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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/10/2026 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
Claims 1, 7, 10-12, 24, 30, 37-38, 40, 42-44, 47, 50-58, and 62-63 are pending in this application. Claims 2-6, 8-9, 13-23, 25-29, 31-36, 39, 41, 45-46, 48-49, 59-61, and 64 have been cancelled by Applicant.
Examiner Notes
Attempts were made to contact attorney Samuel Megerditchian, and a voicemail was left on 09/16/2026, to propose Applicant submit a terminal disclaimer to overcome NSDP rejections of record and move the case to allowance. However, no response was received.
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, 7, 10-11, 24, 30, 37-38, 40, 42-44, 47, 52-53, 56-58, and 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of US Patent No. 12,521,406 B2 (US ‘406); in view of Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); Bierman et al. (US Pharm., 2006, 31(1)(Oncology Suppl):3-15); and Azanza Perea et al. (Clin. Microbiol. and Infect., 10, 2004, 96-106).
Regarding instant claims 1, 7, 10-11, 24, 30, 37-38, 40, 42-44, 47, 52-53, 56-58, and 63, US ‘406 claims a method of treating a fungal infection with the same compound of instant claim 1 (US ‘406 claim 1) administering an amount that provides a steady 24 hr Area Under the Concentration-Time Curve (AUC0-24) of compound 1A in the subject is at least about 150 µg x hr/ mL (US ‘406 claims 1-2); wherein a loading dose is about 2000 mg (administered as two 1000 mg doses administered over 30 min to 4 h – see US ‘406’s claims 5 and 7), and the maintenance dose is about 600-1500 mg (administered over 30 min to 4 h) (US ‘406 claims 1 and 10); and wherein the dosing is performed by IV infusion or oral administration (US ‘406 claims 1-14) or combinations thereof. US ‘406 also speaks to administration for about 4 to 12 weeks, reading on instant claims 42-43 (US ‘406 claim 15); and wherein treatment increases chances of survival in a subject, decreases galactomannan, and decreases β-d-glucan, as recited in instant claim 47 (US ‘406 claim 16).
US ‘406 does not claim the treatment of patients who have CKD (claims 1, 7, 10, and 53). The teachings of Maziarz and Bierman are relied upon for these disclosures.
Maziarz teaches patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function (late-stage CKD) (page 194, col. 1, lines 1-5). Maziarz further teaches antifungal therapy should be tailored based on (fungal) culture and susceptibility results – susceptible Candida spp. can be treated for 10-14 days – fluconazole-resistant Candida and mould infections will often require longer courses of therapy (page 196, col. 2, last para.).
Bierman teaches fungal infections are a major cause of morbidity and mortality in immunocompromised patients, such as patients infected with HIV, someone taking chronic systemic steroids, or transplant recipients (reading on instant claims 1, 4, 12) (abstract and page 2, lines 1-3). Bierman discloses that amphotericin B is known to have significant adverse effects, including permanent loss of renal function (reading on claims 1, 4, 5, 7, and 10) (page 7, para. 1). Bierman further teaches Fluconazole as having normal doses ranging from 100 to about 800 mg/day, with IV and oral doses having the same bioavailability, and adverse effects including renal dysfunction (reading on claims 1, 7, and 10) (page 7, last para.).
Regarding treatment of an antifungal infection in a subject suffering from a kidney condition, such as chronic kidney disease or proteinuria, as recited in instant claims 1 and 7, Maziarz teaches different treatment regimens for antifungal administration to patients suffering from reduced kidney function or a kidney disease (Table 29.2) including Fluconazole and amphotericin B, which are taught by Bierman to have a negative impact on the kidneys, thus combating the fungal infection whilst worsening kidney prognosis. Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to seek out alternative antifungals to treat patients with existing kidney conditions. One of ordinary skill would have been motivated to do so because US ‘406 discloses their antifungal treatment regimen; and Maziarz teachings that patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function. One would have been further motivated in order to prevent further damage to the already compromised subjects, potentially causing complete renal failure by treating with amphotericin B and fluconazole. One of ordinary skill would have had a reasonable expectation of success in view of US ‘406’s disclosure of APX001 as an antifungal agent and treatment regimen, and Bierman’s teachings on the side effects of standard of care antifungals amphotericin B and fluconazole.
Applicant is reminded that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II. Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding the standard of care therapies causing a contradiction in patients, as recited in instant claims 10 and 53, Bierman teaches amphotericin B and fluconazole, to be associated with renal failure and renal dysfunction. Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer alternative known antifungal treatments, such as APX001, in view of US ‘406. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bierman’s teachings regarding on the detrimental effects of certain antifungal treatments on the kidneys.
Claims 12 and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of US Patent No. 12,521,406 B2 (US ‘406); in view of Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); Bierman et al. (US Pharm., 2006, 31(1)(Oncology Suppl):3-15.); as applied to claims 1, 7, 10-11, 24, 30, 37-38, 40, 42-44, 47, 52-53, 56-58, and 63; further in view of Azanza Perea et al. (Clin. Microbiol. and Infect., 10, 2004, 96-106).
The teachings of US ‘406, Maziarz, and Bierman are disclosed above and incorporated herein.
While US ‘406 in view of Maziarz and Bierman do not teach wherein the subject has HIV/AIDS (claims 12 and 54); the teachings of Azanza Perea are relied upon for these disclosures.
Azanza Perea teaches the majority of systemic fungal infections require long-term therapy that often extends 6-12 months, particularly in immunosuppressed patients (abstract). Table (page 98) shows the length of treatment and modes of administration for different types of fungal infection with different standard of care medicines, with treatments ranging from 1 week (for urinary candidiasis – reading on kidney infection) to up to a year (for pulmonary infections – reading on lung infection), and for patients suffering from AIDS, treatment may have to continue indefinitely (Table 1).
Regarding treatment of a subject who is immunocompromised, infected with HIV/AIDS, or has cancer, as recited in instant claims 12 and 54, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to seek out alternative antifungals to treat patients with existing kidney conditions who are also immunocompromised. One of ordinary skill would have been motivated to do so in because US ‘406 discloses their antifungal treatment; Bierman’s teaches that common standard of care antifungals is detrimental to kidney function, especially if administered long term; and Azanza Perea’s discloses that immunosuppressed patients may require indefinite antifungal therapy. One would have been further motivated in order to prevent further damage to the already compromised subjects, potentially causing complete renal failure by treating with amphotericin B and fluconazole. One of ordinary skill would have had a reasonable expectation of success in view of US ‘406’s disclosure of APX001 as an antifungal agent, Bierman’s teachings on the side effects of standard of care antifungals amphotericin B and fluconazole, and Azanza Perea’s teachings of common treatment regimens for immunocompromised patients with HIV/AIDS.
Claims 50-51 and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of US Patent No. 12,521,406 B2 (US ‘406); in view of Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); Bierman et al. (US Pharm., 2006, 31(1)(Oncology Suppl):3-15.); as applied to claims 1, 7, 10-11, 24, 30, 37-38, 40, 42-44, 47, 52-53, 56-58, and 63; further in view of Chen et al. (JAMA, 2019, 22, 13, 1294-1304) (“Chen”).
The teachings of US ‘406, Bierman, and Maziarz are disclosed above and incorporated herein.
While US ‘406 in view of Bierman and Maziarz does not specifically teach CKD stages 3 or 4 (claims 50-51); the teachings of Chen are relied upon for these disclosures.
Chen discloses the definitions and prognosis of CKD by glomerular filtration rates (GFR); with stages G3 and 4 ranging from mildly to severely decreased rates of functioning of the kidney (Figure 2, page 1297). Chen also teaches tolvaptan as a vasopressin V2 inhibitor which slows the decline of GFR (page 1296, col. 2).
Therefore, regarding claims 50-51, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer the APX001 treatment for to a subject with stages 3 or 4 CKD. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because US ‘406 in view of Bierman and Maziarz disclose APX001 for the treatment of fungal infections in subjects with late-stage CKD; further because Chen teaches stages 3 and 4 CKD are the later stages of CKD, approaching kidney failure.
Regarding claim 62, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer tolvaptan (a second therapeutic agent) in combination with US ‘406 in view of Bierman and Maziarz’s antifungal treatment for subjects with CKD in view of Chen. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because US ‘406 in view of Bierman and Maziarz teach APX001 for the treatment of fungal infections in subjects with CKD; further because Chen teaches GFR values decrease consistently for subjects with worsening CKD, and that tolvaptan is a vasopressin V2 inhibitor which slows the decline of GFR in subjects with CKD.
Claim 55 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of US Patent No. 12,521,406 B2 (US ‘406); in view of Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); Bierman et al. (US Pharm., 2006, 31(1)(Oncology Suppl):3-15.); as applied to claims 1, 7, 10-11, 24, 30, 37-38, 40, 42-44, 47, 52-53, 56-58, and 63; further in view of Nucci et al. (Blood, 2014, 124, 26, 3858-3869).
The teachings of US ‘406, Bierman, and Maziarz are disclosed above and incorporated herein.
While US ‘406 in view of Bierman and Maziarz does not specifically teach treatment wherein the subject has acute myeloid or lymphoid leukemia (AML and ALL, respectively); the teachings of Nucci are relied upon for these disclosures.
Nucci teaches invasive fungal diseases (IFDs) represent an important cause of treatment failure in adults with acute leukemia (AML and ALL), with the host’s fitness for standard therapy playing a role in the risks factors associated with IFD (abstract).
Therefore, regarding claim 55, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer the APX001 treatment for to a subject with CKD who also has AML or ALL as taught by US ‘406 in view of Bierman and Maziarz, further in view of Nucci. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because US ‘406 in view of Bierman and Maziarz teach APX001 for the treatment of fungal infections in subjects with CKD; further because Nucci discloses that IFDs are an important cause of treatment failure in adults with AML or ALL, further because Nucci discloses subjects with aversions to standard therapies (such as CKD) have a higher risk of IFD.
Response to Arguments
Claims/ Claim Objections
Claim amendments are acknowledged and have been entered. No new matter has been added. Claim Objections have been withdrawn.
Specification
Amendments to the specification are acknowledged and have been entered. No new matter has been introduced. Objections to the specification are withdrawn.
Claim Rejections - 35 USC § 112(d)
In view of claim amendments, 35 USC § 112(d) rejections are withdrawn.
Claim Rejections - 35 USC § 103
In view of claim amendments and Applicant’s arguments, the 35 USC § 103 rejections have been withdrawn.
Reasons for withdrawing rejections: Hodges et al. (Open Forum Infectious Diseases, 4, 2017, S534 – previously cited) teaches APX001 (instant compound 1) as a first-in-class, intravenous (IV) and oral (PO) broad spectrum antifungal agent for the treatment of invasive fungal infections due to Candida, Aspergillus and rare molds. APX001 has demonstrated great efficacy with APX001A AUC0-24 target exposures ~80 (µg x h)/mL (background). Hodges teaches APX001 was well tolerated across all doses with no clinically significant adverse events observed; all subjects completed dosing; and there were no dose limiting toxicities (results section – last para.). Hodges teaches administration of single doses of 200 mg as IV infusion, administered over 3 hours. Hodges also teaches that dosing at 500 and 1000 mg achieved >90% bioavailability with AUC0-24 values of 192 and 325 (µg x h)/mL, respectively (results paragraph). Hodges teaches dosing for 14 days at 500 and 1000 mg (reading on maintenance doses comprising once a day administration of about 600 to 1500 mg) (results).
Hodges, however, does not disclose: (i) administration to subjects with CKD; (ii) administration of two loading doses of 1000 mg on the first day of treatment (disclosing only one 1000 mg loading dose on the first day); or (iii) any reason or motivation to double the amount of loading dose administered to treat subjects with CKD.
While Bierman et al. (US Pharm., 2006, 31 (Oncology Suppl): 3-15 – previously cited) and Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology (Oxford University Press, 2017, Ch. 29, 194-196 – previously cited) that amphotericin B and fluconazole are known to have significant adverse effects, including permanent loss of renal function; and that patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function; these references provide no reason or motivation for doubling the dosage amounts of APX001 disclosed by Hodges, especially not for subjects with CKD.
Double Patenting
All NSDP rejections have been withdrawn except for the NSDP rejection over US ‘406, which is maintained herein.
Conclusion
THIS ACTION IS MADE FINAL. 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 JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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