DETAILED ACTION
Status of Application
The response filed 05/19/2026 has been received, entered and carefully considered. The response affects the instant application accordingly:
A declaration from Van Dinh is submitted.
There are no claim amendments.
Applicant had previously elected Group I in response to restriction requirement for the examination, and claims 40-42 are withdrawn being drawn to a non-elected invention.
Claims 27-43 are pending.
Claims 27-39, 43 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 .
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 27-39, 43 are rejected under 35 U.S.C. 103 as being unpatentable over Ni (WO 2016/200688) in view of Shah et al. (U.S. Pat. Pub. 2016/0339105).
Rejection:
Ni teaches an ophthalmic composition comprising a multikinase inhibitor including nintedanib. The composition can be an ophthalmic emulsion.
Ni expressly teaches ophthalmic emulsions comprising:
nintedanib (CBT-001) from 0.001-10%,
castor oil from 0-1.25%,
cyclodextrins (cyclic polysaccharides like sulfobutyl-β-cyclodextrin from 0-5%, alpha-cyclodextrin from 0-4%, 2-hydroxypropyl beta cyclodextrin from 0-5%),
emulsifier/surfactants including polysorbate 80 from 0-1% and polyoxyl-40-stearate,
thickeners/viscosity agents like sodium carboxymethylcellulose from 0-0.5%,
buffers like sodium citrate from 0-0.45%,
and tonicity agents like glycerin from 0-2.2% (Example 3 Table 8).
Ni also teaches topical ocular formulations comprising 0.2% nintedanib and 10% 2-hydroxypropyl beta cyclodextrin were demonstrated and exemplified (Example 1-2, Page 22 line 24-28, Page 27 line 10-17). Ni teaches the inclusion of additional excipients such as antioxidants, chelating agents, and preservatives (Page 18 lines 21-Page 19 line 2). A chelating agent that is taught to be useful in ophthalmic formulations includes edetate disodium from 0-0.01% (Table 6 and 7, see full document specifically areas cited).
While Ni does not teach the exact claimed values for the nintedanib, castor oil, and cyclic polysaccharide (i.e. 2-hydroxypropyl beta cyclodextrin and sulfobutyl-β-cyclodextrin and alpha-cyclodextrin from 0-14%), sodium carboxymethylcellulose, sodium citrate, and tonicity agent; they are encompassed by the general range taught by the prior art (i.e. nintedanib, castor oil, cyclodextrin) wherein optimization within the taught range is not inventive as a means to attain the desired therapeutic effect absent evidence of criticality for the claimed range, or they overlap (i.e. buffer) where even a slight overlap in range establishes a prima facie case of obviousness and would be obvious to modify the amount to attain the desired therapeutic effect arriving at the overlapping values, absent evidence of criticality or unexpected results for the claimed range. Additionally, Ni exemplifies the concentration of nintedanib at 0.2% (falls within about 0.1% and other claimed values) and 2-hydroxypropyl beta cyclodextrin at 10% generally for topical ocular formulations wherein it would be prima facie obvious to utilize these values for the emulsion for the nintedanib and cyclodextrin with a reasonable expectation of success absent evidence of criticality for these values. As Ni teaches the inclusion of other known excipients such as chelating agents, the inclusion of the taught excipients like chelating agents (i.e. edetate disodium from 0-0.01%) in the formulations (i.e. emulsions) is prima facie obvious with a reasonable expectation of success.
Ni does not expressly teach the inclusion of a polyoxylcastor oil, but Ni does expressly teach the inclusion of emulsifiers/surfactants such as polysorbate 80 and poloxyl-40-stearate.
Shah et al. teaches that known ophthalmic surfactants include polyoxyl-40-stearate, polyoxyl 40 hydrogenated castor oil (Cremophor RH-40), polyoxyl hydrogenated castor oil, polysorbate 80, polyoxyl 35 castor oil, and mixtures thereof in a known preferred ophthalmic range of about 0.01-5% [72].
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate polyoxyl 35 castor oil in the composition as suggested by Shah et al. and produce the claimed invention; as Shah teaches the surfactants to be functional equivalents and the incorporation of a known surfactant for its known purpose either as a simple substitution or as an additional surfactant for an additive effect is prima facie obvious with a reasonable expectation of success as the combination of surfactants are taught by Ni and known in the art as demonstrated by Shah et al. when motivated by pricing, availability, or desired properties of the surfactants used to produce the final product absent evidence of criticality for the specific surfactant, and optimization within the known range for the surfactant 0.01-5% as a means to attain the desired therapeutic profile is prima facie obvious absent evidence of criticality claimed range.
Response to Arguments:
Applicant’s arguments are centered on the assertion that Ni does not disclose or suggest a single formulation with all the components claimed, that there is no motivation to combine to the taught nintedanib formulation and the exemplified amount of nintedanib with 2-hydroxypropyl beta cyclodextrin wherein it must be in one area/example, the assertion of hindsight, that Shah is to brinzolamide which is different than nintedanib and does not address the stability of claimed nintedanib formulation and there is not motivation to select polyoxyl 35 castor oil among the surfactants in Shah which is asserted to be critical, and the assertion for unexpected stability citing to the declaration of Dinh and asserting that is it commensurate in scope with the claims.
This is fully considered but not persuasive.
The assertion that Ni must disclose or suggest a single formulation with all the components claimed and that one must utilize only one example is an argument that the prior art reference must be a single reference containing all the claimed elements and have a singular teaching with a working example to be applicable for obviousness which is not the standard for obviousness. Obviousness is not restricted to a single working example or to a single reference as obviousness may be to a combination of references as addressed in the rejection above. Applicant’s assertion that one cannot utilize the teachings of the reference in two areas of Ni is not persuasive as it is not the standard of obviousness as addressed above and the teachings of Ni are not held soley to the one example when the general teaching is for a compsition comrpsing nintedanib and 2-hydroxypropyl beta cyclodextrin and emulsifiers/surfactants and other excipients wherein optimization within the taught range for these components including the exemplified amounts is prima facie obvious with a reasonable expectation of success.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
As for Applicant’s arguments that Shah is to brinzolamide and not nintedanib , this is not persuasive as It is noted that Shah is presented merely to demonstrate that known ophthalmic surfactants include polyoxyl-40-stearate, polyoxyl 40 hydrogenated castor oil (Cremophor RH-40), polyoxyl hydrogenated castor oil, polysorbate 80, polyoxyl 35 castor oil, and mixtures thereof in a known preferred ophthalmic range of about 0.01-5% [72]; as seen by the limited section cited. Wherein the incorporation of a known surfactant for its known purpose either as a simple substitution or as an additional surfactant for an additive effect is prima facie obvious with a reasonable expectation of success as the combination of surfactants are taught by Ni and Shah absent evidence of criticality for the specific surfactant with the range claimed which has not been presented by Applicant.
With regards for the assertion of unexpected stability citing the declaration of Dinh and asserting that is it commensurate in scope with the claims, this is not persuasive. The declaration merely demonstrates what is to be expected with the formulation of the taught composition comprising the recited components which are not commensurate in scope with the claims and contrary to Applicant’s assertion. Unexpected results requires a comparison to the closest prior art that is Ni which teaches the inclusion of castor oil and emulsifiers/surfactants like poloxyl-40-stearate and the claimed polysorbate 80, which is not present in the declaration and does not demonstrate evidence of criticality for the poloxyl-35 castor oil as asserted by Applicant (MPEP 706.02(e)).
Accordingly, the rejection stands.
Claims 27-39, 43 are rejected under 35 U.S.C. 103 as being unpatentable over Ni et al. (WO 2017/210132) in view of Shah et al. (U.S. Pat. Pub. 2016/0339105).
Rejection:
Ni teaches an ophthalmic composition comprising a multikinase inhibitor including nintedanib. The composition can be an ophthalmic emulsion.
Ni expressly teaches ophthalmic emulsions comprising:
nintedanib (CBT-001) from 0.001-10%,
castor oil from 0-1.25%,
cyclodextrins (cyclic polysaccharides like sulfobutyl-β-cyclodextrin from 0-5%, alpha-cyclodextrin from 0-4%, 2-hydroxypropyl beta cyclodextrin from 0-5%),
emulsifier/surfactants including polysorbate 80 from 0-1% and polyoxyl-40-stearate,
thickeners/viscosity agents like sodium carboxymethylcellulose from 0-0.5%,
buffers like sodium citrate from 0-0.45%,
and tonicity agents like glycerin from 0-2.2% (Example 3 Table 4, Pages 13-16).
Ni also teaches topical ocular formulations comprising 0.2% nintedanib and 10% 2-hydroxypropyl beta cyclodextrin were demonstrated and exemplified (Example 1-2, Page 8, Page 9 Table 1, Page 10). Ni teaches the inclusion of additional excipients such as antioxidants, chelating agents, and preservatives (Page 5 first paragraph). A chelating agent that is taught to be useful in ophthalmic formulations includes edetate disodium from 0-0.01% (Page 11 Table 2, Page 12 Table 3, see full document specifically areas cited).
While Ni does not teach the exact claimed values for the nintedanib, castor oil, and cyclic polysaccharide (i.e. 2-hydroxypropyl beta cyclodextrin and sulfobutyl-β-cyclodextrin and alpha-cyclodextrin from 0-14%), sodium carboxymethylcellulose, sodium citrate, and tonicity agent; they are encompassed by the general range taught by the prior art (i.e. nintedanib, castor oil, cyclodextrin) wherein optimization within the taught range is not inventive as a means to attain the desired therapeutic effect absent evidence of criticality for the claimed range, or they overlap (i.e. buffer) where even a slight overlap in range establishes a prima facie case of obviousness and would be obvious to modify the amount to attain the desired therapeutic effect arriving at the overlapping values, absent evidence of criticality or unexpected results for the claimed range. Additionally, Ni exemplifies the concentration of nintedanib at 0.2% (falls within about 0.1% and other claimed values) and 2-hydroxypropyl beta cyclodextrin at 10% generally for topical ocular formulations wherein it would be prima facie obvious to utilize these values for the emulsion for the nintedanib and cyclodextrin with a reasonable expectation of success absent evidence of criticality for these values. As Ni teaches the inclusion of other known excipients such as chelating agents, the inclusion of the taught excipients like chelating agents (i.e. edetate disodium from 0-0.01%) in the formulations (i.e. emulsions) is prima facie obvious with a reasonable expectation of success.
Ni does not expressly teach the inclusion of a polyoxylcastor oil, but Ni does expressly teach the inclusion of emulsifiers/surfactants such as polysorbate 80 and poluoxy-40 stearate.
Shah et al. teaches that known ophthalmic surfactants include polyoxyl 40 stearate, polyoxyl 40 hydrogenated castor oil (Cremophor RH-40), polyoxyl hydrogenated castor oil, polysorbate 80, polyoxyl 35 castor oil, and mixtures thereof in a known preferred ophthalmic range of about 0.01-5% [72].
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate polyoxyl 35 castor oil in the composition as suggested by Shah et al. and produce the claimed invention; as Shah teaches the surfactants to be functional equivalents and the incorporation of a known surfactant for its known purpose either as simple substitution or as an additional surfactant for an additive effect is prima facie obvious with a reasonable expectation of success, as the combination of surfactants are taught by Ni and known in the art as demonstrated by Shah et al. when motivated by pricing, availability, or desired properties of the surfactants used to produce the final product; and optimization within the known range for the surfactant 0.01-5% as a means to attain the desired therapeutic profile is prima facie obvious absent evidence of criticality for the claimed range.
Response to Arguments:
Applicant's arguments are those presented in Ni (WO 2016/200688) in view of Shah et al. which are addressed above.
Accordingly, the rejection stands.
Conclusion
Claims 27-39, 43 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GIGI GEORGIANA HUANG whose telephone number is (571)272-9073. The examiner can normally be reached Monday-Thursday 9:00-5:00pm.
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/GIGI G HUANG/Primary Examiner, Art Unit 1613
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