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 .
Priority
This application is a national stage entry of PCT/IB2021/053536, filed 4/28/2021. This application claims foreign priority to EP20171927.5, filed 4/28/2020.
Claims Status
Receipt of Remarks/Amendments filed on 12/9/2025 is acknowledged. Claims 1-12 are currently pending and presented for examination on the merits for patentability.
Rejection(s) not reiterated from the previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Modified Claim(s) Rejection(s) Necessitated by Amendments
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 1-6 and 8-12 are rejected under 35 U.S.C. 103 as being unpatentable over Cavalieri et al. (WO2016/181365A1) in view of Longin et al. (US 2013/0338100A1; Dec. 19, 2013) and KR102070881B1 (2020-01-29).
Cavalieri throughout the reference teaches a method for the preparation of hyaluronic acid microsponges, wherein hyaluronic acid has a molecular weight ranging from 250,000 (250 KDa) to 1,500,000 (1500 KDa) (Abstract). Cavalieri teaches preparation of a cross-linking agent by reacting 1,1’-carbonyldiimidazole (CDI) with cystamine (diamine compound) to obtain the cross-linking agent. Cavalieri further teaches a cross-linking step wherein the cross-linking agent reacts with hyaluronic acid (biocompatible polymer). The reaction between the cross-linking agent and the hyaluronic acid involves the hydroxyl and carboxylic functional groups of hyaluronic acid, wherein hyaluronic acid reacts with the cross-linking agent through its hydroxyl and carboxylic groups. (see: pg. 3, line 25 – pg. 5, line 5). The hyaluronic acid is used at a concentration ranging from 0.5 to 1.5 g/dL and the cross-linking agent is used at a concentration ranging from 0.05 to 0.15 M (Abstract; pg. 7, line 12-18). The hyaluronic acid microsponges produced have an average diameter of about 4.2 micron and a pore size between 130 and 270 nm. It was found that the hyaluronic acid microsponges had an average diameter of 3.3 ± 0.9 micron in the absence of water and an average diameter of 4.2 ± 0.9 micron when swollen due to the presence of water. This swelling ratio taught in Cavalieri overlaps the swelling ratio higher than 1.5 as recited in the instant claims. Cavalieri teaches incorporating a substance within the hyaluronic acid microsponges, and then cause its release into a physiological environment (i.e., a carrier for drug delivery) (pg. 8, line 10-15). Cavalieri also teaches the use of hyaluronic acid for medical application (pg. 1, line 21-22).
The teachings of Cavalieri have been set forth above.
As discussed supra, Cavalieri teaches hyaluronic acid has a molecular weight ranging from 250,000 (250 KDa) to 1,500,000 (1500 KDa). Cavalieri does not teach a hyaluronic acid with a molecular weight ranging from 10KDa to 200 KDa or 20KDa to 150KDa as recited in the instant claims. Cavalieri also does not teach wherein the cross-linking step occurs without stirring. However, Longin and KR102070881B1 cure this deficiency.
Longin throughout the reference teaches method of crosslinking hyaluronic acid. Longin teaches crosslinking is done with a heating step and without stirring. Crosslinked hyaluronic acid hydrogel prepared with a heating step and without stirring exhibited higher swelling ratio and homogeneity. Longin teaches various molecular weight fractions of hyaluronic acid have been described as advantageous for specific purposes and the hyaluronic acid can have a low average molecular weight, preferably in the range of between 50 KDa and 300 KDa. (see e.g. para 0029-0032; 0051; 0060-0062; example 2 and 3).
KR102070881B1 teaches method for preparing microgel by crosslinking hyaluronic acid. The hyaluronic acid used has a molecular weight which ranges from 100 KDa to 500 KDa. The reference teaches if the molecular weight of hyaluronic acid is less than 100kDa, it is difficult to control the particle size of the microgel and a hydrogel of hundreds of nanometers may be prepared. In addition, the upper limit of the molecular weight of hyaluronic acid may be about 500 kDa, or about 400 kDa. If the molecular weight of hyaluronic acid is too large, the time required for crosslinking may be uneconomical. (see e.g. abstract; description; pages 2 and 4 of the attached English translated copy).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of Cavalieri, Longin and KR102070881B1 and incorporate hyaluronic acid with a low molecular weight (e.g., 10KDa or 20KDa). While Cavalieri teaches that the use of hyaluronic acid with a molecular weight lower than that indicated (250 KDa) fails to achieve a uniform spherical structure and requires longer reaction times, neither the instant claims nor Cavalieri requires that the shape of the resulting structure must be spherical. As discussed supra, both Longin and KR102070881B1 teach crosslinked hyaluronic wherein the hyaluronic acid used can be low molecular weight hyaluronic acid (e.g., 100 KDa as taught by KR102070881B1 and 50 KDa as taught by Longin). Both Longin and KR102070881B1 teaches various molecular weight fractions of hyaluronic acid have been described as advantageous for specific purposes and the hyaluronic acid can have a low average molecular weight. For example, as discussed supra, KR102070881B1 teaches that if the molecular weight of hyaluronic acid is less than 100kDa, it is difficult to control the particle size of the microgel and a hydrogel of hundreds of nanometers may be prepared. In addition, the upper limit of the molecular weight of hyaluronic acid may be about 500 kDa, or about 400 kDa. If the molecular weight of hyaluronic acid is too large, the time required for crosslinking may be uneconomical. Therefore, absence any evidence of criticality, the claimed low molecular weight of the polymer recited in the instant claims would have been prima facie obvious to one skilled in the art because low molecular weight hyaluronic acid is known to be used for crosslinking and the art teaches the advantages and disadvantages of using low or high molecular weight hyaluronic acid.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of Cavalieri and Longin and perform the crosslinking step as taught by Longin. As discussed supra, Longin teaches crosslinking is done with a heating step and without stirring. Crosslinked hyaluronic acid hydrogel prepared with a heating step and without stirring exhibited higher swelling ratio and homogeneity. Cavalieri also suggests that inhomogeneity is not desired in the crosslinked hyaluronic acid (pg. 7, line 19-26). Thus, one skilled in the art would have been motivated to perform the crosslinking step without stirring and with a heating step per the teachings of Longing.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Cavalieri et al. (WO2016/181365A1) in view of Longin et al. (US 2013/0338100A1; Dec. 19, 2013) and KR102070881B1 (2020-01-29) as applied to claims 1-6 and 8-12 above, and further in view of Ravi et al. (J Biomed Mater Res A. 2015 July; 103(7): 2300–2308).
The teachings of above cited references have been set forth above.
As discussed supra, Cavalieri teaches preparation of a cross-linking agent by reacting 1,1’-carbonyldiimidazole (CDI) with cystamine (diamine compound) to obtain the cross-linking agent. Cavalieri does not expressly teach a dihydrochloride salt of cystamine. However, Ravi et al. cures this deficiency.
Ravi also teaches crosslinking hyaluronan wherein the crosslinking agent taught by Ravi also comprises cystamine and specifically cystamine dihydrochloride (see: abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the teachings of Cavalieri and Ravi and incorporate specifically a dihydrochloride salt of cystamine to obtain the cross-linking agent. As discussed supra, Cavalieri already teaches the diamine compound which is cystamine for crosslinking agent and Ravi teaches cystamine dihydrochloride salt can also be used for crosslinking. Therefore, it would have been obvious to one of ordinary skill in the art to substitute cystamine for the dihydrochloride salt of cystamine as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. see MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant argued that the claims are directed towards the use of a single low molecular weight polymer (10 KDa to 200 KDa) whereas Cavalieri discloses use of high molecular weight polymer (250 KDa to 1500 KDa) and Lebreton teaches the use of mixture of low and high molecular weight polymers. It was argued that the amended claims recite the single biocompatible polymer consists of a polymer having an average molecular weight ranging from 10 KDa to 200 KDa.
In response, applicant’s arguments regarding Lebreton are moot because the modified rejection above, necessitated by claim amendments, does not utilize Lebreton.
Regarding applicant’s argument of the claimed low molecular weigh polymer not taught by Cavalieri, the examiner argues that while Cavalieri teaches that the use of hyaluronic acid with a molecular weight lower than that indicated (250 KDa) fails to achieve a uniform spherical structure and requires longer reaction times, neither the instant claims nor Cavalieri requires that the shape of the resulting structure must be spherical. As discussed supra, both Longin and KR102070881B1 teach crosslinked hyaluronic wherein the hyaluronic acid used can be low molecular weight hyaluronic acid (e.g., 100 KDa as taught by KR102070881B1 and 50 KDa as taught by Longin). Both Longin and KR102070881B1 teaches various molecular weight fractions of hyaluronic acid have been described as advantageous for specific purposes and the hyaluronic acid can have a low average molecular weight. For example, as discussed supra, KR102070881B1 teaches that if the molecular weight of hyaluronic acid is less than 100kDa, it is difficult to control the particle size of the microgel and a hydrogel of hundreds of nanometers may be prepared. In addition, the upper limit of the molecular weight of hyaluronic acid may be about 500 kDa, or about 400 kDa. If the molecular weight of hyaluronic acid is too large, the time required for crosslinking may be uneconomical. Therefore, absence any evidence of criticality, the claimed low molecular weight of the polymer recited in the instant claims would have been prima facie obvious to one skilled in the art because low molecular weight hyaluronic acid is known to be used for crosslinking and the art teaches the advantages and disadvantages of using low or high molecular weight hyaluronic acid.
Applicant argued that while Ravi is focused on modifying hyaluronan by controlling the derivatization of its carboxylic moieties with cystamine dihydrochloride, it does not teach or suggest using this reaction in the creation of nanoporous microsponge particles.
In response, firstly, Cavalieri teaches preparation of a cross-linking agent by reacting 1,1’-carbonyldiimidazole (CDI) with cystamine (diamine compound) to obtain the cross-linking agent. Therefore, Cavalieri already teaches use of cystamine to obtain the crosslinking agent. Cavalieri does not expressly teach a dihydrochloride salt of cystamine. Ravi teaches cystamine dihydrochloride salt can also be used for crosslinking. Therefore, it would have been obvious to one of ordinary skill in the art to substitute cystamine for the dihydrochloride salt of cystamine as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. see MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding Longin et al., applicant argued Longin also does not teach utilizing a single crosslinking step wherein crosslinking agent reacts with a single polymer along with the other limitations recited in the claims. It was argued that applicant have discovered that performing crosslinking without agitation provides an improved particle uniformity, ensuring homogeneity and higher quality microsponges.
In response, as discussed supra, Longin is utilized because Cavalieri does not teach wherein the cross-linking step occurs without stirring. Longin teaches crosslinking is done with a heating step and without stirring. Longin teaches crosslinked hyaluronic acid hydrogel prepared with a heating step and without stirring exhibited higher swelling ratio and homogeneity. Cavalieri also suggests that inhomogeneity is not desired in the crosslinked hyaluronic acid (pg. 7, line 19-26). Thus, one skilled in the art would have been motivated to perform the crosslinking step without stirring and with a heating step per the teachings of Longin.
Applicant argued that, unexpectedly, the claimed microsponge particles exhibit an enhanced swelling behavior, which is directly correlated with a higher drug loading capacity and improved release efficiency. Comparative experiments reveal that particles produced from higher MW polymers have substantially lower swelling ratio. Applicant also argued that based on the teachings of Cavalieri, one of ordinary skill would believe that to achieve swelling properties of Cavalieri’s microsponge, one would need to use hyaluronic acid in a molecular weight ranging from 250 KDa to 1500 KDa. In contrast, applicant’s invention demonstrates that it is possible to prepare nanoporous microsponge with a lower molecular weight as claimed.
In response, as discussed supra, Cavalieri teaches that the microsponges had an average diameter of 3.3 ± 0.9 micron in the absence of water and an average diameter of 4.2 ± 0.9 micron when swollen due to the presence of water. This swelling ratio taught in Cavalieri overlaps the swelling ratio higher than 1.5 as recited in the instant claims and disclosed in table I (e.g., 1.6 for Dextran) and thus, applicant’s argument that the claimed microsponge provides unexpectedly enhanced swelling behavior is not found persuasive. Further, the examiner argues that nowhere in the Cavalieri reference does it mentioned that only higher molecular weight hyaluronic acid ranging from 250 KDa to 1500 KDa achieves the swelling rate disclosed in Cavalieri. Regarding the argument that applicant’s invention demonstrates that it is possible to prepare nanoporous microsponge with a lower molecular weight as claimed, the examiner respectfully draws applicant’s attention to MPEP 716.02 which states: The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."). Both the high molecular weight polymer taught by Cavalieri and the low molecular weight polymer claimed in the instant application have overlapping swelling rates and thus, it does not appear that the claimed low molecular weight polymer have any unexpected results which are of both statistical and practical significance.
Conclusion
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 ALI SAEED whose telephone number is (571)272-2371. The examiner can normally be reached M-F 8-5 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, SUE X LIU can be reached at 5712725539. 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.
/A.S/ Examiner, Art Unit 1616
/SUE X LIU/ Supervisory Patent Examiner, Art Unit 1616