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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2 Jan, 2026 has been entered.
Election/Restrictions
Applicants elected compound D2 without traverse in the reply filed on 23 Jan, 2024.
Claims Status
Claims 1-4, 7, 8, 12, 41, 42, 44, 45, 47, 48, 57-59, 65-67, 74, 76, 78, and 79 are pending.
Claims 44, 45, 47, 48, and 57 have been withdrawn due to an election/restriction requirement.
Maintained/Modified Objections
Specification
The amendment filed 14 Aug, 2024 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: the stereochemistry of the threonine. Applicants point to claim 1 and other examples in the spec, and argue that following the synthesis will give the amended stereochemistry. With regards to claim 1 and the other examples, there is no requirement that all examples be consistent, or that the claims read on every example. With regards to the argument of following the synthesis, this requires that a person of skill in the art follow each step of the synthesis, make a judgement that none of these reactions will change the stereochemistry, and assume that no other process occurred to change or racemize the stereochemistry. Given that applicants signed a declaration that the original disclosure was correct, this is not sufficient to provide support for amending.
Applicant is required to cancel the new matter in the reply to this Office Action.
response to applicant’s arguments
Applicants argue that other applications have accepted this amendment, that the core is based on polymyxin B, which has the corrected stereochemistry, and that the synthesis will give the corrected stereochemistry.
Applicant's arguments filed 2 Jan, 2026 have been fully considered but they are not persuasive.
Applicants argue that other applications have accepted this amendment. It is not clear if these follow the same fact pattern, and, for foreign applications, the same standard. This makes the argument too tenuous to be persuasive.
Applicants argue that the examples use a polymyxin B core structure, and that the synthesis will give the corrected stereochemistry. The standard is if a person of skill in the art would recognize the error and also recognize the appropriate correction (MPEP 2163.07(II)). Applicant’s arguments all require that a person of skill in the art do some sort of analysis (comparison of examples, following the stereochemistry through a reaction scheme), which is beyond immediately recognizing an error. There is nothing clearly wrong in the original structure, a different stereochemistry is not an unreasonable modification to a polypeptide. In addition, even if we accept applicant’s analysis as evidence of an error, it merely shows that there are inconsistencies in the specification; it does not show what is the correct stereochemistry.
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) 1-4, 7, 8, 12, 41, 42, 58, 59, 65-67, 74, 76, 78, and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Saadi et al (WO 2013072695, cited by applicants) in view of Velkov et al (J. Med. Chem. (2010) 53(5) p1898-1916) and Leese et al (US 20060004185).
Saadi et al discuss polymyxin derivatives (title). Among the derivatives discussed is 3-pyrrolidine 3 carbonyl polymyxin B nonapeptide (p7, line 22). In applicant’s terminology, R1=a phenylalanine side chain, R2=a leucine side chain, R3=a threonine side chain, R4 is a DAB side chain, R8=methyl, R15=pyrrolidine (5 membered heterocycle with 4 carbons and 1 nitrogen), and X=C(O). This structure was explicitly claimed (claim 11), indicating that it is a compound of interest to the authors of the reference and a reasonable place to start modifying. Pharmaceutical formulations comprising the compounds of the reference with a pharmaceutically acceptable excipient, diluent, and/or carrier are described (p12, 4th paragraph), which may have an additional therapeutic agent, such as rifampicin (p16, 5th paragraph). These are intended to be used to treat bacterial infections (p18, 4th paragraph). 1-4, 7, 8, 12, 41, 42, 74, 78, and 79.
The difference between this embodiment and applicant’s elected species and the remaining claims is that this reference does not have a substituent attached to the pyrrolidine ring.
Velkov et al discuss the structure-activity relationship of polymyxin antibiotics (title). The fatty acid chain of polymyxins inserts into the bacterial outer membrane and weaken the packing of the lipid A fatty acid chains, causing expansion of the outer membrane (3d page, 1st paragraph). Note that when the fatty acid chain of polymyxin is removed, the chemical loses antimicrobial activity (3d page, 1st paragraph), indicating that the fatty acid or something equivalent is important for activity. Some aromatic compounds have been substituted for the fatty acid with good retention of activity (10th page, 4th paragraph), although some aromatics have reduced activity compared to the native compound (10th page, 5th paragraph). Note that modifying the hydrophobic group in this position can change the selectivity of the antibiotic (10th page, 3d and 4th paragraphs). This reference shows that a hydrophobic moiety attached to the end of the polymyxin nonapeptide is important for antimicrobial activity, which suggests that the compound of Saadi et al could be improved with the attachment of a hydrophobic group.
Leese et al also discuss polymyxin B derivatives (abstract). Among the compounds tested is polymyxin B decapeptide with a benzoic acid attached; a variant that is described as having good activity against E. coli. (paragraph 62 and table 1). Note that this compound is explicitly claimed by the authors (claim 10), indicating that it was one that they believed to be important. Similar to Saadi et al, these compounds are intended for treating infections (paragraph 25). This reference shows that an aromatic ring substituted for the alkyl chain in the naturally occurring polymyxin will be an effective antibiotic.
Therefore, it would be obvious to add a benzene ring to the pyrrolidine ring of the compound of Saadi et al, as Velkov et al show that a hydrophobic moiety at this location is important for activity, and Leese et al shows that a benzene ring as the hydrophobic moiety is effective. As Velkov et al show that hydrophobic interactions with this group with the outer membrane of the bacterium is important for activity, an artisan in this field would make this modification with a reasonable expectation of success.
Leese et al and Velkov et al render obvious adding a benzene ring to the compound of Saadi et al. As the pyrrolidine ring is mimicking the native DAB residue, it is clear that the nitrogen should not be used as a point of attachment. While none of the references describe where to add it on the ring, there are only three free carbons. It would be obvious to try the variations, to see which ones work best. Alternatively, the same radical in physically different positions on the same nucleus are not patentable distinctions (MPEP 2144.09(II)). Thus, the combination of references renders obvious claims 1-4, 7, 8, 12, 41, 42, 58, 59, 65, 66, 74, 78, and 79.
The MPEP states that stereoisomers are considered obvious over each other (MPEP 2144.09(II). As Saadi et al do not specify the stereochemistry of the pyrrolidine ring, this renders claim 42 obvious.
response to applicant’s arguments
Applicants point out that Saadi et al uses simpler hydrophobic attachments, and that the Lesse et al and Velkov et al are too general to render the modifications to Saadi et al obvious to generate applicant’s elected species, specifically, where the aromatic ring is placed..
Applicant's arguments filed 2 Jan, 2026 have been fully considered but they are not persuasive.
Applicants point out the differences between Saadi et al and the examined claims, but those differences, in and of themselves, are not sufficient to overcome the rejection.
Applicants argue that the references are too general to describe where the ring is placed. However, as explained in the rejection, there are only a few places it can be placed, making it obvious to try the variants.
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.
first rejection
Claims 1-4, 7, 8, 12, 41, 42, 58, 59, 65-67, 74, and 78 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 21, 22, and 24 of U.S. Patent No. 12,146,004 in view of Leese et al (US 20060004185).
Competing claim 1 describes a genus of polymyxin analogs, while competing claim 22 describes a number of compounds, including a polymyxin B nonapeptide with a modified phenylalanine and a 3-carboxypyrrolidine 4-octane as the fatty acid group. Note that this reads on embodiments of the examined claims, except for the modification of the phenylalanine to a biphenylalanine. Competing claim 21 discusses pharmaceutical formulations, while claim 24 discusses treating bacterial infections.
The difference between the competing claims and the examined claims is that the phenylalanine residue in the compound of the examined claims is a biphenylalanine residue.
Lesse et al also discuss variants of polymyxin (abstract). Their examples have a phenylalanine residue at the same location as the examined claims do (table 1, paragraph 62).
Therefore, it would be obvious to use a phenylalanine residue at this position of the ring in the compound of the competing claims, as a simple substitution of one known element (the phenylalanine residue of Leese) for another (the biphenylalanine residue of the competing claims) yielding expected results (antimicrobial activity). As this is the residue that occurs in the natural variant, an artisan in this field would make this modification with a reasonable expectation of success/
response to applicant’s arguments
Applicants request that this rejection be held in abeyance. However, until the rejection is overcome, it will remain valid.
second rejection
Claims 1-4, 7, 8, 12, 41, 42, 58, 59, 65-67, 74, 78, and 79 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, and 24 of U.S. Patent No. 9, 234,006 in view of Velkov et al (J. Med. Chem. (2010) 53(5) p1898-1916), Leese et al (US 20060004185), and Calleja et al (Nat. Med. (1998) 4(1) p92-96).
Competing claim 1 describes a genus of polymyxin derivatives, while claim 10 is a much smaller Markush group comprising 3-pyrrolidine 3 carbonyl polymyxin B nonapeptide (p7, line 22). In applicant’s terminology, R1=a phenylalanine side chain, R2=a leucine side chain, R3=a threonine side chain, R4 is a DAB side chain, R8=methyl, R15=pyrrolidine (5 membered heterocycle with 4 carbons and 1 nitrogen), and X=C(O). This structure anticipates examined claims 1-4, 7, 8, 12, 41, and 42. Competing claim 24 describes using the material to treat a bacterial infection, anticipating examined claim 78.
The difference between the competing claims and the remaining examined claims is that the competing claims do not have anything attached to the pyrrolidine ring, nor does it discuss a second antibiotic.
Velkov et al discuss the structure-activity relationship of polymyxin antibiotics (title). The fatty acid chain of polymyxins inserts into the bacterial outer membrane weaken the packing of the lipid A fatty acid chains causing expansion of the outer membrane (3d page, 1st paragraph). Note that when the fatty acid chain of polymyxin is removed, the chemical loses antimicrobial activity (3d page, 1st paragraph), indicating that the fatty acid or something equivalent is important for activity. Some aromatic compounds have been substituted for the fatty acid with good retention of activity (10th page, 4th paragraph), although some aromatics have reduced activity compared to the native compound (10th page, 5th paragraph). Note that modifying the hydrophobic group in this position can change the selectivity of the antibiotic (10th page, 3d and 4th paragraphs). This reference shows that a hydrophobic moiety attached to the end of the polymyxin nonapeptide is important for antimicrobial activity, which suggests that the compound of Saadi et al could be improved with the attachment of a hydrophobic group.
Leese et al also discuss polymyxin B derivatives (abstract). Among the compounds tested is polymyxin B decapeptide with a benzoic acid attached; a variant that is described as having good activity against E. coli. (paragraph 62 and table 1). Note that this compound is explicitly claimed by the authors (claim 10), indicating that it was one that they believed to be important. Similar to Saadi et al, these compounds are intended for treating infections (paragraph 25). This reference shows that an aromatic ring substituted for the alkyl chain in the naturally occurring polymyxin will be an effective antibiotic.
Calleja et al discuss rifampicin (title). This is a macrocyclic antibiotic used to treat tuberculosis (abstract), a bacterial infection.
Therefore, it would be obvious to add a benzene ring to the pyrrolidine ring of the compound of Saadi et al, as Velkov et al show that a hydrophobic moiety at this location is important for activity, and Leese et al shows that a benzene ring as the hydrophobic moiety is effective. As Velkov et al show that hydrophobic interactions with this group with the outer membrane of the bacterium is important for activity, an artisan in this field would make this modification with a reasonable expectation of success.
Furthermore, it would be obvious to add rifampicin to the formulation, as a second antimicrobial. The MPEP states that it is obvious to combine two formulations used for the same purpose to form a third formulation for the same purpose (MPEP 2144.06(I)).
response to applicant’s arguments
Applicants request that this rejection be held in abeyance. However, until the rejection is overcome, it will remain valid.
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.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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