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.
Priority
The instant application is a 371 of PCT/EP2021/064441 filed on 05/28/2021, which claims foreign priority to European application no. EP20305562.9 filed on 05/29/2020. The certified copy of the foreign application EP20305562.9 filed on 11/28/2022 is acknowledged.
Status of the Claims
The claim amendments and remarks filed on 11/04/2025 is acknowledged. Claims 1-19 and 26 are cancelled. Claims 20-21, 24-25, 27-29, and 31 are amended. Claims 39-40 are newly added.
Accordingly, claims 20-25 and 27-40 are pending and being examined on the merits herein.
Withdrawn Objections/Rejections
The objection to the drawings is withdrawn in view of the replacement drawings filed on 11/04/2025.
The claim objection to claim 29 is withdrawn in view of the newly amended formula (A2) structure that has sufficient resolution.
The 35 USC 112(b) rejection over claims 27 and 31 are withdrawn in view of the recited “targeting moiety” being clearly defined as a R1 species in claim 27, and the removal of the parenthetical in amended claim 31.
The 35 USC 102 rejection over Sedlak for claims 20-21, 24-26, 31, and 38 is withdrawn in view of amended claim 20 now requiring additional limitations for the SIS and TM moieties, which has narrowed the scope of the claim.
The 35 USC 103 rejections over Sedlak for claims 20 and 32-26, over Sedlak in view of Nandurdikar and Niimi for claims 22-23, and over Sedlak in view of Alouane for claims 27-29 are withdrawn in view of amended claim 20 now requiring additional limitations for the SIS and TM moieties, which has narrowed the scope of the claim.
The following grounds of rejections are amended and new as necessitated by Applicant’s amendments.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 20-25 and 27-40 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 20 recites “… SIS … which comprises … “, and claim 27 “wherein SIS comprises” The term “comprises” is open-ended and does not exclude additional, unrecited elements. See MPEP 2111.03 I. Therefore, claims 20 and 27 are indefinite because it is unclear what other moieties or structures are encompassed by SIS in addition to the recited formula (Ib1) structure
Claims 21-25 and 28-40 depend from claim 20, but do not overcome the described indefinite issue.
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.
Claim(s) 20-25 and 27-40 are rejected under 35 U.S.C. 103 as being unpatentable over Sedlak et al. (Bioorganic & Medicinal Chemistry Letters, 2008 in IDS filed on 11/28/2022) in view of Nandurdikar et al. (Organic Letters, 2010 in PTO-892 dated 08/05/2025), Niimi et al. (Archives of Microbiology, 1997 in PTO-892 dated 08/05/2025), and Alouane et al. (Angewandte Chemie International Edition, 2015 in PTO-892 dated 08/05/2025).
Sedlak et al. discloses a new targeting system for antimycotic drugs: beta-glucosidase
sensitive amphotericin B–star poly(ethylene glycol) conjugate (see Abstract). Sedlak et al. discloses the structure of their compound shown below (also see Scheme 2 on page 2954):
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Here, “AMB” in the top right of the structure corresponds to the amphotericin B drug shown in Figure 1 (see page 2953), which is a polyene macrocyclic membrane-active antifungal antibiotic drug (see left column first page). As illustrated in Scheme 1 and shown below, Sedlak et al. discloses that the enzymatic hydrolysis of the beta-glycosidic bond to produce the glucose unit, and the subsequent 1,6- elimination gives the carbamic acid form of AMB which is decomposed to release the free AMB drug. Sedlak et al. discloses the remaining molecule of the polymeric carrier (sPEG) with covalent bound fragment of substituted 4-hydroxybenzyalcohol is then excreted from the organism (see right column page 2952 through left column page 2953).
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Sedlak discloses the glucose unit is a molecule switch which is sensitive to beta-glucosidases (E.C.3.2.1.21) (see Abstract and Scheme 1) and further discloses that their conjugate was designed on the basis that parasitic fungal pathogens, such as species of Aspergillus, Candida or Trichosporon families possess specific hydrolases b-glucosidases (E.C.3.2.1.21) in their enzymatic outfit (see right column, page 2952).
Here, the beta-glucoside bond that is cleaved by the beta-glucosidase enzyme meets the limitation of a trigger moiety that is cleaved by a pathogen hydrolytic enzyme. Additionally, the linker moiety, which consists of the amide-sPEG and 4-hydroxybenzylalcohol group, meets the limitation of a self-immolative spacer because after enzymatic cleavage of the glucose unit, the linker moiety undergoes a spontaneous 1,6 elimination and decomposes to subsequently release the carbamic acid form of AMB drug and further release the free AMB drug.
Sedlak et al. demonstrated the stability of their compound in phosphate buffer, in which no observable spectral changes (UV-vis spectra) were identified in phosphate buffer of pH 7.4 during a period of 18-20 hours (see left column page 2954). Here, the phosphate buffer used with the compound of Sedlak meets the limitation of a pharmaceutically acceptable excipient because as disclosed in the specification, pharmaceutically acceptable excipients include buffering agents (see page 24 lines 25-35 in spec.). Sedlak et al. discloses that achieving the controlled release using specific hydrolases have been reported for other orally administered intestinal pro-drugs (see right column first page). Sedlak et al. discloses that in contrast to the pharmaceutical dosage forms of AMB used for intravenous application nowadays, they have designed a fundamentally new targeting AMB conjugate that selectively releases AMB by enzymatic action of beta-glucosidase (see left column page 2955).
Sedlak et al. further discloses that Amphotericin B (AMB) (Fig. 1) is a polyene macrocyclic membrane-active antifungal antibiotic drug used in treatment of system fungal infections, and further discloses that it is a potent salvaging medical drug that is applied in the cases of immunosuppressive patients after transplantations of organs, those with acquired immune deficiency syndrome (AIDS) or with tumors and hematological malignities (see left column first page). Sedlak et al. discloses that the clinical application of AMB is restricted by both its poor solubility in water and some side effects, particularly nephrotoxicity (see left column first page). Sedlak et al. discloses that efforts are made to increase the therapeutic index of AMB, and that the aim of their work was to design a conjugate for selective release of AMB to the area of the attacked organ (see left and right column on the first page). Sedlak et al. further demonstrates a model medium imitating the tissue attack by fungal pathogen beta-glucosidase (E.C.3.2.1.21) (Aspergillus niger) in Fig. 2 (see left and right column page 2954). Sedlak et al. discloses that the spectral record of Fig.2 clearly shows an increase in the absorption band at 409 nm, which is specific for monomeric AMB and indicates that such increase with time corresponds with the rate of release of AMB from the carrier (see right column page 2954).
The difference between Sedlak and the claimed invention is that Sedlak does not disclose a TM and SIS moiety as recited in instant claim 20.
Nandurdikar et al. discloses N-acetylglucosamine (GlcNAc)-PROLI/NO prodrugs that are activated by N-acetylglucosaminidase to release nitric oxide (NO) (see Abstract). Nandurdikar et al. illustrates the activation of their glycosylated compound in Figure 2, in which an attached sugar unit is cleaved by a corresponding glycosidase to release their compound (see Figure 2 on page 57). Nandurdikar et al. discloses that glucose was their first choice among all possible sugar protective groups due to its status as an inexpensive and commercially available substrate for glycosylation (see left column page 57). However, Nandurdikar et al. discloses O2-glucosylated-PROLI/NO peracetate did not show a significant amount of intracellular NO release by DAF-FM assay (see right column page 57). Therefore, Nandurdikar et al. discloses their strategy was to develop cell-permeable and biocompatible nitric oxide, and further discloses that N-acetylglucosamine (GlcNAc)-protected diazeniumdiolate prodrugs are activated by their corresponding N-acetylglucosaminidase, and may be cell-permeable and biocompatible (see right column page 57). Nandurdikar et al. demonstrates in Table 1 on page 58 and Figure 3 on page 59 that their novel GlcNAc-PROLI/NO prodrugs efficiently released NO upon activation by N-acetylglucosaminidase isolated from Jack Bean.
Niimi et al. discloses that N-acetylglucosaminidase of Candida albicans is a secreted hydrolytic enzyme that contributes to the yeast’s virulence (see Abstract). Niimi et al. discloses that there was a significant increase in the N-acetylglucosaminidase activity of C. albicans cells released from carbon starvation in medium containing N-acetylglucosamine, and that the increased enzyme activity in N-acetylglucosamine-grown cells correlated with increased transcription of the HEX1 gene, which encodes C. albicans N-acetylglucosaminidase (see Abstract). Niimi et al. discloses that the cellular location of the enzyme and the regulation of production by the carbon source indicate a scavenging role for C. albicans N-acetylglucosaminidase (see Abstract).
Alouane et al. discloses the design of self-immolative spacers for spatio-temporal control and release of drugs, in which a protective moiety (upon stimulation) is removed from one side of the spacer and triggers the release of a desired molecule (see Abstract). Alouane discloses that controlled release of compounds is useful in biomedical application for masking the biological activity of an active compound before it reaches its target and allows for overcoming limitation of small molecules such as low water solubility, lack of specificity to the target, or sub—optimal pharmacokinetics (see page 7493, left column). Alouane et al. discloses that various strategies have been employed to directly release active compounds from their protected precursors, however Alouane et al. discloses that when the protecting group or the active compound is bulky, precursor activation may become difficult and the release of the desired compound not effective (see left column page page 7493). Alouane et al. discloses that to further overcome this limitation, an efficient and increasingly popular approach consists of decoupling precursor activation from compound release by introducing a “self-immolative spacer” between the protecting group and the active compound (see left column page 7493). Alouane et al. discloses self-immolation of spacers based on elimination by electronic cascade or by cyclization (see right column page 7497). Alouane et al. discloses several self-immolative spacer groups that are disassembled via electronic cascade (see Figure 5 on page 7500) such as the spacers shown below:
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Here, compound 6 (R1 is NO2) meets the formula (Ia1) structure as recited in claims 27-28 when R1 is NO2 and R3 is H as well as the formula (A2) structure as recited in claim 29. Alouane et al. discloses that self-immolative spacers containing aromatic rings substituted with strong electron-withdrawing functional groups, such as NO2 (formulas 3, 6, and 11) exhibit a half-life of self-immolation larger than their unsubstituted analogues (see right column page 7500).
It would have been prima facie obvious to combine Sedlak et al. with Nandurdikar et al, Niimi et al, and Alouane et al. before the effective filing date of the claimed invention by substituting the glucose unit of Sedlak with a N-acetylglucosamine unit as disclosed in Nandurdikar et al and Niimi et al. and further substituting the linking moiety of the Sedlak compound with the compound 6 linker of Aluane et al. to arrive at the claimed invention. One of ordinary skill in the art would have been made the substitution of glucose to N-acetylglucosamine with a reasonable expectation of success because Nandurdikar et al. demonstrates that N-acetylglucosamine conjugated prodrugs can effectively be activated by its corresponding N-acetylglucosaminidase enzyme, and Niimi et al. provides guidance that N-acetylglucosaminidase of Candida albicans is a secreted hydrolytic enzyme that contributes to the yeast’s virulence, which further suggests that an N-acetylglucosamine unit can be used as a target to release the antifungal compound to Candida albican pathogens that secrete the N-acetylglucosaminidase enzyme. Furthermore, one of ordinary skill in the art would have made a simple substitution of one known element (linking moiety of Sedlak) for another (compound 6 linker of Alouane) to obtain predictable results because both Sedlak and Alouane disclose the use of the same base self-immolative spacer structure that are based on elimination by electronic cascade and serves the same purpose of controlling the release of a compound upon removal of a protective moiety.
In regards to instant claims 32-37, it would have also been prima face obvious before the effective filing date of the claimed invention to have administered orally or intravenously the compound as suggested by the combined teachings of Sedlak, Nandurdikar, Niimi, and Alouane described above for treating an infectious disease because Sedlak et al. provides guidance that AMB is a known antifungal antibiotic drug for systemic fungal infections and is effective in immunosuppressive patients. Furthermore, Sedlak et al. discloses an expressed advantage of their AMB conjugate for controlled and targeted release of AMB into the attacked organs on the basis that parasitic fungal pathogens, such as species of Aspergillus, Candida or Trichosporon families which possess specific hydrolases b-glucosidases (E.C.3.2.1.21), which will cleave the attached glucose unit on the compound of Sedlak and subsequently release the AMB drug. Furthermore, Sedlak et al. provides guidance that the controlled release mechanism used by their AMB conjugate was also used in other orally administered intestinal pro-drugs, and Sedlak et al. discloses that their compound is designed as an alternative to other pharmaceutical dosage forms of AMB for intravenous application.
Response to Arguments
Applicant’s arguments filed on 11/04/2025 have been fully considered in so far as they apply to
the rejections of the instant office action, but were not persuasive.
Applicant states that an ordinary skilled artisan would not have been motivated to combine Sedlak with Nandurdikar and Niimi because Sedlak specifically teaches that its prodrug contains specific hydrolases, beta-glucosidases, which only occur in some bacteria present in the intestinal micro-flora. Applicant states Nandurdikar teaches the use of a N-acetylglucosaminidase-activated prodrug with cell permeability in normal healthy human cells, while Sedlak teaches the release of amphotericin “selectively only in the area of the attacked organ” and not intracellularly in healthy human cells as taught in Nandurdikar. Therefore, Applicant states that an ordinary skilled artisan would have to change the basic principle of the Sedlak prodrug, which was designed to delivery amphotericin to an organ attacked by parasitic fungal pathogens and not inside healthy human cells. Applicant further states that the glucosylated prodrugs of Nandurdikar did not show a significant amount of intracellular NO release and lack intracellular delivery to human cells, which Applicant states would be consistent with the goals of Sedlak and therefore an ordinary skilled artisan would have still chosen glucose as the targeting moiety. Applicant states that the teachings of Niimi when combined with Sedlak and Nandurdikar do not provide the required motivation to modify the compound of Sedlak to a N-acetylglucosaminidase-activated prodrug. Applicant also states that an ordinary skilled artisan would not arrive at the claimed invention because the prodrug of Sedlak requires the sPEG moiety, and Nandurdikar is silent about a SIS group as defined in claim 20.
Applicant’s argument described above were not found persuasive because Nandurdikar establishes that N-acetylglucosamine can effectively provide the same function of releasing an active molecule by activation from N-acetylglucosaminidase, and Niimi provides further guidance that N-acetylglucosaminidase is also a secreted hydrolytic enzyme of Candida albicans that contributes to the yeast’s virulence, which further suggests that an N-acetylglucosamine unit can be used as a target to release an active compound to Candida albican pathogens that secrete this enzyme. Therefore, when viewing the combinations of these references as a whole, an ordinary skilled artisan could have predictably considered substituting the glucose unit of Sedlak with a N-acetylglucosamine unit as suggested by Nandurdikar and Niimi as described above with a reasonable expectation of success.
It is noted that Nandurdikar teaching the use of a N-acetylglucosaminidase-activated prodrug with cell permeability in normal healthy human cells does not necessarily teach away from using a N-acetylglucosamine unit on a prodrug as a targeting moiety because Nandurdikar is providing guidance that attaching a N-acetylglucosamine unit is an effective prodrug strategy to release a molecule of interest via N-acetylglucosaminidase activation, and it is the further combination with Niimi that suggests that the N-acetylglucosaminidase enzyme can be a target to release an active compound based on Candida albican pathogens secreting this enzyme. Furthermore, the glucosylated prodrug example in Nandurdikar only demonstrates that glucosylated prodrugs may not be as effective to release the NO of Nandurdikar and otherwise does not suggest the glucose moiety being a better targeting moiety or is consistent with the goals of Sedlak to avoid permeability in normal healthy human cells.
Applicant states that an ordinary skilled artisan would not have combined Sedlak with Alouane to substitute the sPEG linker moiety in Sedlak with the SIS linker in Alouane because the sPEG moiety disclosed in Sedlak is suggested to be a necessary feature to improve the therapeutic index and solubility of the AMB drug and that an ordinary skilled artisan would not have considered substituting this sPEG moiety with the SIS linkers of Alouane in order to retain these features. Applicant states that Alouane is a general review of SIS linkers and does not disclose the conception of antifungal prodrugs and is silent about issues related to toxicity and solubility of antifungal drugs.
Applicant’s argument described above were not found persuasive because while Sedlak suggests that the sPEG moiety is used to increase the therapeutic index as well as being water soluble, an ordinary skilled artisan could have still reasonably expected the SIS linkers in Alouane would also increase the therapeutic index and have sufficient solubility to release the AMB drug of Sedlak because Alouane suggests that their SIS linkers are viable prodrug strategies that can help overcome the limitation of small molecules such as low water solubility, lack of specificity to the target, or sub—optimal pharmacokinetics as described above. Furthermore, Alouane discloses that their SIS linkers can help overcome and efficiently release active compounds that are bulky as described above. Therefore, the teachings of Alouane suggest that their SIS linkers would be a viable prodrug strategy for the AMB drug of Sedlak.
Lastly, it is noted Applicant demonstrates in FIG. 4A that fungal-infected mice had comparable survival rates when injected with either their prodrug compound (GOG), Ambisome (non-conjugated AMB) and Fungizone (liposomal formulation of AMB), which indicates the prodrug was as effective as non-prodrug AMBs (see page 8 lines 14-25 and FIG. 4A). Furthermore, Applicant demonstrates in FIG. 5A that their prodrug compound was less toxic compared to unconjugated AMB at a dose of 2 mg / kg.
Here, while Applicant has disclosed that their prodrug compounds are as effective and less toxic than AMB against various fungal infection models disclosed in the specification (see page 8 lines 14-24,Examples 2-4 on pages 34-37, and FIG. 4 and 5), Applicant has not provided sufficient evidence that their prodrug compounds had an unexpected result over the prodrug AMB compound disclosed in Sedlak because an ordinary skilled artisan would reasonably expect that the compound in Sedlak would also be as effective and less toxic than unconjugated AMB based on prodrug strategies being a known method to overcome the limitations of therapeutic compounds such as low water solubility, lack of specificity to the target, or sub—optimal pharmacokinetics as disclosed in Alouane.
Conclusion
No claims are found allowable.
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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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693