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 .
Priority
The instant application is a continuation of application 16/582,720, filed 09/25/2019 and patent US 11,197,821 B2 issued December 14, 2021, and has a provisional of 62/824,233 filed 03/26/2019 and provisional 62/736,417 filed 09/25/2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/28/2023, 01/04/2024, 05/22/2024, and 06/02/2025 were in compliance with the provisions of 37 CFR 1.97 and 37 CFR 1.98. The IDS documents were considered.
Status of claims
Claims 11, 13-37 and 46-51 are pending in this application and are currently under examination. Claims 11, 20-23, 25-26 and 35-36 are amended. Claims 1-10, 12, and 38-45 are cancelled. Claims 46-51 are new.
Applicant’s arguments, filed 01/06/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 11, 13-37 and 46-51 are rejected under 35 U.S.C. 103 as being unpatentable over Thomas (WO 2011/072141 Al ) in view of Todd (WO 2014/116836 A2) and further in view of Ni (WO 2017/210132 Al).
The instant claims are directed to a method of treating dry eye disease in a subject, comprising topically administering an ophthalmic solution comprising reproxalap at 0.25% w/v and a pharmaceutically acceptable excipient comprising a cyclodextrin, wherein the cyclodextrin is sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin wherein the reproxalap and cyclodextrin are present in a ratio of about 1:3 or about 1:4 on a mole:mole basis, wherein the ophthalmic solution is topically administered to the eye with dry eye disease four times a day in an initiation phase or exacerbation phase followed by three times a day, twice a day, or once a day, in a maintenance phase.
Thomas et al. teach topical ophthalmic compositions of a lipophilic compound and an oligomeric or polymeric carrier (Abstract). Thomas teaches an embodiment wherein a topical ophthalmic composition comprises an active lipophilic compound and an oligomeric or a polymeric carrier such as the cyclodextrins of hydroxypropyl-β-cyclodextrin, and β-cyclodextrin sulfobutylether sodium salt in an aqueous solution or a gel dispersion with the lipophilic compound is a derivative of formula Ia as compound A [00015]. Thomas also teaches amount of active agent in the composition will vary dependent on the intrinsic activity of the compound and that compounds of formula Ia (reproxalap) are present in the amounts of 0.1-0.5% w/v and the amount of β-cyclodextrin sulfobutylether sodium salt in the preparation as about 0.01% to 30% weight/volume [00018]. Thomas also discloses “The target tissue, for the biological activity of compounds which reversibly react with RAL, e.g. Compounds A, B and C, is the outer segment of retinal photoreceptor cells. To demonstrate that topical optical (TO) administration of compound A delivers therapeutically useful amounts of, for example, Compound A to the retina, C57BL/6 mice, the parent strain of abcr -/- mice (knockout mouse), were treated intraperitoneally (IP) with 14C-Compound A at 10 mg/kg ("efficacious dose"), specifically a dose that when repeated daily for 56 days reduced A2E formation by 71% (p < 0.01) in the abcr -/- mouse.” [00023].
However, Thomas et al. fail to disclose the ophthalmic solution is topically administered to the eye with dry eye disease four times a day in an initiation phase or exacerbation phase followed by three times a day, twice a day, or once a day, or as needed in a maintenance phase and sodium chloride as tonicity agent at a concentration of about 0.45%- 0.1 % w/v.
Todd et al. teach in an embodiment, “the invention relates to the treatment, prevention, and/or reduction of a risk of an ocular disease, disorder, or condition in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to a subject in need thereof a compound described herein. The ocular disease, disorder, or condition includes, but is not limited to, a corneal disease (e.g., dry eye syndrome)” and “Compounds described herein, such as Compound 9, decrease aldehyde (e.g., MDA and HNE) concentration in a time-dependent manner.” (pg. 7, lines 5-22). Todd teaches “The compound described herein may be administered topically or systemically, as described herein below.” (pg. 8, lines 1-2). Todd also teaches “In one specific exemplification, the invention relates to the treatment, prevention, and/or reduction of a risk of each of the ocular diseases, disorders, or conditions described herein, comprising administering Compound (9):” (pg. 8, lines13-17). Todd also teaches an embodiment of an eye drop formulation of a composition which comprises a concentration of the active pharmaceutical compound of 0.01-20% w/v with or without pH and/or osmotic adjustment to the solution and in one exemplification the composition is made by admixing a therapeutically effective amount of a compound described herein with an oligomeric or a polymeric carrier such as the cyclodextrins of hydroxypropyl-β-cyclodextrin and β-cyclodextrin sulfobutylether sodium salt in a concentration range of 0.01-30% w/v (pg. 64, lines 4-17). Todd also discloses propylene glycol as a pharmaceutically acceptable carrier (pg. 61, lines 17-23). Todd also teaches compositions of the invention comprise the use of sodium chloride and dextrose (pg. 65, lines 10-15). Todd teaches “A therapeutically effective dose, of a compound described herein in an oral formulation, may vary from 0.01 mg/kg to 50 mg/kg patient body weight per day, more particularly 0.01 to 10 mg/kg, which can be administered in single or multiple doses per day.” (pg. 65, lines 24-26). Todd discloses “Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the present invention.” (pg. 83, lines 12-15). Todd also discloses “[o]ne skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.” (pg. 62, lines 1-3). Todd discloses administration of compound 9 (reproxalap) to a subject over a period of 36 days (fig. 6)
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Todd’s compound 9 (Left) Applicants Reproxalap (Right)
Todd however, fails to disclose sodium chloride as tonicity agent at a concentration of about 0.45%-0.1 % w/v.
Ni et al. teach the discloses methods which can be used to treat any ocular indications involving abnormal neovascularization in the front part of the eye. These indications include (pg. 3, 3rd para.) Ni also teaches solutions, suspensions, creams, ointments, Gels, gel-forming liquid, suspension containing liposomes or micelles, spray formulation, or emulsions used for ophthalmic application can include the following components: propylene glycol and agents for the adjustment of tonicity such as sodium chloride or dextrose. (pg. 5, 1st para.) Ni et al discloses an ophthalmic solution which can be used to treat dry eye disease (pg. 3, para 3), with sodium chloride as a tonicity agent in a concentration range of 0 - 0.83% w/v (table 2, pgs. 10-11). Ni also teaches (pg. 7 lines 3-6) "Administration of a composition or formulation can be once a day, twice a day, three times a day, four times a day or more often. Frequency may be decreased during a treatment maintenance phase of the treatment, e.g., once every second or third day instead of every day or twice a day." Ni also teaches that the length of treatment will be readily determined by a physician treating the subject, which can range from 1-365 days.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer a topical ophthalmic pharmaceutical composition in a method of treating dry eye disease in a subject comprising the teachings of hydroxypropyl-β-cyclodextrin, and β-cyclodextrin sulfobutylether sodium salt in amounts of 0.01% to 30% w/v and compound A (reproxalap) in amounts of 0.1-0.5% w/v disclosed by Thomas and the disclosures of compound 9 (reproxalap) and cyclodextrins of hydroxypropyl-β-cyclodextrin and β-cyclodextrin sulfobutylether sodium salt in the treatment of dry eye syndrome. Furthermore, the concentration ranges of reproxalap and cyclodextrins anticipate the ranges of a 1:3 or 1:4 mole:mole ratio where reproxalap (mw 236.70 g/mol) is 2.11e-5 mol at 0.5% and β-cyclodextrin sulfobutylether (mw 1,277.1 g/mol) is 6.33e-5 mol at about 8% w/v for a 1:3 mole ratio and 8.38e-5 mol at about 10.7% w/v for a 1:4 mole ratio. A skilled artisan would have also found the limitations of administering hydroxypropyl-β-cyclodextrin or β-cyclodextrin sulfobutylether in 7% w/v or 11% w/v obvious over the ranges of 0.01% to 30% disclosed by Thomas and Todd. Further still, a skilled artisan would have also found it obvious to topically administer an ophthalmic solution of reproxalap to a subject once or multiple times per day for a period of up to 12 weeks or more following the disclosures of Thomas’s administration of reproxalap for 56 days and Todd’s method of administering reproxalap for 36 days in a composition with dextrose, sodium chloride, and propylene glycol to a subject combined with the disclosure that one skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the route of administration, age and condition of the patient. Finally a person of ordinary skill in the art would have noted that a 2-6, 6-10 or 12 week length of treatment would be rendered obvious over Ni's teaching of treatment from 1-365 days and that a tonicity agent of 0.1 % or 0.3% w/v sodium chloride is obvious over Ni's teaching of 0.1-0.83% w/v of the tonicity agent. See MPEP 2144.05(I) and (II).
A person of ordinary skill in the art would have been motivated to combine the teachings of treating dry eye syndrome and other eye conditions by topically administering reproxalap and cyclodextrins of hydroxypropyl-β-cyclodextrin and β-cyclodextrin sulfobutylether sodium salt as taught by Thomas and Todd with the reasonable expectation of success in treating dry eye disease in a subject because the compounds of reproxalap and cyclodextrins of hydroxypropyl-β-cyclodextrin and β-cyclodextrin sulfobutylether sodium salt as disclosed by Thomas and Todd combined with Ni’s teachings of sodium chloride as a tonicity agent were shown to produce desirable outcomes in subjects with dry eye diseases or conditions.
Conclusion
All claims are rejected, no claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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