. MDRAB pneumonia in an otherwise lethal neutropenic murine model.
It would have been obvious to make a fusion protein of the antimicrobial peptides ALYKKFKKKLLKSLKRLG (SEQ ID NO:3) and CPTAQLIATLKNGRKICLDLQAP (SEQ ID NO:2) and/or a polynucleotides encoding thereof to make an antimicrobial peptides as in instant claim 9.
One of ordinary skill in the art before the effective filing date would have been motivated to do so to potentiate/amplify their antimicrobial activities as described by Yount and Yeaman and because Yeaman's peptides were known to exert potent, broad spectrum antimicrobial activities in vitro, were known to potentiate conventional antimicrobial agents and other antimicrobial peptides, to be active against many organisms that exhibit resistance to multiple antibiotics, and to enhance the antimicrobial functions of leukocytes (e.g., col. 12).
One of ordinary skill in the art, before the effective filing date, would have had a reasonable expectation of success given that Yeaman teaches that ALYKKFKKKLLKSLKRLG (SEQ ID NO:3) can be used as individual antimicrobial agents and antimicrobial agents in combination with other antimicrobial peptides (e.g., cols, 2-14, 42-48, claims) including conjugates (combination/fusion examples, cols. 44-48) and because Yeaman Poster #72, MHSRS 687, 2014, describes a fusion peptide with antibacterial properties of the gamma core CLCX4 of PF-4 kinocidin and the RP-1 peptides (see Poster), having activity against MDRAB (e.g., cols. 1-2). With regards to the limitation wherein the first fragment is at the N-terminal end of the second fragment, although not expressly taught, it would be obvious to place SEQ ID NO: 3 in the N-terminus position to create CPTAQLIATLKNGRKICLDLQAPALYKKFKKKLLKSLKRLG which has 95% sequence identity to SEQ ID NO: 1, reading upon claim 6, wherein AP is a spacer which is 5 amino acids or fewer in length, and also has a length not longer than 100 amino acids and/or 75 amino acids and/or 50 amino acids in length, reading upon instant claims 3- 4, 8-10.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so because Figure 1 of Yeaman shows that SEQ ID NO:2 (ALYKKFKKKLLKSLKRLG) was originally located in the C-terminus of PMP-2 and thus one would be motivated to maintain this position in order to maintain the antibacterial activity of SEQ ID NO:2. AP reads upon a spacer having 5 amino acids or fewer in length. One of ordinary skill in the art would have had a reasonable expectation of success before the effective filing date of the invention because Yeaman also teaches that their peptides are quite amenable to chemical synthesis and recombinant DNA expression techniques (which would necessarily require a polynucleotide encoding the peptide and/or fusion peptide), facilitating their production in quantities necessary for use and evaluation in vitro, and eventual therapeutic applications (e.g., col. 12). Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, and 6-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No 6,743,769, in view of Yount et al (WO2007/149542, above) and Yeaman et al ("Yeaman Poster #72 MHSRS-687", 2014, above).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is anticipated or made prima facie obvious over the invention of US '769, in view of Yount et al and "Yeaman Poster #72”.
Regarding instant claims 1-4, and 6-14, patented claim 1 recites an antimicrobial peptide comprising SEQ ID NO:3, which is identical to instantly claimed SEQ ID NO: 3.
However, patented claims do not expressly claim combining/making a fusion peptide/polynucleotide with CPTAQLIATLKNGRKICLDLO (SEQ ID NO: 2) or a sequence that is at least 85% sequence identical to SEQ ID NO: 2.
Yount discloses novel kinocidin peptides comprising a C-terminal portion of a kinocidin, wherein the C-terminal portion encompasses an α-helical secondary structure and further displays antimicrobial activity. The kinocidin peptides of Yount are derived from and correspond to a C-terminal portion of a kinocidin that includes a Үкс core and that can be a CXC, CC, or C class chemokine (e.g., abstract). Yount teaches novel kinocidin peptides comprising a C-terminal protein of a kinocidin, including the core portion of PF-4 (Human) which is CPTAQLIATLKNGRKICLDLOAP and corresponds to instant SEQ ID NO:2 (e.g., Figure 13, demonstrating the Y-core domain within kinocidins, including PF-4). Yount teaches that, in many contexts of infection or inflammation, pH of interstitial fluids, abscess exudates, and serum is significantly lower than that of plasma. Furthermore, recurring host-defense strategies include mild acidification of mucosal epithelia and the neutrophil phagolysosome. Thus, assessment of IL-8 and subdomain antimicrobial efficacy at pH 7.5 versus 5.5 was designed to reflect such microenvironments. The fact that kinocidins, including IL-8 and the 5 IL-8α antimicrobial domain, exert enhanced antimicrobial efficacy at pH 5.5 is consistent with these concepts. Thus, beyond providing a chemical barrier, such pH modulation may contribute to mucosal surfaces that are inhospitable to microbial colonization. A parallel line of reasoning also supports the concept that kinocidins mutually potentiate the antimicrobial mechanisms of leukocytes. Kinocidins are known to interact with leukocytes via chemokine 0 motifs, and with microorganisms via charge-mediated properties. Thus, pathogens pre-decorated with kinocidins or antimicrobial domains thereof are believed to be more efficiently killed when internalized into the acidic phagolysosome of professional phagocytes. Additional support for this concept is exemplified by studies demonstrating significant quantities of the kinocidin PBP in the 5 phagolysosomes of activated macrophages. In these ways, kinocidins are likely evolved to function in specific contexts to optimize antimicrobial defenses without concomitant host toxicity.
According to Yount, a fungal infection that may be treated according to the invention may be caused by a variety of fungal species including Candida (including C. albicans, C. tropicalis, C. parapsilosis, C. stellatoidea, C. krusei, C. parakrusei, C. lusitanae, C. pseudotropicalis, C. guilliermondi, C. dubliniensis, C.famata or C. glabrata), Aspergillus (including A. fumigatus, A.flavus, A. niger, A. nidulans, A. terreus, A. sydowi, A. flavatus, or A. glaucus), Cryptococcus, Histoplasma, Coccidioides, Paracoccidioides, Blastomyces, Basidiobolus, Conidiobolus, Rhizopus, Rhizomucor, Mucor, Absidia, Mortierella, Cunninghamella, Saksenaea, Pseudallescheria, Paecilomyces, Fusarium, Trichophyton, Trichosporon, Microsporum, Epidermophyton, Scytalidium, Malassezia, Actinomycetes, Sporothrix, Penicillium, Saccharomyces or Pneumocystis.
Other infections that may be treated using a peptide construct according to Yount may be caused by gram-negative bacterial species that include Acidaminococcus, Acinetobacter, Aeromonas, Alcaligenes, Bacteroides, Bordetella, Bránhamella, Brucella, Burkholderia, Calymmatobacterium, Campylobacter, Cardiobaclerium, Chromobacterium, Citrobacter, Edwardsiella, Enterobacter, Escherichia, Flavobacterium, Francisella, Fusobacterium, Haemophilus, Klebsiella, Legionella, Moraxella, Morganella, Neisseria, Pasturella, Plesiomonas, Porphyromonas, Prevotella, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Shigella, Stentrophomonas, Streptobacillus, Treponema, Veillonella, Vibrio, or Yersinia species; Chlamydia; or gram-positive bacterial species that include Staphylococcus, Streptococcus, Micrococcus, Peptococcus, Peptostreptococcus, Enterococcus, Bacillus, Clostridium, Lactobacillus, Listeria, Erysipelothrix, Propionibacterium, Eubacterium, Nocardia, Actinomyces, or Corynebacterium species as well as Mycoplasma, Ureaplasma, or Mycobacteria.
Other infections include infections by protozoa including Plasmodia, Toxoplasma, Leishmania, Trypanosoma, Giardia, Entamoeba, Acanthamoeba, Nagleria, Hartmanella, Balantidium, Babesia, Cryptosporidium, Isospora, Microsporidium, Trichomonas or Pneumocystis species; or infections by other parasites include helminths (e.g., pages 28-29).
Compositions, including therapeutic compositions, of the peptide construct of Yount may be administered systemically or topically. Systemic routes of administration include oral, intravenous, intramuscular or subcutaneous injection (including into depots for long- term release), intraocular or retrobulbar, intrathecal, intraperitoneal (e.g. by intraperitoneal lavage), intrapulmonary (using powdered drug, or an aerosolized or nebulized drug solution), or transdermal. Topical routes include administration in the form of rinses, washes, salves, creams, jellies, drops or ointments (including opthalmic and otic preparations), suppositories, such as vaginal suppositories, or irrigation fluids (for, e.g., irrigation of wounds).
Known antibacterial agents which can be co-administered or combined with the peptide construct according to Yount include antibiotics, which are natural chemical substances of relatively low molecular weight produced by various species of microorganisms, such as bacteria (including Bacillus species), actinomycetes (including Streptomyces) or fungi, that inhibit growth of or destroy other microorganisms. Substances of similar structure and mode of action may be synthesized chemically, or natural compounds may be modified to produce semi-synthetic antibiotics. These biosynthetic and semisynthetic derivatives are also effective as antibiotics. The major classes of antibiotics include (1) the ß-lactams, including the penicillins, cephalosporins or monobactams, including those with ß-lactamase inhibitors; (2) the aminoglycosides, e.g., gentamicin, tobramycin, netilmycin, or amikacin; (3) the tetracyclines; (4) the sulfonamides and/or trimethoprim; (5) the quinolones or fluoroquinolones, e.g., ciprofloxacin, norfloxacin, ofloxacin, moxifloxacin, trovafloxacin, grepafloxacin, levofloxacin or gatifloxacin (6) vancomycin; (7) the macrolides, which include for example, erythromycin, azithromycin, or clarithromycin; or (8) other antibiotics, e.g., the polymyxins, chloramphenicol, rifampin, the lincosamides, or the oxazolidinones.
Furthermore, Yeaman Poster #72, describes a fusion peptide with antibacterial properties of the CLCX4 kinocidin Y-core motif-RP-1 construct (see Poster, Y-RP-1), therefore confirming that such fusion peptides were known to those of ordinary skill in the art. Yeaman Poster #72, MHSRS 687 discloses that increasing rates of life-threatening infection and antibiotic resistance urge development of novel anti-infectives versus multi-drug resistant Acinetobacter baumannii (MDRAB) and like Gram-negative pathogens. Yeaman Poster #72 goes on to teach that few compounds in the development pipeline have novel mechanisms of action against these pathogens, and even fewer have acceptable pharmacology and toxicity profiles (e.g., col. 1). Y-RP-1 is a synthetic metapeptide engineered on kinocidin CXCL4, with promising in vitro and ex vivo efficacies against MDRAB. Peptide efficacies were studied in vitro, ex vivo and in mouse neutropenic MDRAB pneumonia (e.g., cols. 1-2). Y-RP-1has promising efficacy and favorably interacts with gold-standard antibiotics against MDRAB. Systemic peptide administration achieved robust efficacy vs. MDRAB pneumonia in an otherwise lethal neutropenic murine model.
It would have been obvious to make a fusion protein of the antimicrobial peptides ALYKKFKKKLLKSLKRLG (SEQ ID NO:3) and CPTAQLIATLKNGRKICLDLQAP (SEQ ID NO:2) and/or a polynucleotides encoding thereof to make an antimicrobial peptides as in instant claims 9-11 and to treat infection therewith.
One of ordinary skill in the art before the effective filing date would have been motivated to do so to potentiate/amplify their antimicrobial activities as described by Yount and because US'769 claimed antimicrobial peptides.
One of ordinary skill in the art, before the effective filing date, would have had a reasonable expectation of success given Yeaman Poster #72, MHSRS 687, 2014, describes a fusion peptide with antibacterial properties of the gamma core CLCX4 of PF-4 kinocidin and the RP-1 peptides (see Poster), having activity against MDRAB (e.g., cols. 1-2).
With regards to the limitation wherein the first fragment is at the N-terminal end of the second fragment, although not expressly taught, it would be obvious to place SEQ ID NO: 3 in the N-terminus position to create CPTAQLIATLKNGRKICLDLQAPALYKKFKKKLLKSLKRLG which has 95% sequence identity to SEQ ID NO: 1, reading upon claim 6, wherein AP is a spacer which is 5 amino acids or fewer in length, and also has a length not longer than 100 amino acids and/or 75 amino acids and/or 50 amino acids in length, reading upon instant claims 3-4, 8-10. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so because combining the peptide SEQ ID NO: 3 (ALYKKFKKKLLKSLKRLG) with the peptide of Yount (SEQ ID NO: 2) was possible at either terminal end. In the case of the first fragment is attached to the second fragment, AP reads upon a spacer having 5 amino acids or fewer in length.
One of ordinary skill in the art would have had a reasonable expectation of success before the effective filing date of the invention because chemical synthesis and recombinant DNA expression techniques (which would necessarily require a polynucleotide encoding the peptide and/or fusion peptide) were available to those skilled in the art at the time the invention was made.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claims 1-4, 6-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 7,820,619, in view of Yount et al (WO2007/149542, above) and Yeaman et al ("Yeaman Poster #72 MHSRS-687", 2014, above).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is anticipated or made prima facie obvious over the invention of US '619 in view of Yount et al and "Yeaman Poster #72”.
Regarding instant claims 1-4, and 6-14 patented claim 3 recites an antimicrobial peptide comprising ref SEQ ID NO:3, which is identical to instantly claimed SEQ ID NO: 3.
However, patented claims do not expressly claim combining/making a fusion peptide/polynucleotide with CPTAQLIATLKNGRKICLDLO (SEQ ID NO: 2) or a sequence that is at least 85% sequence identical to SEQ ID NO: 2.
Yount discloses novel kinocidin peptides comprising a C-terminal portion of a kinocidin, wherein the C-terminal portion encompasses an α-helical secondary structure and further displays antimicrobial activity. The kinocidin peptides of Yount are derived from and correspond to a C-terminal portion of a kinocidin that includes a Үкс core and that can be a CXC, CC, or C class chemokine (e.g., abstract). Yount teaches novel kinocidin peptides comprising a C-terminal protein of a kinocidin, including the core portion of PF-4 (Human) which is CPTAQLIATLKNGRKICLDLQAP and corresponds to instant SEQ ID NO:2 (e.g., Figure 13, demonstrating the Y-core domain within kinocidins, including PF-4). Yount teaches that, in many contexts of infection or inflammation, pH of interstitial fluids, abscess exudates, and serum is significantly lower than that of plasma. Furthermore, recurring host-defense strategies include mild acidification of mucosal epithelia and the neutrophil phagolysosome. Thus, assessment of IL-8 and subdomain antimicrobial efficacy at pH 7.5 versus 5.5 was designed to reflect such microenvironments. The fact that kinocidins, including IL-8 and the 5 IL-8α antimicrobial domain, exert enhanced antimicrobial efficacy at pH 5.5 is consistent with these concepts. Thus, beyond providing a chemical barrier, such pH modulation may contribute to mucosal surfaces that are inhospitable to microbial colonization. A parallel line of reasoning also supports the concept that kinocidins mutually potentiate the antimicrobial mechanisms of leukocytes. Kinocidins are known to interact with leukocytes via chemokine 0 motifs, and with microorganisms via charge-mediated properties. Thus, pathogens pre-decorated with kinocidins or antimicrobial domains thereof are believed to be more efficiently killed when internalized into the acidic phagolysosome of professional phagocytes. Additional support for this concept is exemplified by studies demonstrating significant quantities of the kinocidin PBP in the 5 phagolysosomes of activated macrophages. In these ways, kinocidins are likely evolved to function in specific contexts to optimize antimicrobial defenses without concomitant host toxicity.
According to Yount, a fungal infection that may be treated according to the invention may be caused by a variety of fungal species including Candida (including C. albicans, C. tropicalis, C. parapsilosis, C. stellatoidea, C. krusei, C. parakrusei, C. lusitanae, C. pseudotropicalis, C. guilliermondi, C. dubliniensis, C.famata or C. glabrata), Aspergillus (including A. fumigatus, A.flavus, A. niger, A. nidulans, A. terreus, A. sydowi, A. flavatus, or A. glaucus), Cryptococcus, Histoplasma, Coccidioides, Paracoccidioides, Blastomyces, Basidiobolus, Conidiobolus, Rhizopus, Rhizomucor, Mucor, Absidia, Mortierella, Cunninghamella, Saksenaea, Pseudallescheria, Paecilomyces, Fusarium, Trichophyton, Trichosporon, Microsporum, Epidermophyton, Scytalidium, Malassezia, Actinomycetes, Sporothrix, Penicillium, Saccharomyces or Pneumocystis.
Other infections that may be treated using a peptide construct according to Yount may be caused by gram-negative bacterial species that include Acidaminococcus, Acinetobacter, Aeromonas, Alcaligenes, Bacteroides, Bordetella, Bránhamella, Brucella, Burkholderia, Calymmatobacterium, Campylobacter, Cardiobaclerium, Chromobacterium, Citrobacter, Edwardsiella, Enterobacter, Escherichia, Flavobacterium, Francisella, Fusobacterium, Haemophilus, Klebsiella, Legionella, Moraxella, Morganella, Neisseria, Pasturella, Plesiomonas, Porphyromonas, Prevotella, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Shigella, Stentrophomonas, Streptobacillus, Treponema, Veillonella, Vibrio, or Yersinia species; Chlamydia; or gram-positive bacterial species that include Staphylococcus, Streptococcus, Micrococcus, Peptococcus, Peptostreptococcus, Enterococcus, Bacillus, Clostridium, Lactobacillus, Listeria, Erysipelothrix, Propionibacterium, Eubacterium, Nocardia, Actinomyces, or Corynebacterium species as well as Mycoplasma, Ureaplasma, or Mycobacteria.
Other infections include infections by protozoa including Plasmodia, Toxoplasma, Leishmania, Trypanosoma, Giardia, Entamoeba, Acanthamoeba, Nagleria, Hartmanella, Balantidium, Babesia, Cryptosporidium, Isospora, Microsporidium, Trichomonas or Pneumocystis species; or infections by other parasites include helminths (e.g., pages 28-29).
Compositions, including therapeutic compositions, of the peptide construct of Yount may be administered systemically or topically. Systemic routes of administration include oral, intravenous, intramuscular or subcutaneous injection (including into depots for long- term release), intraocular or retrobulbar, intrathecal, intraperitoneal (e.g. by intraperitoneal lavage), intrapulmonary (using powdered drug, or an aerosolized or nebulized drug solution), or transdermal. Topical routes include administration in the form of rinses, washes, salves, creams, jellies, drops or ointments (including opthalmic and otic preparations), suppositories, such as vaginal suppositories, or irrigation fluids (for, e.g., irrigation of wounds).
Known antibacterial agents which can be co-administered or combined with the peptide construct according to Yount include antibiotics, which are natural chemical substances of relatively low molecular weight produced by various species of microorganisms, such as bacteria (including Bacillus species), actinomycetes (including Streptomyces) or fungi, that inhibit growth of or destroy other microorganisms. Substances of similar structure and mode of action may be synthesized chemically, or natural compounds may be modified to produce semi-synthetic antibiotics. These biosynthetic and semisynthetic derivatives are also effective as antibiotics. The major classes of antibiotics include (1) the ß-lactams, including the penicillins, cephalosporins or monobactams, including those with ß-lactamase inhibitors; (2) the aminoglycosides, e.g., gentamicin, tobramycin, netilmycin, or amikacin; (3) the tetracyclines; (4) the sulfonamides and/or trimethoprim; (5) the quinolones or fluoroquinolones, e.g., ciprofloxacin, norfloxacin, ofloxacin, moxifloxacin, trovafloxacin, grepafloxacin, levofloxacin or gatifloxacin (6) vancomycin; (7) the macrolides, which include for example, erythromycin, azithromycin, or clarithromycin; or (8) other antibiotics, e.g., the polymyxins, chloramphenicol, rifampin, the lincosamides, or the oxazolidinones.
Furthermore, Yeaman Poster #72, describes a fusion peptide with antibacterial properties of the CLCX4 kinocidin Y-core motif-RP-1 construct (see Poster, Y-RP-1), therefore confirming that such fusion peptides were known to those of ordinary skill in the art. Yeaman Poster #72, MHSRS 687 discloses that increasing rates of life-threatening infection and antibiotic resistance urge development of novel anti-infectives versus multi-drug resistant Acinetobacter baumannii (MDRAB) and like Gram-negative pathogens. Yeaman Poster #72 goes on to teach that few compounds in the development pipeline have novel mechanisms of action against these pathogens, and even fewer have acceptable pharmacology and toxicity profiles (e.g., col. 1). Y-RP-1 is a synthetic metapeptide engineered on kinocidin CXCL4, with promising in vitro and ex vivo efficacies against MDRAB. Peptide efficacies were studied in vitro, ex vivo and in mouse neutropenic MDRAB pneumonia (e.g., cols. 1-2). Y-RP-1has promising efficacy and favorably interacts with gold-standard antibiotics against MDRAB. Systemic peptide administration achieved robust efficacy vs. MDRAB pneumonia in an otherwise lethal neutropenic murine model.
It would have been obvious to make a fusion protein of the antimicrobial peptides ALYKKFKKKLLKSLKRLG (SEQ ID NO:3) and CPTAQLIATLKNGRKICLDLQAP (SEQ ID NO:2) and/or a polynucleotides encoding thereof to make an antimicrobial peptides as in instant claims 9-11 and to treat infection therewith.
One of ordinary skill in the art before the effective filing date would have been motivated to do so to potentiate/amplify their antimicrobial activities as described by Yount and because US'619 claimed antimicrobial peptides.
One of ordinary skill in the art, before the effective filing date, would have had a reasonable expectation of success given Yeaman Poster #72, MHSRS 687, 2014, describes a fusion peptide with antibacterial properties of the gamma core CLCX4 of PF-4 kinocidin and the RP-1 peptides (see Poster), having activity against MDRAB (e.g., cols. 1-2).
With regards to the limitation wherein the first fragment is at the N-terminal end of the second fragment, although not expressly taught, it would be obvious to place SEQ ID NO: 3 in the N-terminus position to create CPTAQLIATLKNGRKICLDLQAPALYKKFKKKLLKSLKRLG which has 95% sequence identity to SEQ ID NO: 1, reading upon claim 6, wherein AP is a spacer which is 5 amino acids or fewer in length, and also has a length not longer than 100 amino acids and/or 75 amino acids and/or 50 amino acids in length, reading upon instant claims 3-4, 8-10.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so because combining the peptide SEQ ID NO: 3 (ALYKKFKKKLLKSLKRLG) with the peptide of Yount (SEQ ID NO: 2) was possible at either terminal end. In the case of the first fragment is attached to the second fragment, AP reads upon a spacer having 5 amino acids or fewer in length.
One of ordinary skill in the art would have had a reasonable expectation of success before the effective filing date of the invention because chemical synthesis and recombinant DNA expression techniques (which would necessarily require a polynucleotide encoding the peptide and/or fusion peptide) were available to those skilled in the art at the time the invention was made.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,543,250.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is anticipated or made prima facie obvious over the invention of US '250, as explained below.
Regarding instant claims 1-2 and 5-6, patented claim 1 recites an isolated peptide comprising the amino acid sequence of instant SEQ ID NO:1 (CPTAQLIATLKNGRKICLDLQALYKKFKKKLLKSLKRLG); (ref SEQ ID NO: 1 ).
Regarding instant claims 3-4, patented claim 2 recite a P residue linker: CPTAQLIATLKNGRKICLDLQPALYKKFKKKLLKSLKRLG SEQ ID NO:14.
Further, regarding the instant dependent claims 7-17, patented claims 4-20 recite essentially the same limitations of the instant claims.
SEQ ID NO:1 anticipates the instantly claimed genus of isolated peptides comprising: (1) a first fragment consisting of the amino acid sequence of SEQ ID NO:2 (CPTAQLIATLKNGRKICLDLQ) or a first amino acid sequence having at least 85% sequence identity to SEQ ID NO: 2; and (2) a second fragment consisting of the amino acid sequence of SEQ ID NO:3 (ALYKKFKKKLLKSLKRLG) or a second amino acid sequence having at least 85% sequence identity to SEQ ID NO: 3, wherein the first fragment and the second fragment are connected directly or connected through a spacer that is 10 amino acids or fewer in length, and wherein the first fragment is at the N- terminal end of the second fragment and it is anticipated by the SEQ ID NO:1 which reads upon "connected directly". The methods of treatment with SEQ ID NO:1 also anticipate the instantly claimed methods.
Thus, the instant claims, as a whole, are prima facie obvious over the claims of US '250.
Conclusion
No claim is allowed.
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CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658
/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658