DRUG DELIVERY SYSTEM FOR LOCALLY DELIVERING THERAPEUTIC AGENTS AND USES THEREOF

§102 §103 §DOUBLEPATENT

DETAILED ACTION The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The preliminary amendment filed on 11/08/2024 has been entered. Claims 2-45 are cancelled. Claims 46-64 are new. Claims 1 and 46-64 are pending in this application. Claims 47, 53, 57, 63, and 64 are withdrawn. Claims 1, 46, 48-52, 54-56, and 58-62 are currently under examination. Priority This application is a 371 of PCT/CN2022/118658 filed on 09/14/2022 and claims foreign priority of PCT/CN2021/118666 filed on 09/16/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 365(c) or 386(c) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). The disclosure of the prior-filed application, Application No. PCT/CN2021/118666, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claims 54 and 59 recites “ PNG media_image1.png 200 400 media_image1.png Greyscale ”, and/or “ PNG media_image2.png 200 400 media_image2.png Greyscale , PNG media_image3.png 200 400 media_image3.png Greyscale , PNG media_image4.png 200 400 media_image4.png Greyscale … PNG media_image5.png 200 400 media_image5.png Greyscale , PNG media_image6.png 200 400 media_image6.png Greyscale , PNG media_image7.png 200 400 media_image7.png Greyscale , PNG media_image8.png 200 400 media_image8.png Greyscale … PNG media_image9.png 200 400 media_image9.png Greyscale , PNG media_image10.png 200 400 media_image10.png Greyscale ” (pages 5 and 8-12), which are not disclosed or supported by the prior-filed Application No. PCT/CN2021/118666. Thus, the priority date of claims 54 and 59 is 09/14/2022. Election/Restrictions Applicant's election without traverse of Group I invention (claims 1 and 46-62) and species ( PNG media_image11.png 200 400 media_image11.png Greyscale wherein the biopolymer is hyaluronic acid comprising carboxylic group as BG1; the therapeutic agent is triamcinolone acetonide comprising hydroxyl group as BG2; the linker comprises a structure of formula (I): PNG media_image12.png 200 400 media_image12.png Greyscale wherein U is -N(R1)-; A is alkyl; B is a direct bond; C is a direct bond; V is -C(=O)-; R1 is hydrogen) in the reply filed on 08/25/2026 is acknowledged. “Lack of unity of invention may be directly evident “ a priori ,” that is, before considering the claims in relation to any prior art, or may only become apparent “ a posteriori ,” that is, after taking the prior art into consideration. For example, independent claims to A + X, A + Y, X + Y can be said to lack unity a priori as there is no subject matter common to all claims. In the case of independent claims to A + X and A + Y, unity of invention is present a priori as A is common to both claims. However, if it can be established that A is known, there is lack of unity a posteriori, since A (be it a single feature or a group of features) is not a technical feature that defines a contribution over the prior art.“ (see MPEP § 1850 [R-01.2024], 37 CFR 1.475, II). Furthermore, as indicated in MPEP, only independent claims are considered. Claims 47, 53, 57, 63, and 64 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Thus, claims 1, 46, 48-52, 54-56, and 58-62 are currently under examination. Information Disclosure Statement Three information disclosure statement (IDS) filed on 03/15/2024, 12/09/2025, and 06/11/2026 have been considered. Claim Objections Claims 1, 51, and 55 are objected to because of the following informalities: In claim 1, change the incorrect recitation “alkyl and” (line 17) to “alkyl, or” because the preceding verb is “selected from”; and replace the recitation “-C(=O)NHCH2O- or” (line 26) with “-C(=O)NHCH2O- and” to comply with the preceding “selected from the group consisting of” Markush group format. In claim 51, delete the excessive recitation “the group consisting of” (line 2 to 3) because the subsequent conjunction “or” is recited before the last species. In claim 55, change the incorrect conjunction “or” (line 2) to “and” to comply with Markush group format beginning with “selected from the group consisting of”. Appropriate correction is required. Claim Rejections - 35 USC § 102 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. (I) Claims 1, 46, 48-52, 54-56, and 58-62 are rejected under 35 U.S.C. 102(a)(1) or 102(a)(2) as being anticipated by Lee et al. (US 2021/0369852, published on Dec. 2, 2021 and filed on Dec. 10, 2020, Continuation-in-part of application No. 16/891,020, filed on Jun. 2, 2020, hereinafter referred to as Lee ‘852, also listed in IDS filed on 06/11/2026) incorporated by Lee et al. (US 2020/0376132, Dec. 3, 2020, Appl. No.: 16/891,020, hereinafter referred to as Lee ‘132, also listed in IDS filed on 06/11/2026). With regard to structural limitations “a drug delivery system (or for a subject; or for injection, oral dosage form, inhalation, or topical application) comprising: a biopolymer (or hyaluronic acid) comprising at least a first binding group BG 1 selected from carboxylic group; a therapeutic agent (or triamcinolone acetonide) comprising at least a second binding group BG2 selected from hydroxyl group; and a linker covalently linking the biopolymer to the therapeutic agent; wherein the linker comprises a structure of formula (I): PNG media_image13.png 200 400 media_image13.png Greyscale (or PNG media_image14.png 200 400 media_image14.png Greyscale , p is 0 to 10; or PNG media_image15.png 200 400 media_image15.png Greyscale ) wherein U is connected to the biopolymer through BG1 such that at least one amide linkage is formed, and U is selected from -N(R1)-; A is alkyl; B is a direct bond; C is a direct bond; V is -C(=O)-; R1 is hydrogen (or PNG media_image16.png 200 400 media_image16.png Greyscale )” (claims 1, 46-52, 54-56, 58-61) and “a pharmaceutical composition comprising the drug delivery system of claim 1 and a pharmaceutically acceptable excipient” (claim 62): Lee ‘852 disclosed a Hyaluronic acid (ΗΑ)-Linker-Drug Conjugate. In some embodiments, the linker is a single amino acid, such as alanine (Ala; preferably, β-alanine), γ-abu (4-aminobutanoic acid), δ-aminovaleric acid (5-aminopentanoic acid), ε-aminocaproic acid (6-aminohexanoic acid), 7-aminohepta-noic acid, 8-aminooctanoic acid, and 11-aminoundecanoic acid. The ΗΑ-β-Ala-Triamcinolone acetonide is synthesized from HA and Boc-β-Ala-Triamcinolone acetonide (page 4/11, [0028 and 0029]; page 10/11, [0094]). Lee ‘132 (incorporated here as parent application of Lee ‘852) disclosed a scheme for synthesizing the HA-C17-E2 hyaluronan conjugate (Fig. 5): PNG media_image17.png 200 400 media_image17.png Greyscale . The hyaluronan conjugate can be formulated, together with a pharmaceutically-acceptable excipient, into a pharmaceutical composition suitable for the desired mode of administration. Certain pharmaceutical compositions are single unit dosage forms suitable for oral, parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), intravitreal, or transdermal administration to a patient. Examples of dosage forms include aerosols (e.g., nasal sprays or inhalers) (page 7/42; page 17/42, [0044]). Thus, these teachings of Lee ‘852 incorporated by Lee ‘132 anticipate Applicant’s claims 1, 46, 48-52, 54-56, and 58-62 because the ΗΑ-β-Ala-Triamcinolone acetonide of Lee ‘852 is PNG media_image16.png 200 400 media_image16.png Greyscale . (II) Claims 1, 46, 48-52, 54-56, and 60-62 are rejected under 35 U.S.C. 102(a)(1) or 102(a)(2) as being anticipated by Lee et al. (US 2020/0376132, Dec. 3, 2020, hereinafter referred to as Lee ‘132, also listed in IDS filed on 06/11/2026). With regard to structural limitations “a drug delivery system (or for a subject; or for injection, oral dosage form, inhalation, or topical application) comprising: a biopolymer (or hyaluronic acid) comprising at least a first binding group BG 1 selected from carboxylic group; a therapeutic agent (for example, 11-deoxycorticosterone) comprising at least a second binding group BG2 selected from hydroxyl group; and a linker covalently linking the biopolymer to the therapeutic agent; wherein the linker comprises a structure of formula (I): PNG media_image13.png 200 400 media_image13.png Greyscale (or PNG media_image14.png 200 400 media_image14.png Greyscale , p is 0 to 10; or PNG media_image15.png 200 400 media_image15.png Greyscale ) wherein U is connected to the biopolymer through BG1 such that at least one amide linkage is formed, and U is selected from -N(R1)-; A is alkyl; B is a direct bond; C is a direct bond; V is -C(=O)-; R1 is hydrogen (or PNG media_image18.png 200 400 media_image18.png Greyscale )” (claims 1, 46-52, 54-56, 60, and 61) and “a pharmaceutical composition comprising the drug delivery system of claim 1 and a pharmaceutically acceptable excipient” (claim 62): Lee ‘132 disclosed a hyaluronic acid (HA)-11-deoxycorticosterone conjugate (XXVII): PNG media_image18.png 200 400 media_image18.png Greyscale . The hyaluronan conjugate can be formulated, together with a pharmaceutically-acceptable excipient, into a pharmaceutical composition suitable for the desired mode of administration. Certain pharmaceutical compositions are single unit dosage forms suitable for oral, parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), intravitreal, or transdermal administration to a patient. Examples of dosage forms include aerosols (e.g., nasal sprays or inhalers) (page 32/42; page 17/42, [0044]). A hyaluronan conjugate that comprises a hyaluronic acid (HA), a sex hormone, and a linker for coupling the sex hormone to one of the disaccharide units of the HA. In some embodiments, the linker is a single amino acid residue, such as, alanine (Ala; preferably, ß-alanine), valine (Val), y-abu (4-aminobutanoic acid), 6-aminovaleric acid (5-aminopentanoic acid), E-aminocaproic acid (6-aminohexanoic acid), 7-aminoheptanoic acid, 8-aminooctanoic acid, and 11-aminoundecanoic acid (page 16/42, [0053, 0056]). Thus, these teachings of Lee ‘132 anticipate Applicant’s claims 1, 46, 48-52, 54-56, and 60-62. 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. 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, 46, 48-52, 54-56, and 58-62 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US 2021/0369852, published on Dec. 2, 2021 and filed on Dec. 10, 2020, Continuation-in-part of application No. 16/891,020, filed on Jun. 2, 2020, hereinafter referred to as Lee ‘852, also listed in IDS filed on 06/11/2026) incorporated by Lee et al. (US 2020/0376132, Dec. 3, 2020, Appl. No.: 16/891,020, hereinafter referred to as Lee ‘132, also listed in IDS filed on 06/11/2026). The above disclosures of Lee ‘852 and Lee ‘132 are incorporated in their entirety here. Lee ‘852 and Lee ‘132 did not explicitly disclose the elected “ PNG media_image11.png 200 400 media_image11.png Greyscale ”, required by claim 59. However, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the ß-alanine with y-abu (4-aminobutanoic acid) linker in the synthesis of ΗΑ-Linker-Triamcinolone acetonide as taught by Lee ‘852 and/or Lee ‘132 because both linkers are disclosed, described above. Thus, one of skill in the art would have a reasonable expectation that by substituting the ß-alanine with y-abu (4-aminobutanoic acid) linker in the synthesis of ΗΑ-Linker-Triamcinolone acetonide, one would achieve Applicant’s claims 1, 46, 48-52, 54-56, and 58-62 and elected compound. "Exemplary rationales that may support a conclusion of obviousness include: (B) Simple substitution of one known element for another to obtain predictable results". See MPEP § 2143 [R-01.2024] [I]. Double Patenting The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. Claims 1, 46, 48-52, 54-56, and 60-62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 66, 67, 68, 70, 72, 79, and 80 of copending Application No. 18/005,356 (APPLICANT: COVAL BIOPHARMA (SHANGHAI) CO., LTD, the claim set of 03/30/2026). Although the claims at issue are not identical, they are not patentably distinct from each other because Appl. ‘356 claims “A drug delivery system for locally delivering a therapeutic agent at a controlled rate, the drug delivery system comprising: a biopolymer comprising at least a first binding group BG1. wherein the biopolymer is hyaluronic acid or chondroitin sulfate; a therapeutic agent comprising at least a second binding group BG2, wherein the therapeutic agent is tofacitinib, oclacitinib, baricitinib, ruxolitinib, nintedanib, or sunitinib; and a linker covalently linking the biopolymer to the therapeutic agent and capable of retaining the therapeutic agent in the location of administration; wherein the linker comprises a structure of formula (I): PNG media_image19.png 200 400 media_image19.png Greyscale wherein U is connected to the biopolymer through BG1, wherein BG1 is carboxylic group and U is -N(R1)- or PNG media_image20.png 200 400 media_image20.png Greyscale , such that an amide linkage is formed… A is selected from a direct bond, alkyl and -(CH2CH2O)m-,… B is selected from the group consisting of a direct bond, alkyl, cycloalkyl,… C is selected from a direct bond,… D is selected from a direct bond, alkyl… BG2 is an amine group; V is connected to the therapeutic agent through BG2 and is selected from one of the following (a) to (k): (a) a direct bond; (b) -N(R2)C(=O)- which… (c) -N(R2)C(S)- which… (d) -OC(=O)- which… (k) -C(=O)- which… R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl… p is an integer from 1 to 4” (claim 1), encompassing or overlapping with claims 1, 46, 48, and 49 of this Application. Also, claims 66, 67, 68, 70, 72, 79, and 80 of Appl. ‘356 read on claims 50, 51, 52, 54, 55/56, 60/61, and 62 of this Application, respectively. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to YIH-HORNG SHIAO whose telephone number is (571)272-7135. The examiner can normally be reached Mon-Thur, 08:30 am to 07:00 pm 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, Renee Claytor can be reached at 571-272-8394. 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. /YIH-HORNG SHIAO/Primary Examiner, Art Unit 1691