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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/15/2026 has been entered.
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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/15/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
The claim amendments and remarks filed on 04/15/2026 is acknowledged. Claims 20, 24, 27, and 29 are amended. Claims 1-19, 21-22, 26, 28, and 39-40 are cancelled.
Accordingly, claims 20, 23-25, 27, and 29-38 are pending and being examined on the merits herein.
Withdrawn Rejections
The cancellation of claims 21-22, 28, and 39-40 renders the rejections over these claims moot.
The 35 USC 112(b) rejection over claims 20, 23-25, 27, and 29-38 are withdrawn because claims 20 and 27 now recite “SIS … consists of … formula (lb1)”, making it clear what structure is encompassed by the SIS.
The 35 US 103 rejection over Sedlak et al. in view of Nandurdikar et al., Niimi et al., and Alouane et al. for claims 20, 23-25, 27, and 29-38 is withdrawn in favor of the new rejections set forth below.
The following grounds of rejection are new.
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, 23-25, 27, 31-36, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Jornada et al. (Molecules, 2015 in PTO-892) in view of Zhang et al. (Bioconjug Chem, 2018), Nandurdikar et al. (Organic Letters, 2010 in PTO-892 dated 08/05/2025), and Niimi et al. (Archives of Microbiology, 1997 in PTO-892 dated 08/05/2025), and Lemke et al. (Appl Microbiol Biotechnol, 2005 in PTO-892).
Jornada discloses prodrug approaches to optimize the physicochemical and pharmacological properties of drugs to improve their solubility and pharmacokinetic features and decrease their toxicity, in which a lack of solubility is one of the main obstacles to drug development (Abstract).
Jornada discloses that a prodrug is a poorly active or inactive compound containing the parental drug that undergoes some in vivo biotransformation through chemical or enzymatic cleavage, enabling the delivery of the active molecule at efficacious levels (last paragraph page 1). Jornada discloses that prodrugs are conventionally classified in two major classes: carrier-linked prodrugs and bioprecursors. Carrier-linked prodrugs can be classified as bipartite prodrugs, in which the carrier is linked directly to the parent drug, and tripartite prodrugs, in which a spacer links the carrier to the parent drug. Carriers are commonly attached by chemical groups such as ester, amide, carbamate, carbonate, ether, imine, phosphate, among others (last paragraph page 1 and Figure 1 page 2).
Jornada provides several examples of prodrugs using a variety of attachment chemistries and water-soluble moieties.
As seen in section 7 (Imine Prodrugs pages 16-17), Jornada discloses imine-linked prodrugs such as Amphotericin B and nystatin prodrugs containing the pyridoxal phosphate as a water-soluble moiety. Jornada discloses that the imine group was used to allow the attachment of both subunits, and high water-soluble prodrugs and with solubilities up to 100 mg/mL were characterized. The structure of these prodrugs is shown below and in Figure 23 (page 16):
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The Amphotericin B structure shown in Jornada meets the structure of the antifungal drug recited in the instant claims.
Furthermore, Jornada discloses carbamate linked prodrugs (pages 12-13) to increase water solubility of poor water-soluble drugs. Jornada discloses a glucuronide prodrug in which the glucuronide moiety was linked by a spacer to the carbamate as shown below in Figure 17 (page 13):
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The spacer and carbamate structure shown in compound 44 is the same structure as the recited formula (lb1) when X is O, R1 is NH2, and R3 is H.
Jornada discloses that the glucuronide moiety resolved the poor water solubility and decreased toxicity (first paragraph page 13). Jornada also discloses another carbamate prodrug structure (compound 47 in Figure 17) in which a water-soluble N-methylpiperazino pro-moiety was linked by a O-alkyl carbamate linker to the pyrazolo[3,4-d]pyrimides. The compound 47 prodrug demonstrates that carbamates can be linker to the drug at an amine position.
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the imine linkage in the Amphotericin B - pyridoxal phosphate prodrug with the carbamate spacer linker structure as shown in compound 44 of Jornada.
One of ordinary skill in the art would have substituted one known element (imine linkage) for another (carbamate spacer linkage) to obtain predictable results and would have a reasonable expectation of success in doing so because Jornada discloses that both linkage chemistries are suitable for attaching a water-soluble moiety to poorly soluble drugs. Furthermore, Jornada provides guidance that the carbamate can be linked through an amine group on the drug, which suggests that the amine group on the Amphotericin B would also be able to linked via a carbamate linker.
Jornada, however, does not teach a trigger moiety such as N-acetylglucosamine that is cleaved by a pathogen hydrolytic enzyme to release the Amphotericin B.
Zhang discloses N-acetylglucosamine (GlcNAc) conjugated atorvastatin with enhanced water solubility and cellular internalization (Abstract).
Zhang discloses that the bioavailability of atorvastatin is relatively low due to its low water solubility, dissolution rate, and membrane permeability (first paragraph left column page 2109).
Zhang designed two atorvastatin derivatives, G-AT and G-K-AT, as shown in Scheme 1 on page 2110. In both prodrugs, the GlcNAc moiety is conjugated to the atorvastatin via a click reaction. Zhang discloses that the conjugates themselves showed no inhibiting activity on HMG-CoA, but restored the activity after releasing atorvastatin via hydrolyzing from an esterase in biological pH for the G-AT and acidic conditions for the G-K-AT (first paragraph right column page 2109).
Zhang demonstrates in Table 1 and Figure 1 (page 2110) that the conjugation of the GlcNAc significantly increased the water solubility of the atorvastatin as well as the inhibition of HMG-CoA reductase activity by atorvastatin.
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).
Lemke discloses that Amphotericin B is an antifungal drug that is still the drug of choice against life-threatening systemic infections with fungi such as Candida albicans or Aspergillus fumigatus (first paragraph right column page 151).
Lemke discloses that invasive fungal infections are a major cause of morbidity and mortality in immunodeficient individuals (such as AIDS patients) and in transplant recipients or tumor patients undergoing immunosuppressive chemotherapy (Abstract).
Lemke discloses that usefulness of Amphotericin B is limited due to dose-dependent side-effects, notably nephrotoxicity, and in order to improve its safety margin, new pharmaceutical formulations of amphotericin B have been designed especially to reduce its detrimental effects on the kidneys (Abstract). Lemke discloses that since the 1980s, a wide variety of new amphotericin B formulations have been brought forward for clinical testing, many of which were approved and reached market value in the 1990s.
Lemke discloses that all polyene antibiotics including Amphotericin B are characterized by very low solubility in water (first paragraph left column page 152). Lemke discloses that AmB is water-soluble at a pH below 2 or above 11, however the molecule is not stable under such extreme conditions (second paragraph left column page 152). Lemke discloses in acidic or alkaline environments, AmB may form salts which show better water solubility but unfortunately also less antimycotic activity than the basic substance (second paragraph left column page 152). Lemke discloses that for parenteral injections, AmB is often given together with sodium desoxycholate as a solubilizing agent, which in water, these two molecules form micellar colloidal complexes. However, only a fraction of AmB is actually solubilized (second paragraph left column page 152). Lemke discloses that due to the low gastrointestinal uptake of oral AmB, intravenous infusion remains the route of choice (last paragraph right column page 155).
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the pyridoxal phosphate as disclosed by Jornada described above with the N-acetylglucosamine moiety as disclosed in Zhang that can be cleaved by the N-acetylglucosaminidase of Candida albicans to release the Amphotericin B as suggested in Nandurdikar, Niimi, and Lemke to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (pyridoxal phosphate) for another (N-acetylglucosamine) to obtain predictable results and would have a reasonable expectation of success in doing so because both Jornada and Zhang demonstrate the conjugation of a water-soluble moiety (pyridoxal phosphate and N-acetylglucosamine) to improve the water solubility of a poorly water-soluble drug. Additionally, Jornada provides guidance of conjugating similar sugar structure (glucuronide moiety) using a carbamate linker to improve the water solubility of a drug.
Furthermore, the teachings of Nandurdikar, Niimi, and Lemke suggest and provide additional guidance that the N-acetylglucosamine can also serve as targeting moiety and release the Amphotericin B via the N-acetylglucosaminidase of Candida albicans because Nandurdikar et al. demonstrates that N-acetylglucosamine conjugated prodrugs are effectively activated by its corresponding N-acetylglucosaminidase enzyme, Niimi et al. provides guidance that N-acetylglucosaminidase of Candida albicans is a secreted hydrolytic enzyme that contributes to the yeast’s virulence, and Lemke discloses that Amphotericin B is the drug of choice for treating Candida albican infections, which together suggests that an N-acetylglucosamine unit can be used as a target moiety to release the Amphotericin B to Candida albican pathogens that secrete the N-acetylglucosaminidase enzyme.
In regards to instant claims 32-36 and 38, it would have also been prima facie obvious before the effective filing date of the claimed invention to have prepared the modified AmB-GlcNAc prodrug as disclosed by the combined teachings of Jornada, Zhang, Nandurdikar, Niimi, and Lemke described above for water-based intravenous infusion and administer to an immunocompromised patient with a candida fungal infection as disclosed in Lemke to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because the combined teachings of Jornada, Zhang, Nandurdikar, Niimi, and Lemke described above provide guidance of conjugating GlcNAc to AmB to form a prodrug to increase its water solubility as well as a targeting moiety for Candida albican, and Lemke provides further guidance of treating Candida albican infection by administering AmB via a water-based intravenous infusion. Furthermore, Lemke discloses formulations of AmB to reduce its toxicity and improve its water solubility for administration, and further suggests treating patients who are immunocompromised as Lemke discloses invasive fungal infections are a major cause of morbidity and mortality for these types of patients.
Claim(s) 29-30 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Jornada et al. (Molecules, 2015 in PTO-892) in view of Zhang et al. (Bioconjug Chem, 2018), Nandurdikar et al. (Organic Letters, 2010 in PTO-892 dated 08/05/2025), and Niimi et al. (Archives of Microbiology, 1997 in PTO-892 dated 08/05/2025), and Lemke et al. (Appl Microbiol Biotechnol, 2005 in PTO-892), as applied to claims 20 and 32 above, and further in view of Alouane et al. (Angewandte Chemie International Edition, 2015 in PTO-892 dated 08/05/2025).
The combined teachings of Jornada, Zhang, Nandurdikar, Niimi, and Lemke are as described above and teach the antifungal prodrug of instant claim 20 and the method of instant claim 32 as discussed above.
The combined references, however, do not teach that the AmB prodrug has a NO2 substituent attached to the phenyl spacer.
Alouane et al. discloses the design of self-immolative spacers (SIS) 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 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 elimination by electronic cascade (see Figure 5 on page 7500) such as the spacers shown below:
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The SIS linkers shown in Figure 5 above contains the same base SIS linking structure of a phenyl ring connected to a CH2-O-(C=O)-N structure as shown in the instant claims. 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 before the effective filing date of the claimed invention to have substituted the NH2 group on the phenyl spacer of the prodrug compound as disclosed by the combined teachings of Jornada, Zhang, Nandurdikar, Niimi, and Lemke described above with the NO2 group as disclosed in Alouane to arrive at the claimed invention.
One of ordinary skill in the art would have made a simple substitution of one known element (NH2) for another (NO2) to obtain predictable results and would have a reasonable expectation of success in doing so because both the combined teachings of Jornada, Zhang, Nandurdikar, Niimi, and Lemke described above and Alouane disclose the use of the same base spacer structure to form prodrugs and serves the same purpose of controlling the release of a compound upon removal of a protective moiety. Furthermore, Alouane provides guidance that the NO2 is a strong electron-withdrawing functional groups that exhibit a half-life of self-immolation larger than their unsubstituted analogues, which suggests the NO2 is a suitable group on this spacer structure to form prodrugs.
In regards to instant claim 29, it would have also been prima facie obvious before the effective filing date of the claimed invention to have moved the position of the NO2 as NH2 group on the phenyl spacer of the prodrug compound as disclosed by the combined teachings of Jornada, Zhang, Nandurdikar, Niimi, and Lemke described above to the position as shown in instant claim 29 and as disclosed in Alouane to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Alouane provides guidance the attachment of the NO2 at this position on the phenyl spacer is suitable for forming prodrugs
Response to Arguments
Applicant’s arguments filed on 04/15/2026 have been fully considered but were not persuasive.
Applicant provides several arguments in regards to the modifications disclosed in the previous rejection for the prodrug AmB structure disclosed in Sedlak.
However, the new rejections made above do not cite Sedlak, rendering Applicant’s arguments moot.
Conclusion
No claim is found allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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