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 . 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.
Priority
The instant application claims foreign priority to Taiwanese application no. TW111133781 filed
on 09/06/2022. The certified copy of the foreign priority application filed on 09/18/2023 is
acknowledged.
Status of the Claims
The claim amendments and remarks filed on 04/22/2026 is acknowledged. Claims 1, 3, 7, and 20 are amended. Claims 4-6 are cancelled.
Accordingly, claims 1-3 and 7-20 are pending and being examined on the merits herein.
Withdrawn Objections/Rejections
The objection to the drawings is withdrawn in view of the newly filed drawings having sufficient resolution and legibility.
The objection to claims 3 and 30 are withdrawn because the missing commas are now added in
The 35 USC 112(a) rejection over claim 20 is withdrawn because the term “preventing” is now removed from the claim.
The cancellation of claims 4-6 renders the 35 USC 103 rejection over these claims moot.
The 35 USC 103 rejection over Cai in view of Prinz for claims 1-2, 7-9, and 11-13, over Cai in view of Prinz and Karlsson for claim 3, and over Cai in view of Prinz and CN’369 for claim 6 are withdrawn because amended claim 1 now requires all of the limitations that were recited in the now cancelled claims 4-6, and these rejections were applied without addressing all of these limitations. Therefore, the scope of amended claim 1 has changed and requires further search and consideration.
The following grounds of rejection are maintained, amended, and new as necessitated by Applicant’s amendments.
Claim Interpretation
The recited steps (a) and (b) in instant claim 1 are being interpreted as forming the auto-crosslinked structure, and the recited step (c) is being interpreted as sterilizing via steam treatment the auto-crosslinked HA gel based on the instant specification, which states that the manner of steam treatment is not particularly limited to the present disclosure, provided that the steam treatment is sufficient to convert the auto-crosslinked hyaluronic acid particles into sterile, high viscosity auto-crosslinked hyaluronic acid gels and further states that the time of steam treatment is set based on the steam temperature and the required viscoelastic properties of the gel, provided that the auto-crosslinked hyaluronic acid can be converted from a granular form to a gel form which is sterile while maintaining its crosslinked state (see paragraph 0071 pages 17-18).
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, 7-9, and 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (Macromolecules, 2017 in PTO-892 dated 01/27/2026) in view of CN106110369B (in PTO-892 dated 01/27/2026, an English translation is also provided in the PTO-892 dated 01/27/2026 and used as the basis for this rejection) and Prinz et al. (WO2019238954A1 in PTO-892 dated 01/27/2026).
Cai teaches physically cross-linked hydrogels from hyaluronan (hyaluronic acid or HA) prepared by a freeze-thaw technique at low pH (see Abstract). Cai teaches that the effect of the freezing–thawing of HA solutions on the formation of physical cryogels is typical for the processes of noncovalent cryostructuration that takes the advantages of mild fabrication conditions and the absence of organic solvents and toxic cross-linking agents (see Abstract). Cai teaches their neutral HA cryogels possessed enhanced thermostability, resistance to acid decomposition, and enzyme degradation which are essentially important properties for biomaterials (see Abstract). Cai teaches that HA-based hydrogels hold realized and potential applications in many fields, such as in osteoarthritis treatment, postoperative adhesion prevention, wound dressing, scaffolding materials, drug delivery, and tissue repair and regeneration (see right column page 6647).
Cai discloses their cross-linked HA gels were prepared according to section “Preparation of Acidic and Neutral HA Cryogels” right column page 6648. Here, HA solution was prepared by weighing an amount of HA and adding distilled water at 10 mg/mL, which meets the limitations of a colloid containing hyaluronic acid as recited in instant claim 1 (see instant specification paragraph 0040 page 10, which states “The term “colloid of hyaluronic acid or a metal salt thereof” used herein refers to a colloid formed of solid powder or solid flocculent which swells by absorbing liquid solvent. Examples of the liquid solvent include, but are not limited to, distilled water, deionized water, or saline or buffer solutions.”). Furthermore, the pH of the HA solution was adjusted to 1.5 using 1 M HCl, and then the acidified HA solution was frozen at -20 C for a specified duration, which meets the limitation of an auto-crosslinking of the colloid containing hyaluronic acid in an acidic environment as recited in instant claim 1. Furthermore, 1 M HCl converts to 1 N HCl because normality (N) is related to molarity (M) by the equation N = M x n where n is the number of ionizable hydrogen ions. The HCl disclosed in Cai has a n value of 1 therefore 1 M HCl = 1 N HCl.
Cai further discloses that the acidified HA gels were neutralized by immersing in PBS solution (pH 7) for 6 hours and then further immersed in a large amount of distilled water for 30 minutes (see section “Preparation of Neutral HA Cryogels” right column page 6648), which meets the limitation of washing the product as recited in instant claim 9.
Cai further demonstrates in Figure 2 on page 6650 the rheological properties of HA gels obtained by different freezing times of 3, 6, 9, and 12 days. Cai demonstrates that upon heating the gel from 25 C to 90 C at 5 C / min, the gel formed by freezing for 3 days melted whereas the gels formed by freezing for 6 days and 12 days maintained their network architectures even at 90 C until most of the water evaporated (see right column first paragraph page 6649). Cai discloses that HA gels obtained by freezing for 12 days had a denser structure than that of the gel obtained by freezing for 6 days (right column first paragraph page 6649), and that HA gels obtained by a longer freezing duration had a higher “melting” temperature and thus presented higher thermotolerance similar to cryogels obtained from PVA (see right column first paragraph page 6649). Cai teaches that long freezing time positively contributed to the alignment of polymer chains in the unfrozen liquid microphase, thereby promoting the formation of aggregation that led to high thermotolerant cryogels (see right column first paragraph page 6649), which suggests that freezing times longer than the disclosed 12 days may further increase the thermotolerance of the HA gels.
Cai also demonstrates that the molecular size of the HA can affect the rheological properties (see Table S1 and Fig. S2 in supplementary information and left column last paragraph through right column first paragraph page 6650). Here, Cai discloses their HA gel samples had molecular weights of 25000, 480000, 730000, 1040000, and 1160000 as well as intrinsic viscosity values (dL/g) of 7.23, 12.18, 16.55, 21.31, and 23.11 (see Table S1 and Fig. S2 and left column first paragraph page 6648). Cai discloses that higher molecular weight HA is necessary to form the cryogels as lower molecular weights do not have sufficient molecular chains to entangle together (left column last paragraph through right column first paragraph page 6650). Cai discloses that a higher molecular weight of HA appeared to be conducive to a higher gel-fraction yield, suggesting that at the same concentration a larger molecular size promoted the association of molecular chains as junction zones of network in the gel (see right column first paragraph page 6650). Cai discloses in Fig. S2 that gels with molecular weights greater than 730000 displayed a mechanical spectrum of a comparatively strong gel, with its G′ almost independent of frequency and much higher than G″.
While Cai teaches a method of manufacturing an auto-crosslinked hyaluronic acid gel by mixing a hyaluronic acid colloid with 1N HCl at -20 C for 3-12 days, Cai does not teach a hyaluronic acid concentration of about 10-30 wt% as well as the recited step (c) recited in instant claim 1.
CN’369 teaches a medical composite hyaluronic acid dressing and its preparation method (paragraph 0002). CN’369 teaches that their composite comprises a hyaluronic acid (HA) – polyvinyl alcohol (PVA) gel that takes advantage of the strong water absorption and good biocompatibility of hyaluronic acid to provide a moist environment for acne and other skin surface wounds (paragraph 0009).
CN’369 teaches that the amounts in their HA-PVA gel are 15-30% HA and 70-85% PVA (paragraph 0013-0018). CN’369 teaches that their HA-PVA gels are formed by first mixing and dissolving HA and PVA in purified water (paragraph 0045) and then performing several freeze-thaw cycles where the mixed solution is frozen at -20 C for 24 hours and then thawed at room temperature for 12 hours (paragraph 0045).
Prinz teaches a sterile hydrogel composition comprising crosslinked thiol-modified hyaluronan (see Abstract). Prinz teaches that their hydrogel composition is sterile and may be used as a medicine, cosmetic or medical device (page 19 lines 28-29). Prinz teaches that the hydrogel can be implanted by injection (page 19 lines 30-31) and that the hydrogel can be filled in a syringe that is further sterilized (see page 10 lines 23-24). Prinz teaches that the term “sterile” is understood to be a composition complying with the microbiological standards as defined for cosmetic or pharmaceutical products, for example in the United States Pharmacopoeia (USP), and that thermal moist-heat sterilization with an autoclave is a standard method, which comprising subjecting the HA gels to high-pressure saturated steam at 121 C for around 15-20 minutes (see page 17 lines 5-15). Prinz teaches that autoclaving parameters can be optimized such as shorter time periods (1 to 5 minutes) or higher temperatures (130-135C) in order to preserve the molecular weight of the HA molecules in the gels (see page 17 lines 11-20).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the amount of HA to be 15-30% wt HA as disclosed in CN’369 and further sterilizing the HA gel by subjecting the HA gel to high-pressure saturated steam at 121 C for 15-20 minutes as disclosed in Prinz to arrive at the claimed invention.
One of ordinary skill in the art would have made the modification of the HA amount with a reasonable expectation of success because CN’369 provides guidance that this wt% range for HA is suitable for forming a HA gel using a similar freeze-thaw gel formation method as the freeze-thaw method disclosed in Cai.
One of ordinary skill in the art would have made motivated to sterilize the HA gel because Prinz provides further guidance of sterilizing HA gels under certain standards such as USP in order to be used as a medical product.
One of ordinary skill in the art would have reasonable expectation of success to sterilize the HA gel because Cai demonstrates that heating HA gels with longer freezing durations such as 12 days had higher thermostability and thermotolerance.
In regards to instant claim 12, even though the combined teachings described above do not teach a pH range of about 6.3 to about 6.8, MPEP 2144.05 I states that “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close” and “under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0”.
Cai teaches a step of neutralizing the acidic HA gel using a PBS solution of pH 7. Therefore, the pH of 7 taught in Cai is merely close to the recited range in instant claim 12 such that a prima facie case of obviousness exists.
Claim(s) 3 is rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (Macromolecules, 2017 in PTO-892 dated 01/27/2026) in view of CN106110369B (in PTO-892 dated 01/27/2026, an English translation is also provided in the PTO-892 dated 01/27/2026 and used as the basis for this rejection) and Prinz et al. (WO2019238954A1 in PTO-892 dated 01/27/2026), as applied to claim 1 above, and further in view of Karlsson et al. (US20160145357A1 in PTO-892 dated 01/27/2026).
The combined teachings of Cai, CN’369, and Prinz are as described above and teach the method of instant claim 1 as discussed above.
The combined references, however, do not teach wherein step (a) comprises providing the colloid containing hyaluronic acid in a granular form, a stripe form, or a string form.
Karlsson discloses a method for making shaped cross-linked hyaluronic acid products (see Abstract). Karlsson discloses that known soft-tissue augmentation treatments involving implants occasionally suffer from the drawback that the implant, or part thereof, migrates away from the desired site of treatment (paragraph 0011), and that their cross-linked hyaluronic acid product has a shape that restricts the possibility for the product to migrate following implantation into a subject (paragraph 0012).
Karlsson disclose their method involves a step of first (i) providing a hyaluronic acid substrate dissolved in a first liquid medium without any cross-linking, then (ii) precipitating the hyaluronic acid substrate by subjecting it to a second liquid medium comprising an amount of one or more first water-soluble organic solvent(s) giving precipitating conditions for hyaluronic acid without any cross-linking; wherein step (i) and/or step (ii) further comprises arranging the hyaluronic acid substrate in a desired shape (paragraphs 20-21), and finally (iii) subjecting the non-cross-linked precipitated hyaluronic acid substrate in the desired shape to a single cross-linking step (paragraph 0022).
Karlsson discloses that the desired shape can be a particle, a fibre, a string, a strand, a net, a film, a disc and a bead (paragraph 0029). Karlsson discloses that it is important to ensure that cross-linking does not occur until the preferred shape has been attained, and that it is advantageous for obtaining and maintaining a desired shape of the final product, since the shaping of the substrate is not limited by pre-existing cross-links, and all cross-links produced in the third step are directed to maintaining the desired shape of the product (paragraph 0087).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the HA gel forming method as taught in the combined teachings of Cai, CN’369, and Prinz described above by shaping the HA colloid solution into a string form as disclosed in Karlsson before performing the freeze thaw crosslinking step to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make this modification because Karlsson provides guidance of shaping HA gels to avoid implant migration from treatment site and also shaping the HA before crosslinking to not limit the desired shape from pre-existing cross-links.
One of ordinary skill would have a reasonable expectation of success in making this modification because Karlsson provides guidance that the shaping of the HA gel can be performed before any cross-linking step is performed.
Claim(s) 10 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (Macromolecules, 2017 in PTO-892 dated 01/27/2026) in view of CN106110369B (in PTO-892 dated 01/27/2026, an English translation is also provided in the PTO-892 dated 01/27/2026 and used as the basis for this rejection) and Prinz et al. (WO2019238954A1 in PTO-892 dated 01/27/2026), as applied to claim 1 above, and further in view of JP2000191702A (in PTO-892 dated 01/27/2026, an English translation is also provided in the PTO-892 dated 01/27/2026 and used as the basis for this rejection).
The combined teachings of Cai, CN’369, and Prinz are as described above and teach the method of instant claim 1 as discussed above.
The combined references, however, do not teach wherein the product of step (b) has an equilibrium swelling capacity of about 12 to about 30 recited in instant claim 10 as well as one of the recited properties for the HA gel in instant claim 14.
JP’702 teaches a method for producing a molded article having in vivo storage properties, particularly a sheet, which is suitable as a medical material, particular as an adhesion preventing material and a wound covering material (see Abstract). JP’702 teaches that the method comprises freezing and thawing an acidic aqueous solution of HA (paragraph 0009), and that the freezing temperature ranges from -30 C to -10 C (paragraph 0009).
It would have been prima facie obvious before the effective filing date to have modified the HA gel as taught in the combined teachings of Cai and Prinz described above by performing longer freezing times greater than 12 days to form the gel as suggested by Cai to make the HA gel, using a starting HA material having a molecular between 730000-1160000 and intrinsic viscosity values between 1.655-2.311 m3/kg as disclosed in Cai, and preforming the freezing temperature between -30 C to -10 C as taught by JP’702 to arrive at the claimed invention.
One of ordinary skill in the art would have motivated to perform longer duration of freezing times past 12 days because Cai discloses that longer freezing times to form the HA gel resulted in increased thermotolerance which may be beneficial for biomaterial applications.
One of ordinary skill in the art would have a reasonable expectation of success because Cai discloses that gels formed from 12 days of freezing had higher thermotolerance than gels formed from 6 days of freezing.
One of ordinary skill in the art would have been motivated to use a starting HA with the molecular weights of 730000-1160000 because Cai suggests that higher molecular weight HA gels promoted the association of molecular chains as junction zones of network in the gel.
One of ordinary skill in the art would have a reasonable expectation of success because Cai demonstrates that HA gels with molecular weights greater than 730000 displayed a mechanical spectrum of a comparatively strong gel, with its G′ almost independent of frequency and much higher than G″.
One of ordinary skill in the art would have made the modification of performing the freezing temperatures between -30 to -10C with a reasonable expectation of success because JP’702 provides guidance that a freezing temperature ranging from -30 to -10 C is suitable for forming the same HA gel using the freeze-thaw method.
Lastly, the recited equilibrium swelling capacity range recited instant claim 10 as well as the properties for the HA gel disclosed in instant claim 14 would be necessarily present in the HA gel as taught in the combined teachings of Cai, Prinz, CN’369, and JP’702 described above because the combined references teach the same method of producing an HA gel that has the same HA amounts (15-30%), freezing temperatures (-30 to -10 C), reaction times (greater than 12 days), HCl concentration mixture (1 N), steam treatment (121 C for 15-20 minutes), and pH (7) as the HA gels shown in Example 2 Table 2 (paragraph 0094) and Table 13 of the instant specification (paragraph 0126). Furthermore, the combined teachings of Cai, Prinz, JP’702, and CN’369 described above discloses using a starting HA having molecular weights between 730000-1160000 with intrinsic viscosities between 1.655-2.311 m3/kg, which overlaps with the HA used in the instant specification (molecular weight between 983000 to 1121000 and intrinsic viscosities between about 1.7 to about 2.0 m3/kg (see paragraph 0046 on page 12).
The HA gels in Table 2 and Table 13 (Example 2) had a HA content of 14.5 wt% and formed using reaction temperature of -10 C and duration of 14, 21, 28 days, 1 N HCl, 121 C steam treatment for 10-40 minutes, and pH 7. Table 2 and 13 further discloses that HA gels formed with these parameters has the recited properties in the instant claims, and the combined references described above teach all of these parameters to form the HA gel using the same freeze-thaw method.
MPEP 2112 section I recite "[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." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus 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”. Furthermore, MPEP 2112.01 section II recites “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Claim(s) 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (Macromolecules, 2017 in PTO-892) in view of Prinz et al. (WO2019238954A1 in PTO-892), JP2000191702A (in PTO-892, an English translation is provided and used as the basis for this rejection) and CN106110369B (in PTO-892, an English translation is provided and used as the basis for this rejection).
The teachings of Cai are as described above.
The teachings of Cai, however, do not teach an auto-crosslinking HA gel having the properties recited in instant claims 15-20.
The independent teachings of Prinz, JP’702, and CN’369 are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the HA gel disclosed in Cai by performing longer freezing times greater than 12 days to form the gel as suggested by Cai, further sterilizing the HA gel by subjecting the gel to high-pressure saturated steam at 121 C for 15-20 minutes as disclosed in Prinz, using a freezing temperature between -30 C to -10 C as taught by JP’702, and to have an HA content of 15-30% wt as taught by CN’369 as well as using a starting HA material having a molecular between 730000-1160000 and intrinsic viscosity values between 1.655-2.311 m3/kg as disclosed in Cai to arrive at the claimed invention to arrive at the claimed invention.
One of ordinary skill in the art would have made the modification of sterilizing the HA gel with a reasonable expectation of success because both Cai and Prinz teach the use of HA gels for various medical application such as a wound dressing material, and Prinz provides further guidance of sterilizing HA gels under certain standards such as USP in order to be used as a medical product.
One of ordinary skill in the art would have motivated to perform longer duration of freezing times past 12 days because Cai discloses that longer freezing times to form the HA gel resulted in increased thermotolerance which may be beneficial for biomaterial applications.
One of ordinary skill in the art would have a reasonable expectation of success because Cai discloses that gels formed from 12 days of freezing had higher thermotolerance than gels formed from 6 days of freezing.
One of ordinary skill in the art would have made the modifications of performing the freezing temperatures between -30 to -10C as well as forming an HA gel having 15-30% HA with a reasonable expectation of success because JP’702 provides guidance that a freezing temperature ranging from -30 to -10 C is suitable for forming the same HA gel using the freeze-thaw method, and CN’369 also provides guidance that this wt% range for HA is suitable for forming a similar HA gel using the same freeze-thaw gel formation method.
One of ordinary skill in the art would have been motivated to use a starting HA with the described molecular weights because Cai suggests that higher molecular weight HA gels promoted the association of molecular chains as junction zones of network in the gel.
One of ordinary skill in the art would have a reasonable expectation of success because Cai demonstrates that HA gels with molecular weights greater than 730000 displayed a mechanical spectrum of a comparatively strong gel, with its G′ almost independent of frequency and much higher than G″.
Lastly, the properties recited in instant claims 15-19 for the HA gel would be necessarily present in the HA gel as taught in the combined teachings of Cai, Prinz, JP’702, and CN’369 described above because the combined references teach the same method of producing an HA gel that has the same HA amounts (15-30%), freezing temperatures (-30 to -10 C), reaction times (greater than 12 days), HCl concentration mixture (1 N), steam treatment (121 C for 15-20 minutes), and pH (7) as the HA gels shown in Example 2 Table 2 (paragraph 0094) and Table 13 of the instant specification (paragraph 0126). Furthermore, the combined teachings of Cai, Prinz, JP’702, and CN’369 described above discloses using a starting HA having molecular weights between 730000-1160000 with intrinsic viscosities between 1.655-2.311 m3/kg, which overlaps with the HA used in the instant specification (molecular weight between 983000 to 1121000 and intrinsic viscosities between about 1.7 to about 2.0 m3/kg (see paragraph 0046 on page 12).
The HA gels in Table 2 and Table 13 (Example 2) had a HA content of 14.5 wt% and formed using reaction temperature of -10 C and duration of 14, 21, 28 days, 1 N HCl, 121 C steam treatment for 10-40 minutes, and pH 7. Table 2 and 13 further discloses that HA gels formed with these parameters has the recited properties in the instant claims, and the combined references described above teach all of these parameters to form the HA gel using the same freeze-thaw method.
MPEP 2112 section I recite "[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." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus 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”. Furthermore, MPEP 2112.01 section II recites “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
In regards to instant claim 20, it would have also been prima facie obvious before the effective filing date of the claimed invention to have administered the HA gel as taught in the combined teachings of Cai, Prinz, JP’702, and CN’369 described above for treating the recited conditions in instant claim 20. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Cai provides guidance that that HA-based hydrogels hold realized and potential applications in many fields, such as in osteoarthritis treatment, postoperative adhesion prevention, wound dressing, scaffolding materials, drug delivery, and tissue repair and regeneration.
Response to Arguments
Applicant’s arguments filed on 04/22/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant states that there is no motivation and reasonable expectation of success to further steam sterilize the HA gels of Cai because the HA gels of Cai are formed by using low concentrations (1% wt) of HA, which Applicant states exhibits weak mechanical strength and low degree of crosslinking. Applicant further states that because of these weak HA gel properties, the ordinary skilled artisan would understand that the HA gel of Cai would not be suitable for further steam sterilization, which Applicant states is known to cause severe degradation.
Applicant’s argument described above was not found persuasive because in regards to no motivation to sterilize the HA gels of Cai, MPEP 2144 IV states that “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.”
Therefore, the ordinary skilled artisan would have a motivation to steam sterilize the HA gel of Cai because as described above, Prinz provides further guidance of sterilizing HA gels under certain standards such as USP in order to be used as a medical product.
In regards to no reasonable expectation of success, as described above, Cai demonstrates that heating HA gels with longer freezing durations such as 12 days had higher thermostability and thermotolerance. Furthermore, it is noted that Prinz recognizes that steam sterilization may degrade the HA and discloses optimizing sterilization parameters such as shorter time periods and at higher temperatures to better preserve the molecular weight of the HA molecules in the gels (page 17 lines 11-20 in Prinz). Therefore, the ordinary skilled artisan would have also been able to recognize that steam sterilization may cause degradation of the HA gels and would have optimized the sterilization process parameters accordingly to preserve the molecular weights of the HA.
Applicant states that Prinz teaches a thiol-modified crosslinked hyaluronan, and further states that the thiol-modified hyaluronan is understood in the art to exhibit significantly stronger crosslinking compared to the auto-crosslinked HA gel of Cai. Therefore, Applicant states that there is nothing to show or suggest in Prinz that the steam treatment described therein would be suitable for the crosslinked HA gel of Cai.
Applicant’s argument described above was not found persuasive because while a thiol-modified crosslinked hyaluronan as disclosed in Prinz may exhibit stronger crosslinking compared to an auto-crosslinked HA gel such as in Cai, this disclosure does not discredit or teach away for an ordinary skilled artisan to perform steam sterilization on the HA gel as disclosed by the combined teachings of Cai, CN’369, and Prinz. Furthermore, as described above, there is a reasonable expectation of success because Cai demonstrates that heating HA gels with longer freezing durations such as 12 days had higher thermostability and thermotolerance, and Prinz provides further guidance of optimizing steam sterilization parameters to preserve the molecular weight of the HA in the gel.
Applicant states in regards to this reasonable expectation of success that Cai shows in Figure 2A that the storage module of their HA gels plateaus after approximately 6 days of freezing, and further states that this indicates no significant increase in gel strength or thermotolerance beyond this point. Therefore, Applicant states that there is no actual evidence to suggest that extending the freezing time beyond 6 days can further enhance the gel strength and the thermotolerance for the HA gels of Cai and would be further suitable to withstand the steam sterilization treatment.
Applicant’s argument described above was not found persuasive because Figure 2A still shows increases in the storage modulus by performing longer freezing times past 6 days. Additionally, Cai discloses that HA gels obtained by freezing for 12 days had a denser structure than that of the gel obtained by freezing for 6 days (right column first paragraph page 6649), and that HA gels obtained by a longer freezing duration had a higher “melting” temperature and thus presented higher thermotolerance similar to cryogels obtained from PVA (see right column first paragraph page 6649). Cai teaches that long freezing time positively contributed to the alignment of polymer chains in the unfrozen liquid microphase, thereby promoting the formation of aggregation that led to high thermotolerant cryogels (see right column first paragraph page 6649), which suggests that freezing times longer than the disclosed 12 days may further increase the thermotolerance of the HA gels. Furthermore, Cai discloses in Fig. S2 that gels with molecular weights greater than 730000 displayed a mechanical spectrum of a comparatively strong gel, with its G′ almost independent of frequency and much higher than G″.
Applicant states that their claimed auto-crosslinked HA gel made under high concentrations of HA (10-30 wt%) and strong acidic environment (0.5-1.5 N acids) provides unexpectedly advantageous effects. Applicant states that the auto-crosslinked HA gel made under these conditions exhibited improved degree of crosslinking and thermotolerance, which allows the HA gel to be steam-sterilized and retain its desired gel properties post-sterilization. Applicant states the improved degree of crosslinking and thermotolerance was determined by measuring various rheological parameters such as the storage and loss modulus (G’ and G’’) as shown in Examples 1-12 of the instant specification.
In response to Applicant’s showing of unexpected results, as stated in MPEP 716.02(e), the showing of unexpected results must be compared to the closest prior art to rebut a prima facie case of obviousness.
The closest prior art to compare is Cai et al.
As described above, Cai teaches a method of manufacturing an auto-crosslinked hyaluronic acid gel by mixing a 10 mg/mL (1% wt) hyaluronic acid colloid with 1N HCl at -20 C for 3-12 days.
Applicant has demonstrated that auto-crosslinked HA gel made under high concentrations of HA (10-30 wt%) and strong acidic environment (0.5-1.5 N acids) and freezing between -10C to -30C for 7 to 42 days exhibited improved degree of crosslinking and thermotolerance as seen by the various rheological parameters that were measured such as the storage and loss modulus (G’ and G’’) in Examples 1-12 of the instant specification.
However, none of these examples provide a comparison to the closest prior art (Cai) because these examples have not compared to auto-crosslinked HA gels that were made using lower concentrations of HA such as the 1% wt hyaluronic acid as disclosed in Cai. Therefore, Applicant has not provided sufficient evidence to rebut the prima facie obviousness over Cai .
Conclusion
No claim is found allowable.
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 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 DAVID H CHO whose telephone number is (571)270-0691. The examiner can normally be reached M-F 8AM-5PM.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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