DETAILED ACTION
Status of the Claims
Claims 7-8, 10-18 and 20-22 are pending in the instant application. Claims 11-18 have been withdrawn based upon Restriction/Election. Claims 7-8, 10 and 20-22 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 .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
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.
Claim Rejections - 35 USC § 112(b)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 7-8, 10 and 22 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 pre-AIA the applicant regards as the invention.
Claim 7 is rejected as being indefinite because the claim recites “the terminal groups a and b are each independently H, amino or hydroxyl x”.” which is unclear because it is unclear what exactly is meant by “hydroxyl x”. Appropriate clarification is required. Claims 8, 10, 20 and 22 are rejected as depending from and doing nothing to clarify the above discussed issue.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 7-8, 10 and 20-22 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); and LIU (WO 2019/238090 A1; published 12/19/2019 with priority to CN 20180614799.1 filed 14-JUN-2018; US 2021/0155752 A1 relied on as an English language translation herein)
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 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 90%, y% is 10%; and the terminal groups a and b are each independently H, amino, or hydroxyl x; a weight ratio of the polypeptide polymer to the bone marrow cavity filler is 1-40:99-60; and the bone marrow cavity filler is polymethacrylic acid bone cement, calcium phosphate bone cement, calcium sulfate bone cement, bioglass, hydroxyapatite, bioceramic, or gelatin sponge (instant claim 7). Applicant further claims the bone marrow cavity filler is polymethacrylic acid (PMMA) bone cement (instant claim 8). Applicant further claims the weight ratio of the polypeptide polymer to the bone marrow cavity filler is 5-15:95-85 (instant claim 10), or 8-12:92-88 (instant claim 22).
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 claims 7, 10 & 22, “a weight ratio of the polypeptide polymer to the bone marrow cavity filler is 8-12:92-88.”). The examiner notes that 5mg/125mg is 4.0 wt.% of polypeptide polymer in the bone cement, and 20mg/125mg is 16.0 wt.%. And this amount overlaps with applicants claimed “weight ratio of the polypeptide polymer to the bone marrow cavity filler.” (MPEP §2144.05(I)) Additionally, CEROVSKY teaches “therapeutically effective amount of at least one peptide” for the very same use as now claimed (p. 5, line 25)(MPEP §2144.05(II)).
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 = OH, and b = H”; instant claims 20-21). The examiner notes that the reaction described by Jiang et al. is identical to that of Example 1 in the instant Specification and therefore the result would have been the same (MPEP §2112(IV)).
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).
Consistent with Jiang et al., LIU teaches anti-bacterial polypeptides (see whole document), and particularly teaches “A series of polymers with different amino acid ratios (ratio from 90% lysine+ 10% benzyl glutamate to 40% lysine+60% benzyl glutamate) were tested for the lowest inhibitory concentration for various bacteria including methicillin-resistant Staphylococcus aureus USA300, methicillin-resistant Staphylococcus aureus USA300LAC, methicillin-resistant Staphylococcus aureus Mu50, Bacillus subtilis BR-151, Escherichia coli JM109, Pseudomonas aeruginosa ATCC9027, multidrug resistant Pseudomonas aeruginosa ATCC15442, sulfamethoxazole and tetracycline naturally resistant Pseudomonas aeruginosa 01, Acinetobacter baumannii ATCC BAA-747.” ([0180], Table 1). The examiner notes the highest activity (lowest MIC values) against methicillin-resistant Staphylococcus aureus was for the 9:1 lysine:benzyl glutamate polymer which is described as a Copolymer of the Mixture of N-ε-Tert-Butoxycarbonyl-DL-Lysine-N-carboxyanhydride and 5-Benzyl-L-Glutamate-N-Carboxyanhydride Initiated by Lithium Hexamethyldisilazide (LiHMDS) consistent with the disclosure of Jiang et al. teaching the same (Jiang et al., p. 743, §4 Conclusions, lines 5-17), as discussed above.
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. and LIU 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.
Response to Arguments:
Applicant's arguments filed 05/25/2026 have been fully considered but they are not persuasive.
Applicant argues that: “First, the Office is respectfully requested to reconsider the teachings of Cerovsky given the present claim amendments (e.g., independent claim 7 no longer recites lysine homopolymers). […] Cerovsky's antimicrobial peptides are thus distinguishable from the claimed copolymer having (i) the recited lysine and benzyl glutamate residues; (ii) the recited chain length; and (iii) the recited abundance of each monomer. Given such structural differences, their functional properties likely would differ. There is no evidence on the record, or adduced by the Office, that a skilled artisan would have been directed to use the presently claimed copolymers to treat or prevent infectious diseases of the bones, as taught by Cerovsky, let alone using the claimed copolymers to fill a bone marrow cavity with any expectation of success.” (paragraph bridging pp. 7-8).
Applicant further argues that: “Some of Jiang' s peptide polymers share structural similarities to the presently claimed copolymers. However, Jiang at best teaches that the disclosed peptide polymers display potent activity against clinically isolated multi drug-resistant Pseudomonas aeruginosa strains in vitro and in vivo. In Jiang, cutaneous infections with P. aeruginosa (a Gram-negative bacterium) were tested. However, Jiang at most suggests that the disclosed polymers may "have great potential for antimicrobial applications." Jiang, right column, page 743. Jiang does not suggest using its polymers to treat or prevent infections of bones or surrounding tissues. Nor does Jiang suggest applying its polymers to fill a bone marrow cavity to treat osteomyelitis. Osteomyelitis is commonly caused by infection of Staphylococcus aureus (a Gram-positive bacterium), more likely methicillin-resistant S. aureus (MRSA). An agent having antibacterial activities toward Gram-negative bacteria may be ineffective against Gram-positive bacteria (e.g., MRSA). Thus, there is no evidence on the record, or adduced by the Office, that a skilled artisan would have been directed to replace Cerovsky's synthetic antimicrobial peptides with Jiang's peptide polymers to treat osteomyelitis, let alone with any expectation of success. The Office fails to establish prima facie obvious by relying upon the combination of Cerovsky and Jiang.” (p. 8, 2nd paragraph).
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).
In response to Applicants argument regarding expectation of success, the examiner argues that it would have been within the ordinary level of skill in the art to formulate a PMMA bone cement with a polypeptide polymer such as disclosed by Jiang et al. per the teachings of CEROVSKY. MPEP §2143.02(II) makes clear that: “Obviousness does not require absolute predictability, but at least some degree of predictability is required.” In the instant case antimicrobial peptide polymers are already taught as combinable with PMMA bone cement by CEROVSKY which clearly provides a reasonable expectation of success in doing so.
Regarding the occurrence of resistant “Osteomyelitis is commonly caused by infection of Staphylococcus aureus (a Gram-positive bacterium), more likely methicillin-resistant S. aureus (MRSA). An agent having antibacterial activities toward Gram-negative bacteria may be ineffective against Gram-positive bacteria (e.g., MRSA).”, CEROVSKY clearly discusses this on page 2, lines 9-13, and suggest antimicrobial peptides as a solution (p. 2, lines 25-29), which are not considered to cause microbial resistance (p. 3, lines 7-8). Jiang et al. clearly teaches their peptide polymer as displaying potent activity against clinically isolated multidrug resistant P. aeruginosa in vivo and in vitro (title). This is also taught by LIU in Table 1 which shows activity against various bacteria showing, consistent with Jiang et al. that the highest activity (lowest MIC values) against methicillin-resistant Staphylococcus aureus was for the 9:1 lysine:benzyl glutamate polymer which is described as a Copolymer of the Mixture of N-ε-Tert-Butoxycarbonyl-DL-Lysine-N-carboxyanhydride and 5-Benzyl-L-Glutamate-N-Carboxyanhydride Initiated by Lithium Hexamethyldisilazide (LiHMDS) consistent with the disclosure of Jiang et al. teaching the same (Jiang et al., p. 743, §4 Conclusions, lines 5-17), as discussed above. MPEP §716.02(c)(II) makes clear that: “‘Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.’” In the instant case expected inhibition of methicillin-resistant Staphylococcus aureus by the polypeptides of Jiang et al./LIU would predictably resulted in the same when combined with the bone cement of CEROVSKY in treating bone diseases which exhibit this type of bacterial infection.
Applicant further argues that: “In Cerovsky's working examples, no animal model of osteomyelitis was established, and no in vivo experimental validation was performed. Cerovsky at best describes an ex vivo osteomyelitis model in the reference examples (e.g., drilling holes in the spongy part of isolated bone samples). A skilled artisan at the time would have understood that in vitro, ex vivo, and in vivo environments are distinct. Any activities observed under in vitro or ex vivo settings do not guarantee efficacy for in vivo settings. The artisan would not have had any expectation of success to employ Cerovsky's peptides, or any antibacterial peptides (including Jiang's copolymers), to predictably treat osteomyelitis.” (p. 8, 3rd paragraph).
In response, MPEP §2143.02(II) makes clear that: “Obviousness does not require absolute predictability, but at least some degree of predictability is required.” In the instant case antimicrobial peptide polymers are already taught as combinable with PMMA bone cement by CEROVSKY which clearly provides a reasonable expectation of success in doing so. The examiner reminds applicant that the instantly rejected claims are compositions of matter, and treating osteomyelitis is simply an intended use.
Applicant further argues that: “As demonstrated by the experimental results (Figure 2a) of Melichercik, vancomycin - a highly potent antibiotic - failed to produce satisfactory efficacy against Staphylococcus aureus in its ex vivo bone model, let alone effective treatment of osteomyelitis in vivo. Given at least the data from Melichercik, a skilled artisan would recognize that demonstrating the in vitro antibacterial activity of an agent alone does not ensure that the agent would be a suitable antibacterial filling material for the bone marrow cavity for treating osteomyelitis. In other words, materials with antibacterial properties are not inherently usable as antibacterial bone marrow cavity-filling materials for osteomyelitis therapy.” (p. 9, 1st paragraph)
In response the examiner argues that vancomycin resistance is discussed by CEROVSKY – “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.” (p. 2, lines 9-13) 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; also see p. 6, lines 15-31). MPEP §716.02(c)(II) makes clear that: “‘Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.’” In the instant case expected inhibition of methicillin-resistant Staphylococcus aureus by the polypeptides of Jiang et al./LIU would predictably resulted in the same when combined with the bone cement of CEROVSKY in treating bone diseases which exhibit this type of bacterial infection.
Applicant further argues that: “Applicant further submits that the presently claimed products offer several unexpected results. First, the claimed antibacterial filling material exhibits excellent compressive strength. Example 4 of the Specification characterizes an embodiment of the claimed antibacterial filling material ("polypeptide polymer PMMA bone cement") as compared with a control ("the blank PMMA bone cement"). […] A skilled artisan would understand that such a low strain range is more consistent with the strain range in practical applications.” (p. 9, last paragraph).
In response the examiner notes that arguments by applicant cannot take the place of evidence, including arguments of unexpected results (MPEP §716.01(c)(II)). The examiner finds no allegations of unexpected results in the as-filed application. MPEP §716.02 makes clear that: “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties.” And Applicants have the burden of explaining proffered data (MPEP §716.02(b)). Furthermore, the results should be with the closest prior art or closer (MPEP §716.02(e)). And any showing of unexpected results must be commensurate with the results (MPEP §716.02(d)). The compressive strength is shown for a single embodiment of the claims, and is therefore not considered commensurate with the same. The comparison between “blank PMMA bone cement” and “polypeptide polymer PMMA bone cement” is not a comparison with the closest prior art. And the argument relies on an unsupported allegation that this is actually an unexpected result.
Applicant further agues that “Second, the presently claimed antibacterial filling materials have potent antibacterial activity in vivo.”
This again is a comparison between “blank PMMA bone cement” and “polypeptide polymer PMMA bone cement” is not a comparison with the closest prior art. Furthermore, based on the teachings of CEROVSKY and the disclosure of Jiang et al. and LIU, the results would have been clearly expected.
Applicant further argues that: “Third, the presently claimed antibacterial filling materials have desirable antibacterial activity in serum.”
This again is a comparison between “blank PMMA bone cement” and “polypeptide polymer PMMA bone cement” is not a comparison with the closest prior art. Furthermore, based on the teachings of CEROVSKY and the disclosure of Jiang et al. and LIU, the results would have been clearly expected.
Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). Applicant is reminded that the submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987).
Conclusion
Claims 7-8, 10 and 20-22 are pending and have been examined on the merits. Claims 7-8, 10 and 22 is rejected under 35 U.S.C. 112(b); and claims 7-8, 10 and 20-22 are rejected under 35 U.S.C. 103. No claims allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
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