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 .
Priority
It is acknowledged that present application claims priority to CN202210125983.6 filed 02/10/2022. Further, it is acknowledged that present application is a 371 of international PCT/CN2023/075505 filed 02/10/2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/08/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the references included have been considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-2, 5-7, 10-11, and 13-16 in the reply filed on 09/15/2026 is acknowledged.
Claims 17-20 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-2, 5-7, 10-11, and 13-16 are pending and under current examination.
Claim Objections
Claim 6 is objected to because of the following informalities: it s. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: it should read as , for clarity. Appropriate correction is required.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 2, 5-7, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Valle (WO 2021233967 A1) in view of Super (US 20100215702 A1), in view of Pan et al. (Sensors and Materials, 2019, 31(2), 311-318), hereinafter Pan, in further view of Lee (KR 102094407 B1; see machine translation retrieved 09/22/2026).
Rgearding claims 1 and 5, Valle teaches an injectable composition containing polycaprolactone (PCL) microparticles (see claim 1) suspended in sodium carboxymethylcellulose (i.e. CMC-Na, see claim 7). Valle describes that the PCL microspheres are irradiated at 15, 20, and 25 kGy irradiation by gamma irradiation for sterilization (pg. 40, line 21). Further, Valle teaches that the microspheres are small spherical particles, with a size range from 0.1-200 µm (pg. 7, line 12). The range of the irradiation dose of instant claims 1 and 5 overlaps with that disclosed in Valle, and the average particle size of the microspheres described in instant claim 1 is fully encompassed with the range described in Valle. As such these ranges are obvious. See MPEP § 2144.05(I).
While Valle teaches the claimed invention as above, it fails to teach the weight-average molecular weight of the PCL microspheres, or that the microspheres have a smooth surface. Super teaches a process for preparing PCL-comprising microparticles, that are used in a biocompatible gel (para. [0001]). Super describes that the microparticles have a diameter between 5-200 µm, and are spherical with smooth surfaces (see claim 27), teaching that essentially spherical microspheres (i.e. roundness closer to 1.0) with smooth surfaces, lead to good injectability of the particles (para. [0090]). Further, Super discloses that the microparticle can have a low molecular weight that is between 1,000 and 50,000 Mn (number average molecular weight, para. [0014]), describing that this molecular weight exhibits a shorter resorption time (para. [0043]). Pan teaches a method of preparing polycaprolactone microspheres for medical applications (see abstract). Pan discloses that the PCL microspheres have a weight-average molecular weight of about 14,000, and a number average molecular weight of 10,000 (pg. 313, line 9). The molecular weight described in instant claim 1 overlaps with that of Pan, and as such is obvious. MPEP § 2144.05(I).
Valle, Super, and Pan are considered to be analogous to the claimed invention because they are in the same field of compositions that comprise PCL microspheres. One of ordinary skill in the art would be motivated to optimize the surface morphology of the microspheres of Valle, to have smooth surfaces for the benefit of improved injectability of the particles, as taught in Super. MPEP § 2143(I)(g). Further, a person of ordinary skill in the art would be motivated to optimize the weight-average molecular weight of the PCL microspheres of Valle to have a molecular weight that overlaps with that of Pan. Pan teaches PCL microspheres that are effective in biological applications, and while Valle does not disclose weight-average molecular weight of the microspheres, one of ordinary skill in the art would be motivated to incorporate the molecular weight of Pan into the microspheres of Valle, since Pan teaches that this molecular weight is effective for PCL microspheres that have biological applications. MPEP § 2143(I)(a).
Regarding claims 1 and 2, while Valle, Super, and Pan teach most elements of the claimed invention, and each teach that the microparticles are spherical, they fail to disclose the roundness measurement of the particles as recited in instant claims 1 and 2. Lee teaches an injectable hydrogel with PCL microspheres (para. [0030]) that are combined with carboxymethylcellulose (para. [0070]). The microparticles of Lee are used in cosmetic applications (para. [0043]). Lee teaches that the microparticles can be spherical, with a sphericity (i.e. roundness) of 0.95 or more (para. [0042]). The roundness disclosed in instant claims 1 and 5 is fully encompassed by the range taught in Lee, and as such are obvious. MPEP § 2144.05(I).
Valle, Super, Pan, and Lee are considered to be analogous to the claimed invention because they are in the same field of PCL microspheres that have biological applications. One of ordinary skill in the art at the time of the effective filing date would be motivated to optimize the sphericity of the PCL microspheres of Valle, because as above Super teaches that spherical microparticles have good injectability. Optimizing or maximizing the morphology of the particles of Valle, to be more spherical and have a sphericity within the range disclosed in Lee would allow for improved injectability of the microspheres, as taught in Super above. MPEP § 2143(I)(g).
Regarding claim 6, Valle defines that the average particle size (D10) implies that 90% by volume of particles have a larger particle size than the D10-value (pg. 9, line 20) and the average particle size (D90) implies that 90% of the particles have a smaller diameter than the D90-value (pg. 9, line 28). Valle teaches that the D10-value of the microspheres can be 10 µm (pg. 10, line 6), while the D90-value is 50 µm (pg. 10, line 14). Therefore, 90% (i.e. ≥ 65%) of the microspheres of Valle have particle size between 10 µm and 50 µm, overlapping with the range disclosed in instant claims 1 and 6. Further, this teaches that less than 10% (i.e. ≤ 20%) of microspheres have a particle size that is less than 10 µm. The size distribution of microspheres recited in instant claim 6 overlaps with that disclosed in Valle, and as such is obvious. MPEP § 2144.05(I).
Regarding claim 7, as above, Valle teaches that the D90-value implies that 10% (i.e. ≤ 15%) of the particles have a larger diameter than the D90-value. Valle discloses that the microparticles can have a D-90 value of 50 µm (pg. 10, line 14), therefore less than 10% of the particles have a greater diameter than 50 µm.
Regarding claim 16, Valle teaches that a syringe can be used to administer the composition (pg. 34, line 28). While Valle does not explicitly state that the syringe is sterilized, it teaches that injectable compositions need to be sterilized prior to administration (pg. 29, line 7), and as such it would be obvious that the apparatus to administer the composition (i.e. syringe) should also be sterilized so that the composition is not contaminated directly before administration.
Claim(s) 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Valle (WO 2021233967 A1) in view of Super (US 20100215702 A1), in view of Pan (Sensors and Materials, 2019, 31(2), 311-318), in further view of Lee (KR 102094407 B1), as evidenced by Natarajan et al. (Journal of Pharmaceutical Sciences, 2011, 100, 195-205), hereinafter Natarajan.
Regarding claims 10 and 11, Valle teaches an example of microspheres that were measured, where the D10-value was 41.19 µm, the D50-value was 68.01 µm, and the D90-value was 113.89 µm (see example 2, pg. 39). Valle further teaches an example where the D10-value measured for the microspheres was 4.54 µm, D50-value was 11.16 µm, and the D90-value was 33.94 µm (see example 4, pg. 40).
Natarajan teaches an injectable composition comprising polycaprolactone microspheres for pharmaceutical administration (see abstract). Natarajan reports polydispersity index (PDI) values for the microspheres, teaching the PDI formula that is used. The PDI values of Natarajan were calculated using the generic polydispersity index formula, where PDI = (D90-D10)/(D50) (pg. 197, line 14). While primary source Valle does not explicitly state the polydispersity index (PDI) values of the PCL microspheres, the known PDI formula, as evidenced by Natarajan, can be used to calculate the PDI for both example 2 and example 4 of Valle. Examples 2 and 4 of Valle are found to have PDI values of 1.07 and 2.63, respectively. The PDI values that can be calculated of Valle teach a range that overlaps with that of instant claims 10 and 11. As such, the ranges of polydispersity indexes disclosed in instant claims are obvious. MPEP § 2144.05(I).
Valle, Super, Pan, Lee, and Natarajan are considered to be analogous to the claimed invention because they are in the same field of PCL microspheres. One of ordinary skill in the art would be motivated to utilize the generic PDI formula disclosed in Natarajan to determine the PDI values of Valle, and arrive at the narrower range disclosed in instant claims 10 and 11.
Claim(s) 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Valle (WO 2021233967 A1) in view of Super (US 20100215702 A1), in view of Pan (Sensors and Materials, 2019, 31(2), 311-318), in further view of Lee (KR 102094407 B1), as evidenced by Sarigöl et al. (Pharm Dev Technol, 2017, 22(6), 706-714), hereinafter Sarigöl.
While Valle, Super, Pan, and Lee teach the claimed invention, and Valle teaches the gamma-irradiation doses that the microspheres are exposed to for sterilization, they fail to disclose the change in roundness of the microspheres following this radiation.
Regarding claims 13 and 14, Sarigöl evaluates gamma-sterilization effects on the physicochemical characterization of PCL microspheres (see abstract). Sarigöl teaches that microspheres were irradiated with a dose of 25 kGy, stating this level of radiation is adequate for the purpose of sterilized pharmaceutical products when the bioburden is not known (pg. 707, col. 2 line 37). Sarigöl further describes that gamma-sterilization did not have any influence on the physical morphology of the PCL formulations (i.e. shape and roundness, pg. 710 col. 2 line 10).
Valle, Super, Pan, Lee, and Sarigöl are considered to be analogous to the claimed invention because they are in the same field of preparing PCL microspheres that are used in medical applications. As above, the microspheres of Valle were exposed to the same levels of gamma-radiation for sterilization, as the microspheres of Sarigöl. As such, since the PCL microspheres of Sarigöl did not have any effect on their morphology following the irradiation, then the same level of gamma-radiation would also not have an effect on the morphology (i.e. shape and roundness) of the microspheres of Valle. If the roundness of microspheres is unchanged following irradiation, the change in roundness is 0 (i.e. ≤ 3.5% and ≤ 2.5%).
Claim(s) 15 is rejected under 35 U.S.C. 103 as being unpatentable over Valle (WO 2021233967 A1) in view of Super (US 20100215702 A1), in view of Pan (Sensors and Materials, 2019, 31(2), 311-318), in further view of Lee (KR 102094407 B1), as evidenced by Kalhapure (US 20210251903 A1).
While Valle, Super, Pan, and Lee teach the claimed invention as above, and Valle teaches that the sterile composition can comprise CMC-Na gel, it does not explain that the CMC-Na gel is sterilized specifically by means of a moist heat sterilization method.
Regarding claim 15, as above, Valle teaches that injectable compositions need to be sterilized prior to administration (pg. 29, line 7), and as such it would be obvious that each component in the composition would be sterilized. Further, Valle describes that the composition has suspending agents such as sodium carboxymethylcellulose (i.e. CMC-Na gel, see claim 7). Kalhapure teaches a sterile aqueous slurry comprising sodium carboxymethylcellulose (CMC-Na gel, see claim 5) that is injectable (see claim 8). The aqueous solution is sterilized by moist heat sterilization, where the potency of the bioactive agent is not reduced by the moist heat sterilization (see claim 13).
Valle, Super, Pan, Lee, and Kalhapure are considered to be analogous to the claimed invention because they are in the same field of sterile compositions that are safe to be administered via injection. One of ordinary skill in the art would be motivated to incorporate the moist heat sterilization method of Kalhapure, to sterilize the CMC-Na gel of Valle. As above, Valle teaches that injectable compositions need to be sterile prior to administration. As such, a person of ordinary skill in the art would be motivated to sterilize the CMC-Na gel using moist heat sterilization, as Kalhapure teaches that this method does not reduce the potency of the bioactive agents. MPEP § 2143(I)(g).
Conclusion
Claims 1-2, 5-7, 10-11, and 13-16 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Makenna Miller whose telephone number is (571)272-9852. The examiner can normally be reached Mon-Fri 7:30-5:00 EST.
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/M.R.M./Examiner, Art Unit 1611
