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 .
Priority
The present application claims priority to the following applications: 63/182,037 and PCT/US2022/027062 with effective filing dates of 30 April 2021 and 29 April 2022, respectively.
Claim Status
This Office Action is in response to Applicant’s Amendment filed, 21 May 2024, wherein the Applicant amended claims 3, 4, 9-11, 27, 29, 33, 37-41, 54-59, and 61-64 and canceled claims 2, 5-8, 12-26, 28, 30-32, 43-53, and 60.
Claims 1, 3-4, 9-11, 27, 29, 33-42, 54-59, and 61-64 are pending.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
1. Claims 1, 3-4, 9-10, 27, 29, and 33-41 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ocuphire Pharma ("Study of the Safety and Efficacy of APX3330 in Diabetic Retinopathy (ZETA-1), NCT04692688, posted 5 Jan 2021, <clinicaltrials.gov/study/NCT04692688>, accessed 5 Jan 2026).
Ocuphire Pharma teaches a study to evaluate the safety and efficacy of APX3330 to treat diabetic retinopathy and diabetic macular edema (page 1, paragraph 1). APX3330 is a compound of Formula (I) as evidenced by Babu (page 110, Figure 1, Compound 7; J Pharmacol Exp Ther, 2018, 367, 108-118).
Ocuphire Pharma further teaches administration of the small molecule, APX3330, as an oral tablet in five 120mg doses (600 mg, page 9, Table 1). Ocuphire Pharma further specifies a dosing regimen in patients of three 120 mg tablets in the morning and two 120 mg tablets in the evening (page 9, Table 1).
Regarding claim 1, Ocuphire Pharma teaches a method of treating a diabetic retinal disease in a human patient, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 480 mg to about 600 mg per day, to thereby treat the diabetic retinal disease, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
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(page 1, paragraph 1; page 9, Table 1).
Regarding claim 3, Ocuphire Pharma teaches a first dose of the APX3330 and a second dose of the APX3330 are orally administered to the patient on the same day (page 9, Table 1).
Regarding claim 4, Ocuphire Pharma teaches APX3330 is orally administered to the patient in an amount of about 600 mg per day (page 9, Table 1).
Regarding claim 9, Ocuphire Pharma teaches about 300 mg of APX3330 is orally administered to the patient in the morning (three doses of 120 mg is 360 mg), and about 300 mg of APX3330 is orally administered to the patient in the evening (two doses of 120 mg is 240 mg; page 9, Table 1).
Regarding claim 10, Ocuphire Pharma teaches about 300 mg (three doses of 120 mg is 360 mg) of APX3330 is orally administered to the patient given in the morning, and then at a time that is from about 8 hours to about 16 hours later about 300 mg (two doses of 120 mg is 240 mg) APX3330 is orally administered to the patient given in the evening (page 9, Table 1).
Regarding claim 27, Ocuphire Pharma teaches the amount of APX3330 is orally administered to the patient daily for at least 4 weeks (page 9, Table 2).
Regarding claim 29, Ocuphire Pharma teaches the amount of APX3330 is orally administered to the patient daily for at least 24 weeks (page 9, Table 2).
Regarding claim 33, Ocuphire Pharma teaches the diabetic retinal disease is diabetic retinopathy (page 1, paragraph 1).
Regarding claim 34, Ocuphire Pharma teaches the diabetic retinopathy is mild diabetic retinopathy (page 1, paragraph 2; page 2, paragraph 4).
Regarding claim 35, Ocuphire Pharma teaches the diabetic retinopathy is moderate diabetic retinopathy (page 1, paragraph 2; page 2, paragraph 4).
Regarding claim 36, Ocuphire Pharma teaches the diabetic retinopathy is moderately severe to severe diabetic retinopathy (page 1, paragraph 2; page 2, paragraph 4).
Regarding claim 37, Ocuphire Pharma teaches the diabetic retinopathy is non-proliferative diabetic retinopathy (page 1, paragraph 2; page 2, paragraph 4).
Regarding claim 38, Ocuphire Pharma teaches the diabetic retinopathy is proliferative diabetic retinopathy (page 1, paragraph 2; page 2, paragraph 4).
Regarding claim 39, Ocuphire Pharma teaches the diabetic retinal disease is diabetic macular edema (page 1, paragraph 1; page 2, conditions).
Regarding claim 40, Ocuphire Pharma teaches the human patient is an adult human patient (page 6, paragraph 1).
Regarding claim 41, Ocuphire Pharma teaches the method reduces a symptom of diabetes as evidenced by the diabetic retinopathy severity score (page 9, Table 2).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
2. Claims 1, 3-4, 11, 33, and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Sooch ("Ocuphire Pharma Announces In-License of Phase 2 Oral Small Molecule Drug Candidate for Diabetic Retinopathy and Diabetic Macular Edema from Apexian Pharmaceuticals," Ocuphire Press Release, 22 Jan 2020, <ir.opusgtx.com/press-releases/detail/309/ocuphire-pharma-announces-in-license-of-phase-2-oral-small-molecule-drug-candidate-for-diabetic-retinopathy-and-diabetic-macular-edema-from-apexian-pharmaceuticals>, accessed 5 Jan 2026) in view of Shahda (J Clinical Oncol, 2019, 37(15 Supp), 3097).
Sooch teaches that APX3330 is a first-in-class, orally-administered, small molecule drug candidate that selectively targets and inhibits the APE1/Ref-1 protein (page 2, paragraph 2). Sooch further teaches that APE1/Ref-1 is a novel upstream regulator of critical transcription factors controlling inflammatory and angiogenesis pathways that are implicated in diabetic retinopathy and diabetic macular edema (page 2, paragraph 2).
Regarding claim 1, Sooch fails to teach a dosing regimen of APX3330.
Shahda teaches administering 240-600 mg of APX3330 for tumor inhibition in humans (page 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the method of administering APX3330 orally to a patient in an amount of 240-600 mg of Shahda to develop a method of treating diabetic retinal disease in a human patient via administration 480-600 mg of APX3330, to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Sooch teaches a method of treating diabetic retinal disease in humans via administering APX3330,
-Sooch teaches APX3330 selectively targets and inhibits the APE1/Ref-1 protein, a novel upstream regulator of critical transcription factors, controlling inflammatory and angiogenesis pathways that are implicated in diabetic retinopathy and diabetic macular edema,
-Sooch teaches there are nearly 8 million patients with diabetic retinopathy and 750,000 patients with diabetic macular edema, which is an unmet market opportunity for new treatments,
-Sooch teaches the current treatment for diabetic retinal diseases requires injections to the white (sclera) of the eye every one to three months (an undesirable treatment from a patient perspective) as compared to an oral treatment,
-Shahda teaches a method of treating cancer via oral administration of APX3330 in human patients in 240-600 mg per day, and
-Shahda teaches APX3330 is a highly selective inhibitor of APE1 protein.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection, to predictably arrive at a method of treating diabetic retinal disease in humans via oral administration of APX3330 in doses of 480-600 mg.
Regarding claim 3, Sooch teaches twice daily dosing of APX3330, which are orally administered to the patient on the same day (page 4, paragraph 1).
Regarding claim 4, Shahda teaches APX3330 is orally administered to the patient in an amount of about 600 mg per day (page 1).
Regarding claim 11, Shahda teaches occurrence of adverse events, G1 fatigue and G3 rash, and subsequent decrease in dose from 720 mg to 600 mg. A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection. MPEP § 2144.05. The range of the claimed invention (480-600 mg) significantly overlaps with the range of Shahda (240-720 mg). Further, the decrease in dose of the claimed invention does not provide an unexpected result in view of Shahda, who describes occurrence of adverse event and subsequent dosing decrease of 120 mg (one tablet of APX3330). Additionally, at the time of the invention, there was a recognized problem in the art (adverse events occurring from administration of APX3330), a finite number of identified predictable potential solutions (decrease in amount of APX3330 administered via removal of 1 tablet), and one of ordinary skill in the art would have pursued the solution of changing the dosing regimen via removal of one tablet as taught by Shahda. Thus, Shahda teaches that if the patient experiences an adverse event due APX3330, then thereafter for a period of at least two days APX3330 is orally administered to the patient in the reduced-daily amount of about 480 mg per day.
Regarding claim 33, Sooch teaches the diabetic retinal disease is diabetic retinopathy (page 2, paragraph 2).
Regarding claim 39, Sooch teaches the diabetic retinal disease is diabetic macular edema (page 2, paragraph 4).
Regarding claim 40, Shahda teaches the human patient is an adult human patient (page 1, paragraph 1).
Regarding claim 41, Sooch teaches the method reduces a symptom of diabetes (page 2, paragraph 2).
3. Claims 9, 10, 42, 54-59, and 61-64 are rejected under 35 U.S.C. 103 as being unpatentable over Sooch ("Ocuphire Pharma Announces In-License of Phase 2 Oral Small Molecule Drug Candidate for Diabetic Retinopathy and Diabetic Macular Edema from Apexian Pharmaceuticals," Ocuphire Press Release, 22 Jan 2020, <ir.opusgtx.com/press-releases/detail/309/ocuphire-pharma-announces-in-license-of-phase-2-oral-small-molecule-drug-candidate-for-diabetic-retinopathy-and-diabetic-macular-edema-from-apexian-pharmaceuticals>, accessed 5 Jan 2026) and Shahda (J Clinical Oncol, 2019, 37(15 Supp), 3097) as applied to claim 1, 3, 4, 11, 33, and 3-41 above, and further in view of Shah (Precision Oncol, 2017, 19, 1-19).
Sooch ("Ocuphire Pharma Announces In-License of Phase 2 Oral Small Molecule Drug Candidate for Diabetic Retinopathy and Diabetic Macular Edema from Apexian Pharmaceuticals," Press Release, 22 Jan 2020, <ir.opusgtx.com/press-releases/detail/309/ocuphire-pharma-announces-in-license-of-phase-2-oral-small-molecule-drug-candidate-for-diabetic-retinopathy-and-diabetic-macular-edema-from-apexian-pharmaceuticals>, accessed 5 Jan 2026) and Shahda (J Clinical Oncol, 2019, 37(15 Supp), 3097) are applied to as discussed in the above 35 U.S.C. 103 rejection above.
Regarding claim 9, while the combination of Sooch and Shahda teaches methods of treating diabetic retinal disease in a human patient via administering 480-600 mg of APX3330, they differ from that of the instantly claimed invention in that they do not explicitly teach a method of treating diabetic retinal disease via orally administering about 300 mg of APX3330 to the patient in the morning and about 300 mg of APX3330 to the patient in the evening.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the
effective filing date of the instantly claimed invention, to exemplify the methods of Sooch and Shahda with the dosing regimen of about 300 mg of APX3330 both in the morning and evening as taught by Shah to arrive at the instantly claimed invention.
One of ordinary skill in the art would have been motivated to combine the doses of Shahda with the dosing regimen of Shah to treat diabetic retinal disease with a reasonable expectation of success, because Shah teaches that APX3330 is supplied as orally administered tablets and patients will receive a fixed dose of APX3330 twice daily each day (page 12, column 2, paragraph 1). Shah further teaches that APX3330 is a highly selective inhibitor of Ref-1/APE1 redox activity and Ref-1/APE is highly expressed in developing murine retinas (page 1, column 2, paragraph 1; page 7, column 2, paragraph 2). Additionally, Shah suggests that inhibition of Ref-1/APE redox activity may prove to be a more efficacious standalone or adjunctive treatment that would modulate HIF-1alpha and VEGF in retinal diseases like wet age-related macular degeneration and diabetic retinopathy (page 7, column 2, paragraph 6). Thus, one of ordinary skill in the art would have substituted one known element for another, and the results would be predictable.
As such, an artisan having ordinary skill in the art would have been motivated to make
such a selection, to predictably arrive at instant claim 9: a method of treating diabetic retinal disease via administering about 300 mg of APX3330 in the morning and administering about 300 mg of APX3330 in the evening.
Regarding claim 10, Shah teaches twice daily fixed oral administration of APX3330, and Shahda teaches administering 600 mg per day orally of APX3330, which suggests that about 300 mg is administered orally in the evening about 12 hours after the first oral administration of APX3330 of about 300 mg in the morning (page 12, column 2, paragraph 1).
Regarding claim 42, Shah teaches a method of treating a disease or condition selected from wet age-related macular degeneration, retinal neovascularization, or choroidal neovascularization (page 7, column 2, paragraphs 3 and 5). Shahda teaches orally administering to a human patient in need thereof APX3330 in an amount from about 240 mg to about 600 mg per day, to thereby treat the disease or condition (page 1, paragraph 1). A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection. MPEP § 2144.05. The range of the claimed invention (120-600 mg) significantly overlaps with the range of Shahda (240-720 mg). Further, the range of the claimed invention does not provide an unexpected result in view of Shahda, who describes a method of treating diseases associated with APE1/Ref-1 protein in humans via oral administration of APX3330 (page 1, paragraph 1). Sooch teaches administration of APX3330 for ocular diseases (diabetic retinal disease) in human patients (page 2, paragraph 2). Thus, the combination of Shah, Shahda, and Sooch teaches instant claim 42: a method of treating a disease or condition selected from wet age-related macular degeneration, or retinal neovascularization, choroidal neovascularization, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 120 mg to about 600 mg per day, to thereby treat the disease or condition, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof.
Regarding claim 54, Shah teaches that APX3330 is extremely well-tolerated at dose levels consistent with development as a cancer agent (page 12, column 1, paragraph 4). Shah further teaches that Eisai examined the preclinical and clinical data, which demonstrated a safety profile that supported development of APX3330 for the treatment of various cancers (page 12, column 1, paragraph 4). Additionally, Shah specifies (a) APX3330 has linear pharmacokinetics with little accumulation; (b) the absorption, distribution, metabolism, and excretion (ADME) of APX3330 is well understood, and (c) APX3330 was well absorbed orally with a bioavailability of ≥60%, which Shah notes greatly de-risks the drug due to its lack of toxicity (page 12, column 1, paragraph 4). Thus, Shah teaches the ADME of APX3330 is known in the art (page 12, column 1, paragraph 4). Further, Shahda teaches the claimed dosing range of APX3330 (page 1, paragraph 1). Thus, the combination of Shah and Shahda teaches a method of administering APX3330 that reduces any renal impairment experienced by the patient, as evidenced by Center for Drug Evaluation and Research (“Pharmacokinetics in Patients with Impaired Renal Function – Study Design, Data Analysis, and Impact on Dosing: Guidance for Industry,” Food and Drug Administration, March 2024, 1-18). The Center for Drug Evaluation and Research defines that the kidneys are involved in elimination of drugs and that the degree of renal excretion of an unchanged drug or its metabolites is the net result of glomerular filtration, tubular secretion, tubular reabsorption, and metabolism in the kidneys (page 5, paragraph 2). Thus, the combination of Shah and Shahda teaches the method reduces any renal impairment experienced by the patient.
Regarding claim 55, Shah teaches that APX3330 provides a neuroprotective effect (page 13, Figure 7).
Regarding claim 56, Shah teaches that Eisai concluded there were improvements in transaminase levels (page 12, column 1, paragraph 4).
Regarding claim 57, Shah teaches that Eisai concluded there were improvements in transaminase levels (page 12, column 1, paragraph 4).
Regarding claim 58, Shah teaches the ADME of APX3330 is known in the art (page 12, column 4, paragraph 1), and Shahda teaches the claimed dosing range of APX3330 (page 1, paragraph 1). The Center for Drug Evaluation and Research defines that the kidneys are involved in elimination of drugs and that the degree of renal excretion of an unchanged drug or its metabolites is the net result of glomerular filtration, tubular secretion, tubular reabsorption, and metabolism in the kidneys (page 5, paragraph 2). Thus, the combination of Shah and Shahda teaches any reduction in glomerular filtration rate in the patient is no greater than 15%.
Regarding claim 59, Shah teaches that Eisai examined the preclinical and clinical data, which demonstrated a safety profile that supported development of APX3330 for the treatment of various cancers (page 12, column 1, paragraph 4). Further, Shahda teaches the claimed dosing regimen of APX3330 (480-600 mg). Under the principles of inherency, if a prior art device, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art device. When the prior art device is the same as a device described in the specification for carrying out the claimed method, it can be assumed the device will inherently perform the claimed process. In re King, 801 F.2d 1324, 231 USPQ 136 (Fed. Cir. 1986) See MPEP § 2112.02. Thus, it flows naturally from the teachings of Shah and Shahda that the result of the claimed invention would be achieved. Thus, the combination of Shah and Shahda teaches the incidence of any eye disorder due to APX3330 occurs no more frequently than one patient for every ten patients subjected to the same treatment.
Regarding claim 61, Shah teaches that Eisai examined the preclinical and clinical data, which demonstrated a safety profile that supported development of APX3330 for the treatment of various cancers (page 12, column 1, paragraph 4). Further, Shahda teaches the claimed dosing regimen of APX3330 (480-600 mg). Under the principles of inherency, if a prior art device, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art device. When the prior art device is the same as a device described in the specification for carrying out the claimed method, it can be assumed the device will inherently perform the claimed process. In re King, 801 F.2d 1324, 231 USPQ 136 (Fed. Cir. 1986) See MPEP § 2112.02. Thus, it flows naturally from the teachings of Shah and Shahda that the result of the claimed invention would be achieved. Thus, the combination of Shah and Shahda teaches the incidence of any gastrointestinal disorder due to APX3330 occurs no more frequently than one patient for every ten patients subjected to the same treatment.
Regarding claim 62, Shah teaches that Eisai examined the preclinical and clinical data, which demonstrated a safety profile that supported development of APX3330 for the treatment of various cancers (page 12, column 1, paragraph 4). Further, Shahda teaches the claimed dosing regimen of APX3330 (480-600 mg). Under the principles of inherency, if a prior art device, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art device. When the prior art device is the same as a device described in the specification for carrying out the claimed method, it can be assumed the device will inherently perform the claimed process. In re King, 801 F.2d 1324, 231 USPQ 136 (Fed. Cir. 1986) See MPEP § 2112.02. Thus, it flows naturally from the teachings of Shah and Shahda that the result of the claimed invention would be achieved. Thus, the combination of Shah and Shahda teaches the incidence of any nervous system disorder due to APX3330 occurs no more frequently than one patient for every twenty patients subjected to the same treatment.
Regarding claim 63, Shah teaches that Eisai concluded there were improvements in transaminase levels (page 12, column 1, paragraph 4). Further, Shahda teaches the claimed dosing regimen of APX3330 (480-600 mg). Under the principles of inherency, if a prior art device, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art device. When the prior art device is the same as a device described in the specification for carrying out the claimed method, it can be assumed the device will inherently perform the claimed process. In re King, 801 F.2d 1324, 231 USPQ 136 (Fed. Cir. 1986) See MPEP § 2112.02. Thus, it flows naturally from the teachings of Shah and Shahda that the result of the claimed invention would be achieved. Thus, the combination of Shah and Shahda teaches a method further characterized by achieving a reduction in blood plasma concentration of alanine aminotransferase due to APX3330.
Regarding claim 64, Shah teaches that Eisai concluded there were improvements in transaminase levels (page 12, column 1, paragraph 4). Further, Shahda teaches the claimed dosing regimen of APX3330 (480-600 mg). Under the principles of inherency, if a prior art device, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art device. When the prior art device is the same as a device described in the specification for carrying out the claimed method, it can be assumed the device will inherently perform the claimed process. In re King, 801 F.2d 1324, 231 USPQ 136 (Fed. Cir. 1986) See MPEP § 2112.02. Thus, it flows naturally from the teachings of Shah and Shahda that the result of the claimed invention would be achieved. Thus, the combination of Shah and Shahda teaches a method further characterized by achieving a reduction in blood plasma concentration of aspartate aminotransferase due to APX3330.
4. Claims 27, 29, and 34-38 are rejected under 35 U.S.C. 103 as being unpatentable over Sooch ("Ocuphire Pharma Announces In-License of Phase 2 Oral Small Molecule Drug Candidate for Diabetic Retinopathy and Diabetic Macular Edema from Apexian Pharmaceuticals," Ocuphire Press Release, 22 Jan 2020, <ir.opusgtx.com/press-releases/detail/309/ocuphire-pharma-announces-in-license-of-phase-2-oral-small-molecule-drug-candidate-for-diabetic-retinopathy-and-diabetic-macular-edema-from-apexian-pharmaceuticals>, accessed 5 Jan 2026) and Shahda (J Clinical Oncol, 2019, 37(15 Supp), 3097) as applied to claim 1, 3, 4, 11, 33, and 39-41 above, and further in view of Ocuphire Pharma ("Prospectus," U.S. Securities and Exchange Commission, Registration No. 333, 4 Feb 2021, 1-85).
Sooch ("Ocuphire Pharma Announces In-License of Phase 2 Oral Small Molecule Drug Candidate for Diabetic Retinopathy and Diabetic Macular Edema from Apexian Pharmaceuticals," Press Release, 22 Jan 2020, <ir.opusgtx.com/press-releases/detail/309/ocuphire-pharma-announces-in-license-of-phase-2-oral-small-molecule-drug-candidate-for-diabetic-retinopathy-and-diabetic-macular-edema-from-apexian-pharmaceuticals>, accessed 5 Jan 2026) and Shahda (J Clinical Oncol, 2019, 37(15 Supp), 3097) are applied to as discussed in the above 35 U.S.C. 103 rejection above.
Regarding claim 27, while the combination of Sooch and Shahda teach methods of treating diabetic retinal disease in a human patient via administering 480-600 mg of APX3330, they differ from that of the instantly claimed invention in that they do not explicitly teach a method of treating diabetic retinal disease in a human patient wherein the amount of APX3330 is orally administered to the patient daily for at least 4 weeks.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the
effective filing date of the instantly claimed invention, to exemplify the methods of Sooch and Shahda with the timeline specified by Ocuphire Pharma to arrive at the instantly claimed invention.
One of ordinary skill in the art would have been motivated to combine the doses of Shahda with the timeline of Ocuphire Pharma to treat diabetic retinal disease with a reasonable expectation of success, because Ocuphire Pharma teaches APX3330 is a twice-a-day oral tablet designed to target multiple pathways relevant to retinal and choroidal vascular diseases such as diabetic retinopathy and diabetic macula edema which if left untreated may result in permanent visual acuity loss and eventual blindness (page 1, paragraph 4). Ocuphire Pharma further teaches APX3330 has been dosed more than a year in humans and completed over 15 single- and repeat-dose toxicology studies in rats and dogs (page 17, paragraph 2). Thus, one of ordinary skill in the art would have substituted one known element for another, and the results would be predictable.
As such, an artisan having ordinary skill in the art would have been motivated to make
such a selection, to predictably arrive at instant claim 27: the amount of APX3330 is orally administered to the patient daily for at least 4 weeks.
Regarding claim 29, Ocuphire Pharma teaches the amount of APX3330 is orally administered to the patient daily for at least 24 weeks (page 17, paragraph 2).
Regarding claim 34, Ocuphire Pharma teaches the diabetic retinopathy is mild diabetic retinopathy (page 1, paragraph 4).
Regarding claim 35, Ocuphire Pharma teaches the diabetic retinopathy is moderate diabetic retinopathy (page 1, paragraph 4).
Regarding claim 36, Ocuphire Pharma teaches the diabetic retinopathy is moderately severe to severe diabetic retinopathy (page 1, paragraph 4).
Regarding claim 37, Ocuphire Pharma teaches the diabetic retinopathy is non-proliferative diabetic retinopathy (page 1, paragraph 4).
Regarding claim 38, Ocuphire Pharma teaches the diabetic retinopathy is proliferative diabetic retinopathy (page 1, paragraph 4).
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.
5. Claims 1 and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 9,040,505 in view of Shahda (J Clinical Oncol, 2019, 37(15 Supp), 3097.
U.S. Patent No. 9,040,505 claims a method of inhibiting a physiological disorder associated with altered angiogenesis via administering to a subject an effective amount of 3-(5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)-2- nonyl-2-propenoic acid (APX3330), which selectively inhibits the redox function of Ape1/Ref-1, and the physiological disorder associated with altered angiogenesis is selected from diabetic retinopathy, degenerative maculopathy, and advanced macular degeneration (claims 1 and 42).
Regarding claim 1, ‘505 fails to teach orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 480 mg to about 600 mg per day.
Shahda teaches administering 240-600 mg of APX3330 for tumor inhibition in humans (page 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the method of administering APX3330 orally to a patient in an amount of 240-600 mg of Shahda to develop a method of treating diabetic retinal disease in a human patient via administration of 480-600 mg of APX3330, to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-‘505 teaches a method of inhibiting a physiological disorder associated with altered angiogenesis in an effective amount via administering APX3330, and such physiological conditions are selected from diabetic retinopathy, degenerative maculopathy, and advanced macular degeneration,
-‘505 teaches APX3330 selectively targets and inhibits the APE1/Ref-1 protein,
-Shahda teaches a method of treating cancer via oral administration of APX3330 in human patients in 240-600 mg per day, and
-Shahda teaches APX3330 is a highly selective inhibitor of APE1 protein.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection, to predictably arrive at a method of treating diabetic retinal disease in humans via oral administration of APX3330 in doses of 480-600 mg.
Regarding claim 42, ‘505 teaches a method of inhibiting a physiological disorder associated with altered angiogenesis in an effective amount via administering APX3330, and such physiological conditions are selected from degenerative maculopathy and advanced macular degeneration (claims 1-3 of ‘505). Shahda teaches orally administering to a human patient in need thereof APX3330 in an amount of from about 240 mg to about 600 mg per day, to thereby treat the disease or condition (page 1, paragraph 1). A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection. MPEP § 2144.05. The range of the claimed invention (120-600 mg) significantly overlaps with the range of Shahda (240-720 mg). Further, the range of the claimed invention does not provide an unexpected result in view of Shahda, who describes a method of treating diseases associated with APE1/Ref-1 protein in humans via oral administration of APX3330 (page 1, paragraph 1). Thus, the combination of ‘505 and Shahda teaches instant claim 42: a method of treating a disease or condition selected from wet age-related macular degeneration and dry-aged macular degeneration, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 120 mg to about 600 mg per day, to thereby treat the disease or condition, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof.
Conclusion
No claim is allowed.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622