DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/06/2026 has been entered.
DETAILED ACTION
Claims 1-3 and 6-15 are pending in the instant application.
Priority
The instant application claims priority to the U.S. Provisional Application Serial No. 62/965,660 filed January 24, 2020.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3 and 6-15 are rejected under 35 U.S.C. 103 as being unpatentable over Wall (WO 2019/094383 A1), Maddirala et al. (Prevention and reversal of selenite-induced cataracts by N-acetylcysteine amide in Wistar rats, BMC Ophthalmology, 2017), Santus et al. (Oxidative Stress and Respiratory System: Pharmacological and Clinical Reappraisal of N-Acetylcysteine, COPD: Journal of Chronic Obstructive Pulmonary Disease, 2014), Kim et al. (N-Acetylcysteine increase Corneal Endothelial Cell Survival in a Mouse Model for Fuchs Endothelial Corneal Dystrophy. Exp Eye Res. 2014 October; doi 10.1016/j.exer.2014.06.002), and Campochiaro et al. (WO 2016/073931 A1).
Wall teaches methods of making deuterium-enriched n-acetylcysteine amide (D-NACA) and (2R,2R’)-3,3’-disulfanediyl bis(2-acetamidopropanamide) (diNACA) and using D-NACA and DiNACA to treat diseases involving oxidative stress (Abstract). The invention relates in general to the field of making diNACA to treat diseases associated with oxidative damage including, but not limited to, antivenom, beta-thalassemia, cataract, chronic obstructive pulmonary disease, macular degeneration, contrast-induced nephropathy, asthma, lung contusion, methamphetamine-induced oxidative stress, multiple sclerosis, Parkinson’s disease, platelet apoptosis, Tardive dyskinesia, Alzheimer disease, HIV-1 associated dementia, mitochondrial diseases, myocardial myopathy, neurodegenerative diseases, pulmonary fibrosis, retinitis pigmentosa, age-related macular degeneration, skin pigmentation, antimicrobial infection and/or Friedreich’s ataxia (page 1, lines 6-17). Wall also teaches a method of treating a disease associated with oxidative damage, comprising administering a pharmaceutical composition comprising diNACA to a patient in need thereof. The method, wherein the disease is an eye disease or disorder (Claims 12-13). The major metabolites of diNACA are NACA and N-acetylcysteine (NAC) afforded by cleavage of the sulfur bond (page 18, lines 30-32). DiNACA is administered in admixture with suitable pharmaceutical salts, buffers, diluents, extenders, excipients and/or carriers. DiNACA maybe formulated to provide maximum and/or consistent dosing for the particular form for oral, rectal, topical (including ophthalmic), inhalation, intranasal, injection (intravenous or intraocular) or parenteral administration (page 11, lines 6-15).
Wall does not teach the use of NAC or NACA for the treatment of cataract or COPD.
Maddirala teaches that cataracts if an oxidative stress disease. N-acetylcysteine (NAC), a glutathione (GSH) prodrug, has previously been tried in selenite-induced cataracts in vivo and was shown to prevent oxidative damage to the lens, slowing down cataractogenesis. Additionally, N-acetylcysteine amide (NACA), an analog of NAC, has been shown to be more effective than NAC, owing to its neutral amide group, which increases its lipophilicity (page 2, left col). Maddirala teaches that oxidative stress plays a role in cataract formation, particularly in glutathione maintenance. For this reason, a GSH prodrug would be effective as a therapeutic agent for prevention and reversal of cataracts. NACA protects by increasing GSH, reducing MDA levels, restoring enzyme activities, and normalizing calcium levels (page 10, Conclusion).
Santus discloses that COPD patients have increased oxidative stress and decreased antioxidants, such as GSH (Abstract). Santus discloses that another interesting in vitro study demonstrated that after influenza virus and RSV infection, there is an increase in intracellular levels of H2O2 and a decrease in intracellular thiols. NAC restored this imbalance by decreasing the H2O2 concentration and restoring thiol levels. As a result, virus titers decreased and viral proliferation was inhibited (page 709, NAC Section). Santus teaches the mechanism of action of NAC and its’ antioxidant and anti-inflammatory properties (See Figure 3 below).
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Kim et al. teach that N-acetylcysteine (NAC) increases survival in cultured corneal endothelial cells exposed against oxidative stress. Systemic NAC ingestion increases corneal endothelial cell survival which is associated with increased antioxidant (Abstract). Kim et al. suggest that chronic NAC treatment acts via its effect on oxidative stress among other cell stress pathways in the corneal endothelium (page 8, last paragraph).
Campochiaro discloses a method for the treatment of retinitis pigmentosa in a human that comprises administering to the human a therapeutically effective amount of N-acetylcysteine amide (NACA) (Abstract). One of ordinary skill in the art would immediately envisage that a prodrug of NACA, diNACA, would breakdown into NACA molecules and help treat retinitis pigmentosa.
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to create a composition comprising either diNACA, NACA, or NAC to treat diseases or disorders of oxidative stress as taught by Wall, Maddirala, Santus, Kim and Campochiaro. This is combining prior art elements according to known methods to yield predictable results such as treating diseases or disorders of oxidative stress.
Regarding claim 2, the method of administration is discussed and addressed above.
Regarding claim 3, the method of administration is discussed and addressed above.
Regarding claim 6, Kim et al. teach that N-acetylcysteine (NAC) increases survival in cultured corneal endothelial cells exposed against oxidative stress. Systemic NAC ingestion increases corneal endothelial cell survival which is associated with increased antioxidant (Abstract). Kim et al. suggest that chronic NAC treatment acts via its effect on oxidative stress among other cell stress pathways in the corneal endothelium (page 8, last paragraph). One of ordinary skill in the art would envisage that a prodrug of NAC, diNACA, would breakdown into NAC molecules and increase survival of corneal endothelial cells exposed against oxidative stress.
Regarding claim 7, Wall teaches diNACA to be administered in admixture with suitable pharmaceutical salts, buffers, diluents, extenders, excipients and/or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) (page 11, lines 6-8).
Regarding claim 8, Wall teaches the method of using diNACA for treating an eye disease such as cataract (claim 15). Wall further teaches that variations may be applied to compositions and/or methods. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the claims (page 35, lines 12-19).
Regarding claim 9, methods of administration is addressed and discussed above.
Regarding claims 10-11, Wall teaches an example of ophthalmic suspension (page 26, example 1). Such compound may be used in an amount from about 0.1 mg to about 1 g per day (page 27, line 21). The range of 0.01-150 mg/Kg falls within the range taught by Wall. In view of MPEP 2144.05, in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Furthermore, it is well within the ordinary level of skill in the art to determine the correct dosage and it would therefore have been obvious to do so in the instant case.
Regarding claim 12, Wall teaches parenteral solutions to include antioxidizing agents such as sodium bisulfite, sodium sulfite and/or ascorbic acid. Citric acid and its salts and sodium EDTA may also be included to increase stability (page 15, lines 25-32).
Regarding claim 13, the dose for administration is addressed and discussed above in claims 10-11.
Regarding claim 14, Wall teaches diNACA to be administered consistent with conventional pharmaceutical practices (page 11, lines 6-15).
Regarding claim 15, the administration of diNACA to prevent or reduce corneal endothelial cell loss is addressed and discussed in claim 6.
Response to Arguments
Applicant’s arguments filed 01/06/2026 have been fully considered but the rejection is maintained.
On page 5 of remarks, applicant argues that Wall teaches a method of making a deuterated diNACA, and that the activity of the molecule is unpredictable. However, Wall discloses that the invention relates in general to the field of making diNACA, pharmaceutical compositions, and methods of making and using NACA-d3 to treat diseases associated with oxidative damage including macular degeneration (pg 1, lines 5-11). Wall does not exclude the use of diNACA for treating diseases associated with oxidative damage.
On page 5 of remarks, applicant continues to argue that not a single approval for NAC as an antioxidant has been sought or granted. However, as taught by Wall above, diNACA is used for treating diseases associated with oxidative damage. The major metabolites of diNACA are NACA and NAC (pg 18, lines 30-32). One of ordinary skill in the art would immediately envisage that diNACA’s major metabolites would have similar antioxidant activities.
Applicant argues that the use of diNACA as a prodrug, wherein NACA is detectable 7 days after administration is not taught. Applicant argues that NAC’s half-life is 5.6 hours and the half-life of NACA is even shorter. However, Wall already discusses that dosing the patient with diNACA affords greater bioavailability in tissues like the retina and aqueous humor compared to dosing with NACA, presumably due to the higher lipophilicity of diNACA compared to NACA and the resulting in-vivo cleavage to two NACA-like molecules. One of ordinary skill in the art would immediately envisage that the use of diNACA as a prodrug would result in higher bioavailability of NACA. The detectable duration of NACA would be dependent on various factors such as individual patient, dose, dosing regimen, patient’s metabolism, and others. This is not surprising and unexpected. Therefore, claims remain rejected.
It is anticipated that the next office action will be a FINAL rejection; applicants are strongly encouraged to consider taking their case to PTAB.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN SEUNGJAI KWON whose telephone number is (571)272-7737. The examiner can normally be reached Mon - Fri 8:00 - 5:00.
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615