DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 12/02/2025, in which claim 1 is amended.
Claims 1-4 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/KR2020/014908, filed on 10/29/2020, which claims foreign priority to KR 10-2019-0138127, filed on 10/31/2019.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 12/02/2025, with respect that claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou, Yeo, and Supper has been fully considered and is persuasive, as the scope of the claim 1 has been amended to limit that the succinic anhydride is added to the dissolved product at a molar ratio of an amine of chitosan to the succinic anhydride of 1:0.35 to 1:0.7.
This rejection has been withdrawn.
The following are new grounds of rejection necessitated by Applicant’s amendment, in which claim 1 is amended to recite wherein the succinic anhydride is added to the dissolved product at a molar ratio of an amine of chitosan to the succinic anhydride of 1:0.35 to 1:0.7.
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.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (Carbohydrate Polymers 2015; PTO-892 12/23/2024), in view of Yeo et al. (ACS Biomater. Sci. Eng. 2017; IDS 04/28/2022) and Supper et al. (Langmuir, 2013; PTO-892 09/11/2025).
Zhou describes recent advances in chitosan thermosensitive hydrogels, which have been developed to form a gel in situ, precluding the need for surgical implantation. These gels offer wide applications in the biomedical field including local drug delivery and tissue engineering. (abstract). These thermosensitive hydrogels have been prepared with chitosan and β-glycerophosphate, which is liquid at room temperature and solidifies into gel as the temperature increases to body temperature (page 534, paragraph 6). The solution behavior, rheological and physicochemical properties, and gelation process of the hydrogel are affected not only by the molecule weight, deacetylation degree, and concentration of chitosan, but also by the kind and concentration of glycerophosphate (abstract). Zhou describes the synthesis of an in situ gelling thermosensitive chitosan/β-glycerophosphate formulation by preparing chitosan and β-glycerophosphate solutions in deionized water, then adding the β-glycerophosphate solution dropwise to the chitosan solution under stirring (page 528, paragraph 1).
The teachings of Zhou differ from that of the instantly claimed invention in that Zhou does not teach succinylated chitosan or adding glucose-6-phosphate.
Yeo discloses a water-soluble chitosan derivative, zwitterionic chitosan (ZWC), which showed anti-inflammatory effects in various in vitro models (abstract). ZWC is synthesized by partial succinylation of chitosan amine groups, and is water-soluble at both acidic and basic pH, unlike unmodified chitosan, which is only soluble at pH lower than 6.5 (page 1854, paragraph 1). Yeo teaches that the unique advantage of ZWC is its water solubility at neutral pH, which increases the availability of ZWC molecules in tissues and helps avoid the foreign body reactions to the water-insoluble precipitates typical of unmodified chitosan (page 1858, paragraph 2). Yeo discloses a method for preparing partially succinylated chitosan (page 1854, paragraph 4) comprising dissolving chitosan in 1% acetic acid (corresponds to step a of claim 1), centrifuging at 4000 rcf, after which the supernatant was collected and freeze dried to obtain an acetate salt form of chitosan (corresponds to step b of claim 1). 400 mg of chitosan acetate was dissolved in 60 mL of deionized water (corresponds to step c of claim 1). Succinic anhydride was added as solid to the chitosan solution 5−10 min under vigorous stirring (corresponds to step d of claim 1). The succinic anhydride was added in an amount to achieve a molar feed ratio of anhydride to amine (An/Am ratio) of 0.7. The pH of the reaction mixture was maintained at 6−6.5 and subsequently increased to 8−9 with NaHCO3 and reacted overnight at room temperature under stirring (corresponds to step e of claim 1). The reaction mixture was dialyzed against water with a MW cutoff of 3500 Da maintaining the pH at 8−9 with 1 N NaOH. The purified ZWC was freeze-dried (corresponds to step f of claim 1).
Supper teaches that thermo-sensitive gelling systems, like chitosan/polyol-phosphate, are candidates with a high potential for the design of biodegradable drug delivery systems (abstract). Supper provides a rheological study of chitosan/polyol-phosphate systems that are thermosensitive gelling systems and investigates the mechanism of the gelation process comparing different chitosan/polyolphosphate systems varying in the chemical structure of the polyol parts of the gelling agents (abstract). Supper teaches that thermosensitive gelling systems are polymeric aqueous solutions of low viscosity at room temperature and undergo a sol/gel transition upon a temperature rise, intrinsically induced by the in vivo parenteral injection (page 10229, paragraph 1). Supper teaches that the solubility of chitosan macromolecules in acidic conditions is ensured by the charge repulsion of amino groups. Upon addition of gelling agents, the phosphate parts neutralize the majority of the positive charges on chitosan. As a result, the charge repulsion between the polymer molecules are reduced, potentially inducing the formation of a gel. The presence of polyol in the structure of a gelling agent prevents or delays the gel formation, the chitosan remains soluble even at physiological pH, in function of temperature (page 10234, paragraph 1). The polyol gelling agent does this by forming a protective layer that remains stable at neutral pH and low temperature, resulting in the reduction of the self-interactions between the chitosan chains, and thus preventing the formation of a macromolecular gel (paragraph bridging pages 10234-10235). Supper compares the effects of β-GP, α-D-glucose 1-phosphate (G1-P), and D-glucose 6-phosphate (G6-P) as representative gelling agents in the formation of thermosensitive chitosan hydrogels (page 10230, paragraph 2). The stability of the polyol protective layer produced by the gelling agent was found to increase in the following order: β-GP < G1-P < G6-P (page 10235, paragraph 2). Furthermore, the sol/gel transition temperature is lower for hydrogels made with β-GP than with G1-P, than with G6-P (page 10235, paragraph 2). G6-P has a sol/gel transition temperature of 38.8 °C in a 0.43 mmol/g solution (paragraph bridging pages 10231-10232). Supper also teaches that whatever the gelling agent, an increase of concentration results in lowering of the gel transition temperature (page 10235, paragraph 3). Similar to β-GP, G1-P and G6-P could neutralize chitosan solutions up to physiological pH while keeping them in the solution state at room temperature and allowing gelation to take place upon heating (page 10236, paragraph 2).
It would have been prima facie obvious to combine the teachings of Zhou, Yeo, and Supper before the effective filing date of the claimed invention by substituting the chitosan and β-glycerophosphate of Zhou with the succinylated chitosan of Yeo and the D-glucose 6-phosphate of Supper to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to substitute the chitosan of Zhou with the succinylated chitosan of Yeo because Yeo teaches that succinylated chitosan offers the unique advantage of water solubility at neutral pH, which increases the availability of the succinylated chitosan in tissues and helps avoid the foreign body reactions to the water-insoluble precipitates typical of unmodified chitosan. One of ordinary skill in the art would have been motivated to optimize the identity of the gelling agent by substituting the β-glycerophosphate of Zhou with the D-glucose-6-phosphate of Supper because Supper teaches that the identity of the gelling agent is a result effective variable which alters the gelation temperature of the thermosensitive hydrogel. Thus the identity of the gelling agent is a result effective variable on the temperature of the sol/gel transition. One of ordinary skill in the art would have a reasonable expectation of success because Zhou teaches a thermosensitive chitosan hydrogel for in vivo use in drug delivery, Yeo teaches a preferable chitosan derivative for in vivo use, and Supper teaches that the D-glucose 6-phosphate was capable keeping chitosan solutions in the solution state at room temperature while allowing gelation upon heating to form hydrogels for use in drug delivery systems.
Regarding instant claim 1 step (a), Yeo does not expressly teach that the step of dissolving chitosan in acetic acid to form chitosan acetate is performed with stirring. However, Yeo teaches that addition of solid succinic anhydride to the reaction mixture was accomplished with vigorous stirring in order to accomplish the reaction. Thus one of ordinary skill in the art would also expect to stir the reaction mixture in which chitosan is reacted with acetic acid in order to accomplish the dissolving of chitosan.
Regarding instant claim 1 step (d), Yeo does not expressly state that the succinic anhydride is added at room temperature. However, Yeo teaches that the succinic anhydride is reacted at room temperature and does not teach that any heating or cooling is required during the synthesis of ZWC. Thus one of ordinary skill in the art would understand that the succinic anhydride is added at room temperature.
Regarding instant claim 1 step (e), MPEP 2144.05(I) teaches that in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists, and that the overlapping endpoint of the prior art and claimed range is sufficient to support an obviousness rejection. Thus, Yeo’s teaching that the pH is adjusted to 8-9 renders obvious the claimed limitation of adjusting the pH to 7-8. Furthermore, although Yeo does not expressly disclose that the pH is adjusted with NaOH , Yeo also suggests that 1N NaOH is a suitable solution for adjusting the pH of the chitosan succinate hydrogel, and thus it would have been obvious that both NaOH and NaHCO3 solutions are suitable for the same purpose of adjusting the pH of the succinylated chitosan reaction mixture, and that the NaHCO3 solution can be substituted for the NaOH solution for addition to the reaction mixture to achieve the predictable result of a pH adjusted solution.
Although the combined teachings of Zhou, Yeo, and Supper do not teach that the mechanical strength of the hydrogel becomes higher as the degree of succinylation decreases, the instant claims do not require any particular degree of succinylation, and the combined teachings of the prior art teach and suggest the instantly claimed method steps, which would provide a hydrogel of the same chemical composition as that of the instantly claimed method, and thereby necessarily have the same property of increasing mechanical strength with increasing degree of succinylation. MPEP 2112.01(II) states that products of identical chemical composition cannot have mutually exclusive properties. Furthermore, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2112(I) states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer."
Response to Arguments
Applicant's arguments filed 12/02/2025 have been fully considered but they are not persuasive.
Insofar as Applicant’s arguments are applicable to the current rejections, Applicant argues that Yeo fails to teach wherein succinic anhydride is added to the dissolved chitosan acetate product at a molar ratio of an amine of chitosan to the succinic anhydride of 1:0.35 to 1:0.7, let alone that such a composition has higher mechanical strength as the degree of succinylation decreases, as recited in amended claim 1 (Remarks, page 6, paragraph 3). This is not persuasive.
As discussed in the above grounds of rejection, Yeo teaches that the succinic anhydride was added in an amount to achieve a molar feed ratio of anhydride to amine (An/Am ratio) of 0.7, which is a molar ratio of an amine of chitosan to the succinic anhydride of 1:0.7. Furthermore, although the combined teachings of Zhou, Yeo, and Supper do not teach that the mechanical strength of the hydrogel becomes higher as the degree of succinylation decreases, the instant claims do not require any particular degree of succinylation. Furthermore, the combined teachings of the prior art teach and suggest the instantly claimed method steps, which would provide a hydrogel of the same chemical composition as that of the instantly claimed method, and thereby necessarily have the same property of increasing mechanical strength with increasing degree of succinylation. A hydrogel made by the same method and having the same chemical composition as that of the instantly claimed hydrogel will necessarily have the same properties. MPEP 2112.01(II) states that products of identical chemical composition cannot have mutually exclusive properties. Furthermore, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2112(I) states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." In addition, Applicant has not demonstrated that the feature of changes in mechanical strength corresponding to changes in degree of succinylation of the hydrogel produced by the instant method is an unexpected result. Thus the combined teachings of Zhou, Yeo, and Supper render obvious the instant claims.
Applicant further argues that one of ordinary skill in the art would not have had a reasonable expectation of success in using glucose-6-phosphate in a method of preparing a succinylated chitosan hydrogel for use in vivo because the cited art fails to teach that adding glucose-6-phosphate to a succinylated chitosan produced using the method of Yeo would result in a succinylated chitosan hydrogel (Remarks paragraph bridging page 8-9). This is not persuasive.
The rejection does not rely on Yeo to teach a hydrogel. Rather, Zhou teaches a thermosensitive chitosan hydrogel for in vivo use in drug delivery. One of ordinary skill in the art would have been motivated to substitute the succinylated chitosan of Yeo because Yeo teaches a preferable chitosan derivative for in vivo use. Regarding glucose-6-phosphate, Supper teaches that both β-glycerophosphate and G6-P are gelling agents suitable for the formation of thermosensitive chitosan systems. Supper teaches that the solubility of chitosan macromolecules in acidic conditions is ensured by the charge repulsion of amino groups. Upon addition of gelling agents, the phosphate parts neutralize the majority of the positive charges on chitosan. As a result, the charge repulsion between the polymer molecules are reduced, potentially inducing the formation of a gel. One of ordinary skill in the art would understand that both chitosan and the succinylated chitosan produced using the method of Yeo are under acidic conditions and both would be suitable for forming these interactions. Thus, one of ordinary skill in the art would have a reasonable expectation of success substituting the chitosan and β-glycerophosphate of Zhou with the succinylated chitosan of Yeo and the D-glucose 6-phosphate of Supper to arrive at the instantly claimed invention.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 12/02/2025.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah Grace Hibshman whose telephone number is (703)756-5341. The examiner can normally be reached Monday-Thursday 7:30am-5:30pm (EST). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached on (571) 270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693