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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/24/2025 has been entered.
Response to Amendment
Applicant’s response of 11/24/2025 has been received and entered into the application file. Claims 1-6, 8-11, 14-17, and 25-26 are pending in this application.
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 1-6, 8-11, 14-16, and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Campochiaro et al. (WO 2019/103915 A1, published: 05-31-2019) and Wall (WO 2019/094383 A1, published: 05-16-2019), Shams et al. (Treatment of corneal cystine crystal accumulation in patients with cystinosis. Clin. Ophthalmology. 10-10-2014), Vaisbich et al. (Oxidative stress in cystinosis patients. 2011 Nephron extra 73-77), Cherqui et al. (The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives, Nat Rev Nephrol. 2017) and evidenced by Katz et al. (Contrast Sensitivity Function in Nephropathic Cystinosis, Arch Ophthalmol Vol 105, 1987).
Campochiaro et al. teach compositions and methods for treatment of eye diseases caused by oxidative damage, such as retinitis pigmentosa in a subject in need thereof. The method comprising identifying the subject and providing an effective amount of N-Acetylcysteine amide (NACA) (Abstract). In another aspect, the NACA is provided orally, peritoneally, intravenously, sublingually, topically, topical ocularly, intraocularly, intravitreally (page 2, lines 18-20). In another aspect, the NACA is administered orally in the form of a tablet, a capsule, a pellet, or a liquid (page 2, line 29). In another aspect, the dose of NACA is between 1-10 mg/day, 10-200 mg/day or 60-80 mg/day (page 3, lines 3-5). The reference claims a method for treating an eye disease caused by oxidative damage in a subject in need thereof (claim 1). Claim 1 of the reference does not specify a specific eye disease caused by oxidative damage.
Wall teaches methods of making deuterium-enriched N-Acetylcysteine amide (D-NACA) and (2R,2R’)-3,3’-disulfanediyl bis(2-acetamidopropanamide) (diNACA) to treat diseases involving oxidative stress including, but not limited to, cataract, macular degeneration, lung contusion, methamphetamine-induced oxidative stress, Alzheimer disease, mitochondrial diseases among others (Abstract). In another embodiment, the invention includes a method of treating a disease associated with oxidative damage, comprising administering a pharmaceutical composition. In one aspect, the disease is a disease of the eye (page 7, lines 18-20). In some embodiments, diNACA may be coupled to one or more soluble, biodegradable polymers as drug carriers or as a prodrug (page 12, line 12). The composition can comprise pharmaceutically acceptable salts such as ascorbic acid and phosphoric acid (pages 12-13, bridging paragraph). Wall also teaches that the major metabolites of diNACA are NACA and N-acetylcysteine (NAC) (page 18, line 30). Wall teaches an ophthalmic suspension of diNACA (example 1, page 26). Doses of a compound provided will vary depending on factors. Generally, a compound may be used in an amount of from about 0.1 mg to about 1 g per day (page 27, line 17). The reference claims a pharmaceutical composition comprising diNACA, a composition comprising pharmaceutically acceptable salts, excipients, adjuvants, or additives, and a method of treating a disease associated with oxidative damage (claims 1, 5, 12).
Shams et al. teach the basic pathogenesis of cystinosis, the ocular manifestations of the disease, and the treatment of corneal crystals (Abstract). Cystinosis is caused by a disruption of the carrier-mediated system that transports cystine out of the lysosomes. Accumulation of cystine within the lysosomes results in the formation of characteristic crystals accumulating within numerous tissues (page 2077, Introduction). The oral cystine-depleting agent, cysteamine, is the main treatment of choice in cystinosis (page 2081, Treatment section). The topical formulation of cysteamine can effectively dissolve corneal crystals and, therefore, significantly improve symptoms of photophobia, blepharospasm, and pain (page 2081, right column, 1st paragraph). Other modalities with the potential for extended delivery of ocular drugs include fornix inserts, punctal plugs, subconjunctival inserts, and contact lenses. Hsu et al. observed that loading daily contact lenses with vitamin E in addition to cysteamine increased the release duration of the drug (page 2082, left column, last paragraph).
Furthermore, Vaisbich et al. teach that cystinosis is an oxidative stress disease. Studies have demonstrated altered ATP metabolism, increased apoptosis, and cell oxidation. An increased number of autophagosomes and autophagic vacuoles have been observed in cystinotic fibroblasts and renal epithelial cells.
Cherqui discloses cystinosis and its’ pathogenic insights and therapeutic perspectives (Abstract). The review summarizes decades of research into the pathogenesis of renal Fanconi syndrome in cystinosis, focusing on findings that have provided insights into the pathogenic roles of global metabolic and oxidation defects (page 3, 2nd paragraph). Cystine efflux from lysosomes is widely considered to serve as a source for cysteine. Reduced glutathione (GSH) is the major antioxidant in the cystosol, facilitating the neutralization of free radicals such as reactive oxygen species. Accordingly, altered glutathione metabolism and increased oxidative stress have ben proposed to cause the Fanconi syndrome in cystinosis. A significant decrease in total glutathione content and increase in superoxide dismutase activity, which enhances oxidative stress, were observed in cultured human cystinotic fibroblasts and were corrected by administration of exogenous cysteine. Fibroblasts derived from patients were unable to increase glutathione synthesis in response to oxidative stress. (pg 8, Oxidative Stress Section). Of interest, a pilot clinical trial in which N-acetyl-cysteine was administered for 3 months 23 patients with nephropathic cystinosis demonstrated a significant reduction in oxidative stress and improved renal function (pg 9, 2nd paragraph).
Katz et al. teach that cystinosis is a rare metabolic disorder in which nonprotein cystine accumulates within most body organs due to a defect in lysosomal cystine transport. The pathognomonic ocular manifestations of cystinosis are the presence of distinctive iridescent crystals within ocular tissue and a pigmentary retinopathy (Abstract). Furthermore Katz et al. disclose that in nephropathic cystinosis, the retina shows patchy depigmentation of the periphery, which manifests histologically as degeneration and loss of the pigment epithelium (page 1668, right col, last paragraph). Campochiaro et al. teach compositions and methods for treatment of eye diseases caused by oxidative damage, such as retinitis pigmentosa in a subject in need thereof. The method comprising identifying the subject and providing an effective amount of N-Acetylcysteine amide (NACA) (Abstract). One of ordinary skill in the art would immediately envisage that NACA would have potential benefit of improving symptoms of retinitis pigmentosa and in relation, cystinosis.
Wall also teaches that the major metabolites of diNACA are NACA and N-acetylcysteine (NAC) (page 18, line 30). To one skilled in the art given the information above, NACA and diNACA are expected to reduce the amount of cystine inside the cells by their intrinsic mechanism. Removal of cystine from inside the cells would help prevent or treat cystinosis.
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to include NACA, diNACA, NAC, and/or cysteamine as active ingredients in a pharmaceutical composition for treatment of cystinosis. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 2, pharmaceutically acceptable carrier is addressed and discussed above.
Regarding claim 3, formulations are addressed and discussed above.
Regarding claim 4, biodegradable polymers and ocular inserts are addressed and discussed above.
Regarding claims 5-6, Shams et al. teach that single-use, daily contact lenses worn for 2 hours a day have the potential to achieve the same therapeutic effect as an hourly instillation of cysteamine drops (page 2082, right column, 1st paragraph).
Regarding claims 8-9, one skilled in the art would recognize that pharmaceutical doses will vary depending on age, condition, indication, and other clinical factors. Additionally, Campochiaro et al. teach daily dosages as addressed and discussed above. 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 10, Wall teaches that a second active agent may be used (page 27, line 19).
Regarding claim 11, Wall teaches that parenteral solutions may contain citric acid, sodium EDTA, sodium bisulfite, sodium sulfite and/or ascorbic acid (page 15, lines 25-33).
Regarding claim 14, oral formulations are addressed and discussed above.
Regarding claims 15-16, Wall teaches that the invention relates to a method of making diNACA and treating diseases associated with oxidative damage. This encompasses specific conditions that are not specifically mentioned (page 1, line 10). The reason for obviousness is addressed and discussed above in claim 1.
Regarding claims 25-26, teachings of claim 1 are addressed and discussed above.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Campochiaro et al. (WO 2019/103915 A1, published: 05-31-2019) and Wall (WO 2019/094383 A1, published: 05-16-2019), Shams et al. (Treatment of corneal cystine crystal accumulation in patients with cystinosis. Clin. Ophthalmology. 10-10-2014), Vaisbich et al. (Oxidative stress in cystinosis patients. 2011 Nephron extra 73-77), and Cherqui et al. (The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives, Nat Rev Nephrol. 2017) as applied to claims 1-6, 8-11, 14-16, and 25-26 above, and further in view of Yigit et al. (Release of N-acetylcysteine and N-acetylcysteine Amide from Contact Lenses, Eye & Contact Lens: Science & Clinical Practice. 2013).
Teachings of above references are discussed above.
Yigit et al. investigate the use of contact lenses to release N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) for the treatment of eye diseases (Objective). Results show that NAC or NACA was released from the lenses for the first 24 hours with an increasing pattern. The lenses used in the study were supposed to be worn for 1 day therefore, it can be said that these lenses could achieve the delivery of drugs for their intended time of wear (page 339, left col, 1st paragraph).
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above with delivery method of NAC and/or NACA in ophthalmic or ocular insert as taught by Yigit et al. for treatment of eye diseases such as cystinosis. This is combining prior art elements according to known methods to yield predictable results such as an ocular insert for potential treatment of cystinosis.
Regarding claims 17 and 25, it is noted that the "transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. MPEP § 2111.03. “For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, “consisting essentially of” will be construed as equivalent to ‘comprising' .” MPEP § 2163(II)A.I. The specification does not clearly indicate what the “basic and novel characteristics” are; Paragraph 0161 of the Specification says ophthalmic examination and nothing about consisting essentially of or consisting of. What is needed is the “basic and novel characteristics” of the subject matter of the claim and therefore “consisting essentially of” will be construed as equivalent to ‘comprising’. “If an applicant contends that additional steps or materials in the prior art are excluded by the recitation of “consisting essentially of,” applicant has the burden of showing that the introduction of additional steps or components would materially change the characteristics of applicant' s invention.” MPEP § 2111.03.
Response to Arguments
Applicant’s arguments filed 11/24/2025 have been fully considered but they are not persuasive.
On pages 6-7 of remarks, applicant argues that the combination of references does not provide a reasonable expectation of success. Applicants argue that clinical trials are, at best, experimental and fails to support of finding of obviousness. Like the evidence in the In re Cyclobenzaprine litigation, the disclosure of a planned study in the cited art provides no reasonable expectation of success in using any dosing regimen of NAC, much less NACA or diNACA.
As discussed above, Cherqui clearly teaches that administration of N-acetyl-cysteine in nephropathic cystinosis patients demonstrated a significant reduction in oxidative stress and improved renal function. Wall teaches that the major metabolites of diNACA are NACA and N-acetylcysteine (NAC) (pg 20). Additionally, the major metabolite of NACA is N-acetylcysteine (NAC) (pg 21). To one skilled in the art given the information above, NACA and diNACA would be expected to metabolize into NAC which would then reduce the amount of cystine inside the cells by their mechanism. Removal of cystine from the cells would help prevent or treat cystinosis.
On page 7 of remarks, applicant argues that the antioxidants are not interchangeable; antioxidants may have an antioxidant activity only under certain circumstances. Specific to the application, applicant argues that there is no reasonable expectation of success from the substitution of NAC for any other antioxidant, including NACA and diNACA. However, Wall teaches that the major metabolites of diNACA are NACA and N-acetylcysteine (NAC). One of ordinary skill in the art would expect diNACA to breakdown into NACA and NAC. NAC would still inherently have an antioxidant activity since it is closely related to diNACA and NACA; it is not a random antioxidant unrelated to diNACA.
Applicants argue that the dosing selected was based on the known side effects of cysteamine – at doses equivalent, NACA and diNACA have superior activity. As previously taught, Wall discloses that the dose of diNACA may be used in amount of from about 0.1 mg to about 1 g per day. One of ordinary skill in the art would expect any and all doses within this range to be routinely practiced.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615