DETAILED ACTION
Claims 1-20 are pending in the instant application.
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
The instant application claims priority to the U.S. Provisional Application Serial No. 63/541256 filed September 28, 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted are in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement was considered by the examiner. Please see attached initialed Forms 1449.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 17 is rejected under 35 U.S.C. 102(a)(1)(a)(2) as being anticipated by Cho et al. (KR 20200048476 A).
Cho discloses crosslinked hyaluronic acid composition wherein the hyaluronic acid and ions are combined and by ion-bonding form a gel (Abstract). The divalent or higher metal cation is aluminum or zinc (pg 2, 3rd to last sentence). The composition is in the form of a gel (pg 2, 2nd to last sentence). Cho discloses a method of preparing a hyaluronic acid hydrogel comprising combining an aqueous cation solution mixed with an aqueous HA solution (pg 1, last 3 lines).
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 1 is rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (KR 20200048476 A), Mojarradi et al. (WO 2019/001784 A1), Woo et al. (WO 2022114478 A1).
Cho discloses crosslinked hyaluronic acid composition wherein the hyaluronic acid and ions are combined and by ion-bonding form a gel (Abstract). The divalent or higher metal cation is aluminum or zinc (pg 2, 3rd to last sentence). The composition is in the form of a gel (pg 2, 2nd to last sentence). Cho discloses a method of preparing a hyaluronic acid hydrogel comprising combining an aqueous cation solution mixed with an aqueous HA solution (pg 1, last 3 lines).
Mojarradi discloses a method of preparing an injectable hydrogel composition comprising the steps: providing an amide crosslinked glycosaminoglycan, swelling the glycosaminoglycan in a solution comprising a divalent cation to form a hydrogel composition (Abstract). Hyaluronic salts with divalent cations are known in the field (pg 1, line 30). The divalent cation is preferably Ca+, Cu2+, Mg2+ and Zn2+. Zn2+ concentration is in the range of 0.01 to 4 mM (pg 4). The term stability, as used herein, is used to denote the ability of the sterilized injectable hydrogel composition to resist degradation during storage and handling prior to use. It is known that the addition of constituents to a glycosaminoglycan, such as hyaluronic acid or hyaluronic acid gel, may affect the stability of said glycosaminoglycan. Stability of a hydrogel composition comprising a glycosaminoglycan can be determined by a range of different methods. Methods for determining stability include, but are not limited to, assessing homogeneity, color, clarity, pH, gel content and rheological properties of the composition. Stability of a hydrogel composition comprising a glycosaminoglycan is often determined by observing or measuring one or more of said parameters over time (pg 13, lines 22-32). One of ordinary skill in the art would immediately envisage that different pH levels can impart varying stability for the hydrogel composition. Mojarradi also discloses general procedure for alkaline hydrolysis – the crosslinked HA can be swelled in 0.25 M NaOH in pH 13 (pg 29, line 16).
Woo discloses a method of producing hyaluronic acid bead gels comprising a reaction step of putting hyaluronic acid in an aqueous alkali solution, adding a crosslinking agent, stirring the reaction (Abstract). Woo discloses that crosslinking hyaluronic acid can be triggered by cations through ionic-bonding (pg 2, 4th to last paragraph).
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to arrive at a method of preparing a hyaluronic acid (HA) hydrogel comprising combining an aqueous HA solution and an aqueous divalent cation solution in alkaline pH levels. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Claims 2-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (KR 20200048476 A), Mojarradi et al. (WO 2019/001784 A1), Woo et al. (WO 2022114478 A1) as applied to claim 1 above, and further in view of Xie et al. (Alginate microfibers as therapeutic delivery scaffolds and tissue mimics, Minireview, 2022) and Gu et al. (US 2014/0113821 A1).
Xie discloses a concise overview of a polysaccharide, alginate, and its’ resultant hydrogel microfibers (Abstract). Xie teaches that polysaccharides, such as alginate, can be mixed with Ca2+ solution in a dropwise manner to form alginate hydrogel microbeads (pg 2104, left col). One of ordinary skill in the art would immediately envisage that when you mix a polysaccharide, such as alginate or hyaluronic acid with carboxyl moieties, with divalent cations in a dropwise manner, microbeads or beads are able to form.
Xie does not explicitly mention stirring during combining.
Gu discloses a method of preparing a hydrogel for delivery of an active agent (Abstract). Gu discloses that polysaccharide-based hydrogel polymers may be formed into a variety of different physical forms – depending on the concentration, addition of a hydrogel solution in a drop-wise manner to stirring aqueous calcium chloride yields the formation of structures ranging from nanofibrous networks to microparticles and larger spherical milli-spheres ([01021]).
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have mixed HA solution and cation solution in a dropwise manner or stirring to create differently shaped hydrogels. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 3, hydrogel bead is discussed above.
Regarding claim 4, Woo discloses that the crosslinking reaction is accomplished by stirring the reaction mixture (Abstract). Stirring or dropwise mixing is taught above.
Regarding claim 5, Gu discloses that a polysaccharide-based hydrogel polymer encapsulating an active agent may be formed, for example, through the addition of the active agent to be encapsulated to a mixture of curdlan (beta-1,3-glucan) in an alkaline solution ([0086]). One of ordinary skill in the art would consider any acidic or alkaline solutions when preparing a polysaccharide-based hydrogel polymer. The alkaline pH level would also include pH of about 12-13.5.
Regarding claim 6, alkaline pH level and stirring are taught above.
Regarding claims 7-8, Mojarradi discloses that the crosslinked material can be swelled in 0.25 M NaOH (pg 29, line 17). Furthermore, one of ordinary skill in the art would adjust the pH of the mixture with a strong base including NaOH.
Regarding claim 9, Mojarradi discloses that the concentration of HA is in the range of 2-50 mg/mL (pg 11, lines 19-23). Stability of a hydrogel composition comprising a glycosaminoglycan can be determined by a range of different methods. Methods for determining stability include, but are not limited to, assessing homogeneity, color, clarity, pH, gel content and rheological properties of the composition. Stability of a hydrogel composition comprising a glycosaminoglycan is often determined by observing or measuring one or more of said parameters over time (pg 13, lines 22-32). Likewise, one of ordinary skill in the art would be motivated to experiment with creating HA hydrogels with different parameters including the concentration of HA. Furthermore, Woo discloses that the concentration of HA may be 0.01 to 0.1% by weight (pg 3, 3rd paragraph).
Regarding claim 10, Cho discloses that the concentration of ions may be 0.01 to 0.1% by weight (pg 3, paragraph 3). Furthermore, Mojarradi discloses that the divalent ion concentration can range from 0.05 to 4 mM (pg 4, line 19).
Regarding claim 11, divalent cations are taught above.
Regarding claims 12-13, Cho discloses that the equivalent ratio of the metal cation of the divalent and the hyaluronic acid may be 1:1 to 1:3 (pg 3, 5th paragraph). As already discussed above, one of ordinary skill in the art would routinely experiment with various concentrations of HA or divalent cation when preparing HA hydrogel. Cho already teaches the concentrations of ions as discussed in claim 10.
Regarding claim 14, Gu discloses crosslinking through ionic interaction via calcium chloride ([0114]). Furthermore, one of ordinary skill in the art would routinely experiment with various salt forms for a divalent cation.
Regarding claim 15, Woo discloses that the reaction step comprises hyaluronic acid or a salt thereof in an aqueous alkali solution (Abstract).
Regarding claim 16, Mojarradi discloses that the molecular weight of a single hyaluronic acid molecule is typically in the range of 0.1-10 MDa, but other molecular weights are possible (pg 6, lines 10-11). Woo teaches that the hyaluronic acid molecular weight can be 1,000 to 10,000,000 Da (daltons) pg 2, 4th paragraph).
Regarding claim 17, divalent cations are taught above.
Regarding claim 18, hydrogel created by the method is taught above.
Regarding claim 19, Mojarradi teaches that the hydrogels are widely used in the biomedical field (pg 1, line 12).
Regarding claim 20, Mojarradi discloses that the hydrogel can be injected (pg 1, line 3).
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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