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 .
Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 19th, 2026 has been entered.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: “A Method for the Treatment of Fungal Infections in Patients with Chronic Kidney Disease”.
Information Disclosure Statement
The information disclosure statement filed 03/19/2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because all the references cited therein had been submitted in previous IDS. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
Specifically, the Bellmann, Pappas, Vazquez, and Mansbach references are cited in the IDS filed 04/19/2024; and WO 2020/047510 A1 was cited in the IDS from 08/29/2023.
The information disclosure statement (IDS) submitted on 04/20/2026 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, 28-33, 35-40, 42-44, 47, 49-59, and 61-63 are pending in this application. Claims 2-6, 8-9, 13-23, 25-27, 41, 45-46, 48, 60, and 64 have been cancelled by Applicant.
Claim Objections
Claims 40 and 57 are objected to because of the following informalities:
Claim 40 reads: “claim1” in line 1. Add missing a space, to read “claim 1”.
Claim 57 reads “claim1 1…” in line 1. Correct as appropriate – see 112(b).
Appropriate correction is required.
Claim Interpretation
Regarding chronic kidney disease (CKD), Chen et al. (JAMA, 2019, 22, 13, 1294-1304 – cited herein); end-stage kidney disease is an outcome of late-stage CKD (importance box).
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.
Claim 57 is 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 57 reads “the method of claim1 1…” – it is unclear if Applicant intended “the method of claim 1…” and the additional 1 is a typo, OR if Applicant intended “the method of claim 11…”. For the purposes of applying art, it will be assumed applicant intended “the method of claim 1…” – see claim objection.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 30, 33, 35-36, 39-40, 44, and 61 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 33 is rejected for failing to further limit claim 1, from which it depends. Amended claim 1 requires the maintenance dose be administered once daily, starting on the second day. Thus, claim 33 does not further narrow the limitations of claim 1.
Claims 30, 35-36 and 44 are rejected for failing to further limit claim 1, from which they depend. Amended claim 1 reads: “wherein, starting on the second day of treatment: a) (…) over a period of about 30 minutes to about 3 hours by IV infusion (…)”. Claims 30 and 35-36 broaden this range, stating administration over a period “of about 30 minutes to about 4 hours.” Claim 44 speaks to infusion of the first maintenance dose for at least two days (?) (line 13).
Claims 35, 39-40 and 61 are rejected for failing to further limit claim 1, from which it depends. Amended claims 1 reads: “wherein, starting on the second day of treatment: a) (…); or b) (…).” Claim 35 speaks to maintenance doses starting on the second, third, or fourth days of treatment. Claim 39 reads: “wherein, starting on the second, third, or fourth day of treatment: a) (…); or b) (…).” Claims 40 and 61 read: “starting on the fourth day of treatment: a) (…) or b) (…).” As it pertains to embodiments of claims 35, 39-40, and 61 in which the limitations “a)” or “b)” start on the third or fourth days of treatment (instead of on the second day, as specified in claim 1), the claims fail to further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Hodges et al. (Open Forum Infectious Diseases, 4, 2017, S534 – previously cited) (“Hodges”); in view of Bierman et al. (US Pharm., 2006, 31 (Oncology Suppl): 3-15 – previously cited) (“Bierman”); and Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology (Oxford University Press, 2017, Ch. 29, 194-196 – previously cited) (“Maziarz”).
Regarding instant claim 1, Hodges 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 (reading on administering a loading dose of about 2000 mg) (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).
Regarding the instantly claimed ranges for AUC0-24 values, and the loading and maintenance doses, Applicant is advised, 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 claim 52, Hodges teaches their compound showed 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.). Thus, Hodges suggests no contraindications for patients with CKD.
Hodges does not specifically teach: (i) treatment of a subject with chronic kidney disease (CKD); or (ii) treatment with an antifungal for 1-4 weeks. The teachings of Bierman, and Maziarz are relied upon for these disclosures.
Bierman teaches fungal infections are a major cause of morbidity and mortality in immunocompromised patients, someone taking chronic systemic steroids, or transplant recipients (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 (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 (page 7, last para.).
Maziarz teaches patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function. Infection remains the second leading cause of death in patients with chronic renal failure and end stage renal disease (reading on late-stage CKD) (page 194, col. 1, lines 1-5). Maziarz teaches peritoneal dialysis (PD) as an effective alternative to hemodialysis with end-stage renal disease (page 194, col. 2, para. 2), and further teaches regimens of dosing and spectrum of antifungal agents in PD-associated fungal peritonitis (Table 29.2, page 196). 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 mold infections will often require longer courses of therapy (page 196, col. 2, last para.).
Regarding treatment with APX001 wherein the subject has a contradiction to standard of care due to CKD, or proteinuria, as recited in 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 CKD. One of ordinary skill would have been motivated to do so in view of Hodges’ disclosure of APX001 as an antifungal with low toxicities and with no clinically significant adverse effects; Bierman’s teachings on the side effects of standard of care antifungals amphotericin B and fluconazole, which include permanent loss of renal function; and Maziarz teachings that patients with chronic renal failure (late-stage CKD) have a higher incidence of fungal infection than those with normal renal function. Thus, 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 Hodges’ s disclosure of APX001 and its efficacy as an antifungal agent with low toxicity (results – last paragraph).
Regarding length of treatment administration, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the APX001 treatment for 1-4 weeks in view of Hodges, further in view of Maziarz. One of ordinary skill would have been motivated to treat for 1-4 weeks, or longer, as long as symptoms of the fungal infection persist, as taught by Maziarz, who discloses antifungal therapy should be tailed based on (fungal) culture and susceptibility results – susceptible Candida spp. can be treated for 10-14 days – fluconazole-resistant Candida and mold infections will often require longer courses of therapy to prevent return of the infection or development of resistance. One of ordinary skill would have had a reasonable expectation of success in view of Hodges disclosure of APX001 as a low-toxicity anti-fungal treatment; and Maziarz teachings on antifungal therapy regimens for patients with compromised kidneys.
Regarding administration of a maintenance dose starting on the second day of treatment, wherein the maintenance dose can be 600 to about 900 mg or about 1200 mg of APX001 administered via IV infusion over 30 min to about 3 hours OR 700 to about 1000 mg of APX001 administered orally once daily, as recited in instant claims 1, 33, 35-40, 44, and 61, Hodges teaches administration of single doses of 200 mg as IV infusion, administered over 3 hours and oral dosing with APX001 for 14 days at 500 and 1000 mg. Bierman teaches their antifungal treatment regimen should be initiated with two IV loading doses of 6 mg/kg every 12 h followed by maintenance treatment (page 9, para. 2, lines 10-13). 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 APX001 loading doses over the first 24 hours of treatment (day 1) followed by maintenance doses starting on the second day of treatment. One of ordinary skill would have been motivated to administer maintenance treatments in order to keep effective concentrations of active ingredient in the subject’s plasma, resulting in more efficient treatment of the fungal infection. One of ordinary skill would be motivated to administer maintenance treatments via IV infusion if the subject afflicted with a fungal infection is unable to take an oral dose. If the subject is able to take oral doses, one of ordinary skill would be motivated to administer the oral dose instead of an IV dose, as this would circumvent the need for potentially expensive, time consuming, and painful IV treatments and replace it with administration of a pill, which the subject could do in their own home. One of ordinary skill would have had a reasonable expectation of success in view of Hodges’s teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, further in view of Bierman’s teachings on the administration of common standard of care antifungal treatments.
Regarding specific standard of care therapies causing a contradiction in patients, as recited in instant claims 10 and 53, Bierman teaches amphotericin B and fluconazole (reading on an azole antifungal) 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 Hodges, to patients with existing kidney conditions. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Hodges’ s disclosure of APX001 and its efficacy as an antifungal agent with low toxicity and Bierman’s teachings regarding on the detrimental effects of certain antifungal treatments on the kidneys.
Regarding claims 11, 58, and 63, Hodges teaches APX001 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 – reading on at least treatment of candidiasis and aspergilloma (claim 58).
Regarding claim 28, Hodges teaches administration of single doses of APX001, 200 mg, as IV infusion over 3 hours.
Regarding administration of the loading dose as two doses of APX001 by IV infusion, as recited in instant claims 29-32, 59, and 61, Hodges teaches administration of single doses of APX001, 200 mg, as IV infusion over 3 hours and dosing at 500 and 1000 mg (results paragraph). Bierman teaches their antifungal treatment regimen should be initiated with two IV loading doses of 6 mg/kg every 12 h (page 9, para. 2, lines 10-13). 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 the APX001 loading dose as two doses. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Hodges’s teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, further in view of Bierman’s teachings on the administration of common standard of care antifungal treatments. Applicant is advised that a person with ordinary skill has good reason to pursue known options within his or her technical grasp.
Further regarding claim 61, as outlined above, the claimed method of treatment and dosing regimen is obvious in view of the art of record. See above.
Furthermore, Applicant is reminded, 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. 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.
Claims 12, 24, 42-43, 54, and 56-57 are rejected under 35 U.S.C. 103 as being unpatentable over Hodges et al. (Open Forum Infectious Diseases, 4, 2017, S534 – previously cited) (“Hodges”); in view of Bierman et al. (US Pharm., 2006, 31 (Oncology Suppl): 3-15 – previously cited) (“Bierman”); and Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology (Oxford University Press, 2017, Ch. 29, 194-196 – previously cited) (“Maziarz”); as applied to claims 1, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63; further in view of Azanza Perea et al. (Clin. Microbiol. and Infect., 10, 2004, 96-106 – previously cited) (“Azanza Perea”).
The teachings of Hodges, Bierman, and Maziarz are disclosed above and incorporated herein.
While Hodges in view of Bierman and Maziarz does not teach: (i) treatment of fungal patients who are also immunocompromised with HIV/AIDS or cancer (claim 12); (ii) localized fungal infections (claim 24); or (iii) antifungal treatment regimens that last more than 4 weeks (claims 42-44). 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 1 (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 in some cases specifies treatment is continued while symptoms persist or until complete resolution (Table 1).
Regarding treatment of a subject who is immunocompromised, infected with HIV/AIDS, as recited in instant claims 12 and 54, Azanza Perea teaches the majority of systemic fungal infections require long-term therapy that often extends 6-12 months, particularly in immunosuppressed patients (abstract), with patients suffering from AIDS requiring indefinite administration of antifungal therapy (Table 1, oseophageal candidiasis). 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 who are also immunocompromised. One of ordinary skill would have been motivated because Maziarz teaches that patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function; further because Bierman’s teachings that common standard of care antifungals are detrimental to kidney function, especially if administered long term; further because Azanza Perea’s discloses that indefinite treatment may be needed. 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 Hodges’ s disclosure of APX001 and its efficacy as an antifungal agent with low toxicity (results – last paragraph), 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.
Regarding the method of treatment wherein the fungal infection is localized to a specific system or a combination of systems, as recited in instant claims 24 and 56-57, Azanza Perea teaches the length of treatment and modes of administration for different types of localized 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) (Table 1). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to treat a localized or systemic fungal infection with APX001 for as long as symptoms of the fungal infection persist, in view of Hodges and Azanza Perea. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Hodges’s disclosure on the efficacy and low toxicity of APX001; and Azanza Perea’s teachings on the common lengths of treatment of common localized mycotic infections.
Regarding administration of APX001 for about 4 weeks to about 6 weeks, as recited in instant claim 42, or 4-12 weeks, as recited in claim 43, Azanza Perea discloses the duration of therapy for the main types of mycoses ranging from 7-14 days (for urinary candidiasis) to about a year (for diffuse pneumonia) and if immunosuppression is present, indefinite treatment is recommended (Table 1, page 98). 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 APX001 for 4-6 weeks or 4-12 weeks, or for as long as symptoms of the fungal infection persist, in view of Azanza Perea. One of ordinary skill would have been motivated to do so in order to make sure infection is completely eliminated prior to discontinuing treatment, as early termination of treatment may result in return of the infection and the development of resistance to the drug. One of ordinary skill would have had a reasonable expectation of success in view of Hodges’s teachings on the efficacy of APX001 as an antifungal drug with low toxicities and excellent IV and oral bioavailability, further in view of Azanza Perea’s teachings on the wide variations in length of treatment of common mycoses.
Claim 47 is rejected under 35 U.S.C. 103 as being unpatentable over Hodges et al. (Open Forum Infectious Diseases, 4, 2017, S534 – previously cited) (“Hodges”); in view of Bierman et al. (US Pharm., 2006, 31 (Oncology Suppl): 3-15 – previously cited) (“Bierman”); and Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology (Oxford University Press, 2017, Ch. 29, 194-196 – previously cited) (“Maziarz”); as applied to claims 1, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63; further in view of Matsukura et al. (US 2009/0233883 A1, Pub. Date: September 17th, 2009 – From IDS – previously cited).
The teachings of Hodges, Bierman, and Maziarz are disclosed above and incorporated herein.
While Hodges in view of Bierman and Maziarz does not specifically teach wherein the treatment regimen increases the chances of survival in a subject or decreases β-d-glucan levels in a subject (claim 47); the teachings of Matsukura are relied upon for these disclosures.
Matsukura teaches APX001 as a β-glucan synthetase inhibitor (para. 0004) and further discloses mice infected with Candida survived longer after two intravenous doses of APX001 administered 30 min and 9 hours after infection (showing increased chances of survival) (para. 0394-0395 and Table 3).
Therefore, it would have alternatively been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to expect a decrease in β-glucan levels in a subject in view of Matsukura. Therefore, it would have been prima facie obvious to expect an increase in the chances of survival, as taught by Matsukura, who shows a significant improvement in the mean survival days of mice infected with Candida increase from about 2.4 days (for mice who received no treatment) to about 7.4 days (for mice who received two doses of 2.5 mg/kg) and 12.8 days (for mice who received two doses of 13 mg/kg). One of ordinary skill would have had a reasonable expectation of success in view of Hodges’s teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, further in view of Matsukura’s disclosures on the improved survival of infected mice after only two doses of APX001.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Hodges et al. (Open Forum Infectious Diseases, 4, 2017, S534 – previously cited) (“Hodges”); in view of Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology (Oxford University Press, 2017, Ch. 29, 194-196 – previously cited) (“Maziarz”).
Regarding instant claim 49, Hodges 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).
Applicant is reminded, 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. 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.
Regarding administration to a subject, wherein the administration is not required based on kidney status of the subject, applicant is advised that a recitation of the intended use of the claimed invention, such as the use of APX001 for subjects without a special kidney status, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02. The teachings of Hodges do not preclude administration of APX001 to a subject with or without special requirements based on kidney status, therefore, the cited art reads on the instantly claimed invention.
Hodges does not specifically teach: (i) treatment with an antifungal for at least 1-4 weeks. The teachings of Maziarz 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 (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.).
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 the APX001 treatment for 1-4 weeks in view of Hodges and Maziarz. One of ordinary skill would have been motivated to treat for 1-4 weeks, or longer, as long as symptoms of the fungal infection persist, as taught by as taught by Maziarz, depending on the type of infection and susceptibility of the culture to the drug. One of ordinary skill would have had a reasonable expectation of success in view of Hodges teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, and Maziarz guidance on common lengths of treatment regimens.
Claims 50-51 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Hodges et al. (Open Forum Infectious Diseases, 4, 2017, S534 – previously cited) (“Hodges”); in view of Bierman et al. (US Pharm., 2006, 31 (Oncology Suppl): 3-15 – previously cited) (“Bierman”); and Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology (Oxford University Press, 2017, Ch. 29, 194-196 – previously cited) (“Maziarz”); as applied to claims 1, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63; further in view of Chen et al. (JAMA, 2019, 22, 13, 1294-1304) (“Chen”).
The teachings of Hodges, Bierman, and Maziarz are disclosed above and incorporated herein.
While Hodges 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 Hodges 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 Hodges 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 Hodges 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 under 35 U.S.C. 103 as being unpatentable over Hodges et al. (Open Forum Infectious Diseases, 4, 2017, S534 – previously cited) (“Hodges”); in view of Bierman et al. (US Pharm., 2006, 31 (Oncology Suppl): 3-15 – previously cited) (“Bierman”); and Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology (Oxford University Press, 2017, Ch. 29, 194-196 – previously cited) (“Maziarz”); as applied to claims 1, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63; further in view of Nucci et al. (Blood, 2014, 124, 26, 3858-3869).
The teachings of Hodges, Bierman, and Maziarz are disclosed above and incorporated herein.
While Hodges 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 Hodges 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 Hodges 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.
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, 28-33, 35-40, 42-44, 47, 49, 52-53, 56-59, 61, 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) (previously cited as copending Application No. 17/908,079 (Copending ‘079)); 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, 28-33, 35-40, 42-44, 47, 49, 52-53, 56-59, 61, and 63, US ‘406 claims a method of treating a fungal infection with the same compound of instant claims 1 and 49 (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 and a maintenance dose are administered the loading dose comprising 2000 mg of compound 1, reading on instant claim 27 (US ‘406 claim 1); and wherein the dosing is performed by IV infusion or oral administration (US ‘406 claims 1-14) or combinations thereof, as recited in instant claims 28-40 and 44. 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 speak to 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, 4, 5, 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 in view of 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 Bierman’s teachings on the side effects of standard of care antifungals amphotericin B and fluconazole.
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.
This is a provisional nonstatutory double patenting rejection.
Claims 12 and 54 are provisionally 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) (previously cited as copending Application No. 17/908,079 (Copending ‘079)); 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, 28-33, 35-40, 42-44, 47, 49, 52-53, 56-59, 61, 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 view of Bierman’s teachings that common standard of care antifungals is detrimental to kidney function, especially if administered long term, further in view of Azanza Perea’s disclosure 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.
This is a provisional nonstatutory double patenting rejection.
Claims 50-51 and 62 are provisionally 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) (previously cited as copending Application No. 17/908,079 (Copending ‘079)); 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, 28-33, 35-40, 42-44, 47, 49, 52-53, 56-59, 61, 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.
This is a provisional nonstatutory double patenting rejection.
Claim 55 is provisionally 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) (previously cited as copending Application No. 17/908,079 (Copending ‘079)); 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, 28-33, 35-40, 42-44, 47, 49, 52-53, 56-59, 61, 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.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 7, 10-12, 24, 28-33, 35-40, 44, 52-59, 61, and 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 91-111 of copending Application No. 18/905,680 (Copending ‘680); in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); and Bierman et al. (US Pharm., 2006, 31(1) (Oncology Suppl):3-15.).
Regarding instant claims 1, 7, 10-12, 24, 28-33, 35-40, 44, 52-59, 61, and 63, Copending ‘680 claims the compound of Formula (III) and Formula (IIIA), which reads on the instant compound 1 and 1A (instant claims 1 and 49).
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Copending ‘680 further speaks to a method of treating a fungal disease in a subject in need thereof, comprising administering the compound of Formula III (reading on instant compound 1 and 52 and on all the instant claims) (Copending ‘680 claim 104). Copending ‘680 further speaks to treatment of a patient who is immunocompromised (reading on CKD, HIV and leukemia, as stated in instant claims 1, 7, 12, and 54-55) (Copending ‘680 claims 108 and 110). Copending ‘680 also mentions specific and localized fungal infections (Copending ‘680 claims 106 and 107) reading on instant claims 11, 24, and 56-57.
Copending ‘680 does not speak to: (i) administration such that a steady 24 hr Area Under the Concentration-Time Curve (AUC0-24) of compound 1A in the subject is at least about 100-200 µg x hr/ mL (instant claim 1); (ii) administration of compound 1 for 1-4 weeks (instant claims 1); (iii) specific dosage forms, amounts, or forms of administration (instant claims 1, 40, 44, 59, and 61); or (iv) specific dosages or methods of administration. The teachings of Hodges, Maziarz, and Bierman are relied upon for these disclosures.
Hodges teaches APX001 (instant compound 1) as a first-in-class, intravenous (IV) and oral (PO) broad spectrum antifungal agent, which has demonstrated great efficacy with APX001A AUC0-24 target exposures ~80 µg x h/mL (reading on claims 1 and 8) (background). Hodges discloses IV infusion of 200 mg of APX001 over 3 hours (reading on claims 30, 35-36, and 39-40), followed by single tablet doses of 100, 300, and 500 mg, each separated by a 14-day washout period (methods). Hodges discloses after 14 days of dosing at 500 and 1000 mg, AUC0-24 were 192 and 325 µg x h/mL, respectively.
Maziarz teaches patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function (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 voriconazole treatment regimen should be initiated with two IV loading doses of 6 mg/kg every 12 h, with maintenance therapy intravenously of 4 mg/kg every 12 h or 200 mg orally twice a day (for patients weighing more than 40 kg) and 100 mg (for patients weighing less than 40 kg) (page 9, para. 2, lines 10-13).
Regarding length of treatment administration, as in instant claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the APX001 treatment for 1-4 weeks in view of Copending ‘680, Hodges, further in view of Maziarz and Bierman. One of ordinary skill would have been motivated to treat for 1-4 weeks, or longer, as long as symptoms of the fungal infection persist, as taught by Maziarz, who discloses antifungal therapy should be tailed based on (fungal) culture and susceptibility results – susceptible Candida spp. can be treated for 10-14 days – fluconazole-resistant Candida and mold infections will often require longer courses of therapy to prevent return of the infection or development of resistance. One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘680 and Hodges disclosure of APX001 as a low-toxicity anti-fungal treatment; and Maziarz teachings on antifungal therapy regimens for patients with compromised kidneys.
Regarding administration of a maintenance dose starting on the second day of treatment, wherein the maintenance dose can be 600 to about 900 mg or about 1200 mg of APX001 administered via IV infusion over 30 min to about 3 hours OR 700 to about 1000 mg of APX001 administered orally once daily, as recited in instant claims 1, 33, 35-40, 44, and 61, Copending ‘680 and Hodges teach administration of single doses of 200 mg as IV infusion, administered over 3 hours and oral dosing with APX001 for 14 days at 500 and 1000 mg. Bierman teaches their antifungal treatment regimen should be initiated with two IV loading doses of 6 mg/kg every 12 h followed by maintenance treatment (page 9, para. 2, lines 10-13). 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 APX001 loading doses over the first 24 hours of treatment (day 1) followed by maintenance doses starting on the second day of treatment. One of ordinary skill would have been motivated to administer maintenance treatments in order to keep effective concentrations of active ingredient in the subject’s plasma, resulting in more efficient treatment of the fungal infection. One of ordinary skill would be motivated to administer maintenance treatments via IV infusion if the subject afflicted with a fungal infection is unable to take an oral dose. If the subject is able to take oral doses, one of ordinary skill would be motivated to administer the oral dose instead of an IV dose, as this would circumvent the need for potentially expensive, time consuming, and painful IV treatments and replace it with administration of a pill, which the subject could do in their own home. One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘680 and Hodges’s teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, further in view of Bierman’s teachings on the administration of common standard of care antifungal treatments.
Regarding specific standard of care therapies causing a contradiction in patients, as recited in instant claims 10 and 53, Bierman teaches amphotericin B and fluconazole (reading on an azole antifungal) 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 Copending ‘680 and Hodges, to patients with existing kidney conditions. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘680 and Hodges’ s disclosure of APX001 and its efficacy as an antifungal agent with low toxicity and Bierman’s teachings regarding on the detrimental effects of certain antifungal treatments on the kidneys.
Regarding claims 11, 58, and 63, Hodges teaches APX001 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 – reading on at least treatment of candidiasis and aspergilloma (claim 58).
Regarding claim 28, Hodges teaches administration of single doses of APX001, 200 mg, as IV infusion over 3 hours.
Regarding administration of the loading dose as two doses of APX001 by IV infusion, as recited in instant claims 29-32, 59, and 61, Hodges teaches administration of single doses of APX001, 200 mg, as IV infusion over 3 hours and dosing at 500 and 1000 mg (results paragraph). Bierman teaches their antifungal treatment regimen should be initiated with two IV loading doses of 6 mg/kg every 12 h (page 9, para. 2, lines 10-13). 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 the APX001 loading dose as two doses. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘680 and Hodges’s teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, further in view of Bierman’s teachings on the administration of common standard of care antifungal treatments. Applicant is advised that a person with ordinary skill has good reason to pursue known options within his or her technical grasp.
Further regarding claim 61, as outlined above, the claimed method of treatment and dosing regimen is obvious in view of the art of record. See above.
Furthermore, Applicant is reminded, 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. 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.
This is a provisional nonstatutory double patenting rejection.
Claims 42-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 91-111 of copending Application No. 18/905,680 (Copending ‘680) in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); and Bierman et al. (US Pharm., 2006, 31(1) (Oncology Suppl):3-15.); as applied to claims 1, 7, 10-12, 24, 28-33, 35-40, 44, 52-59, 61, and 63; further in view of Azanza Perea et al. (Clin. Microbiol. and Infect., 10, 2004, 96-106.).
The teachings of Copending ‘680, Hodges, Maziarz, and Bierman are disclosed above and incorporated herein.
While Copending ‘680 in view of Hodges, Maziarz, and Bierman does not teach antifungal treatment regimens that last several weeks (claims 42-43). The teachings of Azanza Perea et al. 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) to up to a year (for pulmonary infections), and in some cases specifies treatment is continued while symptoms persist or until complete resolution, mentioning patients with AIDS may require indefinite administration (oesophangeal candidiasis).
Regarding administration of APX001 for about 4 weeks to about 6 weeks, as recited in instant claim 42, or 4-12 weeks, as recited in claim 43, Azanza Perea discloses the duration of therapy for the main types of mycoses ranging from 7-14 days (for urinary candidiasis) to about a year (for diffuse pneumonia) and if immunosuppression is present, indefinite treatment is recommended (Table 1, page 98). 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 Copending ‘680’s APX001 for 4-6 weeks or 4-12 weeks, or for as long as symptoms of the fungal infection persist, in view of Azanza Perea. One of ordinary skill would have been motivated to do so in order to make sure infection is completely eliminated prior to discontinuing treatment, as early termination of treatment may result in return of the infection and the development of resistance to the drug. One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘680 and Hodges’s teachings on the efficacy of APX001 as an antifungal drug with low toxicities and excellent IV and oral bioavailability, further in view of Azanza Perea’s teachings on the wide variations in length of treatment of common mycoses.
This is a provisional nonstatutory double patenting rejection.
Claim 47 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 91-111 of copending Application No. 18/905,680 (Copending ‘680) in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); and Bierman et al. (US Pharm., 2006, 31(1) (Oncology Suppl):3-15.); as applied to instant claim 1, 7, 10-12, 24, 28-33, 35-40, 44, 52-59, 61, and 63; further in view of Matsukura et al. (US 2009/0233883 A1, Pub. Date: September 17th, 2009 – From IDS)
The teachings of Copending ‘680, Hodges, Maziarz, and Bierman are disclosed above and incorporated herein.
While Copending ‘680 in view of Hodges, Maziarz, and Bierman does not teach treatment wherein chances of survival are increased or wherein β-d-glucan decreases (instant claim 47); the teachings of Matsukura et al. are relied upon for these disclosures.
Regarding instant claim 47, Matsukura teaches APX001 as a β-glucan synthetase inhibitor (para. 0004) and further discloses mice infected with Candida survived longer after two intravenous doses of APX001 administered 30 min and 9 hours after infection (para. 0394-0395 and Table 3).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to expect a decrease in β-glucan levels in a subject in view of Matsukura. Applicant is advised, a recitation of the intended use of the claimed invention, such as the use of APX001 as a β-glucan inhibitor in the instant application, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02
Furthermore, it would have been prima facie obvious to expect an increase in the chances of survival, as taught by Matsukura, who shoes a significant improvement in the mean survival days of mice infected with Candida increase from about 2.4 days (for mice who received no treatment) to about 7.4 days (for mice who received two doses of 2.5 mg/kg) and 12.8 days (for mice who received two doses of 13 mg/kg). One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘680’s and Hodges’s teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, further in view of Matsukura’s disclosures on the improved survival of infected mice after only two doses of APX001.
This is a provisional nonstatutory double patenting rejection.
Claim 50-51 and 62 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 91-111 of copending Application No. 18/905,680 (Copending ‘680) in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); and Bierman et al. (US Pharm., 2006, 31(1) (Oncology Suppl):3-15.); as applied to instant claim 1, 7, 10-12, 24, 28-33, 35-40, 44, 52-59, 61, and 63; further in view of Chen et al. (JAMA, 2019, 22, 13, 1294-1304) (“Chen”).
The teachings of Copending ‘680, Bierman, and Maziarz are disclosed above and incorporated herein.
While Copending ‘680 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 Copending ‘680 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 Copending ‘680 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 Copending ‘680 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.
This is a provisional nonstatutory double patenting rejection.
Claim 49 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 91-111 of copending Application No. 18/905,680 (Copending ‘680); in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); and Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196).
Regarding instant claim 49, Copending ‘680 claims the compound of Formula (III) and Formula (IIIA), which reads on the instant compound 1 and 1A (instant claims 1 and 49).
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Copending ‘680 further speaks to a method of treating a fungal disease in a subject in need thereof, comprising administering the compound of Formula III (Copending ‘680 claim 104).
Copending ‘680 does not speak to: (i) administration such that a steady 24 hr Area Under the Concentration-Time Curve (AUC0-24) of compound 1A in the subject is at least about 100-200 µg x hr/ mL; or (ii) administration of compound 1 for 1-4 weeks. The teachings of Hodges and Maziarz et al. are relied upon for these disclosures.
Hodges teaches APX001 has demonstrated great efficacy with APX001A AUC0-24 target exposures ~80 µg x h/mL (reading on claims 1 and 8) (background).
Maziarz teaches patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function (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.).
Regarding instant claim 49, Hodges teaches APX001 has demonstrated great efficacy with APX001A AUC0-24 target exposures ~80 (µg x h)/mL (background).
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 an effective amount of Copending ‘680’s APX001 such that plasma concentrations of APX001A were kept over the desired target exposure of ~80 (µg x h)/mL, as taught by Hodges. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Hodges.
Applicant is advised, 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. 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.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art
Regarding administration to a subject, wherein the administration is not required based on kidney status of the subject, applicant is advised that a recitation of the intended use of the claimed invention, such as the use of Copending ‘680’s APX001 for subjects without a special kidney status, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02. The teachings of Hodges do not preclude administration of APX001 to a subject with or without special requirements based on kidney status, therefore, the cited art reads on the instantly claimed invention.
Regarding length of treatment administration, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the APX001 treatment for 1-4 weeks in view of Hodges and Maziarz. One of ordinary skill would have been motivated to treat for 1-4 weeks, or longer, as long as symptoms of the fungal infection persist, as taught by as taught by Maziarz, depending on the type of infection and susceptibility of the culture to the drug. One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘680 and Hodges teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, and Maziarz guidance on common lengths of treatment regimens.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 231-232, 234-239, 241-248, 250-265 of copending Application No. 17/271,020 (Copending ‘020); in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); and Bierman et. al. (US Pharm., 2006, 31(1)(Oncology Suppl):3-15.).
Regarding instant claims 1, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63, Copending ‘020 claims a pharmaceutical composition comprising instantly claimed compound 1 (APX001) in a buffered solution for IV injection.
Copending ‘020 does not speak to: (i) treatment of a fungal infection; (ii) administration such that a steady 24 hr Area Under the Concentration-Time Curve (AUC0-24) of APX001A in the subject is at least about 100-200 µg x hr/ mL (instant claims 1 and 8); (iii) administration for 1-4 weeks (claim 1); (iv) administration to immunocompromised or individuals with contradictions to standard of care antifungal medications (instant claims 4-5, 7, 10); or (v) specific dosage forms, amounts, or forms of administration (instant claims 26-38). The teachings of Hodges, Maziarz, and Bierman et al. are relied upon for these disclosures.
Hodges teaches APX001 (instant compound 1) as a first-in-class, intravenous (IV) and oral (PO) broad spectrum antifungal agent, which has demonstrated great efficacy with APX001A AUC0-24 target exposures ~80 µg x h/mL (reading on claims 1 and 8) (background). Hodges discloses IV infusion of 200 mg of APX001 over 3 hours (reading on claims 30, 35-36, and 39-40), followed by single tablet doses of 100, 300, and 500 mg, each separated by a 14-day washout period (methods). Hodges discloses after 14 days of dosing at 500 and 1000 mg, AUC0-24 were 192 and 325 µg x h/mL, respectively.
Maziarz teaches patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function (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, 4, 5, 7, and 10) (page 7, last para.). Bierman further teaches voriconazole treatment regimen should be initiated with two IV loading doses of 6 mg/kg every 12 h, with maintenance therapy intravenously of 4 mg/kg every 12 h or 200 mg orally twice a day (for patients weighing more than 40 kg) and 100 mg (for patients weighing less than 40 kg) (page 9, para. 2, lines 10-13) (reading on claims 40 and 44).
Regarding treatment with APX001 wherein the subject has a contradiction to standard of care due to CKD, or proteinuria, as recited in 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 CKD. One of ordinary skill would have been motivated to do so in view of Copending ‘020 and Hodges’ disclosure of APX001 as an antifungal with low toxicities and with no clinically significant adverse effects; Bierman’s teachings on the side effects of standard of care antifungals amphotericin B and fluconazole, which include permanent loss of renal function; and Maziarz teachings that patients with chronic renal failure (late-stage CKD) have a higher incidence of fungal infection than those with normal renal function. Thus, 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 Copending ‘020 and Hodges’ s disclosure of APX001 and its efficacy as an antifungal agent with low toxicity (results – last paragraph).
Regarding length of treatment administration, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the APX001 treatment for 1-4 weeks in view of Copending ‘020 and Hodges, further in view of Maziarz. One of ordinary skill would have been motivated to treat for 1-4 weeks, or longer, as long as symptoms of the fungal infection persist, as taught by Maziarz, who discloses antifungal therapy should be tailed based on (fungal) culture and susceptibility results – susceptible Candida spp. can be treated for 10-14 days – fluconazole-resistant Candida and mold infections will often require longer courses of therapy to prevent return of the infection or development of resistance. One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘020 and Hodges disclosure of APX001 as a low-toxicity anti-fungal treatment; and Maziarz teachings on antifungal therapy regimens for patients with compromised kidneys.
Regarding administration of a maintenance dose starting on the second day of treatment, wherein the maintenance dose can be 600 to about 900 mg or about 1200 mg of APX001 administered via IV infusion over 30 min to about 3 hours OR 700 to about 1000 mg of APX001 administered orally once daily, as recited in instant claims 1, 33, 35-40, 44, and 61, Copending ‘020 and Hodges teaches administration of single doses of 200 mg as IV infusion, administered over 3 hours and oral dosing with APX001 for 14 days at 500 and 1000 mg. Bierman teaches their antifungal treatment regimen should be initiated with two IV loading doses of 6 mg/kg every 12 h followed by maintenance treatment (page 9, para. 2, lines 10-13). 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 APX001 loading doses over the first 24 hours of treatment (day 1) followed by maintenance doses starting on the second day of treatment. One of ordinary skill would have been motivated to administer maintenance treatments in order to keep effective concentrations of active ingredient in the subject’s plasma, resulting in more efficient treatment of the fungal infection. One of ordinary skill would be motivated to administer maintenance treatments via IV infusion if the subject afflicted with a fungal infection is unable to take an oral dose. If the subject is able to take oral doses, one of ordinary skill would be motivated to administer the oral dose instead of an IV dose, as this would circumvent the need for potentially expensive, time consuming, and painful IV treatments and replace it with administration of a pill, which the subject could do in their own home. One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘020 and Hodges’s teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, further in view of Bierman’s teachings on the administration of common standard of care antifungal treatments.
Regarding specific standard of care therapies causing a contradiction in patients, as recited in instant claims 10 and 53, Bierman teaches amphotericin B and fluconazole (reading on an azole antifungal) 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 Hodges, to patients with existing kidney conditions. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘020 and Hodges’ s disclosure of APX001 and its efficacy as an antifungal agent with low toxicity and Bierman’s teachings regarding on the detrimental effects of certain antifungal treatments on the kidneys.
Regarding claims 11, 58, and 63, Hodges teaches APX001 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 – reading on at least treatment of candidiasis and aspergilloma (claim 58).
Regarding claim 28, Hodges teaches administration of single doses of APX001, 200 mg, as IV infusion over 3 hours.
Regarding administration of the loading dose as two doses of APX001 by IV infusion, as recited in instant claims 29-32, 59, and 61, Hodges teaches administration of single doses of APX001, 200 mg, as IV infusion over 3 hours and dosing at 500 and 1000 mg (results paragraph). Bierman teaches their antifungal treatment regimen should be initiated with two IV loading doses of 6 mg/kg every 12 h (page 9, para. 2, lines 10-13). 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 the APX001 loading dose as two doses. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘020 and Hodges’s teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, further in view of Bierman’s teachings on the administration of common standard of care antifungal treatments. Applicant is advised that a person with ordinary skill has good reason to pursue known options within his or her technical grasp.
Further regarding claim 61, as outlined above, the claimed method of treatment and dosing regimen is obvious in view of the art of record. See above.
Furthermore, Applicant is reminded, 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. 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.
Regarding claim 52, Hodges teaches APX001 has low toxicities and provides no indication that their antifungal treatment is contraindicated for subjects with CKD.
Regarding claims 58 and 63, Hodges teaches APX001 as an antifungal for the treatment of Candida infections
This is a provisional nonstatutory double patenting rejection.
Claims 12, 24, 42-43, 54, 56-57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 231-232, 234-239, 241-248, 250-265 of copending Application No. 17/271,020 (Copending ‘020) in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); and Bierman et. al. (US Pharm., 2006, 31(1)(Oncology Suppl):3-15.); as applied to claims 1, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63; further in view of Azanza Perea et al. (Clin. Microbiol. and Infect., 10, 2004, 96-106.).
The teachings of Copending ‘020, Hodges, Maziarz, and Bierman et al. are disclosed above and incorporated herein.
While Copending ‘020, in view of Hodges, Maziarz, and Bierman et al., does not teach (i) treatment of fungal patients who are also immunocompromised, with HIV/AIDS or cancer (claims 12 and 54); (ii) localized fungal infections (claims 24 and 56-57); or (iii) antifungal treatment regimens that last several weeks (claims 42-43). 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 in some cases specifies treatment is continued while symptoms persist or until complete resolution mentioning patients with AIDS may require indefinite administration (oesophangeal candidiasis - 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, Azanza Perea teaches the majority of systemic fungal infections require long-term therapy that often extends 6-12 months, particularly in immunosuppressed patients (abstract), with patients suffering from AIDS requiring indefinite administration of antifungal therapy (Table 1, oseophageal candidiasis). 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 who are also immunocompromised. One of ordinary skill would have been motivated to do so in view of Maziarz teachings that patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function, further in view of Azanza Perea’s disclosure that indefinite treatment may be needed, further in view of Bierman’s teachings that common standard of care antifungals are detrimental to kidney function, especially if administered long term. 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 Copending ‘020’s disclosure of an IV formulation of APX001, Hodges’ s disclosure of APX001 and its efficacy as an antifungal agent with low toxicity (results – last paragraph), 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.
Regarding the method of treatment wherein the fungal infection is localized to a specific system or a combination of systems, as recited in instant claims 24 and 56-57, Azanza Perea teaches the length of treatment and modes of administration for different types of localized 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) (Table 1). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to treat a localized or systemic fungal infection with APX001 for as long as symptoms of the fungal infection persist, in view of Copending ‘020, Hodges, and Azanza Perea. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘020’s disclosure of an IV formulation of APX001, Hodges’s disclosure on the efficacy and low toxicity of APX001, and Azanza Perea’s teachings on the common lengths of treatment of common localized mycotic infections.
Regarding administration of APX001 for about 4 weeks to about 6 weeks, as recited in instant claim 42, or 4-12 weeks, as recited in claim 43, Azanza Perea discloses the duration of therapy for the main types of mycoses ranging from 7-14 days (for urinary candidiasis) to about a year (for diffuse pneumonia) and if immunosuppression is present, indefinite treatment is recommended (Table 1, page 98). 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 Copending ‘020’s APX001 for 4-6 weeks or 4-12 weeks, or for as long as symptoms of the fungal infection persist, in view of Azanza Perea. One of ordinary skill would have been motivated to do so in order to make sure infection is completely eliminated prior to discontinuing treatment, as early termination of treatment may result in return of the infection and the development of resistance to the drug. One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘020 IV formulation and Hodges’s teachings on the efficacy of APX001 as an antifungal drug with low toxicities and excellent IV and oral bioavailability, further in view of Azanza Perea’s teachings on the wide variations in length of treatment of common mycoses.
This is a provisional nonstatutory double patenting rejection.
Claim 47 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 231-232, 234-239, 241-248, 250-265 of copending Application No. 17/271,020 (Copending ‘020); in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); and Bierman et. al. (US Pharm., 2006, 31(1)(Oncology Suppl):3-15.); as applied to claims 1, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63; further in view of Matsukura et al. (US 2009/0233883 A1, Pub. Date: September 17th, 2009 – From IDS).
The teachings of Copending ‘020, Hodges, Maziarz, and Bierman are disclosed above and incorporated herein.
While Copending ‘020, in view of Hodges, Maziarz, and Bierman, does not teach treatment wherein chances of survival are increased or wherein β-d-glucan decreases (instant claim 47), the teachings of Matsukura are relied upon for these disclosures.
Regarding instant claim 47, Matsukura teaches APX001 as a β-glucan synthetase inhibitor (para. 0004) and further discloses mice infected with Candida survived longer after two intravenous doses of APX001 administered 30 min and 9 hours after infection (para. 0394-0395 and Table 3).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to expect a decrease in β-glucan levels in a subject in view of Matsukura. Applicant is advised, a recitation of the intended use of the claimed invention, such as the use of APX001 as a β-glucan inhibitor in the instant application, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Furthermore, it would have been prima facie obvious to expect an increase in the chances of survival, as taught by Matsukura, who shoes a significant improvement in the mean survival days of mice infected with Candida increase from about 2.4 days (for mice who received no treatment) to about 7.4 days (for mice who received two doses of 2.5 mg/kg) and 12.8 days (for mice who received two doses of 13 mg/kg). One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘020’s IV formulation of APX001 and Hodges’s teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, further in view of Matsukura’s disclosures on the improved survival of infected mice after only two doses of APX001.
This is a provisional nonstatutory double patenting rejection.
Claims 50-51 and 62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 231-232, 234-239, 241-248, 250-265 of copending Application No. 17/271,020 (Copending ‘020); in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); and Bierman et al. (US Pharm., 2006, 31(1) (Oncology Suppl):3-15.); as applied to instant claim 1, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63; further in view of Chen et al. (JAMA, 2019, 22, 13, 1294-1304) (“Chen”).
The teachings of Copending ‘020, Hodges, Maziarz, and Bierman, are disclosed above and incorporated herein.
While Copending ‘020 in view of Hodges, Maziarz, and Bierman 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 Copending ‘020’s 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 Copending ‘020 in view of Hodges, Maziarz and Bierman 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 Copending ‘020 in view of Hodges, Maziarz, and Bierman’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 Copending ‘020 in view of Hodges, Maziarz, and Bierman 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.
This is a provisional nonstatutory double patenting rejection.
Claim 55 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 231-232, 234-239, 241-248, 250-265 of copending Application No. 17/271,020 (Copending ‘020); in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196); and Bierman et al. (US Pharm., 2006, 31(1) (Oncology Suppl):3-15.); as applied to instant claim 1, 7, 10-11, 28-33, 35-40, 44, 52-53, 58-59, 61, and 63; further in view of Nucci et al. (Blood, 2014, 124, 26, 3858-3869).
The teachings of Copending ‘020, Hodges, Maziarz, and Bierman are disclosed above and incorporated herein.
While Copending ‘680 in view of Hodges, Maziarz, and Bierman 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 Copending ‘020 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 Copending ‘020 in view of Hodges, Maziarz, and Bierman 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.
This is a provisional nonstatutory double patenting rejection.
Claim 49 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 231-232, 234-239, 241-248, 250-265 of copending Application No. 17/271,020 (Copending ‘020); in view of Hodges et al. (Open Forum Infectious Diseases, Volume 4, Issue suppl_1, Fall 2017, Page S534.); and Maziarz et al. (In Kibbler et al., Oxford Book of Medical Mycology, Oxford University Press, 2017, Ch. 29, 194-196).
Regarding instant claim 49, Copending ‘020 claims a pharmaceutical composition comprising instantly claimed compound 1 in a buffered solution for IV injection.
Copending ‘020 does not speak to: (i) treatment of a fungal infection; (ii) administration such that a steady 24 hr Area Under the Concentration-Time Curve (AUC0-24) of compound 1A in the subject is at least about 100 µg x hr/ mL; or (iii) administration of APX001 for 1-4 weeks. The teachings of Hodges and Maziarz et al. are relied upon for these disclosures.
Hodges teaches APX001 (instant compound 1) as a first-in-class, intravenous (IV) and oral (PO) broad spectrum antifungal agent, which has demonstrated great efficacy with APX001A AUC0-24 target exposures ~80 µg x h/mL (background).
Maziarz teaches patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function (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.).
Regarding instant claim 49, Hodges teaches APX001 as a first-in-class, intravenous (IV) and oral (PO) broad spectrum antifungal agent, which has demonstrated great efficacy with APX001A AUC0-24 target exposures ~80 µg x h/mL (background).
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 an effective amount of Copending ‘020’s APX001 IV formulation such that plasma concentrations of APX001A were kept over the desired target exposure of ~80 (µg x h)/mL, as taught by Hodges. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Hodges.
Applicant is advised, 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. 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.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art
Regarding administration to a subject, wherein the administration is not required based on kidney status of the subject, applicant is advised that a recitation of the intended use of the claimed invention, such as the use of Copending ‘020’s APX001 for subjects without a special kidney status, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02. The teachings of Hodges do not preclude administration of APX001 to a subject with or without special requirements based on kidney status, therefore, the cited art reads on the instantly claimed invention.
Regarding length of treatment administration, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the APX001 treatment for 1-4 weeks in view of Hodges and Maziarz. One of ordinary skill would have been motivated to treat for 1-4 weeks, or longer, as long as symptoms of the fungal infection persist, as taught by as taught by Maziarz, depending on the type of infection and susceptibility of the culture to the drug. One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘020’s IV formulation of APX001, Hodges teachings on the efficacy of APX001 as an antifungal treatment with low toxicities and good IV and oral bio-availabilities, and Maziarz guidance on common lengths of treatment regimens.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Claims
Claim amendments are acknowledged and have been entered. No new matter has been added.
Claim Rejections - 35 USC § 112(d)
Applicant’s arguments, see page 13, filed 03/19/2026, with respect to 35 USC § 112(d) rejection of claims have been fully considered and are persuasive. Therefore, the 35 USC § 112(d) rejection of claims has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of claim amendments.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 03/19/2026 have been fully considered but they are not persuasive.
Applicant cites WO 2020047510 – not relied upon for any rejections of record – as allegedly being more relevant than instantly cited Hodges, to say that in their study with the same compound and dosing regimen as instant claim 1, they “exclude patients with severe or moderate renal impairment from their study. Applicant states that instant amendments make for a more tailored dosage regimen. Applicant cites a Mansbach poster to say that clearance of APX001 in the urine was more than 20%, allegedly suggesting that regimens of compound 1 need to be modified for patients with CKD. Applicant cites Pappas et al. to say that Fosmanogepix showed similar urinary and fecal excretion after both oral and IV infusion, and that this data allegedly supports the hypothesis that compound 1 dosing regimens for patients with renal impairment would likely need to be modified. Applicant further cites Vazquez to say that patients with severe or moderate renal impairment were initially excluded, but were eligible to participate in the study based on later assessment. Applicant argues that a skilled artisan would be surprised that the dosing regimen for non-CKD patients can be used for patients with CKD.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, contrary to what Applicant states, Hodges 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 (reading on administering a loading dose of about 2000 mg) (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).
Bierman teaches fungal infections are a major cause of morbidity and mortality in immunocompromised patients, someone taking chronic systemic steroids, or transplant recipients (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 (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 (page 7, last para.).
Maziarz teaches patients with chronic renal failure have a higher incidence of fungal infection than those with normal renal function. Infection remains the second leading cause of death in patients with chronic renal failure and end stage renal disease (reading on late-stage CKD) (page 194, col. 1, lines 1-5). Maziarz teaches peritoneal dialysis (PD) as an effective alternative to hemodialysis with end-stage renal disease (page 194, col. 2, para. 2), and further teaches regimens of dosing and spectrum of antifungal agents in PD-associated fungal peritonitis (Table 29.2, page 196). 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 mold infections will often require longer courses of therapy (page 196, col. 2, last para.).
Therefore, it would have been prima facie obvious to one of ordinary skill to treat a fungal infection in a subject with CKD by administering Hodges’ APX001 in view of the teachings from Bierman and Maziarz. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Hodges teaches APX001 as an antifungal agent for the treatment of Candida infections with demonstrates low toxicities all subjects completed dosing; and there were no dose limiting toxicities; Bierman’s teaching that standard of care medicines for fungal infections, such as amphotericin B and fluconazole lead to renal dysfunctions, thus exacerbating CKD in patients already suffering from the condition; further in view of Maziarz’s teaching that fungal infections are one of the leading causes of death in subjects with end stage renal disease (reading on late-stage CKD) and their suggestions for length of treatment.
One would have been further motivated to treat a subject with renal dysfunction or CKD with Hodges’ APX001 with a reasonable expectation of success in view of Bellman (cited by Applicant – cited in IDS); since treatment of fungal infections in patients with renal dysfunction or CKD is known to be so challenging, one of ordinary skill would have been motivated to treat with Hodges’ low toxicity agent and achieved effective concentrations of the drug in the patient, since Hodges’ discloses different dosages achieve predictable, linear plasma concentrations due to the >90% oral bioavailability of their drug (see results). Thus, one of ordinary skill would have had a reasonable expectation of success in dosing a subject with CKD for the treatment of fungal infections with APX001, despite the subjects reduced ability to eliminate the drug, as taught by Bellman.
Applicant’s reference to WO 2020047510, Vazquez, Pappas, and Manbach is not persuasive. Applicant cites these references merely to state that subjects with severe or moderate renal impairment were not included in a study of compound 1; and that the compound 1 from the instant claims is excreted through urine. Applicant admits that these disclosures would have persuaded one of ordinary skill to modify dosing regiments for subjects with renal impairment, and that it is surprising that that the dosing regimen for non-CKD patients in WO 2020047510 can be used for patients with CKD.
This is not persuasive. Hodges discloses their compound as being well tolerated across all doses with no clinically significant adverse events observed; all subjects completed dosing; and there were no dose limiting toxicities. One of ordinary skill would have been aware of the risks of antifungal treatment in a subject with CKD, as taught by Bierman in view of Maziarz, therefore, one of ordinary skill would have had a reasonable expectation of success in finding an appropriate treatment regimen comprising Hodges’ low toxicity antifungal. 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. 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.
Double Patenting
Applicant's arguments filed 03/19/2026 have been fully considered but they are not persuasive.
Applicant states that amendments to claim 1 overcome the rejections. As discussed above, this is not the case. The instant claims remain rejected over non-statutory double patenting (NSDP) rejections over US Application No. 18/905,680 and 17/271,020 and US Patent No. 12,521,406 B2 (previously cited as Copending app. 17/908,079).
Conclusion
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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