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.
Response to Amendment
The amendment filed December 22, 2025 has been entered. Claims 14, 31, 33 have been amended, claims 5-7, 10-13, 15-30, 32, 34-35, and 37-44 are cancelled, and claim 45 has been added. Applicant’s amendments to the claims have overcome the claim objection and 112(d) rejections previously set forth in the Non-Final Office Action mailed September 22, 2025. As such, these rejections and objections are hereby withdrawn.
Applicant’s arguments filed December 22, 2025 were fully considered but they were not persuasive. Maintained/New rejections necessitated by Applicant’s amendment are addressed below.
Claims 1-4, 8-9, 14, 31-33, 36 and 45 are pending in this application.
Priority
This application is 371 National Stage Application of PCT/US20/45566, filed August 10, 2020, which claims the benefit of priority to U.S. Provisional Patent Application No. 62/884,464, filed August 8, 2019, and U.S. Provisional Patent Application No. 62/951,753, filed December 20, 2019.
Information Disclosure Statement
The information disclosure statement filed December 22, 2025 has been considered by the Examiner.
Election/Restrictions
Applicant’s election of Group I claims and the following elected species:
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in the reply filed on August 4, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 36 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-4, 8-9, 14, 31, 33, and 45 are encompassed by the election and are examined herein.
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.
Claims 1-4, 8-9, 14, 31, 33, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Nikolaevna (RU 2688658 C1, cited in previous action, the English translation has been provided by the Examiner) in view of Burke (US 9,738,677, IDS filed September 25, 2024).
Regarding claims 1-4, 8-9, 14, 31, 33, and 45: Nikolaevna teaches amphotericin B N-(2-aminoethyl)amide derivatives that have reduced toxicity and improved stability for the treatment of fungal infections (English translation, abstract). Nikolaevna teaches the amphotericin B N-(2-aminoethyl)amide derivatives has more pronounced antifungal properties and lower toxicity compared to amphotericin B (English translation, pg. 2, technical field). Nikolaevna teaches the derivatives can be used in a pharmaceutical composition with a pharmacologically acceptable carrier (English translation, pg. 4, para. 7-8). Nikolaevna teaches the compound is represented by the following structure
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(English translation, pg. 15, formula 1, pgs. 16-17, scheme 1, last structure). The instant specification discloses the structure of Amphotericin B (AmB), which has one carboxylic acid group
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(pg. 7, lines 5-8). Thus Nikolaevna teaches the preparation of an AmB derivative with the following structure:
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.
The compound of Nikolaevna differs from the elected compound in the stereochemistry at the C2’ position of the mucosamine is opposite:
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(Nikolaevna, native AmB stereochemistry)
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(claimed) (i.e. epimer).
However, Burke teaches an amphotericin B derivative with opposite stereochemistry at C2’ position of the mucosamine (abstract col. 2, lines 1-65). Burke teaches that opposite stereochemistry at this position has the added benefit of maintaining antifungal potency while having lower toxicity to human cells (abstract).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the compound of Nikolaevna by switching the stereochemistry of the C2’ position of the mucosamine group as taught by Burke. A person of ordinary skill in the art would have the motivation to do so with a reasonable expectation of success in order to improve the AmB analogues by maintaining antifungal activity and lowering toxicity to subjects.
Claims 1-4, 8-9, 14, 31, 33, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Falkowski (US Patent No. 4,783,527, IDS filed August 1, 2023) in view of Burke (US 9,738,677, IDS filed September 25, 2024).
Regarding claims 1-4, 8-9, 14, 31, 33, and 45: Falkowski teaches the preparation of amide derivatives of polyene macrolide antibiotics which have higher anti-fungal activities together with improved in-vitro selective toxicities compared with the parent antibiotics (col. 2, lines 65-68, col. 3, lines 1-5). Falkowski teaches the polyene macrolide are modified by replacing the carboxylic acid moiety with an amide group (abstract). Falkowski teaches the preparation of amphotericin B 3-aminopropylamide (col. 6, lines 35-43). The instant specification discloses the structure of Amphotericin B (AmB), which has one carboxylic acid group
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(pg. 7, lines 5-8). Thus Falkowski teaches the preparation of an AmB derivative with the following structure:
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.
The compound of Falkowski differs from the elected compound in the stereochemistry at the C2’ position of the mucosamine is opposite:
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(Falkowski)
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(claimed) (i.e. epimer). Falkowski does not teach inclusion in a pharmaceutical composition and a pharmaceutically acceptable carrier.
However, Burke teaches an amphotericin B derivative with opposite stereochemistry at C2’ position of the mucosamine (abstract col. 2, lines 1-65). Burke teaches that opposite stereochemistry at this position has the added benefit of maintaining antifungal potency while having lower toxicity to human cells (abstract). Burke teaches the compounds can be utilized in pharmaceutical compositions with a carrier (col. 2, lines 45-67).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the compound of Falkowski by switching the stereochemistry of the C2’ position of the mucosamine group as taught by Burke. A person of ordinary skill in the art would have the motivation to do so with a reasonable expectation of success in order to improve the AmB analogues by maintaining antifungal activity and lowering toxicity to subjects. It would also have been prima facie obvious to formulate with a pharmaceutical carrier, as Burke establishes this is a known technique in the art of antifungal therapeutics.
Maintained/New 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 1-4, 8-9, 14, 31, and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/877,792 (unpublished, cited in previous action). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claims 1-4, 8-9, 14, 31, and 45: The copending claims teach a composition comprising a lipid polymer excipient and a compound of the following formula:
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(copending claim 1). The copending claims specifically teach the compound may be the elected compound
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(copending claim 19). The copending claims teach wherein the compositions can be used to treat a fungal infection (copending claim 51).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 33 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/877,792 (unpublished, cited in previous action) as applied to claims 1-4, 8-9, 14, 31, and 45 above in view of Burke (US 9,738,677, IDS filed September 25, 2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claim 33: As discussed above the elected compound is encompassed by the copending claims.
They do not teach formulation with a pharmaceutical carrier.
However, Burke teaches an amphotericin B derivative with opposite stereochemistry at C2’ position of the mucosamine (abstract col. 2, lines 1-65). Burke teaches that opposite stereochemistry at this position has the added benefit of maintaining antifungal potency while having lower toxicity to human cells (abstract). Burke teaches the compounds can be utilized in pharmaceutical compositions with a carrier (col. 2, lines 45-67).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the composition of the copending application by including a pharmaceutical carrier as taught by Burke. A person of ordinary skill would have had the motivation to do so with a reasonable expectations of success given that Burke establishes inclusion of a carrier is a routine practice in the art of anti-fungal therapeutics.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments filed December 22, 2025 have been fully considered but they are not persuasive.
On pages 11-12 of Applicant’s response, Applicant argues the combination of Nikolaevna and Burke does not teach or suggest combining any C16 AmB amide derivatives with C2’-epi stereochemistry at the mycosamine moiety would produce AmB derivatives having decreased toxicity against mammalian cells in addition to increased antifungal potency (bridging para.). Applicant argues there is no motivation to combine the references and structural features disclosed therein and arrive at the presently claimed compounds (bridging para.).
However, the Examiner notes that the argument pertaining to increased antifungal potency is related to the installation of the C16 group on AmB and C2 epimerization is related to decreased toxicity in mammalian cells as demonstrated in the instant specification (pgs. 136-137, table 11, wherein BC corresponds to the claimed compound as shown on page 134 of the instant specification). As discussed above, Nikolaevna teaches a C16 AmB amide derivative which only differs from the claimed invention in that it lacks the claimed stereochemistry (i.e. C2’-epimer). Nikolaevna teaches the amphotericin B N-(2-aminoethyl)amide derivatives has more pronounced antifungal properties and lower toxicity compared to amphotericin B (English translation, pg. 2, technical field). Burke teaches an amphotericin B derivative with opposite stereochemistry at C2’ position of the mucosamine (abstract col. 2, lines 1-65). Burke teaches that opposite stereochemistry at this position has the added benefit of maintaining antifungal potency while having lower toxicity to human cells (abstract). Thus, a person of ordinary skill in the art would recognize the added benefit of reversing the stereochemistry at the C2’ position of the mucosamine (i.e. the epimer), thus having the requisite motivation to do so. The art recognizes both the added benefit of C16 amide modification to improve potency and C2’ epimer to reduce overall toxicity, thus, such a result cannot be considered unexpected.
On page 12 of Applicant’s response, Applicant argues there is no operative synthetic methods that would enable a person of ordinary skill in the art to make the claimed derivatives with any reasonable expectation of success, such as inverting the stereochemistry (para. 2).
However, wherein epimers of the C2 position as well as C16 modified AmB derivatives are known in the art, synthesizing the claimed compound would be within the technical grasp of the skilled artisan. Falkowski teaches the preparation of amphotericin B 3-aminopropylamide (col. 6, lines 35-43), which only differs from the claimed compound in that it lacks the correct stereochemistry at the C2’ position and there is no evidence in the prior art that the epimerization of the C2 position would render such a synthesis inoperable. In short there no evidence in the prior art that such a method would not be within the technical grasp of the skilled artisan attempting to make the claimed compound.
On page 12 of Applicant’s response, Applicant argues that the instantly claimed compound exhibits an unexpectedly improved effect for antifungal activity over C2’-epi AmB, while maintaining reduced toxicity (para. 3). Applicant argues that Burke recognizes that C2’-epi Amb has reduced toxicity compared to modified native AmB, but the C2’-epi AmB also has reduced antifungal activity as compared with AmB. On pages 12-13 Applicant argues that the C16 amide group to the C2’-epi AmB scaffold reverses that effect, providing improved antifungal activity compared to the C2’-epi AmB alone, and comparable antifungal activity to that of native AmB without problematic toxicity (bridging para.). On page 13 of Applicants response, Applicant argues that modification of AmB with a C2’-epi reduces toxicity at a loss of antifungal activity, and further installation of the C16 amide group recovers antifungal activity (paras. 1-2, table 1). In short, Applicant is arguing the unexpected benefit of both improving antifungal activity with C16 amide incorporation and reducing toxicity with C2’ epimer.
However, Applicants evidence of unexpected results is found to not be persuasive. The Examiner notes that the argument pertaining to increased antifungal potency is related to the installation of the C16 group on AmB and C2 epimerization is related to decreased toxicity in mammalian cells as demonstrated in the instant specification (pgs. 136-137, table 11, wherein BC corresponds to the claimed compound as shown on page 134 of the instant specification). As discussed above, Nikolaevna teaches a C16 AmB amide derivative which only differs from the claimed invention in that it lacks the claimed stereochemistry (i.e. C2’-epimer). Nikolaevna teaches the amphotericin B N-(2-aminoethyl)amide derivatives has more pronounced antifungal properties and lower toxicity compared to amphotericin B (English translation, pg. 2, technical field). Burke teaches an amphotericin B derivative with opposite stereochemistry at C2’ position of the mucosamine (abstract col. 2, lines 1-65). Burke teaches that opposite stereochemistry at this position has the added benefit of maintaining antifungal potency while having lower toxicity to human cells (abstract). Thus, a person of ordinary skill in the art would recognize the added benefit of reversing the stereochemistry at the C2’ position of the mucosamine (i.e. the epimer), thus having the requisite motivation to do so. The art recognizes both the added benefit of C16 amide modification to improve potency and C2’ epimer to reduce overall toxicity, thus, such a result cannot be considered unexpected.
On page 14 of Applicant’s response, Applicant repeats the arguments above, but applied to the teachings of Falkowski and Burke (paras. 2-3). Applicant argues there is nothing in Falkowski that suggests its improved therapeutic benefit and decreased toxicity (para. 2). Applicant argues that Falkowski teaches other antifungal derivatives were found to be more potent compared to AmB derivatives, thus a person of ordinary skill in the art would not have selected the AmB derivative for further modification.
However, similar to as discussed above, Falkowski teaches the preparation of amide derivatives of polyene macrolide antibiotics which have higher anti-fungal activities together with improved in-vitro selective toxicities compared with the parent antibiotics (col. 2, lines 65-68, col. 3, lines 1-5). Falkowski teaches the polyene macrolide are modified by replacing the carboxylic acid moiety with an amide group (abstract). Falkowski teaches the preparation of amphotericin B 3-aminopropylamide (col. 6, lines 35-43), which only differs from the claimed compound in that it lacks the correct stereochemistry at the C2’ position. Burke teaches an amphotericin B derivative with opposite stereochemistry at C2’ position of the mucosamine (abstract col. 2, lines 1-65). Burke teaches that opposite stereochemistry at this position has the added benefit of maintaining antifungal potency while having lower toxicity to human cells (abstract). Thus, a person of ordinary skill in the art would recognize the added benefit of reversing the stereochemistry at the C2’ position of the mucosamine (i.e. the epimer), thus having the requisite motivation to do so. The art recognizes both the added benefit of C16 amide modification to improve potency and C2’ epimer to reduce overall toxicity, thus, such a result cannot be considered unexpected. With respect to Falkowski teaching other more potent derivatives, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (See MPEP 2123 (II)). Given that Falkowski teaches generally that the modifications have improved activity over there parent compounds, and explicit disclosure of a C16 amphotericin modified analog, a person of ordinary skill in the art would understand this derivative as a valuable starting position for further modification in AmB based therapeutic methods.
To summarize, Applicant argues that the claimed compound which possesses a C16 amide modification and C2’ epimer exhibits improved fungal potency and reduced toxicity as a result of these two modification of AmB.
The Examiner argues that the data provided by Applicant, which is supported by the prior art, demonstrates that C2 epimerization reduces toxicity in AmB derivatives, and C16 modification improves/restores activity in AmB derivatives. Both Nikolaevna and Falkowski acknowledge that C16 amide modification has a net improvement on antifungal potency on AmB derivatives, while Burke acknowledges that C2’ epimerization has a net reduction in toxicity for AmB derivatives. Thus, it would be obvious to incorporate these features with a reasonable expectation of success in improving antifungal potency and reducing toxicity that is not considered unexpected.
Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 103 rejections are maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this action.
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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/S.L.G./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693