DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 17 April, 2026 has been entered.
Election/Restrictions
Applicants elect compound 15 without traverse in the reply filed on 27 Aug, 2025.
Claims Status
Claims 1, 25-35, and 37-43 are pending.
Claims 25, 26 and 30-32 have been withdrawn due to an election/restriction requirement.
Maintained/Modified Rejections
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 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.
Claim(s) 1, 27-29, and 33-35 and 37-43 are rejected under 35 U.S.C. 103 as being unpatentable over Okano et al (PNAS (2017) 114(26) pE5052-5061, cited by applicants) in view of Antonoplis et al (ACS Chem. Biol. (2019) 14(9) p2065-2070, cited by applicants).
Okano et al discuss modified vancomycin derivatives (title). This involves three modifications compared to the native material; a chlorobiphenyl group on the glycan, to inhibit transglycosylase and cell wall biosynthesis, at the C-terminus to induce cell membrane permeability, and at one of the amide carbonyl groups, to bind to D-Ala-D-Ala as well as D-Ala-D-Lac (fig 11, pe5060, 1st column, bottom of page). Note that D-Ala-D-Lac is a mechanism of vancomycin resistance (pe5053, 2nd column, 2nd paragraph), so this modification is a mechanism of overcoming antibiotic resistance. Placing a positive charge on the C-terminus of the peptide provides for improved antimicrobial activity against vancomycin resistant organisms, but by a mechanism independent of D-Ala-D-Lac binding (pE5054, 2nd column, 1st paragraph). Among the modifications tested were a dimethyl and trimethyl amine attached via an aminopropane linker (fig 3, pe5054, 2nd column, bottom of page, compounds 9 and 10). This was combined with a chlorobiphenyl modification, which proved to be a synergistic combination (pe5055, 1st column, 1st paragraph). These were tested against S. aureus, MRSA, and vancomycin resistant strains of E. faecalis and E. faecium (fig 2, pE5054, 1st column, top of page). Note that one of the analogs with the highest activity has a chlorobiphenyl modification and a trimethyl amine modification (fig 4, pe5055, 2nd column, top of page). Hemolysis assays were run in PBS (pS19, 2nd paragraph), and NMR was run using deuterated acetic acid (pS25) pharmaceutically acceptable excipients.
The difference between this reference and the examined claims is that this reference uses an amine group instead of a guanidinyl group.
Antonoplis et al discuss arginine conjugates of vancomycin (title) for treatment of multidrug resistant bacteria (p2, 1st paragraph). Octaarginine labeled vancomycin improved activity in gram positive bacteria, but not gram negative bacteria (3d page, 2nd paragraph). Reducing the number of arginines to two gave efficacy against gram negative bacteria, which was increased when the number of arginines was reduced to one (3d page, 3d paragraph). The amino acids were conjugated to the C terminus of the vancomycin peptide chain (fig 1, p9, entire page). Note that this structure is very similar to those of Okano et al, save that the chain length is slightly longer, and functionalized with a carboxyl group (from the arginine). This reference discusses modifications of vancomycin to generate variants with activity against gram negative bacteria.
Therefore, it would be obvious to use an arginine side chain of Antonoplis et al in the conjugates of Okano et al, to increase the activity with gram negative bacteria, as described by Antonoplis et al. As Okano et al states that a positive charge at this location is important, and this modification preserves the positive charge, an artisan in this field would attempt this modification with a reasonable expectation of success.
Antonoplis et al render obvious replacing the trimethylaminepropane group with the side chain of vancomycin, reproducing compound 15 and rendering obvious claims 1, 27-29, 33-35.
Antonoplis et al discuss treatment of bacterial infections, and mention both Gram positive and Gram negative capability, rendering obvious claims 37-40, 42, and 43.
Okano et al discuss testing against S. aureus, MRSA, and vancomycin resistant strains of E. faecalis and E. faecium, rendering obvious claim 41.
response to applicant’s arguments
Applicants have not submitted new arguments with their request for continued examination, so the arguments presented in the response after final on 16 March, 2026 will be answered.
Applicants argue that the rejection is based on hindsight reasoning, that there is no reasonable expectation of success, and claim unexpected results of improved permeabilizing ability, activity against drug resistant bacteria, and durability.
Applicant's arguments filed 16 March, 2026 have been fully considered but they are not persuasive.
Applicants have presented a jumbled and confusing argument of hindsight reasoning and lack of an expectation of success based on the fact that Okano et al does not explain the mechanistic differences the modifications make. It is not clear how these factors relate to each other. The test for hindsight reasoning is if the rejection takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, there is no impermissible hindsight. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicants have not described any portion of the rejection based on applicant’s disclosure. Nor is it clear why the fact that Okano et al does not determine the exact mechanistic details changes the fact that the positive charge at a specific location is important, which is the basis for a reasonable expectation of success in the rejection.
Applicants argue that the claimed materials give improved bacterial permeability and better activity against drug resistant bacteria. There are a number of issues with this argument. First, unexpected results must be commensurate in scope with the claims (MPEP 716.02(d)). Outside of claims 35, 38, 40, and 43, it is not clear that this is the case, as it appears that only one embodiment has been tested. Second, unexpected results are compared to the closest prior art (MPEP 716.02(e)), which is presumed to be the primary reference. As noted in the rejection, Okano et al discusses modifications that overcome drug resistance; there is no data presented by applicants showing that the compound of Okano et al (referred to as compound 4 by applicants) is inferior to those of applicants in this regard. Third, it is applicant’s burden to establish that the results are of both practical and statistical significance (MPEP 716.02(b)(I)). The only experiment showing a difference between compound 4 and any compounds of applicant’s invention is fig 2a, which is a permeabilization experiment. This shows that compounds 15 (applicant’s elected species) and compound 19 increase permeability of a specific strain of E. faecalis more than compound 4 (the compound of Okano et al), in what appears to be a mechanistic study. However, there are no error bars, and it is not clear that this difference is statistically significant, or that the same difference is noted with other strains of the bacteria. Nor is it clear what the practical significance of this finding is; nowhere is it demonstrated that this correlates to a large difference in activity.
It is not clear what applicants mean by durability. From context, it appears to have something to do with how changes to the structure affect the ability to kill drug resistant bacteria (p40, 3d paragraph). If it is not clear what this is, applicants have not met their burden to show that the effect is unexpected and of practical and statistical significance.
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, 27-29, and 33-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8, and 12 of U.S. Patent No. 10,934,326 in view of Antonoplis et al (ACS Chem. Biol. (2019) 14(9) p2065-2070, cited by applicants).
Competing claim 1 describes a genus of vancomycin derivatives similar to that of examined claim 1, save that A=(CH2)3 and a trimethylamine group is on the end rather than a guanidinyl group. Competing claim 4 specifies that X=O. Competing claim 5 describes pharmaceutical formulations with a pharmaceutically acceptable diluent. Competing claim 6 describes a method of treatment of a bacterial infected mammal, comprising administering the vancomycin derivatives of the claims, while competing claim 7 specifies Gram positive bacteria. Competing claim 8 specifies the bacteria are selected from S. aureus, MRSA, and vancomycin resistant strains of E. faecalis and E. faecium. Competing claim 12 specifies the treatment is with an analog where X=O.
The difference between the competing claims and the examined claims is that the competing claims have a trimethylamine group instead of a guanidinyl group.
Antonoplis et al discuss arginine conjugates of vancomycin (title) for treatment of multidrug resistant bacteria (p2, 1st paragraph). Octaarginine labeled vancomycin improved activity in gram positive bacteria, but not gram negative bacteria (3d page, 2nd paragraph). Reducing the number of arginines to two gave efficacy against gram negative bacteria, which was increased when the number of arginines was reduced to one (3d page, 3d paragraph). The amino acids were conjugated to the C terminus of the vancomycin peptide chain (fig 1, p9, entire page). Note that this structure is very similar to those of Okano et al, save that the chain length is slightly longer, and functionalized with a carboxyl group (from the arginine). It is suggested that the charge of the amino acid is important (4th page, 1st paragraph). This reference discusses modifications of vancomycin to generate variants with activity against gram negative bacteria.
Therefore, it would be obvious to use an arginine side chain of Antonoplis et al in the conjugates of the competing claims, to increase the activity against gram negative bacteria, as described by Antonoplis et al. As Antonoplis et al suggest that a positive charge at this location is important, and this modification preserves the positive charge, an artisan in this field would attempt this modification with a reasonable expectation of success.
response to applicant’s arguments
Applicants repeat their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
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 FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
Examiner interviews are available via telephone and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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