DETAILED ACTION
Status of the Claims
Claims 7-20 are pending in the instant application. Claims 11-18 have been withdrawn based upon Restriction/Election as discussed below. Claims 7-10, 19 and 20 are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . In response to Applicant’s comments regarding the Drawings (p. 5, item 4) Examiner’s are no longer accepting/rejecting drawings “The Office no longer considers drawings as formal or informal. Drawings are either acceptable or unacceptable. Drawings will be accepted by the Office of Patent Application Processing (OPAP) if the drawings are readable and reproducible for publication purposes.” MPEP §608.02(b)(I).
Restriction/Election
Applicant's election with traverse of Group I drawn to compositions of matter (antibacterial compositions, currently claims 7-10, 19 and 20) in the reply filed on 11/07/2025 is acknowledged. The traversal is on the ground(s) that Moussa et al. does not teach or suggest any polypeptide polymer. This is not found persuasive because Applicant has amended the claim around the Moussa et al. reference, however, the claims are still considered nonobvious as detailed below.
Applicants have elected the following species in the reply filed (a) a polymethylmethacrylate (PMMA) bone cement and the polypeptide of Example 1 – D,L-lysine, L-benzylglutamate, n= 27, x%=90%, y% = 10%, a = c1 alkyl (methyl), and b = H. The examiner agrees that the Election of Species is for initial search purposes only.
The requirement is still deemed proper and is therefore made FINAL.
Claims 11-18 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/07/2025.
Priority
The instant Application is a 371 of PCT/CN02021/130974 filed 11/16/2021 and claims priority to CN-2021-10162718.0 filed 02/05/2021.
The U.S. effective filing date has been determined to be 11/16/2021, the filing date of PCT/CN02021/130974. Applicant's claim for a priority date of, 02/05/2021, the filing date of document CN-2021-10162718.0, is acknowledged, however no English translation of the foreign priority document has been provided such that the examiner can confirm written description (112(a)) support therein.
Information Disclosure Statement
The information disclosure statement submitted on 01/11/2023 was/were filed before/after the mailing date of the first office action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Claim Rejections - 35 USC § 112(b)
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 10 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 pre-AIA the applicant regards as the invention.
Claim 10 is rejected as being indefinite because the claim recites “a weight ratio of the polypeptide polymer and the bone marrow cavity filler is 1-40:99-60.” which is unclear because “a weight ratio” could be interpreted as the polypeptide polymer to the bone marrow cavity filler, or alternatively, the bone marrow cavity filler to the polypeptide polymer. Appropriate clarification is required.
Applicant is referred to Ex parte Miyazaki (BPAI 11/19/2008) (Horner, APJ) (precedential). A five member expanded panel of the Board held that "if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 USC 112, second paragraph, as indefinite." Miyazaki, slip op. at 11-12.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 7-10, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over CEROVSKY (WO 2018/133887 A1; published July, 2018) in view of Jiang et al. (“Peptide polymer displaying potent activity against clinically isolated multidrug resistant Pseudomonas aeruginosa in vitro and in vivo,” 2019, RSC; Biomaterial Science, Vol. 8, pp. 739-745).
Applicants Claims
Applicant claims an antibacterial material for filling a bone marrow cavity comprising a polypeptide polymer and a bone marrow cavity filler, wherein the polypeptide polymer is a homopolymer comprising a lysine residue or a copolymer comprising a lysine residue and a benzyl glutamate residue,
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the configuration of the lysine residues or the benzyl glutamate resides is L, D, or DL; the chain length n is 1-1000, x% is 30% to 100%, y% is 0-70%; and the terminal groups a and b are each independently H, amino, C1-C5 alkyl, C1-C5 alkyleneamino, C6-C15 aryl, C2-C15 alkenyl, C2 -C15 alkynyl, C1-C15 alkenehydroxyl, C1-C15, alkylene aldehyde group, C1-C15 alkylene ester group, thio-C1-C15 alkylene ester group, 5-15-membered heteroalkyl, or 5-12-membered heterocyclyl (instant claim 7). Applicant further claims the bone marrow cavity filler is polymethacrylic acid (PMMA) bone cement, calcium phosphate bone cement, calcium sulfate bone cement, bioglass, hydroxyapatite, bioceramic, or gelatin sponge (instant claim 8). Applicant further claims the weight ratio of the polypeptide polymer and the bone marrow cavity filler is 1-40:99-60 (instant claim 10).
Applicants have elected the following species in the reply filed (a) a polymethylmethacrylate (PMMA) bone cement and the polypeptide of Example 1 – D,L-lysine, L-benzylglutamate, n= 27, x%=90%, y% = 10%, a = c1 alkyl (methyl), and b = H.
Determination of the scope
and content of the prior art (MPEP 2141.01)
CEROVSKY teaches “Synthetic antimicrobial peptides and their use for treatment or prevention of infectious diseases of bones or surrounding infected tissues and/or to prevent or eliminate the infectious agent from joint and bone replacements and sealants, and for the prevention of infectious complications after implantation of joint replacements and after osteosynthesis.” (Abstract, see whole document). And that: “Treatment of osteomyelitis (bone infection) must be comprehensive and long-term. It is based on antimicrobial therapy (currently using antibiotics), combined with surgical treatment and adjuvant therapy. The key problem is the solution of "dead space" in bone after debridement, which involves removing sequesters, eradication of infection and solving problems with the formation of bacterial biofilms. One of the ways to increase the therapeutic potential and to fill in the cavity of the bone affected with infection is the use of local carriers mixed with antibiotics. Infection of implants used in orthopaedics, such as joint replacements, materials used for their fixation and osteosynthesis materials represent another serious problem. In these cases, the infection is associated with the formation of microbial biofilms on the implant surfaces. Microbial biofilms are for example very easily formed on an implant prepared from bone cement, which is based on polymethyl methacrylate. Even in this case, the solution is to mix the cement with antibiotics just prior to use, or to use cement, whose powder component contains antibiotics from the producer.” [emphasis added](p. 1, lines 18-30).
CEROVSKY teaches “The big problem in orthopaedics, however, is the resistance of some microbes to currently available antibiotics or antifungal agents. These are mainly methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Streptococcus species and Pseudomonas aeruginosa. Alarming is the occurrence of Staphylococcus aureus resistant to vancomycin, as this is often used as a last resort antibiotic. A very serious danger is caused by yeast infections of the Candida genus. These microbes colonize bone tissue or implants, and adhere to the surface with the consequent formation of biofilms. The infected bone tissue is difficult to treat, since microbes in the biofilm are many times more resistant to antimicrobials compared to planktonic microbes. In the case of biofilms formed on an implant, such as a joint replacement, the solution is to remove the implant from the body, mechanical removal of the biofilm, the necrotic tissue, and wear-induced granuloma, disinfection, local application of antimicrobial agents and treatment of the resulting "dead" space with several weeks of systemic administration of antimicrobial agents. Subsequent insertion of a new, usually a more complex implant may be made either at one time, or more frequent procedure - two-stage re-implantation using so-called spacers containing antibiotics or antifungal agents. These procedures are always long, exhausting for the patient and very costly.” (p. 2, lines 9-24).
CEROVSKY teaches “Very promising therapeutic method could be the use of antimicrobial peptides (AMPs) released from the local carriers to the site of bone infection, or their incorporation into implants and bone cements. Since the AMPs kill bacteria or yeasts with a totally different mechanism than traditional antibiotics and in doing so do not generate bacterial resistance, they have so far only been considered as a supplement to traditional antibiotics or their substitution.” [emphasis added](p. 2, lines 25-29). And that: “Generally it is also known that antimicrobial peptides in bacteria do not cause resistance, which is known in the heretofore used conventional antibiotics.” (p. 3, lines 7-8).
CEROVSKY teaches that: “The advantage of using antimicrobial peptides incorporated into a carrier is mainly in achieving high local concentrations of peptides without systemic toxicity, since peptides are then easily metabolized in the body.” (p. 7, lines 10-12). And teaches antimicrobial peptide carriers include polymethylmethacrylate (PMMA)(p. 7, line 17)(instant claim 8, Elected species of bone marrow cavity filler).
Regarding the amount of the antimicrobial peptide used with the carrier (PMMA), CEROVSKY teaches that: “Bone cement (Palacos®r, Hereaus Medical GmbH, Germany) containing the peptide is prepared by mixing the peptide from the series of peptides I to XIII or their above described enantiomers with a powdered polymeric component of cement (poly-methylacrylate, poly-methyl methacrylate, benzoyl peroxide) and subsequently with a liquid monomer component (methyl methacrylate, N, N-dimethyl-p-toluidine). For the preparation of a paste for filling the infected holes, 125 mg powder component of cement is used, 5 mg - 20 mg (preferably 10 mg) of peptide is stirred in, or 7 mg of vancomycin, or 10 mg of fluconazole, or 10 mg of amphotericin B; […].” (p. 16, lines 2-12)(instant claim 10, “a weight ratio of the polypeptide polymer and the bone marrow cavity filler is 1-40:99-60.”). Additionally, CEROVSKY teaches “therapeutically effective amount of at least one peptide” (p. 5, line 25).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of CEROVSKY is that CEROVSKY does not expressly teach the polypeptide is the polypeptide of Example 1 – D,L-lysine, L-benzylglutamate, n= 27, x%=90%, y% = 10%, a = c1 alkyl (methyl), and b = H (instant claims 7, 9, 19 & 20).
Jiang et al. teaches “Peptide polymer displaying potent activity against clinically isolated multidrug resistant Pseudomonas aeruginosa in vitro and in vivo” (title, see whole document). Jiang et al. teaches “Multidrug resistant (MDR) Pseudomonas aeruginosa has caused serious nosocomial infections owing to its high intrinsic resistance and ease of acquiring resistance to common antibiotics. There is an urgent need to develop antimicrobial agents against MDR Pseudomonas aeruginosa. Here we report a 27-mer peptide polymer 90 : 10 DLL : BLG, as a synthetic mimic of a host defense peptide, that displayed potent in vitro and in vivo activities against multiple strains of clinically isolated MDR Pseudomonas aeruginosa, performing even better than antibiotics within our study. This peptide polymer also showed negligible hemolysis and low cytotoxicity, as well as quick bacterial killing efficacy. The structural diversity of peptide polymers, their easy synthesis from lithium hexamethyldisilazide-initiated fast N-carboxyanhydride polymerization, and the excellent reproducibility of their chemical structure and biological profiles altogether suggested great potential for antimicrobial applications of peptide polymers as synthetic mimics of host defense peptides.” (abstract).
Jiang et al. teaches that: “Host defense peptides (HDP), also called antimicrobial peptides (AMP), can keep their activity upon MDR bacteria including P. aeruginosa. However, the application of HDP is limited owing to their innate shortcomings, including low stability in vivo, moderate activity, expensive manufacturing costs and difficult synthesis in large quantities. To address these problems, plenty of synthetic mimics of HDP have been developed and some of them have shown potent activity against drug-sensitive and/or drug-resistant microbes.” (p. 739, col. 2, lines 5-13). And “In this study, we focused on the promising copolymer 90 : 10 (D,L-lysine) : (γ-benzyl-L-glutamate) (90 : 10 DLL : BLG) and demonstrated its potent antimicrobial performance upon multiple strains of clinically isolated P. aeruginosa both in vitro and in vivo. Racemic Nε-tertbutyloxycarbonyl-D,L-lysine (Boc-DLL) NCA was used to obtain a peptide polymer that is resistant to protease in addressing HDP’s prominent shortcoming for biological application (Fig. 1a).” (p. 739, col. 1, last two lines through p. 740, col. 1, 1st paragraph).
Jiang et al. teaches the structure of the peptide polymer 90 :10 DLL:BLG as follows:
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(p. 740, Figure 1)(instant claim 1, polypeptide polymer structure, and elected species “D,L-lysine, L-benzylglutamate, n= 27, x%=90%, y% = 10%, a = c1 alkyl (methyl), and b = H”).
Jiang et al. teaches that: “For cytotoxicity against HVSMC, this polymer displayed no cytotoxicity at its MIC. In addition to the potent antibacterial activity and low toxicity, the peptide polymer 90 : 10 DLL : BLG also had quick bacterial killing efficacy. The in vitro killing kinetics study revealed that 90 : 10 DLL : BLG killed 4.6 log of the clinically isolated P. aeruginosa 1407 in 3 h and 1 h using 2 × MIC and 4 × MIC, respectively, which is obviously faster than the performance of streptomycin, which killed the same amount of P. aeruginosa 1407 in 4 h and 3 h using 2 × MIC and 4 × MIC, respectively (Fig. 4).” (p. 743, col. 1, lines 4-10 through col. 2, 1st paragraph). And that: “We also evaluated the peptide polymer 90 : 10 DLL : BLG for its in vivo antimicrobial efficacy in a rat full-thickness wound model of P. aeruginosa infection, using saline and polymyxin B as the blank control and positive control, respectively (Fig. 5). The clinically isolated MDR P. aeruginosa 2512, resistant to all tested antimicrobial drugs except polymyxin B, was used to induce infection. One day post-P. aeruginosa infection, the saline-treated wound tissue showed serious infection, having 8.0 log g−1 colony forming units (CFU) of P. aeruginosa. Happily, both polymyxin B and the peptide polymer showed effective in vivo antibacterial activity, with a 1.6 and 2.1 log reduction in CFU for polymyxin B and the peptide polymer, respectively. It is noteworthy that in our in vivo study the peptide polymer 90 : 10 DLL : BLG was even superior to polymyxin B, the last-line antibiotic for treatment of MDR infections.” (p. 743, col. 2, 2nd paragraph).
Jiang et al. teaches that: “The peptide polymer 90 : 10 DLL : BLG showed potent antibacterial activity against all these clinically isolated strains of P. aeruginosa in vitro and in vivo, and was even superior to the performance of the antibiotics used within our study. This peptide polymer also showed negligible hemolysis and low cytotoxicity, as well as quick bacteria-killing efficacy. Moreover, the superfast and easy synthesis of peptide polymers from LiHMDS-initiated NCA polymerization, the large variety of peptide polymer structures, and the excellent reproducibility of the NCA polymerization chemistry altogether indicate that peptide polymers as synthetic mimics of host defense peptides have great potential for antimicrobial applications.” (p. 743, §4 Conclusions, lines 5-17).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the antimicrobial peptides in the PMMA bone cement taught by CEROVSKY with the peptide polymer 90 : 10 DLL : BLG taught by Jiang et al. to be effective antimicrobial peptides as “This peptide polymer also showed negligible hemolysis and low cytotoxicity, as well as quick bacteria-killing efficacy.” and was “superfast and easy synthesis” of the antimicrobial peptide. A prima face case of obviousness based upon a substitution rationale requires (1) a finding of fact that the prior art contained a product which differed from the claimed product by the substitution of some components with other components; (2) a finding of fact that the substituted components and their functions were known in the art; (3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and (4) whatever additional findings based upon the Graham factual inquiries may be necessary, in view of the case under consideration, to explain a conclusion of obviousness (MPEP § 2143-B). In the instant case CEROVSKY teaches a combination of an antimicrobial peptide with a carrier such as PMMA in a composition such as a bone cement, which differs from the claimed product by the substitution of the antimicrobial peptide of Jiang et al. with other antimicrobial peptides of CEROVSKY. And given that both CEROVSKY teach the advantages of antimicrobial peptides (do not generate bacterial resistance, different mechanism of action than traditional antibiotics, activity against multi-drug resistant P. aeruginosa) and that the antimicrobial peptides are of the same drug class, one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. And furthermore, Jiang et al. teaches the advantages in terms of manufacturing of the antimicrobial peptide species copolymer 90 : 10 (D,L-lysine) : (γ-benzyl-L-glutamate), particularly Jiang et al. teaches that prior art peptides have been “limited owing to their innate shortcomings, including low stability in vivo, moderate activity, expensive manufacturing costs and difficult synthesis in large quantities.” (p. 739, col. 2, 2nd paragraph), and the copolymer 90 : 10 (D,L-lysine) : (γ-benzyl-L-glutamate) is taught to allow for “superfast and easy synthesis of peptide polymers from LiHMDS-initiated NCA” (p. 743, §4 Conclusions).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because it would have required no more than an ordinary level of skill in the art to substitute the antimicrobial peptide copolymer of Jiang et al. with the antimicrobial peptide of CEROVSKY in a PMMA bone cement. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Conclusion
Claims 7-10, 19 and 20 are pending and have been examined on the merits.
Claims 10 is rejected under 35 U.S.C. 112(b); and claims 7-10, 19 and 20 are rejected under 35 U.S.C. 103. No claims allowed at this time.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619