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 .
DETAILED ACTION
Claims 1 and 4-20 are pending. Claims 5-20 remain withdrawn. Claims 1 and 4 are under examination.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 27 October 2025 has been entered.
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 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Martinez et al. (US 20190365853 A1, published December 5, 2019) in view of Huang et al. (Antibacterial properties of Acinetobacter baumannii phage Abp1 endolysin (PlyAB1), BMC Infectious Diseases 2014, 14:681), Gertsmans et al. (Synthetic biology of modular endolysins, Biotechnology Advances 36 (2018) 624–640), Sequence Search Results, and Sequence Alignments.
Regarding claim 1, Martinez teaches the fusion of a modulating agent to an additional moiety, and that the moiety can also be a modulating agent (Martinez [0264]). Martinez teaches that the modulating agents can be globular endolysin LysAB2 (Martinez [0264] and Table 5 Page 62) and cecropin A (CeA) (Martinez Table 6 Page 65). Furthermore, the first 8 amino acids of the sequence for the cecropin A in Martinez is 100% identical to the instant SEQ ID NO. 1 (see below alignment).
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However, Martinez does not teach the globular endolysin PlyAB1.
Huang teaches the globular endolysin PlyAB1, and its marked lytic activity on pathogenic organisms (Huang Abstract).
However, neither Martinez nor Huang specifically teach fusing CeA to the C-terminal end of the globular endolysin, nor the use of only the first 8 amino acids of the cecropin A.
Gertsmans teaches that fusing endolysins to the peptide cecropin A (CeA) enhances the antibacterial activity of such fusion proteins (Gertsmans Page 631 paragraph 3 sentences 1-2), and moreover that a positively charged C-terminus also enhances the antibacterial activity of endolysins towards Gram-negative bacteria (Gertsmans Page 631 paragraph 4 sentence 1). Gertsmans teaches that cecropin A is a polycationic (and thus positively charged) peptide chain (Gertsmans Page 631 paragraph 3 sentence 2), and that residues 1-8 of the polycationic peptide cecropin A (KWKLFKKI) fused to the C-terminus of an endolysin enhanced the antibacterial activity against A. baumannii and P. aeruginosa (Gertsmans Pg. 631 para. 3 sent. 2). Gertsmans also teaches that fusion of peptides with cationic charge and hydrophobic amino acids to the C-terminus of a endolysin enhanced the bacterial activity against E. coli (Gertsmans Pg. 631 para. 3 sent. 6). Gertsmans also teaches C-terminal amphipathic helices increases the permeability of the endolysin to the outer membrane of the bacteria (Gertsmans Pg. 631 para. 4 sent. 2). Taken together, Gertsmans teaches and/or suggests that fusing amino acids 1-8 of polycationic cecropin A to the C-terminus of an endolysin comprising C-terminal amphipathic helices will increase the overall effectiveness of the potential fused product by increasing the antibacterial effectiveness of the product as well as the outer membrane permeability of the product.
MPEP §2144.06(II) states “[i]n order to rely on equivalence as a rationale supporting an obviousness rejection, the equivalency must be recognized in the prior art, and cannot be based on applicant’s disclosure or the mere fact that the components at issue are functional or mechanical equivalents. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958)” and “[a]n express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to fuse the globular endolysin PlyAB1 to the peptide cecropin A (CeA) to form a single fusion protein. Furthermore, it would have been prima facie obvious to substitute the globular endolysin PlyAB1 for the globular endolysin LysAB2 taught by Martinez because the endolysin PlyAB1 was an art recognized equivalent for the same purpose, has similar structure to LysAB2 including an amphipathic C-terminal helix (as evidenced by the Rule 132 Declaration filed 30 July 2024 Pg. 4), and also had a shared capability of antimicrobial properties. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Martinez teaches the option of advantageously fusing a globular endolysin to the peptide cecropin A (CeA), and Gertsmans further teaches that specifically amino acids 1-8 of cecropin A advantageously enhances the antimicrobial function of the endolysin. Furthermore, cecropin A was known in the art to advantageously enhance the antimicrobial function of endolysins, as taught by Gertsmans (Gertsmans Page 631 paragraph 3 sentences 1-2). Thus, fusing endolysin PlyAB1 to cecropin A as taught by Martinez in view of Huang would be expected by one of ordinary skill in the art to enhance the overall antimicrobial function of the resulting fusion protein.
It also would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to fuse the peptide CeA to the C-terminus of a globular endolysin. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Gertsmans taught that a positively charged C-terminus on globular endolysins advantageously enhances its antibacterial activity towards Gram-negative bacteria (Gertsmans Page 631 paragraph 4 sentence 1). Gertsmans also notes that cecropin A is a polycationic (and thus positively charged) peptide chain (Gertsmans Page 631 paragraph 3 sentence 2), and that C-terminal amphipathic helices increases the permeability of the endolysin to the outer membrane (Gertsmans Pg. 631 para. 4 sent. 2). Since PlyAB1 has an amphipathic helix on the C-terminus, the resulting fusion would not only have enhanced antibacterial activity, but also have enhanced outer membrane permeability.
Regarding claim 4, Martinez does not explicitly identify polypeptides comprising a sequence that matches the sequences of the present application SEQ ID Nos. 30
However, Martinez teaches that the fusion of disclosed modulating agents such as globular endolysin (Martinez Table 5 Page 62) and cecropin A (CeA) (Martinez Table 6 Page 65) can further include flexible peptide linkers (Martinez [0271]), and that such flexible peptide linkers can comprise sequences having primarily Gly and Ser amino acids, also known as “GS” linkers (Martinez [0272]).
Instant SEQ ID NO. 30 is the amino acid sequence of globular endolysins PlyAB1 fused to the sequence of peptide CeA by way of a Gly Gly Ser Gly Gly (GGSGG) linker sequence.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to fuse the peptide CeA to globular endolysin PlyAB1 by way of a GGSGG flexible linker sequence. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Martinez teaches that fusions between two disclosed modulating agents such as a globular endolysin and cecropin A (CeA) can include flexible peptide linker sequences having primarily Gly and Ser amino acids, and that flexible linkers are advantageously useful for joining domains that require a certain degree of movement (Martinez [0272]).
Response to Arguments
Applicant's arguments and the Fourth Leung Declaration filed 27 October 2025 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments that the long felt need for an effective treatment for A. baumannii infection has not been satisfied by another before the invention (Remarks pg. 7-8 and Fourth Leung Declaration pg. 3 last para. through pg. 4), Gertsmans teaches that residues 1-8 of the polycationic peptide cecropin A (KWKLFKKI) fused to the C-terminus of an endolysin enhanced the antibacterial activity against A. baumannii and P. aeruginosa (Gertsmans Pg. 631 para. 3 sent. 2); thus there was a clear direction in the prior art that fusing residues 1-8 of cecropin A (KWKLFKKI) to the C-terminus of an endolysin is an effective route for treating A. baumannii infections.
Regarding Applicant’s arguments that PlyAB1-KWK fusion not only matched LysAB2-KWK fusion, but also exhibited higher antibacterial activity (Remarks’ and Fourth Leung Declaration’s Fig. 3), and has a promising clinical potential for managing bacterial infections in vivo (Remarks pgs. 9-11 and Fourth Leung Declaration pgs. 5-8), the antibacterial activity of the PlyAB1-KWK fusion as presented in Fig. 3 does not appear to be unexpected in view of the prior art. The PlyAB1-KWK fusion protein is performing just as the prior art suggested it would, that is it exhibits antibacterial activity at a level very comparable to LysAB2. This supports the notion pointed out in the rejection that globular endolysins PlyAB1 and LysAB2 are equivalents of each other useful for the same purpose, and thus would be obvious to substitute one with the other.
Regarding Applicant’s arguments that PlyAB1’s storage stability is unexpectedly excellent, and is expected to match that of LysAB2 (Remarks pgs. 12-13 and Fourth Leung Declaration pg. 9), the storage stability of PlyAB1 is not a claimed feature. Regardless, these results also support the conclusion that PlyAB1 and LysAB2 are very comparable to endolysins, so are prior art recognized substitutes for each other useful for the same purpose.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander M Duryee whose telephone number is (571)272-9377. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
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/Alexander M Duryee/Examiner, Art Unit 1657
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657