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
This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/US2021/035948, filed 06/04/2021, which claims the priority benefit of PRO Application No. 63/034,935, filed 06/04/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/08/2024 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Election/Restrictions
Claims 1, 12, 17, 22, 24, 26, 28, 31, 33 64, 73, 79, 81, 83, 85 and 86 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/20/2026.
Status of the Application
Claims 35, 45, 49, 51, 53, 55, 57-58, 60, and 63 are currently pending and under examination. Claims 1-34, 36-44, 46-48, 50, 52, 54, 56, 59, 61-62, and 64-88 been canceled by applicant without prejudice or disclaimer.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 35 is objected to because of the following informalities: the acronyms for LC-MS, and HPLC are not defined in the claims nor the specification. Appropriate correction is required.
Claim 53 is objected to because of the following informalities: a space is missing between “11%” and “w/v” in line 2 of claim 53. Appropriate correction is required.
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.
Claims 35, 45, 49, 51, 53, 55, 57-58, 60, and 63 are 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 35 recites the limitation "wherein the subject is treated with a lower dosing frequency of reproxalap for a reduction of greater than about 20% in the measured level of the aldehyde marker of oxidative stress" in claim 35 page 2 last line through page 3 line 1. There is insufficient antecedent basis for this limitation in the claim.
Instant claim 35 does not disclose the treatment frequency of administering reproxalap to the eye and therefore a skilled artisan would be unable to determine what dosing frequency applicant intends as the claim is currently written. This rejection may be overcome by amending claim language to clearly identify the frequency of administering reproxalap.
Claim 35 recites the limitation "wherein the subject is treated with the same or higher dosing frequency of reproxalap for a reduction of about 20% or less in the measured level of the aldehyde marker of oxidative stress" in claim 35, page 3, lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
Instant claim 35 does not disclose the treatment frequency of administering reproxalap to the eye and therefore a skilled artisan would be unable to determine what dosing frequency applicant intends as the claim is currently written. This rejection may be overcome by amending claim language to clearly identify the frequency of administering reproxalap. Claims 45, 49, 51, 53, 55, 57-58, 60, and 63 are also rejected due to being dependent on the limitations of instant claim 35.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 55 recites the broad recitation “up to six times a day”, and the claim also recites “four times a day (QID)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
This rejection may be overcome by amending claim language to delete the “or administered four times a day (QID)” portion of the claim language.
Claim Rejections - 35 USC § 112
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 57 is 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 57 states the limitation of “[t]he method of claim 35, wherein the subject is treated with a lower dosing frequency of reproxalap for a reduction of about 25% or greater in the measured level of the aldehyde marker of oxidative stress.”, which does not further limit the limitation of “wherein the subject is treated with a lower dosing frequency of reproxalap for a of greater than about 20% in the measured level of the aldehyde marker of oxidative stress,” found in claim 35 page 2 last line through page 3 line 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 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 35, 45, 49, 51, 53, 55, 57-58, 60, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Todd (WO 2014/116836 A2) in view of Ni et al. (WO 2017/210132 Al) in view of Aldeyra Therapeutics, "Aldeyra Therapeutics Announces Positive Results from Dry Eye Disease Phase 2a Clinical Trial" and further in view of Zhang et al., "A chemiluminescence method to detect malondialdehyde in plasma and urine".
The instant claims are directed to a method of treating dry eye disease in a subject
comprising:
(i) measuring the level of an aldehyde marker of oxidative stress in the eye of a subject with dry eye disease prior to treatment, wherein the aldehyde marker of oxidative stress in dry eye disease is formaldehyde, acetaldehyde, acrolein, glyoxal, methylglyoxal, hexadecanal, octadecanal, hexadecenal, succinic semi-aldehyde, malondialdehyde, 4-hydroxynonenal ( 4-HNE or HNE), 4-hydroxy-2E-hexenal, 4-hydroxy-2E,6Z-dodecadienal, retinaldehyde, leukotriene B4 aldehyde, or octadecenal;
(ii) treating the subject with an aldehyde trapping agent, wherein the aldehyde trapping agent is0.1 % to 0.5% w/v reproxalap and wherein the reproxalap is administered topically to the eye with a 5% to 20% sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin; and
(iii) measuring the level of the aldehyde marker of oxidative stress in the eye of the subject following treatment, wherein measuring the level of the aldehyde marker of oxidative stress is conducted on a sample of tears obtained from the subject; wherein the level of the aldehyde marker of oxidative stress measured is in the form of adducts of the aldehyde marker of oxidative stress present in the eye, wherein the adducts comprise stable adducts formed with proteins in the eye selected from malondialdehyde or hydroxynonenal; and wherein the adducts are detected by LC-MS, ultraviolet spectrometry (UV), HPLC, mass spectrometry (MS), monoclonal antibody detection assay, gas chromatography (GC), GC/MS, QC/flame ionization detector (FID), capillary electrophoresis with amperometric detection (CEAD), liquid chromatography/fluorescence detection, enzyme linked immunosorbent assay (ELISA) or a combination thereof; wherein the subject is treated with a lower dosing frequency of reproxalap for a reduction of greater than about 20% in the measured level of the aldehyde marker of oxidative stress, and wherein the subject is treated with the same or higher dosing frequency of reproxalap for a reduction of about 20% or less in the measured level of the aldehyde marker of oxidative stress.
Todd et al. teach treatment, prevention, and/or reduction of a risk of a disease, disorder, or condition in which aldehyde toxicity is implicated in the pathogenesis, including ocular disorders, by the use of a primary amine to scavenge toxic aldehydes, such as malondialdehyde (MDA) (Abstract). Todd teaches in an embodiment treatment of an ocular disease, disorder, or condition which includes, but is not limited to, a corneal disease (e.g., dry eye syndrome) and that Compound 9 decrease aldehyde (e.g., MDA and HNE) concentration in a time-dependent manner. (pg. 7, lines 5-22).
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Todd’s Compound (Left) Applicants Reproxalap/ADX-102 (Right)
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 and in one exemplification the composition is made by admixing the cyclodextrins of hydroxypropyl-β-cyclodextrin or β-cyclodextrin sulfobutylether sodium salt in a concentration range of 0.01-30% w/v (pg. 64, lines 4-18). 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." (pg. 62, lines 1-3). Todd discloses Compound 9 also reacted with MDA and formed MDA adducts, in both the imine form and the oxaminal form (pg. 68, lines 3-4).
However, Todd et al. fail to disclose administering reproxalap is administered four times a day (QID) in an initiation and/or exacerbation phase and a lower dosing frequency during a maintenance phase nor detecting adducts by LC-MS, ultraviolet spectrometry (UV), HPLC, mass spectrometry (MS), monoclonal antibody detection assay, gas chromatography (GC), GC/MS, QC/flame ionization detector (FID), capillary electrophoresis with amperometric detection (CEAD), liquid chromatography/fluorescence detection, enzyme linked immunosorbent assay (ELISA) or a combination thereof before or after treatment.
Ni et al. teach a method of treating any ocular indications involving abnormal neovascularization in the front part of the eye including treating dry eye (pg. 3, 2nd para.). Ni Also teaches administering an ophthalmic solution in a maintenance after an initial treatment phase “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. The dose and the administration frequency can be adjusted based on the judgment of the treating physician, for example, taking into account the clinical signs, pathological signs and clinical and subclinical symptoms of a disease of the conditions treated with the present methods, as well as the patient's clinical history.” (pg. 7, 1st para.).
However, Ni fails to disclose measuring the level of the aldehyde marker of oxidative stress in the eye of the subject before or following treatment with the scientific instruments disclosed above.
Aldeyra teaches ADX-102 (reproxalap) (0.1 % ophthalmic solution, 0.5% ophthalmic solution, and 0.5% lipid formulation) as a treatment for dry eye disease wherein the level of malondialdehyde (MDA) is measured before and after treatment with the disclosure of proinflammatory aldehyde mediators sequestered by ADX-102, were significantly reduced in the tears of patients (p=0.009) supporting the differentiated mechanism of action relative to other therapies in dry eye disease.
However, Aldeyra does not specifically disclose the instruments used to measure the levels of MDA in a patient.
Zhang et al. teach that many methods have been developed to detect MDA, including high-performance liquid chromatography (HPLC) with ultraviolet detection, capillary electrophoresis with ultraviolet detection, HPLC with fluorescence detection, liquid chromatography with electrogenerated chemiluminescence (CL) (pg. 16, left col., 2nd para.).
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 composition of 0.01-20% w/v compound 9 (reproxalap) and 0.01-30% w/v of cyclodextrins hydroxypropyl-β-cyclodextrin or β-cyclodextrin sulfobutylether sodium salt in a method of treating dry eye disease as taught by Todd and taught to be adjustable to patient response and disease progression with the method of administering a composition up to 4 times a day or more by Ni and Aldeyra and Ni who disclosed administering an ophthalmic composition for treating dry eye disease in a maintenance phase after an initial phase of treatment to treat indications of neovascularization from dry eye diseases, A skilled artisan would have also maintained observation of treatment progress by measuring the levels of aldehyde marker Malondialdehyde (MDA) before and after administering the composition to determine effectiveness of the treatment method. One of ordinary skill would have selected a known effective method of measuring the levels of Malondialdehyde using HPLC the methods disclosed by Zhang. See MPEP 2144.05 (II).
A person of ordinary skill in the art would have been motivated to combine Todds disclosure of treating a dry eye disease with a composition of reproxalap and cyclodextrins hydroxypropyl-β-cyclodextrin or β-cyclodextrin sulfobutylether with Ni’s disclosure of dose frequency and a maintenance phase with Aldeyra’s disclosure of measuring MDA as a way to track patient progress by using the High‑Performance Liquid Chromatography (HPLC) detection methods disclosed by Zhang with the reasonable expectation of success in treating dry eye disease in a subject. See MPEP 2144 (II) which states:
“Indeed, we have repeatedly held that an implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the ‘improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal—and even common-sensical—we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves.”
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
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623
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