DETAILED ACTION
Election/Restrictions
Newly submitted claims 51-57 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons the newly added claims are directed to an ophthalmic composition comprising reproxalap, or a pharmaceutically acceptable salt thereof, at about 0.2% w/v to about 0.3% w/v, and a pharmaceutically acceptable excipient comprising a cyclodextrin, wherein the cyclodextrin is sulfobutylether-B-cyclodextrin or hydroxypropyl-B-cyclodextrin, or a pharmaceutically acceptable salt thereof; and wherein the ophthalmic solution is formulated for topical administration to the eye. This is distinct from the originally presented claims that were directed to a method of treating allergic conjunctivitis in a subject comprising topically administering to an eye of a subject in need thereof a therapeutically effective amount of an ophthalmic solution comprising about 0.25% w/v reproxalap or its pharmaceutical salt, and a pharmaceutically acceptable excipient is about 11% w/v of sulfobutylether B-cyclodextrin (SBECD), or a pharmaceutically acceptable salt thereof.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 51-57 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Status of Application
The response filed 06/30/2025 has been received, entered and carefully considered. The response affects the instant application accordingly:
Claim 51-57 has been added.
Claims 1, 10-11, 15, 17, 21, 25-27, 30-31, 34, 37, 39-43, 47-48, 51-57 are pending.
Claims 1, 10-11, 15, 17, 21, 25-27, 30-31, 34, 37, 39-43, 47-48 are present for examination at this time.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement filed 06/30/2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication, pending unpublished U.S. application with the application specification including the claims and any drawing of the application or that portion of the application which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Standing Grounds of Rejection
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.
Claims 1, 10-11, 15, 17, 21, 25-27, 30-31, 34, 37, 39-43, 47-48 are rejected under 35 U.S.C. 103 as being obvious over Young et al. (U.S. Pat. 2017/0266220).
Rejection:
Young et al. teaches treating or preventing allergic conjunctivitis with cyclodextrin (abstract, claims 1, 5, 17, 29, 34, 42, 54). Young et al. also teaches that the cyclodextrin can be combined with an active agent such as NS2 with the structure of
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(reproxalap, ADX-102) at a range of about 0.2%w/v-about 4% and particular concentrations of about 0.2%w/v and about 0.3%w/v [58, 104-105]. The cyclodextrins include sulfobutylether-β cyclodextrin (SBECD) and hydroxypropyl-β-cyclodextrin (HPCD) at various amounts for these cyclodextrins including about 7%, about 10%, and about 12% [93, 97-98, 100, 102, 104-105] to be combined with the compound of formula I [105]. Young also teaches the molar ratio of the cyclodextrin with the active to include about 3:1 and about 5:1 (active:cyclodextrin of about 1:3 and about 1:5 respectively). Young also teaches the inclusion of known excipients including tonicity agents and buffers [12 like phosphate buffers [116-117]. Young et al. teaches treating patients with moderate to severe allergic conjunctivitis with a solution with NS2 and cyclodextrin (Example 1). The patients were confirmed to have allergic conjunctivitis (at least a 2-year history, confirmatory CAPT, skin prick test ([154-163, 181], Example1). Prophylactic action (prevention), onset of action, and duration of action were examined [175, 177, 277]. Patients were dosed with the treatment 30min before allergen exposure/instillation (initiation phase), evaluated for symptoms, and continued dosing at home qid (four times a day) (i.e. first and second treatment phases, initiation and maintenance and/or exacerbation phase). The solution contained 0.5%w/v NS2 and 9.5%w/v sulfobutylether-β cyclodextrin in phosphate buffered water [184] with one drop instilled into the eye four times a day for about 17 days [188]. There was a reduction of ocular itching and tearing with NS2 compared to vehicle ([286-287], exceeding 1-point reduction over baseline (no treatment) see [286-287], Figures 5-6, see full document specifically areas cited).
Young et al. does not expressly exemplify the drug at about 0.25% and the sulfobutylether-β cyclodextrin at about 11%w/v but Young does expressly teach NS2 concentrations of about 0.2% and about 0.3% with sulfobutylether-β cyclodextrin at about 10%, and about 12%; wherein it would be prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to exemplify the reproxalap at the taught concentrations of Young (i.e. about 0.2% includes 0.24% and about 0.3% includes 0.25% (as “about” is up to 20% [55], falling within about 0.25%), about 10% (falling within about 11%)) but also the points between them (i.e. 0.25%, 11%) and produce the claimed invention with a reasonable expectation of success absent evidence of criticality for the claimed values. Additionally; it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the amount of the reproxalap and cyclodextrin in the example with the express taught values (reproxalap about 0.2% and about 0.3%, cyclodextrin about 10% and about 12%) as wherein there is an overlap in values or they are merely close, a prima facie case of obviousness exists as the one of skill in the art would expect them to have the same properties with a reasonable expectation of success absent evidence of criticality for the claimed values as the normal desire of scientists/artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages (see MPEP 2144.05).
Response to Arguments:
Applicant's arguments filed 06/30/2025 are centered on the assertion that the art is unpredictable and the office action has not adequately explained why one would have been motivated to reduce the amount of reproxalap used in the clinical example of 0.5% which had clinically significant results such as the ocular itch scores, that Young does not exemplify 0.25% reproxalap cited in the instant claims, the assertion that the optimal or critical concentration of reproxalap was unknown and could not be predicted, and the assertion of evidence of criticality for the reproxalap concentration in Figures 1-3.
This is fully considered but not persuasive.
As for the assertion that the art is unpredictable and the office action did not adequately explain why one would be motivated to reduce the exemplified amount of 0.5% reproxalap in Young which presented with clinically significant results, that Young did not exemplify the recited 0.25% reproxalap, and the assertion that the optimal or critical concentration of reproxalap was unknown and could not be predicted, this is not persuasive nor accurate as Young establishes that reproxalap is useful in the treatment of allergic conjunctivitis with cyclodextrin, with the reproxalap useful in the range of about 0.2%w/v-about 4% and particular concentrations of about 0.2%w/v and about 0.3%w/v (teaching and citing specific/optimizable concentrations for exemplification); and the cyclodextrins can be sulfobutylether-β cyclodextrin (SBECD) at various amounts including about 10% and about 12% where Young addresses the predictability of using these components for the method; contrary to Applicant’s assertions,. While 0.5% reproxalap is exemplified with sulfobutylether-β cyclodextrin and does not exemplify 0.25% reproxalap, the teachings of Young are not held solely to the example when the general teaching is for a clear range for reproxalap (about 0.2%w/v-about 4%) with particular concentrations of about 0.2%w/v and about 0.3%w/v that are embraced by the breath claims which is about 0.25% and cyclodextrins can be sulfobutylether-β cyclodextrin (SBECD) at various amounts including about 10% and about 12%; wherein it would be prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to exemplify the reproxalap at the taught concentrations of Young that are established to be useful (i.e. about 0.2% includes 0.24% and about 0.3% includes 0.25% (as “about” is up to 20% [55], falling within about 0.25%), and about 10% (falling within about 11%)) for the cyclodextrin as expressly taught by young as a means of attaining the composition with the desired therapeutic profile with a reasonable expectation of success absent evidence of criticality for the claimed composition.
As for Applicant’s assertion for evidence of criticality for the reproxalap concentration in Figures 1-3, this is fully considered but not persuasive as it is not commensurate in scope with the instant claims as Figures 1-3 are for a formulation of 0.25% reproxalap and 7% sulfobutylether-8 cyclodextrin but the instant claims are for a method of treating allergic conjunctivitis with a formulation of 0.25% reproxalap and 11% sulfobutylether-8 cyclodextrin which is not that of Figures 1-3.
It is noted that Figure 1 is not persuasive as the p-values merely demonstrate that both formations (0.25% reproxalap/7% sulfobutylether-B cyclodextrin and 0.5% reproxalap/9.5% sulfobutylether-B cyclodextrin) are statistically significant over vehicle, not evidence of criticality between the formulations.
However, Figure 2 does demonstrate that the formulation with 0.25% reproxalap and 7% sulfobutylether-8 cyclodextrin was superior than 0.5% reproxalap with 9.5% sulfobutylether-8 cyclodextrin which is twice the amount of active (more active should have more effect, not less active with more effect) which is unexpected and evidence of criticality but is not commensurate with the instant claims which is to the method with . formulation of 0.25% reproxalap and 11% sulfobutylether-8 cyclodextrin. Figure 3 also demonstrates that 0.25% reproxalap with 7% sulfobutylether-8 cyclodextrin was superior than 0.5% reproxalap with 9.5% sulfobutylether-B cyclodextrin which is twice the amount of active which is unexpected (more active should have more effect which is not the case as 0.25% reproxalap with 7% sulfobutylether-8 cyclodextrin was similar if not superior at half the concentration) demonstrating evidence of criticality, but is not commensurate with the instant claims which is to the method with . formulation of 0.25% reproxalap and 11% sulfobutylether-8 cyclodextrin. The term “about” is defined by the specification to be within 10% of the value.
Accordingly, the rejection stands.
Claims 1, 11, 15, 17, 21, 25-27, 30-31, 34, 37, 39-43, 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Jordan et al. (U.S. Pat. Pub. 2012/0302601) and Brady et al. (WO 2017/196881).
Rejection:
Jordan et al. teaches an ophthalmic composition comprising
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also known as reproxalap (ADX-102, or NS2) with cyclodextrin such as hydroxypropyl β-cyclodextrin and β-cyclodextrin sulfobutyl ether [15, 18-21]. The amount of active will generally be from 0.001-1.0%w/v and more particularly 0.1-0.5%w/v and the amount of cyclodextrin the amount of β-cyclodextrin sulfobutylether from 5-25% with illustrated concentrations of 9.5-20% with compositions that can be buffered like a phosphate buffer - to a pH range of 5.5-8.5 more particularly 6.5-7.5, and excipients like preservatives [18-19]. Jordan et al. exemplifies compound A with 9.5% β-cyclodextrin sulfobutylether (Example 1, [22]) and compound A at 0.15% with β-cyclodextrin sulfobutylether (see Table 1 [25], see full document specifically areas cited) .
While Jordan does not expressly teach the exact claimed value of reproxalap or β-cyclodextrin sulfobutylether, Jordan does teach ranges that embrace them (reproxalap from 0.1-0.5%w/v and β-cyclodextrin sulfobutylether from 5-25%) and exemplifies the reproxalap at 0.15% and β-cyclodextrin sulfobutylether at 9.5% and 20%; wherein it would be prima facie obvious to optimize within the taught ranges including around and between the exemplified values to arrive at the claimed value (i.e. 0.25% reproxalap and values falling within the claimed value such as 0.20% and 0.23%, about 9.5% β-cyclodextrin sulfobutylether embraces values that are about 11% (i.e.11, and both 10% and 10.5% are about 9.5% and about 11%) with reasonable expectation of success absent evidence of criticality for the claimed value.
Jordan does not teach treating allergic conjunctivitis but does teach an ophthalmic formulation comprising reproxalap and cyclodextrins like β-cyclodextrin sulfobutyl ether and hydroxypropyl β-cyclodextrin such as the exemplified formulations addressed above (i.e. Table 1 above).
Brady et al. teaches that topical ocular NS2
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is known to be useful in treating allergic conjunctivitis and that the drug active was showed to be effective for treating allergic conjunctivitis in a trial as after a single eye drop, the topical ocular NS2 significantly reduced the ocular itching and tearing in allergic conjunctivitis (presented with symptoms of allergic conjunctivitis) and the positive effects continued after 14 days of dosing ([50, 135-137], claims 3 and 18). Brady also teaches that treatment includes prevention of the disorder such as causing the symptoms of the disorder not to develop in a subject that may be exposed to or predisposed to the disease [41].
Wherein it would be obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the known reproxalap formulation for treating allergic conjunctivitis as suggested by Brady et al. and produce the claimed invention; as it is prima facie obvious to use a known topical ophthalmic reproxalap formulation for treating an ophthalmic condition the reproxalap active is known to be useful for in the known regimen with a reasonable expectation of success. It is also prima facie obvious that the patient would have a history of allergic conjunctivitis to be diagnosed with the condition as one would have to diagnosis the condition prior to treating the condition. It is also prima facie obvious upon diagnosis, to treat the condition for as long as needed (i.e. first day (e.g. initiation phase, first phase), duration of treatment (e.g. 13 days, maintenance and/or exacerbation phase, second phase)) and to adjust the frequency of administration (e.g. from 1 drop ad day to 2-4 drops a day) as needed to manage and treat the condition with a reasonable expectation of success absent evidence of criticality for the frequency of administration. As Brady teaches that treatment includes prevention of the disorder/symptoms developing in a patient from exposure, it is prima facie obvious upon diagnosis to prevent the allergic conjunctivitis from occurring from exposure (allergen) by administration of the NS2 any convenient time prior to exposure (prevention, first phase, initiation) and/or upon exposure (i.e. 0 hr prior to exposure, first phase, initiation) with a reasonable expectation of success; and to and to adjust the frequency of administration (e.g. from 1 drop a day to 2-4 drops a day) as needed to manage the condition (second phase, maintenance and/or exacerbation phase) with a reasonable expectation of success absent evidence of criticality for the frequency of administration. As Brady addresses that the topical reproxalap active is known to reduce the ocular itching and tearing in allergic conjunctivitis, and the amount of reproxalap in the prior art are within the general range of the instant specification (about 0.1-about 0.5% of reproxalap), wherein the amount itch reduction would be expected to be the same.
Response to Arguments:
Applicant's arguments filed 06/30/2025 are centered on the assertion that the art is unpredictable and the office action has not adequately explained why one would have been motivated to reduce the amount of reproxalap used in the example of Brady, that neither Jordan or Brady exemplify 0.25% reproxalap, that Brady does not test other formulations for uveitis and does not suggest the critical or optimal concentration for allergic conjunctivitis treatment, that Jordan does not mention allergic conjunctivitis, that neither Jordan or Brady exemplify 0.25% reproxalap, and the assertion of evidence of criticality for the reproxalap concentration in Figures 1-3.
This is fully considered but not persuasive.
The assertion that the art is unpredictable is not persuasive as Jordan establishes that reproxalap known to be useful for the eye and ophthlamically formulated with reproxalap from 0.1-0.5%w/v and β-cyclodextrin sulfobutylether from 5-25% and exemplifies the reproxalap at 0.15% and β-cyclodextrin sulfobutylether at 9.5% and 20%; wherein it is prima facie obvious to optimize within the taught ranges including around and between the exemplified values to arrive at the claimed values (i.e. 0.25% reproxalap and values falling within the claimed value such as 0.20% and 0.23%, about 9.5% β-cyclodextrin sulfobutylether embraces values that are about 11% (i.e.11, and both 10% and 10.5% are about 9.5% and about 11%) with reasonable expectation of success absent evidence of criticality for the claimed value which have not been presented.
Applicant’s arguments that the office action did not adequately explain why one would be motivated to reduce the exemplified amount of 0.5% reproxalap in Brady, that Brady does not exemplify the recited 0.25% reproxalap or test other formulations for uveitis and does not suggest the optimal or critical concentration of reproxalap for allergic conjunctivitis are to the reference individually, and one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Additionally, Brady is presented with Jordan merely to show that reproxalap is known to be useful in treating allergic conjunctivitis and showed to be effective for treating allergic conjunctivitis in a trial as after a single eye drop, the topical ocular NS2 significantly reduced the ocular itching and tearing in allergic conjunctivitis (presented with symptoms of allergic conjunctivitis) and that treatment includes prevention of the disorder such as causing the symptoms of the disorder not to develop in a subject that may be exposed to or predisposed to the disease, establishing that use of reproxalap for allergic conjunctivitis is known and predicable contrary to Applicant’s assertions; wherein using a known reproxalap cyclodextrin ophthalmic formulation for its known utility is prima facie obvious absent evidence of criticality.
With regards to the assertion that Jordan does not mention allergic conjunctivitis and does not exemplify 0.25% reproxalap is to the reference individually, and one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Additionally while 0.15% reproxalap is exemplified with β-cyclodextrin sulfobutylether at 9.5% and 20%; and teachings of Jordan are not held solely to the example when the general teaching is for a clear range for reproxalap and cyclodextrin wherein it would be prima facie obvious to optimize within the taught ranges particularly around the exemplified values with a reasonable expectation of success to attain the desired therapeutic profile.
As for Applicant’s assertion for evidence of criticality for the reproxalap concentration in Figures 1-3, this is fully considered but not persuasive as it is not commensurate in scope with the instant claims as Figures 1-3 are for a formulation of 0.25% reproxalap and 7% sulfobutylether-8 cyclodextrin but the instant claims are for a method of treating allergic conjunctivitis with a formulation of 0.25% reproxalap and 11% sulfobutylether-8 cyclodextrin which is not commensurate in scope with that of Figures 1-3.
It is noted that Figure 1 is not persuasive as the p-values merely demonstrate that both formations (0.25% reproxalap/7% sulfobutylether-B cyclodextrin and 0.5% reproxalap/9.5% sulfobutylether-B cyclodextrin) are statistically significant over vehicle, not evidence of criticality between the formulations.
However, Figure 2 does demonstrate that the formulation with 0.25% reproxalap and 7% sulfobutylether-8 cyclodextrin was superior than 0.5% reproxalap with 9.5% sulfobutylether-8 cyclodextrin which is twice the amount of active (more active should have more effect, not less active with more effect) which is unexpected and evidence of criticality but is not commensurate with the instant claims which is to the method with . formulation of 0.25% reproxalap and 11% sulfobutylether-8 cyclodextrin. Figure 3 also demonstrates that 0.25% reproxalap with 7% sulfobutylether-8 cyclodextrin was superior than 0.5% reproxalap with 9.5% sulfobutylether-B cyclodextrin which is twice the amount of active which is unexpected (more active should have more effect which is not the case as 0.25% reproxalap with 7% sulfobutylether-8 cyclodextrin was similar if not superior at half the concentration) demonstrating evidence of criticality, but is not commensurate with the instant claims which is to the method with . formulation of 0.25% reproxalap and 11% sulfobutylether-8 cyclodextrin. The term “about” is defined by the specification to be within 10% of the value.
Accordingly, the rejection stands.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Jordan et al. (U.S. Pat. Pub. 2012/0302601) and Brady et al. (WO 2017/196881) as applied to claims 1, 11, 15, 17, 21, 25-27, 30-31, 34, 37, 39-43, 47-48 above, further in view of Winfield (Pharmaceutical Practice – Ophthalmic products (Tonicity)).
Rejection:
The teachings of over Jordan et al. in view of Brady et al. are addressed above.
Jordan et al. in view of Brady et al. does not expressly teach the incorporation of tonicity agents does include various components for the administration of the ophthalmic composition.
Winfield teaches that known conventional components for ophthalmic formulations include tonicity agents as where possible eye drop are made to be isotonic with lachrymal fluid (Tonicity).
Wherein it would be one of obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to include a tonicity agent as suggested by Winfield and produce the claimed invention; as it is prima facie obvious to incorporate known conventional excipients like tonicity agents as it is known that when possible ophthalmic formulation s should be made isotonic with lachrymal fluid with their addition with a reasonable expectation of success.
Response to Arguments:
Applicant's arguments are to Jordan et a. and Brady et al. which are addressed above.
Accordingly, the rejection stands.
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.
Claims 1, 11, 15, 17, 21, 25-27, 30-31, 34, 37, 39-43, 47-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-31, 34-35 of U.S. Patent No. 9687481.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims are directed to the treatment of allergic conjunctivitis with the instant claimed compound with the instant claimed sulfobutylether-β cyclodextrin with values that embrace the instant claims wherein it would be prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the amount of drug and cyclodextrin within the patented range and produce the claimed invention with a reasonable expectation of success absent evidence of criticality for the claimed values as it is the normal desire of scientists/artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages (see MPEP 2144.05). The patent also defines treating to include inhibiting the disease/disorder such as impeding its progress, reliving the disease and ameliorating at least one symptom wherein it would be obvious to administer/treat the condition prior to (first phase, initiation) or at the time of allergen contact/exposure ((i.e. 0 hr prior to exposure, first phase, initiation) to inhibit the disease/disorder and its progress and ameliorating at least one symptom of the allergic conjunctivitis with a reasonable expectation of success; and to and to adjust the frequency of administration (e.g. from 1 drop a day to 2-4 drops a day) as needed to manage the condition (second phase, maintenance and/or exacerbation phase) with a reasonable expectation of success absent evidence of criticality for the frequency of administration
It is also prima facie obvious that the patient would have a history of allergic conjunctivitis to be diagnosed with the condition as one would have to diagnosis the condition prior to treating the condition. It is also prima facie obvious upon diagnosis, to treat the condition for as long as needed (i.e. first day (e.g. initiation phase, first phase), duration of treatment (e.g. 13 days, maintenance and/or exacerbation phase, second phase)) and to adjust the frequency of administration (e.g. from 1 drop ad day to 2-4 drops a day) as needed to manage and treat the condition with a reasonable expectation of success absent evidence of criticality for the frequency of administration. As the amount of reproxalap in the patented claims embrace values of the instant specification (e.g. about 0.1-about 0.5% of reproxalap), the amount itch reduction would be expected to be similar if not the same.
Response to Arguments:
Applicant's arguments are centered on the assertion that the ranges overlap with the claims and asserts evidence of criticality as asserted above to overcome obviousness which is not persuasive as it is not commensurate in scope with the instant claims as addr3essed above.
Accordingly, the rejection stands.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-31, 34-35 of U.S. Patent No. 9687481 as applied to claims 1, 11, 15, 17, 21, 25-27, 30-31, 34, 37, 39-43, 47-48 above, in view of Winfield (Pharmaceutical Practice – Ophthalmic products (Tonicity, pH adjustment)).
The teachings of the patented claims are addressed above.
The patented claims do not expressly teach the incorporation of tonicity agents or buffers but does recite topical administration to the eye of the aqueous composition for treating allergic conjunctivitis.
Winfield teaches that known conventional components for ophthalmic formulations include buffers for pH adjustment to reduce stinging, and tonicity agents as when possible eye drop are made to be isotonic with lachrymal fluid (Tonicity).
Wherein it would be one of obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to include a buffer and tonicity agent as suggested by Winfield and produce the claimed invention; as it is prima facie obvious to incorporate known conventional excipients like tonicity agents and buffers as it is known that when possible ophthalmic formulation should be made with reduced stinging and be isotonic with lachrymal fluid with a reasonable expectation of success.
Response to Arguments:
Applicant's arguments are to the patent and the assertion of evidence of criticality which is addressed above.
Accordingly, the rejection stands.
Claims 1, 10-11, 15, 17, 21, 25-27, 30-31, 34, 37, 39-43, 47-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, 19-24 of U.S. Patent No. 11197821 in view of Young et al. (U.S. Pat. 2017/0266220).
The patented claims are directed to the treatment of dry eye with the administration of an ophthalmic solution with about 0.2%w/v-about 0.3%w/v reproxalap and a cyclodextrin that is either hydroxypropyl-β-cyclodextrin (HPCD) or sulfobutylether-β cyclodextrin (SBECD), wherein the reproxalap and cyclodextrin is at a molar ratio of about 1:2, about 1:3, about 1:4, about 1:5 (ratios equates to values of about 7% HPCD and SBECD, 11%SBECD) , and the solution is topically administered to the eye four times a day in an initiation or exacerbation phase followed by a maintenance phase of 3x/day or 2x/day or 1x/day or as needed. There are also claims to the reproxalap being about 0.25%w/v with the cyclodextrin being sulfobutylether-β cyclodextrin at about 7% or about 11%w/v, the inclusion of tonicity agents and phosphate buffer, additional degrees of frequency of administration, and administration of a dose to address symptoms like ocular itchiness.
The patented claims do not expressly teach treating allergic conjunctivitis but does teach a reproxalap ophthalmic formulation with cyclodextrin (hydroxypropyl-β-cyclodextrin or sulfobutylether-β cyclodextrin) with the recited concentrations or ratios, or values that closely embrace it (about 0.2-about 0.3%), that is useful for treating the eye.
Young et al. teaches treating or preventing allergic conjunctivitis with cyclodextrin in combination with an active agent such as NS2 with the structure of
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(reproxalap, ADX-102) at a range of about 0.2%w/v-about 4% and particular concentrations of about 0.2%w/v and about 0.3%w/v [58, 104-105]. The cyclodextrins include hydroxypropyl-β-cyclodextrin (HPCD) and sulfobutylether-β cyclodextrin (SBECD) at various amounts for these cyclodextrins including about 7%, about 10%, and about 12% [93, 97-98, 100, 102, 104-105] to be combined with the compound of formula I [105]. Young also teaches same molar ratio of the active:cyclodextrin in the patented claims (i.e. about 1:3 and about 1:5, abstract, claims 1, 5, 17, 29, 34, 42, 54). Young et al. teaches treating patients with moderate to severe allergic conjunctivitis with a solution with NS2 and cyclodextrin (Example 1). The patients were confirmed to have allergic conjunctivitis (at least a 2-year history, confirmatory CAPT, skin prick test ([154-163, 181], Example1). Prophylactic action (prevention), onset of action, and duration of action were examined [175, 177, 277]. Patients were dosed with the treatment 30min before allergen exposure/instillation (initiation phase), evaluated for symptoms, and continued dosing at home qid (four times a day) (i.e. first and second treatment phases, initiation and maintenance and/or exacerbation phase). The solution contained 0.5%w/v NS2 and 9.5%w/v sulfobutylether-β cyclodextrin in phosphate buffered water [184] with one drop instilled into the eye four times a day for about 17 days [188]. There was a reduction of ocular itching and tearing with NS2 compared to vehicle ([286-287], exceeding 1-point reduction over baseline (no treatment) see [286-287], Figures 5-6).
Wherein it would be obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to utilize a known patented reproxalap formulation for treating allergic conjunctivitis as suggested by Young et al. and produce the claimed invention; as it is prima facie obvious to use a known topical ophthalmic reproxalap formulation that falls within the teachings of Young, for treating an ophthalmic condition the reproxalap active is known to be useful for in the known regimen in the patented claims and Young with a reasonable expectation of success. It is also prima facie obvious that the patient would have a history of allergic conjunctivitis to be diagnosed with the condition as one would have to diagnosis the condition prior to treating the condition. Additionally; it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the amount of the reproxalap within the patented values (about 0.2%-about 0.3% to attain about 0.25%) with a reasonable expectation of success absent evidence of criticality for the claimed values. As the amount of reproxalap in the patented claims are within the general range of the instant specification (about 0.1-about 0.5% of reproxalap), wherein the amount itch reduction would be expected to be the same.
Response to Arguments:
Applicant asks that the rejection be held in abeyance.
There is no terminal disclaimer.
Accordingly, the rejection stands.
Claims 1, 10-11, 15, 17, 21, 25-27, 30-31, 34, 37, 39-43, 47-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11, 13-38 of copending Application No. 17/450623 in view of Young et al. (U.S. Pat. 2017/0266220).
The copending claims are directed to the treatment of dry eye with the administration of an ophthalmic solution with about 0.2%w/v-about 0.3%w/v reproxalap and a cyclodextrin that includes sulfobutylether-β cyclodextrin (SBECD) and hydroxyalkyl-β-cyclodextrin (HPCD) wherein the reproxalap and cyclodextrin is at a molar ratio of about 1:2, about 1:3, about 1:4, about 1:5 (ratios equates to values of about 7% HPCD and SBECD, 11%SBECD), and the solution is topically administered to the eye in various regimen including four times a day, and four times a day in an initiation or exacerbation phase followed by a maintenance phase of 3x/day or 2x/day or 1x/day or as needed. There are also claims to the reproxalap being about 0.25%w/v with the cyclodextrin being hydroxypropyl-β-cyclodextrin (HPCD) or sulfobutylether-β cyclodextrin at about 7% or about 11%w/v, the inclusion of tonicity agents and phosphate buffer, additional degrees of frequency of administration, and administration of a dose to address symptoms like ocular itchiness.
The copending claims do not expressly teach treating allergic conjunctivitis but does teach a reproxalap ophthalmic formulation with cyclodextrin (hydroxypropyl-β-cyclodextrin or sulfobutylether-β cyclodextrin) with the recited concentrations or ratios, or values that closely embrace it (about 0.2-about 0.3%), that is useful for treating the eye.
Young et al. teaches treating or preventing allergic conjunctivitis with cyclodextrin in combination with an active agent such as NS2 with the structure of
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189
424
media_image1.png
Greyscale
(reproxalap, ADX-102) at a range of about 0.2%w/v-about 4% and particular concentrations of about 0.2%w/v and about 0.3%w/v [58, 104-105]. The cyclodextrins include hydroxypropyl-β-cyclodextrin (HPCD) and sulfobutylether-β cyclodextrin (SBECD) at various amounts for these cyclodextrins including about 7%, about 10%, and about 12% [93, 97-98, 100, 102, 104-105] to be combined with the compound of formula I [105]. Young also teaches same molar ratio of the active:cyclodextrin in the copending claims (i.e. about 1:3 and about 1:5, abstract, claims 1, 5, 17, 29, 34, 42, 54). Young et al. teaches treating patients with moderate to severe allergic conjunctivitis with a solution with NS2 and cyclodextrin (Example 1). The patients were confirmed to have allergic conjunctivitis (at least a 2-year history, confirmatory CAPT, skin prick test ([154-163, 181], Example1). Prophylactic action (prevention), onset of action, and duration of action were examined [175, 177, 277]. Patients were dosed with the treatment 30min before allergen exposure/instillation (initiation phase), evaluated for symptoms, and continued dosing at home qid (four times a day) (i.e. first and second treatment phases, initiation and maintenance and/or exacerbation phase). The solution contained 0.5%w/v NS2 and 9.5%w/v sulfobutylether-β cyclodextrin in phosphate buffered water [184] with one drop instilled into the eye four times a day for about 17 days [188]. There was a reduction of ocular itching and tearing with NS2 compared to vehicle ([286-287], exceeding 1-point reduction over baseline (no treatment) see [286-287], Figures 5-6).
Wherein it would be obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to utilize a known reproxalap formulation for treating allergic conjunctivitis as suggested by Young et al. and produce the claimed invention; as it is prima facie obvious to use a known topical ophthalmic reproxalap formulation that falls within the teachings of Young, for treating an ophthalmic condition the reproxalap active is known to be useful for in the known regimen in the copending claims and Young with a reasonable expectation of success. It is also prima facie obvious that the patient would have a history of allergic conjunctivitis to be diagnosed with the condition as one would have to diagnosis the condition prior to treating the condition. Additionally; it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the amount of the reproxalap within the copending values (about 0.2%-about 0.3% to attain about 0.25%) with a reasonable expectation of success absent evidence of criticality for the claimed values. As the amount of reproxalap in the copending claims are within the general range of the instant specification (about 0.1-about 0.5% of reproxalap), wherein the amount itch reduction would be expected to be the same.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments:
Applicant asks that the rejection be held in abeyance.
There is no terminal disclaimer.
Accordingly, the rejection stands.
Conclusion
Claims 1, 10-11, 15, 17, 21, 25-27, 30-31, 34, 37, 39-43, 47-48 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GIGI G HUANG/Primary Examiner, Art Unit 1613