DETAILED ACTION
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/10/2025 has been entered.
Status of Application
The response filed 10/10/2025 has been received, entered and carefully considered. The response affects the instant application accordingly:
Claims 27 have been amended.
Claim 43 has been added.
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had previously elected Group I in response to restriction requirement for the examination, and claims 40-42 are withdrawn being drawn to a non-elected invention.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 .
Applicant has filed a terminal disclaimer to U.S. Patent No. 11666533 and copending Application No. 17/272105 on 10/10/2025.
The double patenting rejections to U.S. Patent No. 11666533 and copending Application No. 17/272105 no 10/10/2025 are withdrawn as a result of approved on 10/10/2025.
All grounds not addressed in the action are withdrawn as a result of amendment or terminal disclaimer.
New grounds of rejection are set forth in the current office action.
Current 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 there is not motivation to select polyoxyl 35 castor oil among the 14 surfactants taught in Shah; and the assertion that the instant claims are commensurate in scope with the showing of for the nanoemulsion composition of nintedanib with 10% 2-hydroxypropyl beta-cyclodextrin, 0.25% castor oil, 1% polysorbate 80, and 2% polyoxyl-35-castor oil which presents with a maximum solubility of 7.9mg/g that Applicant cites as synergy compared to the theoretical solubility of 2.91 mg/mg for the mixture in the specification.
This is fully considered but not persuasive.
As addressed above, Ni teaches the inclusion of various emulsifiers/surfactants such as polysorbate 80 and poloxyl-40-stearate and Shah establishes that known emulsifiers/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; 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 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 with the range claimed which has not been presented by Applicant.
As for the assertion that the claims are commensurate in scope with the showing of synergy in the specification, this is not persuasive. The showing is for the nanoemulsion composition with a maximum solubility of 7.9mg/g of nintedanib - wherein the nanoemulsion composition contains 0.79% nintedanib (7.9mg/g =0.79%), 10% 2-hydroxypropyl beta-cyclodextrin, 0.25% castor oil, 1% polysorbate 80, and 2% polyoxyl-35-castor oil; which is significantly greater than the theoretical solubility of 2.91 mg/mg for the mixture of nintedanib, 2-hydroxypropyl beta-cyclodextrin, castor oil, polysorbate 80, and polyoxyl-35-castor oil which is unexpected (synergy). Unexpected results must be commensurate in scope with the claimed invention to overcome a prima facie case of obviousness, and the instant claims are not commensurate in scope with this showing as they are significantly broader wherein they are not commensurate in scope with this showing.
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.
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/GIGI G HUANG/Primary Examiner, Art Unit 1613