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 .
Request for Continued Examination (RCE)
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/14/26 has been entered.
Priority
This application is a 371 of PCT/JP2021/037841 (10/13/2021),
and claims foreign priority to JAPAN 2020-173195 (10/14/2020).
Status
Claims 1, 2, 5, 8-16, 18-23 are currently pending.
Rejections not reiterated in this action are withdrawn.
Claim Rejections - 35 USC § 103
Claim 1-2, 5, 8-16, 18-23 are rejected under 35 U.S.C. 103 as being unpatentable over Horn et al. (US20150290125) in view of Ahmad et al. (International Journal of Photoenergy, Volume, 2016, Article ID 8135608, 19 pages).
Horn teaches storage stable ophthalmological composition with the same muscarinic antagonist also known as otenzepad (claim 2; [0152]: “ otenzepad (a.k.a. AF-DX 116 or 11-{[2-(diethylamino)methyl]-1-piperidinyl}acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepine-6-one)”, in a preferred embodiment “otenzepad at a concentration from about 0.002% to about 0.05% w/v”) formulated with components including citric acid (claim 4), “tris” which is the same compound as trometamol ([0130]: “2-Amino-2-hydroxymethyl-propane-1,3-diol (Tris)”) at a pH of 4.75-5.0 (claim 1: “wherein the pH of the composition is from about 4.75 to about 5.0”; claim 7: “a buffer selected from acetate buffer, citrate buffer, phosphate buffer and citrophosphate buffer at a concentration of about 3 millimolar; optionally citric acid monohydrate at a concentration from about 0.1% to about 0.2% w/v“; claim 15: “c) buffering the pH of the composition to from about 4.0 to about 6.0; and d) maintaining the composition at a temperature from about 2 to about 8° C.“).
Ahmad teaches that it was well known to test for and formulate drugs to ensure photostability of the pharmaceutical composition including through optimal choice of stabilizers and pH, including specifically citric acid (p. 1, 13).
Regarding claim 1, Horn teaches all of the elements of the claims including otenzepad, citric acid, and trometamol, but not in a single embodiment. One of ordinary skill in the art following the teaching of Horn would have considered a formulation comprising otenzepad as claimed therein and would have known from the teaching of Horn the importance of pH and buffering on stability as specifically taught by Horn ([0099]: “the present invention to provide a method of stabilizing aqueous aceclidine by combining effective excipients, pH ranges and temperature ranges”) and suggested by Ahmad. Thus, one of ordinary skill in the art was motivated to including buffering agents including citric acid and trometamol and arrive at the claimed invention through routine experimentation with a reasonable expectation of success because Horn specifically teaches the elements.
Regarding claim 2, Horn teaches “buffering the pH of the composition to from about 4.0 to about 6.0, preferably 4.75” ([0089]) which one of ordinary skill in the would have considered and arrived at the claimed invention.
Regarding claims 5 and 8, as with claim 1, Horn teaches a formulation comprising trometamol.
Regarding claim 9 specifying the amount of otenzepad, Horn teaches in a preferred embodiment “otenzepad at a concentration from about 0.002% to about 0.05% w/v” ([0152]) which one of ordinary skill in the would have considered and arrived at the claimed invention with a reasonable expectation of success.
Regarding claims 10-11 specifying the amount of buffering agent, Horn teaches buffering concentrations including 0.1% to 0.2% w/v (claim 7: “a buffer selected from acetate buffer, citrate buffer, phosphate buffer and citrophosphate buffer at a concentration of about 3 millimolar; optionally citric acid monohydrate at a concentration from about 0.1% to about 0.2% w/v“) which one of ordinary skill in the would have considered and arrived at the claimed invention with a reasonable expectation of success.
Regarding claims 12-14 specifying ocular topical installation of an eye drop, Horn teaches “topical instillation in the eye” ([0106]) of an eye drop composition ([0280]-[0281]).
Regarding claim 15 specifying storage 50C or less, Horn teaches stability of the composition in cold storage at 4C (Example 10, [0308]-[0316]) which one of ordinary skill in the would have considered and arrived at the claimed invention with a reasonable expectation of success.
Regarding claim 18 specifying the concentrations of otenzepad, citric acid, and trometamol, Horn teaches in a preferred embodiment “otenzepad at a concentration from about 0.002% to about 0.05% w/v” ([0152]) and Horn teaches buffering concentrations including 0.1% to 0.2% w/v (claim 7: “a buffer selected from acetate buffer, citrate buffer, phosphate buffer and citrophosphate buffer at a concentration of about 3 millimolar; optionally citric acid monohydrate at a concentration from about 0.1% to about 0.2% w/v“) which one of ordinary skill in the would have considered and arrived at the claimed invention with a reasonable expectation of success.
Regarding claims 16, 19-23 specifying steps of forming the formulation, Horn teaches a method of stabilizing the formulation by buffering to composition (claim 15) as well as the amounts of the components ([0152]; claim 7) and storing at 4C ([308]-[0316]) which one of ordinary skill in the would have considered and arrived at the claimed invention with a reasonable expectation of success.
With each of the above claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art in the same field of endeavor. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed with a reasonable expectation of success.
Response to Remarks - 35 USC § 103
Applicant argues that Horn primarily teaches aceclidine and not stable compositions comprising otenzepad and further Horn neither teaches nor suggests that the stability of an active agent other than "aceclidine" (for example, otenzepad) would be improved by combining effective excipients, pH ranges, and temperature ranges.
This argument is not persuasive because Horn is primarily concerned with producing storage stable compositions for treatment of presbyopia through optimization of components of the composition. Horn specifically claims the same cycloplegic agent compound as in the instant claims “AF-DX 384” (aka otenzepad) in claim 2. Although Horn’s examples of cycloplegic agents are to tropicamide, Horn teaches these are preferable equivalents ([0029]) that one of ordinary skill in the art would have considered such a substitution of a known equivalent as an obvious substitution (MPEP 2144.06) in the same composition that is optimized for stability.
Applicant argues that the claimed invention shows an unexpected result of stability due to the selection of pH and buffering agents and that the present disclosure demonstrates that the residual rate of AFDX0250 for the formations comprising (i) citric acid in combination with (ii) any of malic acid or a salt thereof, trometamol or a salt thereof, e-aminocaproic acid or a salt thereof, or L-glutamine or a salt thereof (referred to as “tertiary component”), as is recited in claims 1 and 16, are significantly higher than that of the formulation comprising citric acid alone.
This argument is not persuasive because Horn teaches that the pH and buffering agents improved the stability of the composition in the same manner. In addition, it was well-known to optimize stability by choice of stabilizers, buffer, and pH as taught by Ahmad. Thus, one of skill in the art would have considered the result as expected. The Examiner has also considered the experimental data in the instant specification and not found it persuasive as to the nonobviousness of the claims because the results are what one of skill in the art would have expected from the teaching of Horn in view of Ahmad.
Regarding the data in tables 12-14 of the specification, Exs. 24-35 show high levels of stability with a composition that does not have the tertiary component as in the claims. Thus, it is not clear how the alleged unexpected result is commensurate in scope with the claimed invention.
Regarding the specific photostability now argued in view of the claim amendments, the method for evaluating the different compositions is unclear with respect to aspects of the illumination. For example, the specification describes the method as: “2-2. Test Method. Each of the test formulations prepared in the above 2-1 (3 mL) was filled in a container and exposed to 1.2 million lux-hr of light at 1000 lux/hr or shaded with aluminum foil.” This does not indicate the amount of time, wavelength, and is ambiguous as to what the intensity applied actually was (“lux-hr” or “lux/hr”).
Weighing all of the evidence of record against evidence supporting prima facie obviousness by a preponderance of the evidence, the Examiner concludes that Applicant has not met their burden in establishing an unexpected result of a statistical and practical significance commensurate with the claimed invention sufficient to overcome the obviousness rejection. MPEP 716.02.
Conclusion
No claims allowed.
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/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626
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