DETAILED ACTION
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 .
Claims 1-9, 11-16, 18, 26, and 28-30 are pending in the application.
Election/Restrictions
Applicant’s election of Group I, claims 1-9, 11 and 12 in the reply filed on August 25, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 13-16, 18, 26, and 28-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 25, 2026.
Claims 1-9, 11-16, 18, 26, and 28-30 are pending in the application. Claims 13-16, 18, 26, and 28-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions. Claims 1-9 and 11-12 will presently be examined to the extent they read on the elected subject matter of record.
Priority
This application is a National Stage Entry of PCT/SG2022/050473 filed July 7, 2022, which claims benefit to Singapore Foreign Application No. 10202108149Q filed July 26, 2021 and Singapore Foreign Application No. 10202112107V filed October 29, 2021.
Information Disclosure Statement
Receipt of Disclosure Information Statements filed January 19, 2024 and May 5, 2025 is acknowledged.
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.
Claim 2 is 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 2 recites the anti-angiogenic agent as claimed in claim 1, wherein the copolymer comprises at least urethane/carbamate linkage(s) and/or allophanate linkage(s). It is unclear from the recitation if the “at least urethane/carbamate linkage(s)” comprises a combination of urethane and carbamate or urethane or carbamate. In reviewing the original specification, the examples indicate a “urethane linkage”. Applicant should clarify the meaning of “at least urethane/carbamate linkage(s)”. For compact prosecution, claim 2 is being interpreted as “urethane or carbamate linkage(s).
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 4, 8, 9, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by the Xue Publication (2019, Biomaterials Science, Xue et al.). The Xue Publication cited by Applicant on the IDS dated January 19, 2024.
Regarding claims 1, 2, and 4, Xue et al. disclose block copolymers of PEG-PPG-PCL (EPC) linked together by urethane bonds were synthesized. The copolymer was composed of a hydrophilic PEG group, a hydrophobic PPG group and a biodegradable PCL. Xue et al. disclose the polymers at PEG/PPG ratios of 6:1, 4:1, 2:1, 1:1(multi-block copolymer first poly(alkylene glycol) block, PEG; second poly(alkylene glycol) block (PPG); polycaprolactone (PCL) with a urethane linkage) (page 4607, col. 2, Results, 3.1 Polymer synthesis and characterization, paragraph 1).
Regarding claim 1, Xue et al. disclose the multiblock polymers are formulated into hydrogels by an increase in temperature and formation of a bridged micelle network (see Fig. 1B) (PEG-PPG-PCL micelles). With an increase in PEG/PPG ratio, there is an increase in hydrophilicity. This leads to a decrease in hydrophobicity of the micelle core and consequent destabilization of both micelle and thermogel formation, and an increase in sol-to-gel transition temperature (page 4607, col. 2, Results, 3.1 Polymer synthesis and characterization, paragraph 2).
Regarding claims 8 and 9, Xue et al. disclose to study the effectiveness of EPC thermogels for protein release, anti-VEGF Aflibercept was encapsulated with EPC thermogels of different compositions at a polymer concentration of 10% (bioactives encapsulated by copolymer micelles; comprises anti-VEGF bioactives) (page 4607, col. 2, Results, 3.2 Turnable release properties of the thermogel, paragraph 1-page 4608, col. 1, bridge paragraph).
Regarding claim 12, Xue et al. disclose that choroid explants are a well-established ex vivo model to test both anti-angiogenic compounds for their effects on vessel outgrowth. The thermogel with or without anti-VEGF was placed in a transwell on top of the choroidal explants. The thermogel depot could release anti-VEGFs in a sustained manner and the released anti-VEGF would diffuse and interact with the choroidal explants. This represents a topical ophthalmic formulation. Xue et al. further disclose the optimized EPC 4:1 thermogel was tested for therapeutic delivery of bioactive anti-VEGF into a persistent retinal neovascularization rabbit model. These rabbit models exhibit VEGF dependent persistent retinal neovascularization, and vascular leakage can be visualized by fundus fluorescein angiography. This vascular leakage can be inhibited for at least 28 days by injection of Aflibercept alone or by injection of 20% thermogel loaded with Aflibercept, and recurrence starts occurring from 35 days onwards (anti-angiogenic agent formulated as a topical ophthalmic formulation) (page 4612, col. 1, 3.4 Therapeutic anti-angiogenesis effects ex vivo and in vivo, first full paragraph 1).
Regarding the limitation in the preamble of an anti-angiogenic agent, the properties possessed by the composition of the instant application, anti-angiogenic agent, would be possessed by the prior art. Xue et al. disclose block copolymers of PEG-PPG-PCL (EPC) linked together by urethane bonds were synthesized that form micelles. Where the claimed and prior art product(s) are identical or substantially identical, the burden of proof is on applicant to establish that the prior art product(s) do not necessarily or inherently possess the characteristics of the instantly claimed product(s), see In re Best, 195 USPQ 430.
Xue et al. meet all the limitations of the claims and thereby anticipate the claims.
Claims 1, 2, 4, and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by the Liu Publication (2019, Nature Biomedical Engineering, Liu et al.). The Liu Publication cited by Applicant on the IDS dated January 19, 2024.
Liu et al. disclose long-term biocompatibility of the polymer endotamponade in rabbit vitrectomy models and its surgical efficacy and biocompatibility in a non-human primate retinal-detachment model (Abstract).
Regarding claims 1, 2, and 4, Liu et al. disclose the developed copolymer thermogel consists of hydrophilic PEG, thermosensitive poly(propylene glycol) (PPG) and hydrophobic, biodegradable poly(ɛ-caprolactone) (PCL) segments linked together via urethane bonds (termed EPC) (multi-block copolymer first poly(alkylene glycol) block, PEG; second poly(alkylene glycol) block (PPG); polycaprolactone (PCL) with a urethane linkage). It serves as a starting material, and specific properties were tailored for ophthalmic use (page 599, col. 1, Results, Synthesis and rheological characterization of the thermogel, paragraph 1).
Regarding claim 1, Liu et al. disclose EPC-7% mostly forms a densely packed gel, with a much lower ‘loose’ micelle concentration, and thus exerts minimal surfactant effect (multi-block copolymer in the form of one or more micelles). With the EPC-7% both retinal structure and function are maintained at 6 months in rabbits and 1 year in NHP, long after the EPC-7% gel is degraded and undetectable for 3-month post-implantation (page 606, col. 2, Discussion, paragraph 2).
Regarding claim 5, Liu et al. disclose the gelation temperature decreases from 27.7˚C to 12.3˚C, over a range of 3 to 12 wt.% EPC concentrations. This allows the EPC thermogel to be injected while the sol-gel transition state for EPC-3% and EPC 7% at 25˚C (polymer concentration in the range of from 0.01 wt.% to 6 wt.%) (page 599, col. 1, Results, Synthesis and rheological characterization of the thermogel, paragraph 2).
Regarding the limitation in the preamble of an anti-angiogenic agent, the properties possessed by the composition of the instant application, anti-angiogenic agent, would be possessed by the prior art. Liu et al. disclose copolymer thermogel consists of hydrophilic PEG, thermosensitive poly(propylene glycol) (PPG) and hydrophobic, biodegradable poly(ɛ-caprolactone) (PCL) segments linked together via urethane bonds that form micelles. Where the claimed and prior art product(s) are identical or substantially identical, the burden of proof is on applicant to establish that the prior art product(s) do not necessarily or inherently possess the characteristics of the instantly claimed product(s), see In re Best, 195 USPQ 430.
Liu et al. meet all the limitations of the claims and thereby anticipate the claims.
Claim Rejections - 35 USC § 102/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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6 and 12 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as being obvious over Loh et al. (US 2020/0276357) as evidenced by the Xue Publication (2019, Biomaterials Science, Xue et al.) and the Liu Publication (2019, Nature Biomedical Engineering, Liu et al.). The Xue Publication and Liu Publication cited by Applicant on the IDS dated January 19, 2024.
Regarding claims 1 and 2, Loh et al. disclose a material comprising a multi-block thermogelling polymer, said multi-block thermogelling polymer comprising a hydrophilic polymer block; a thermosensitive polymer block; and a hydrophobic polymer block, wherein the hydrophilic polymer block, the thermosensitive polymer block and the hydrophobic polymer block are chemically coupled together by at least one of urethane/carbamate, carbonate, ester linkages or combinations thereof, and wherein the material is suitable for use as a vitreous substitute (Abstract; page 2, paragraph 9; page 15, claim 1).
Regarding claims 1 and 4, Loh et al. disclose the polymer is a tri-component multi-block thermogelling polymer which consists of hydrophilic poly(ethylene glycol) (PEG), thermosensitive poly(propylene glycol) (PPG), and hydrophobic biodegradable polyesters such as, but not limited to, biodegradable poly(ε-caprolactone) (PCL) segments linked together via urethane bonds (page 9, paragraph 129).
Regarding claim 3, Loh et al. disclose the one or more hydrophilic blocks, one or more thermosensitive blocks and one or more hydrophobic blocks are mixed in a molar ratio of 1-10:1:0.01-1.5 (page 2, paragraph 25; page 4, paragraph 53; page 6, paragraph 74).
Regarding claim 5, Loh et al. disclose the material comprises about 1% to about 30% w/v of the multi-block thermogelling polymer in an aqueous medium. In various embodiments, the material comprises up to about 30 wt. % of polymer in water/aqueous solution/buffer solution, or from about 1 wt. %, about 2 wt. %, about 3 wt. %, about 4 wt. %, about 5 wt. %, about 6 wt. % (page 4, paragraph 54). The ranges disclosed by Loh et al. is the same as the ranges claimed in claim 5.
Regarding claim 6, Loh et al. disclose the material may have a high-water content of more than about 90%, by weight (page 5, paragraph 55).
Regarding claim 12, Loh et al. disclose a material, polymer or flowable/injectable composition/formulation or biomimetic/synthetic vitreous humour/tamponading agent disclosed herein for use in drug delivery in the eye, stem cell transplantations of the eye, for use in the prevention/prophylaxis of recurrent retinal detachment such as from proliferative vitreoretinopathy or for use in the prophylaxis or treatment of ophthalmological disorders/deteriorations of the eye such as retinal detachment, vitreous hemorrhage, epi-retinal membranes and macular holes (page 7, paragraph 88).
Loh et al. further disclose a method of treating ophthalmological disorders/deteriorations of the eye, the method comprising administering/injecting/infusing/delivering a therapeutically effective amount of the material, polymer or flowable/injectable composition/formulation or biomimetic/synthetic vitreous humour/tamponading agent disclosed herein to a subject/patient in need thereof, wherein the composition/polymer is capable of being resident in the eye and providing support for the retina until treatment is completed (page 7, paragraph 91). It would have been obvious to one of ordinary skill in the art that administering to the subject/patient with an ophthalmological disorder would include topical administration of the material, polymer or flowable composition to the eye or part of the eye, including the retina, without evidence to the contrary, as a person with ordinary skill has good reason to pursue known options within his or technical grasp. Note: MPEP 2141 [R-6] KSR International CO. v. Teleflex lnc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding the limitation in the preamble of an anti-angiogenic agent and the limitation of the formation of micelles, the properties possessed by the composition of the instant application, anti-angiogenic agent, would be possessed by the prior art. Loh et al. disclose copolymer thermogel consists of hydrophilic PEG, thermosensitive poly(propylene glycol) (PPG) and hydrophobic biodegradable poly(ɛ-caprolactone) (PCL) segments linked together via urethane bonds. Where the claimed and prior art product(s) are identical or substantially identical, the burden of proof is on applicant to establish that the prior art product(s) do not necessarily or inherently possess the characteristics of the instantly claimed product(s), see In re Best, 195 USPQ 430.
Further regarding the limitation of the formation of micelles, as evidenced by the Xue Publication and Liu Publication, disclosed hereinabove, compositions comprising the multi-block copolymer, PEG-PPG-PCL linked with urethane bonds form micelles, as evidenced by the Xue and Liu Publications. As such, because the multi-block copolymer of Loh et al. is the exact same as the multi-block copolymer of the Xue Publication and the Liu Publication, Loh et al.’s would have the same properties because compounds and compositions do not change properties.
As such, Loh et al. meet all the limitations of the claims and thereby anticipate and are obvious over the claims
Claims 1, 2, 4, 8, 9, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over the Xue Publication (2019, Biomaterials Science, Xue et al.). The Xue Publication cited by Applicant on the IDS dated January 19, 2024.
Applicant’s Invention
Applicant claims an anti-angiogenic agent comprising: a multi-block copolymer in the form of one or more micelles, wherein the copolymer comprises a first poly(alkylene glycol) block, a second poly(alkylene glycol) block and a polyester block. Applicant claims the one or more bioactive(s) is encapsulated by the copolymer micelles at an encapsulation efficiency of more than 25%.
Determination of the scope of the content of the prior art
(MPEP 2141.01)
The teachings of the Xue Publication (Xue et al.) with respect to the 35 U.S.C. 103 rejection is hereby incorporated and are therefore applied in the instant rejection as discussed above.
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
Xue et al. do not specifically disclose the one or more bioactive(s) is encapsulated by the copolymer micelles at an encapsulation efficiency of more than 25%, as claimed in claim 11.
Finding a prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to use the teachings of Xue et al. and use experimentation and optimization to determine encapsulation efficiency. Xue et al. disclose the multiblock polymers are formulated into hydrogels by an increase in temperature and formation of a bridged micelle network. Xue et al. disclose to study the effectiveness of EPC thermogels for protein release, anti-VEGF Aflibercept was encapsulated with EPC thermogels of different compositions at a polymer concentration of 10%. It would have been obvious to one of ordinary skill in the art to use the teachings of Xue et al. to determine the amount of result effective bioactive and copolymer micelles to use as a matter of routine optimization. The adjustment of particular conventional working conditions (e.g., determining result effective amounts of the ingredients beneficially taught by the cited references) is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results. As such, the skilled artisan would have been motivated to use the teachings of Xue et al. as a starting point to determine result effective amounts of bioactive and the encapsulation efficiency, as a person with ordinary skill has good reason to pursue known options within his or technical grasp. Note: MPEP 2141 [R-6] KSR International CO. v. Teleflex lnc. 82 USPQ 2d 1385 (Supreme Court 2007).
Therefore, the claimed invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 1, 2, 4, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over the Liu Publication (2019, Nature Biomedical Engineering, Liu et al.) in view of the Mandal Publication (2017, Journal of Controlled Release, Mandal et al.) and the Zibiao Publication (2012, Biomacromolecules, Zibiao et al.) The Liu Publication cited by Applicant on the IDS dated January 19, 2024.
Applicant’s Invention
Applicant claims an anti-angiogenic agent comprising: a multi-block copolymer in the form of one or more micelles, wherein the copolymer comprises a first poly(alkylene glycol) block, a second poly(alkylene glycol) block and a polyester block. Applicant claims the one or more micelles have a hydrodynamic size of from 1 nm to 100 nm, as claimed in claim 7.
Determination of the scope of the content of the prior art
(MPEP 2141.01)
The teachings of the Liu Publication (Liu et al.) with respect to the 35 U.S.C. 103 rejection is hereby incorporated and are therefore applied in the instant rejection as discussed above.
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
Liu et al. do not specifically disclose the composition one or more micelles have a hydrodynamic size of from 1 nm to 100 nm, as claimed in claim 7. It is for this reason the Mandal Publication and the Zibiao Publication are added as secondary references.
Mandal et al. teach that over the past decade, polymer micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior and posterior segments of the eye (page 96, Abstract). Mandal et al. teach the past decades have witnessed a significant progress in the development of nano-sized (1-200 nm) ocular drug delivery systems (page 97, col. 1, Introductions, paragraph 1).
Zibiao et al. teach the synthesis of hyperbranched amphiphilic polyurethane multiblock copolymers consisting of poly(propylene glycol) (PPG), poly(ethylene glycol) (PEG), and polycaprolactone (PCL) segments as in situ thermogels (Abstract). Zibiao et al. teach that particle size and size distribution were determined by dynamic light scattering (page 3979, col. 1, 2.5 Particle Size Measurements, paragraph 1). Zibiao et al. teach the reversible transition of the micelle solution in particle size was demonstrated. The micelle solution was prepared for the measurement at 25˚C. The hydrodynamic diameter of the micelles increased from 50 nm at 25˚C into much larger value of about 250 nm at 60˚C. Cooling the solution at 25˚C for 30 min resulted in formation of small micelles again (page 3982, col 2, paragraph 2-page 3983, col. 2 and Table 2).
Finding a prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to combine the teachings of Liu et al., Mandal et al. and Zibiao et al. to determine the optimal hydrodynamic size of the one or more micelles. Liu et al. disclose the developed copolymer thermogel consists of hydrophilic PEG, thermosensitive poly(propylene glycol) (PPG) and hydrophobic, biodegradable poly(ɛ-caprolactone) (PCL) segments linked together via urethane bonds (termed EPC). Liu et al. disclose EPC-7% mostly forms a densely packed gel, with a much lower ‘loose’ micelle concentration, and thus exerts minimal surfactant effect. With the EPC-7% both retinal structure and function are maintained at 6 months in rabbits and 1 year in NHP, long after the EPC-7% gel is degraded and undetectable for 3-month post-implantation. It would have been obvious to one of ordinary skill in the art to use prior art teachings to determine the hydrodynamic size of the micelles. Mandal et al. teach the past decades have witnessed a significant progress in the development of nano-sized (1-200 nm) ocular drug delivery systems, the claimed ranges of the instant invention fall within this teaching of Mandal et al. Zibiao teach the preparation of similar thermogels as those taught by Liu et al. that comprise PPG-PEG-PCL segments, linear and hyperbranched wherein the micelles formed at 25˚C fall within the range currently claimed, including 50 nm, 42 nm, 53 nm, and 29 nm. The skilled artisan would have been motivated to use teachings of the prior art that fall within the claimed range to determine the most optimal hydrodynamic size of the micelle that will provide effective treatment of ocular diseases, as a person with ordinary skill has good reason to pursue known options within his or technical grasp. Note: MPEP 2141 [R-6] KSR International CO. v. Teleflex lnc. 82 USPQ 2d 1385 (Supreme Court 2007).
Therefore, the claimed invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Andriae M Holt whose telephone number is (571)272-9328. The examiner can normally be reached Monday-Friday, 8:00 am-4:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at 571-272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ANDRIAE M HOLT/Examiner, Art Unit 1614
/TRACY LIU/Primary Examiner, Art Unit 1614
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