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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-8, 19, in the reply filed on 4/28/2025 is acknowledged.
Applicant’s election without traverse of:
(i) “Ethanol” as a single representative solvent (claim 7;
(ii) “1,4-butanediol diglycidyl ether” (aka, BDDE) as single representative first crosslinking agent and single representative second crosslinking agent (claim 8); and
(iii) “hyaluronic acid, gelatin or a combination of hyaluronic acid and gelatin” recited in claim 8 as a single representative biocompatible polymer (Examiner selects hyaluronic acid for ease of examination);
claims 1-8 and 19 encompass the elected species, in the reply filed on 4/28/2025 is acknowledged.
Claims 9-18, 20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/28/2025.
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.
Claim(s) 1-2, 5-8, 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tsai et al. (US 2004/0127698 A1; 2004); in view of Seong et al. (“Hyaluronic Acid-Based Hybrid Hydrogel Microspheres with Enhanced Structural Stability and High Injectability; ACS Omega; 2019 Aug 12; 4: 13834-13844; DOI: 10.1021/acsomega.9b01475).
Tsai teaches a method of producing a double-crosslinked hyaluronate material; a hyaluronic acid or a salt thereof is sequentially reacted with an epoxide compound and a carbodiimide compound to produce a more biodegradation-resistant hyaluronate material (abstract).
Regarding the subjecting step of claim 1, Tsai discusses research concerning Applicant elected hyaluronic acid (HA) [0004], a naturally occurring mucopolysaccharide, widely distributed in connective tissues, mucous tissues (clearly biocompatible); studies of crosslinking HA in an aqueous solution by a diepoxy compound as crosslinking agent [0006]. Among crosslinking agents, gels of HA can be formed by adding epoxide, such as Applicant elected BDDE, to basic (i.e., alkaline) HA solution [0017]. Prior art crosslinking has resulted in materials having limited resistance to biodegradation [0023]. The object is to provide a method for producing double-crosslinked hyaluronate material [0024], having excellent resistance to biodegradation or deterioration by hydrolysis, as well as mechanical strength.
The crosslinking method includes step (a) subjecting HA or a salt of HA to a first crosslinking using, in one embodiment, an epoxide compound as crosslinking agent, and then subjecting the product of step (a) to a second crosslinking reaction using, in one embodiment the epoxide compound as crosslinking agent, obtaining a double crosslinked hyaluronate material. Epoxide compounds useful for crosslinking HA include Applicant elected 1,4-butanediol diglycidyl ether (BDDE) (claim 3).
Example 1 used a solution of sodium hyaluronate (0.1 g powder in 10 ml of distilled water, as a film, was placed in excessive EDC solution (2% by weight of EDC in acetone water (70/30)), to undergo crosslinking reaction. Resulting film was washed in 80% acetone in water, a cleaning solution, and then crosslinking by EGDGE (epoxide) at 2% in acetone water (70/20). The film was washed in a cleaning solution (50% acetone in water) several times, then in distilled water. The epoxide (EGDGE) and EDC sequential double-crosslinked hyaluronate material was dried and subjected to in vitro hyaluronidase degradation test. Example 2 utilized higher EDC and EGDGE concentrations (EDC 4, 10 and 20%; EGDGE 10% each), Table 2. Degradation levels were all less than 1% (Tables 1-2), whereas comparative examples had higher levels of degradation.
Regarding Applicant elected ethanol as organic solvent phase for extracting crosslinked particles, and performing secondary crosslinking, washing solutions include organic solvents in mixtures with water; ethanol is among those named; organic solvent range from 10-95% [0046], (50% ethanol used in example 5), & [0040], rendering obvious the ethanol organic solvent phase with Applicant elected ethanol.
Regarding claims 4-5, Example 1 utilized about 1 wt% HA concentration with 2 wt% of each crosslinking agent, i.e., each ratio of about 200 parts first and second crosslinking agent to 100 parts HA, reading on ratios of both claims 4-5.
Regarding claim 6, basic (alkaline) mixed solvents are taught ([0017]-[0019]; see pH 10 value in Example 7, for instance), render obvious the organic solvent extraction step and alkaline solvent limitations of claim 6.
Tsai teaches most of the method claimed in the rejected claims; however, regarding independent claim 1, the claim requires HA to be “in an emulsion state” when subjected to first crosslinking agent. Tsai teaches many unique forms, including, for example, solution in water, and gels [0038], [0045], none of the forms are reasonably construed to satisfy the “in an emulsion state”.
Seong teaches HA based hydrogel microspheres with enhanced structural stability and high injectability (title). Injectabilty HA-based hybrid hydrogel microspheres were fabricated using a water-in-oil emulsion process; the increase in biostability and mechanical strength were attributed to relatively uniform size and spherical shape of hydrogel formulated, and increased crosslinking density, compared to conventionally fabricated gel microparticles. Fig 1 (A), top route depicts HA in NaOH solution (alkaline), and then cross-linking of the emulsion (olive oil + HA solution), leading to the spheres discussed (microparticle size).
Seong establishes that emulsion state results in microparticles with better properties. The skilled artisan would have found it obvious to substitute the Tsai process, using, for instance, BDDE as first and second crosslinking agent, and HA in the solution or gel form, with HA in the form of an emulsion taught by Seong, rendering obvious the double crosslinking method of the rejected claims. There would have been a reasonable expectation of similar sphere microparticles forming, but having double crosslinking, further enhancing strength and biostability.
Applicant argues that, in the amended claims, primary crosslinking proceeds in an emulsion state, then first crosslinked microparticles are extracted, followed by the secondary crosslinking.
The experimental portion of Seong indicates HA microspheres were prepared using a w/o emulsion technique; then BDDE was mixed with prepared HA solution and emulsified. Crosslinking was performed for 4 days with stirring because long-term cross-linking at low temperature has been identified to be more beneficial in enhancing physical properties. The examiner construes the HA to be in emulsion state, and first crosslinking added, reading on this order of claim 1. When combining with the double cross-linking process of Tsai, it would have been obvious to extract the cross-linked HA microspheres (emulsion particles), per the Seong experimental section (13842, right top), and then reintroduce the second cross-linking agent of Tsai, rendering obvious the second cross-linking step of amended claim 1. This is also consistent with description of HA in microsphere form, at least prior to undergoing second crosslinking agent, per Tsai [0045].
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., suitability for cell culture, sterilization treatment, and long-term culture) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding relative amounts of HA: first crosslinker, the first crosslinking agent in Table 1 of Tsai is 2 wt% (construed as 200 parts first crosslinker to 100 parts of HA), rendering obvious an amount within the range of claim 1, when double crosslinking is used. Additionally, the examples render obvious the claimed amounts, as a result of routine optimization. While other ratios are also taught, the range renders obvious the claimed range, within the variations taught. Thus, the method of the amended claims would have been obvious.
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 TIMOTHY P THOMAS whose telephone number is (571)272-8994. The examiner can normally be reached M-Th 6:30-5:00.
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, Ali Soroush can be reached at (571)272-9925. 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.
TIMOTHY P. THOMAS
Primary Examiner
Art Unit 1614
/TIMOTHY P THOMAS/Primary Examiner, Art Unit 1614
Prosecution Insights