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 .
Response to Amendment
Applicant’s response of 05/19/2025 has been received and entered into the application file. Claims 1, 3-17, and 21-30 are pending in this application.
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.
Claims 1, 3-11 and 13-17, and 21-30 are rejected under 35 U.S.C. 103 as being unpatentable over Hirakura et al. (US 2007/0031503 A1) and Olsson et al. (WO 2017/114867 A1) further evidenced by Choi et al. (Modulation of biomechanical properties of hyaluronic acid hydrogels by crosslinking agents, Society for Biomaterials, 2015).
Hirakura et al. teach a hyaluronic acid modification product comprising hyaluronic acid and a polymer bonded together, the polymer selected from polylactic acid, polyglycolic acid and lactic acid-glycolic acid copolymer which provides a drug carrier encapsulating a low molecular drug efficiently leading to a sustained release of such drug. The hyaluronic acid modification product of the present invention also provides a drug carrier comprising injectable fine particles minimal in agglomeration between the particles, and having excellent biocompatibility (Abstract). Hirakura et al. disclose that HA modification products, which comprise HA and PLA, PGA or PLGA grafted together display excellent safety, biodegradability and in vivo stability ([0010]). The polymer may be bonded to the carboxyl group of hyaluronic acid or its derivative. The polymer may be bonded to the carboxyl group of hyaluronic acid or its derivative by an amide bond via a spacer ([0035]). The drug carrier can be in the form of fine particles such as microspheres or nanospheres. The particle size is not limited, but is preferably 200 micrometer or less; allowing the drug carrier to pass through a needle without clogging the needle ([0051]). A pharmaceutical composition containing the drug carrier and a drug is provided; the composition may further contain one or more polymers selected from PLA, PGA, or PLGA. The drug may be encapsulated in fine particles formed by the hyaluronic acid modification product ([0052]). The polymer can be introduced by using a condensing agent such as DMTMM or EDC or NHS. The polymer can be introduced after converting the terminal carboxyl group of the polymer into a highly reactive ester or amide ([0055]). The HA and the polymers are covalently-bonded ([0109]). Furthermore, when HA or its derivative and the polymer are bonded, they may be bonded via a spacer portion in order to help control bonding. The HA derivative may contain the spacer portion for bonding to the polymer. The spacer portion having a hydrazide group or an amino group can be introduced, for example, by reacting a compound having a plurality of amino groups (dihydrazide, diamine, hydrazine compound or the like) with the carboxyl group of the glucuronic acid portion in hyaluronic acid ([0109]). The surface of carboxylic acids of the PLGA microspheres obtained in Example 1-2 were activated using EDC and NHS in phosphate buffer (pH 5.8) ([0196]).
Hirakura et al. do not explicitly disclose diaminotrehalose (DATH) as a crosslinker.
Olsson et al. teach a hydrogel product comprising glycosaminoglycan molecules as the swellable polymer, wherein the glycosaminoglycan molecules are covalently crosslinked via crosslinks comprising a spacer group selected from the group consisting of di-, tri-, tetra-, and oligosaccharides (Abstract). Olsson et al. disclose a process of preparing a hydrogel product comprising the steps of: (a) providing a solution of glycosaminoglycan molecules; (b) activating carboxyl groups on the glycosaminoglycan molecules with a coupling agent to activate the molecules; (c) crosslinking the activated glycosaminoglycan molecules via their activated carboxyl groups using a di- or multi-nucleophile functional crosslinker (pages 4-5). Olsson teaches that the process may be performed in a one-pot approach in aqueous media, involving the covalent coupling of di- or multi-nucleophile functional crosslinker directly to inherent carboxylic acid groups on the native GAGs using a suitable coupling agent (page 23). The preferred coupling agent is DMTMM or EDC combined with NHS (page 6, lines 20-30). Olsson et al. disclose in example 2, crosslinking of HA with diaminotrehalose (DATH). DATH was added to the DMTMM. The pH of the DMTMM-solution was adjusted to 6-7 and then added to the HA (pg 32, Example 2). Olsson teaches that crosslinking of the GAG molecule may be achieved by activation with a coupling agent, followed by reaction with a crosslinking agent. The GAG molecule concentration and the extent of crosslinking affect the mechanical properties, e.g., the elastic modulus G’, the stability properties, of the gel. The degree of modification of GAG molecule gels generally ranges between 0.01 and 15 mole %; the degree of modification (mole %) describes the amount of crosslinking agent that is bound to the GAG molecule, i.e., molar amount of bound crosslinking agent relative to the total molar amount of repeating disaccharide units (page 16). Therefore, one of ordinary skill in the art would be motivated to experiment with various mole % of crosslinking agent bound to GAG molecule. The amended limitation of “wherein the crosslinked hyaluronic acid hydrogel comprises the di- or multi-nucleophilic functional crosslinker in an amount of 0.1-10 mol %” is taught by Olsson. Likewise, the concentration of GAG molecule and the extent of crosslinking would alter the mechanical properties such as the elastic modulus G’.
Choi further reinforces this concept by teaching that modulation of both mechanical properties and bio-compatibilities of hyaluronic acid hydrogels is very important. Pure HA solution was converted into a hydrogel by using butanediol diglycidyl ether (BDDE) as a crosslinking agent. The mechanical properties of the obtained HA hydrogels were evaluated by measuring their crosslinking degrees, elastic modulus (Abstract). The experimental results indicated that increased amounts of BDDE led to increased elastic modulus (page 3075, right Col, last paragraph). Therefore, one of ordinary skill in the art would recognize that modifying elastic modulus for HA hydrogels is routinely practiced.
Hirakura et al. teach a method of manufacturing a composition comprising a crosslinked HA with solid particles such as PLA, PGA, or PLGA; the composition can be activated with DMTMM or EDC/NHS as discussed above. Olsson et al. teach that a hydrogel product comprising HA with DMTMM and DATH can be used as injectable formulations for corrective and aesthetic treatments (See page 24). 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 or Hirakura et al. with Olsson et al. 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. The resulting composition would comprise embedded solid particles by mixing a crosslinker, a coupling agent, polymers, and hyaluronic acid as discussed above.
Regarding claims 3-5, polylactic acid polymers are discussed above.
Regarding claims 6-7, one of ordinary skill in the art would, through routine experimentation, experiment with porous or non-porous insoluble solid polymers. And it would have been obvious to do so in this case.
Regarding claim 8, Hirakura et al. teach preparation of PLGA microspheres wherein the PLGA7510 was dissolved to prepare a 10% (w/v) solution ([0195)].
Regarding claims 9-10, one of ordinary skill in the art would, through routine experimentation, experiment with varying sizes of hydrogel compositions for various uses.
Regarding claim 11, Olsson et al. teach that the crosslinked molecule is present in the form of gel particles with an average size in the range of 0.01-5 mm (page 18, lines 29-31).
Regarding claim 13, Olsson et al. teach that the crosslinked gel is sterilized (pg 25, lines 10-12).
Regarding claim 14, Olsson et al. teach that the resulting material is treated with heat (pg 36, line 5).
Regarding claim 15, pre-activating is discussed above.
Regarding claims 16-17, carboxyl groups grafted via amide bonds are discussed above.
Regarding claims 21-22, triazine-based coupling agent is discussed above.
Regarding claim 23, hydrogel embedded with the solid particles is discussed above.
Regarding claim 24, crosslinking via amide bonds is discussed above. Olsson teaches the crosslinked GAG molecules have an average size in the range of 0.01-5 mm (Claim 17). Olsson teaches that the invention relates to the field of hydrogels containing crosslinked polysaccharides (page 1, lines 3-4). A combination of teachings of Hirakura and Olsson would arrive at a composition comprising solid particles embedded within gel particles.
Regarding claim 25, Olsson et al. teach a hydrogel product is in the form of an injectable formulation (Claim 8).
Regarding claim 26, the crosslinker concentration in mol % is discussed above. Furthermore, Olsson discloses various mole % of crosslinkers (Table 2).
Regarding claim 27, the elastic modulus for a HA hydrogel can be routinely altered as discussed above. Olsson discloses elastic modulus of 1.6 and 1.5 kPa (Table 3).
Regarding claims 28-30, elastic modulus can be changed depending on the concentrations of hyaluronic acid and crosslinker.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Hirakura et al. (US 2007/0031503 A1) and Olsson et al. (WO 2017/114867 A1) further evidenced by Choi et al. (Modulation of biomechanical properties of hyaluronic acid hydrogels by crosslinking agents, Society for Biomaterials, 2015) as applied to claim 1-11 and 13-30 above, and further in view of Smith et al. (Hyaluronic acid dermal fillers: can adjunctive lidocaine improve patient satisfaction without decreasing efficacy or duration? Dovepress, 2011).
Smith et al. teach that HA dermal fillers are the most widely used injectables to augment facial volume without surgery. Adjunctive lidocaine significantly decreased pain during injection and post-injection with corresponding increased patient satisfaction (Abstract). Several studies that examined and compared HA fillers with and without lidocaine revealed significantly less pain and, in some, less erythema, swelling, and bruising with adjunct lidocaine (pg 135, right col, Studies comparing outcomes of HA fillers with and without lidocaine section).
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 added lidocaine into hydrogel compositions taught by Hirakura et al. and Olsson et al. to reduce pain and improve patient outcomes. 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.
Response to Arguments
Applicant’s arguments filed 05/19/2025 have been fully considered but they are not persuasive.
On page 6 of remarks, applicant argues that Olsson does not teach “a one-pot approach in aqueous media”.
The instant application’s method is as follows – hyaluronic acid, water-insoluble solid particles (one or more polymers, preferred is polylactic acid), a crosslinker, and a coupling agent is mixed in a one-pot process.
Olsson discloses that the process may be performed in a one-pot approach in aqueous media, involving the covalent coupling of di- or multi-nucleophile functional crosslinkers directly to inherent carboxylic acid groups on the native GAGs using a coupling agent (pg 23). The paragraph that follows this teaching states that the process for generating the crosslinked hydrogel typically involves preparing a mixture of GAG molecule, such as hyaluronic acid together with a crosslinker agent and coupling agent (pg 24). One of ordinary skill in the art would immediately envisage that the mixing of these ingredients could be done in a one-pot process.
Hirakura discloses that hyaluronic acid and a polymer such as polylactic acid can be bonded together as discussed in the Non-Final Rejection of February 21st, 2025. Furthermore, Hirakura teaches that mixing polylactic acid and hyaluronic acid is routinely practiced in the art (See claims 33, 34, 38, 41). One of ordinary skill in the art would immediately envisage that any of routine polymer with hyaluronic acid could be used in the process taught by Olsson.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615