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 .
This action is in response to the amendment received on July 2nd, 2026
Any objections or rejections not reiterated below are hereby withdrawn.
Claims 1-12 have been withdrawn. The applicant has cancelled claims 16 and 18.
Claims 13, 17, and 19-24 are pending and were examined on the merits.
Withdrawal of Objections and Rejections
Applicant’s arguments, filed July 2nd, 2026, with respect to the objection to claim 20 have been fully considered and are persuasive. The applicant has amended claim 20 to recite “surface expression of CD301b”. The objection to claim 20 has been withdrawn.
Applicant’s arguments, filed July 2nd, 2026, with respect to the rejection of claim have been fully considered and are persuasive. The applicant has amended claim 13 to recite “mixing the crosslinked hyaluronic acid with the exosomes, after the step of dialyzing” in step (d). The rejection of claim has been withdrawn.
Applicant’s arguments, filed July 2nd, 2026, with respect to the rejection of claim 13 under 35 U.S.C. 112(a) have been fully considered and are persuasive. The applicant has amended claim 13 to recite “exosomes derived from human adipose stem cells”. The rejection of claim 13 under 35 U.S.C. 112(a) has been withdrawn.
Applicant’s arguments, filed July 2nd, 2026, with respect to the rejection of claims the rejection of claims 13, 17, and 19-24 under 35 U.S.C. 103 have been fully considered and are persuasive. The prior art reference Son (KR 1020200023613 A) teaches away from using BDDE (1,4-butanediol diglycidyl ether) rather than PEGDMA (glycoldimethacrylate) crosslinkers (comparative example 2, manufacturing examples 1-3, and experimental examples 1 and 2) in an exosome-containing hyaluronic acid nano-hydrogel. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the applicant's amendment and the prior art.
The rejection of claims 14-16 and 18 under 35 U.S.C. 103 is withdrawn, these claims having been cancelled by the applicant.
Pending Objections and Rejections
Specification
The disclosure is objected to because of the following informalities: The following chemical formulas .
Appropriate correction is required.
The use of the term Tween, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 103
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.
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.
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 13, 17, and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Yi et al. (WO 2019088656 A1), abbreviated "Yi".
Claim 13 recites “A method for reducing skin wrinkles, comprising a step of administering to a subject in need thereof a filler composition containing exosomes derived from human adipose stem cells, hyaluronic acid, and 1,4-butanediol diglycidyl ether (BDDE) as active ingredients, wherein a dry weight ratio of the hyaluronic acid:BDDE in the filler composition is 1:0.02 to 0.03”. Claim 17 recites “The method according to claim 13, wherein the hyaluronic acid is crosslinked with BDDE to form a hydrogel”. Claim 19 recites “The method according to claim 13, wherein the filler composition activates anti-inflammatory macrophages”. Claim 20 recites “The method according to claim 19, wherein the filler composition increases surface expression of CD301b, an anti-inflammatory marker, in macrophages”. Claim 21 recites “The method according to claim 19, wherein the filler composition increases fibroblast proliferation and collagen production by activating anti-inflammatory macrophages”.
Yi recites the technical field of their invention: “The present invention relates to a stabilized exosome filler composition, and more particularly, to a filler composition that contains exosome in a hyaluronic acid-based filler composition to increase the stability of the exosome. The present invention also relates to a stabilized exosome filler composition capable of increasing the stability of exosome and adding a cosmetic effect by hyaluronic acid-based filler” (Yi, Description, Technical Field; instant claim 13).
Yi recites the use of crosslinkers, in their invention, including a 1,4-butanediol diglycidyl ether BDDE crosslinker: “The stabilized exosome filler composition of one embodiment of the present invention may further comprise a non-crosslinked hyaluronic acid gel and / or a crosslinked hyaluronic acid gel. The crosslinked hyaluronic acid gel may be prepared by mixing 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis (2,3-epoxypropoxy) butane, 1,4-bisglycidyloxybutane” (Tech Solution, paragraph 7; instant claims 13 and 17)
Yi recites exosomes in a “biological solution”: “As used herein, the term "biological solution " means a liquid solution of biogenic origin, in which the exosome is dispersed, suspended, precipitated, suspended or mixed” (Tech Solution, paragraph 3). Yi defines the term exosome as used in their disclosure: “As used herein, the term " exosome " is intended to mean an exosome that is secreted from cells of various animals, plants, bacteria, fungi, algae and the like, preferably stem cells, (E. G., Exosome-like vesicles) having a nano-sized bezacl structure and a composition similar to exosome” (Tech solution, paragraph 4; claim 13). Yi further recites that the biological solution may be obtained from human adipose stem cells:
“As one example that does not limit the present invention, the biological solution may be a stem cell culture solution. The type of the stem cell is not limited, but may be a mesenchymal stem cell, for example, a fat, a bone marrow, an umbilical cord or a cord blood-derived stem cell, more preferably a fat-derived stem cell. The type of the adipose-derived stem cell is not limited as long as it does not cause a risk of infection by a pathogen and does not cause an immune rejection reaction, but it may be preferably a human adipose-derived stem cell” (machine translation, page 6 of 14, paragraph 4; instant claim 13).
Yi recites an administration mode of the filler composition, implying administration to a subject: “The stabilized exosome filler composition of one embodiment of the present invention is preferably applied in an injectable administration mode. However, it is not limited thereto and does not exclude various methods of administration known in the art” (machine translation, page 6 of 14 line 1 from the bottom, page 7 of 14 lines 1 and 2 from the top; instant claim 13).
Yi recites a method for controlling the condition of mammalian skin, including improvement of skin wrinkles, and skin elasticity improvement, implying administration to a mammalian subject:
“Another embodiment of the present invention provides a cosmetic method for controlling the condition of mammalian skin except for the treatment using the stabilized exosome filler composition. In the cosmetic method of the present invention, conditioning of the skin means improvement of the condition of the skin and / or prevention of the condition of the skin, and improvement of the condition of the skin means visual and / Or a tactile perceptible positive change. For example, improvement of skin condition may be improvement of skin wrinkles, skin regeneration, skin moisturization, skin elasticity improvement, volume increase (for example, volume-up, skin distension, etc.)” (machine translation, page 7 of 14, text lines 6-12 from the top; instant claim 13).
Instant claims 19-21 are distinguished from Yi in that Yi does not explicitly recite the physiological effects of activating anti-inflammatory macrophages (claim 19), increasing surface expression of CD301b, an anti-inflammatory marker, in macrophages (claim 20), increasing fibroblast proliferation and collagen production by activating anti-inflammatory macrophages (claim 21). However, these physiological effects are inherent to the composition disclosed by Yi for controlling the condition of mammalian skin, including the improvement of wrinkles and improvement of skin elasticity. See Appeal 2021-003546 (15/514,651) ("[T]he examiner further finds that the effects of the treatment recited in appellant's claims would be 'inherent' to the 'administration of the same compound to the same patient population for the treatment of the same disease' ... after fully considering the record, we agree with, and adopt examiner's findings and reasoning in support of the obviousness rejection ... we, therefore, affirm."). See also MPEP § 2112.01(II) ("A chemical composition and its properties are inseparable … if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present") (instant claims 19-21).
Instant claim 13 is distinguished from Yi in that Yi does not explicitly recite “a dry weight ratio of the hyaluronic acid:BDDE in the filler composition is 1:0.02 to 0.03” (instant claim 13). However, it is not clear that this ratio recited in instant claim 13 is unexpected over Yi, because Yi does not teach away from this ratio. Therefore, the method recited in claim 13 is considered encompassed by the teachings of Yi without evidence to the contrary. One of skill in the art could use a scale instrument to weigh the hyaluronic acid and BDDE separately. One of skill in the art could compare different gel compositions in terms of exosome stability (Yi, Example 6). Therefore, the weight ratio range of hyaluronic acid: BDDE of 0.001 to 0.05 is obvious to one of skill in the art over the course of routine optimization (instant claim 13).
Please note, since the Office does not have the facilities for examining and comparing Applicants’ methods with the methods (including compositions thereof) of the prior art, the burden is on applicant to show a novel or unobvious difference between the claimed methods and the methods of the prior art (and compositions thereof). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), and “as a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
Claims 13, 17, and 19-24 are rejected under 35 U.S.C. 103 as being unpatentable over Yi (WO 2019088656 A1) as applied to claims 13, 17, and 19-21 above, and further in view of Yi (WO 2019088656 A1), and Lee and Bae (KR 10-2186646 B1), foreign patent document "f" on the information disclosure statement received on March 22nd, 2024, abbreviated "Lee".
Claim 22 recites “The method according to claim 13, wherein the filler composition is prepared by steps of: (a) extracting exosomes from stem cells; (b) crosslinking hyaluronic acid by adding BDDE thereto; (c) dialyzing the crosslinked hyaluronic acid using a dialysis membrane; and (d) mixing the cross linked hyaluronic acid with the exosomes, after the step of dialyzing”. Claim 23 recites “The method according to claim 22, wherein the crosslinking in step (b) is performed at a temperature of 20°C to 60°C for 12 to 36 hours”. Claim 24 recites “The method according to claim 22, wherein the dialyzing in step (c) is performed for 36 to 60 hours”.
As of record above, Yi recites using exosomes secreted from stem cells (Yi, Tech solution, paragraph 4; claim 22 step (a)). Yi recites isolation and purification of exosomes using tangential flow filtration (instant claim 22, step (a)).
As of record above, Yi recites crosslinking hyaluronic acid using BDDE (Tech Solution, paragraph 7; instant claim 22, step (b)). It is within the knowledge of one of skill in the art to perform this step either before or after extracting the exosomes from stem cells, as neither of these two steps (as claimed) depends on the completion of the other (instant claim 22).
Claim 22 is distinguished from Yi, in that Yi does not explicitly recite dialyzing the crosslinked hyaluronic acid using a dialysis membrane (instant claim 22, step (c)). Lee teaches a method of making a cross-linked hyaluronic acid composition in which the cross linker can be BDDE (machine translation page 8 of 17, lines 2-19 from the bottom). Lee recites a crosslinking step, followed by a dialysis stage of removing (more accurately, minimizing the concentration of the unreacted cross-linker included in the cross-linked composition (Summary of Invention, Means to solve the problem, paragraph 7; instant claim 22, steps (b) and (c)). Minimizing the concentration of unreacted cross linker would have been obvious to improve the safety of the composition, by avoiding reaction between the cross-linker and chemicals comprising the body of the subject organism. Therefore, it would have been obvious to one of skill in the art to improve on the method recited by Yi by dialyzing the crosslinked hyaluronic acid (instant claim 22, step (c)). One of skill in the art would have been motivated to perform this dialysis step before adding the exosome, to minimize the possibility of losing exosome during dialysis, for instance through accidental tears in the dialysis membrane or small openings where the membrane is clipped (instant claim 22, steps (c) and (d)). It is within the knowledge of one of skill in the biochemical arts to perform dialysis using a dialysis membrane to change the solvent environment of a polymer, and to select a dialysis membrane that allows the passage of unreacted BDDE, but not the polymer, based on the molecular weight cutoff of the membrane (instant claim 22, step (c)).
Yi recites mixing the exosome prepared in example 2 with hyaluronic acid gel, to prepare a stabilized exosome filler composition (Example 5; instant claim 22, step (d)).
Although neither Yi nor Lee explicitly recite performing the dialysis step for 36-60 hours, this
time range is achievable over routine optimization. One of skill in the art could measure dialysis time
using a timer, and could measure the content of remaining crosslinker by filtering the dialyzed
composition and analyzing the filtrate using an HPLC-MS/MS instrument. The dialysis time could be
optimized to minimize crosslinker content in the dialyzed material, and to be completed upon
equilibration, i.e. when the BDDE concentration in the dialyzed material stabilizes. Therefore, the
dialysis time of 36-60 hours is obvious to one of skill in the art over routine optimization (instant claim
24).
Although Yi does not explicitly recite performing the crosslinking step crosslinking in claim 22 step (b) at a temperature of 20°C to 60°C for 12 to 36 hours, Lee recites that the crosslinking temperature of 22-28 C and reaction time of 12-18 hours (machine translation page 9 of 17, lines 17-21 from the top; instant claim 23). There is motivation to combine the teachings of Lee with those of Yi to obtain guidance for making a BDDE-crosslinked hyaluronic acid gel taught by Yi, of record above (Tech Solution, paragraph 7; instant claim 23). There is a reasonable expectation of success at combining these teachings of Lee with those of Lee, by using a thermometer to measure reaction temperature, and a timer to measure reaction time (instant claim 23).
Yi and Lee are relied upon for the reasons discussed above. If not expressly taught thereby,
based upon the overall beneficial teachings provided by the references with respect to providing the
steps for making and using a filler composition, the adjustments of particular conventional working conditions (e.g., the selection from among known components and determining one or more suitable ranges (amounts, proportions, ratios thereof) in which to provide the method of using a filler composition, is deemed merely a matter of judicious selection and routine optimization which is well
within the purview of the skilled artisan.
From the teachings of Son in view of Lee, the invention as a whole, drawn to a method of
reducing wrinkles using a filler composition as described in Claims 13, 17, and 19-24, would have been
obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, and
one of ordinary skill in the art would have had a reasonable expectation of success in producing the
claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Please note, since the Office does not have the facilities for examining and comparing Applicants’ methods with the methods (including compositions thereof) of the prior art, the burden is
on applicant to show a novel or unobvious difference between the claimed methods and the methods of the prior art (and compositions thereof). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and
In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), and “as a practical matter, the Patent Office is
not equipped to manufacture products by the myriad of processes put before it and then obtain prior
art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685,
688 (CCPA 1972).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 Robert F Spaine whose telephone number is (571)272-9099. The examiner can normally be reached 8:00 AM - 4:00 PM United States Eastern Time, Monday-Friday.
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/R.F.S./Examiner, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655
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