CTNF 18/832,464 CTNF 101333 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. 12-151 AIA 26-51 12-51 Status of claims Claims 2, and 8-9 are original. Claims 1, 3-7, 10-11, 14, and 18 are currently amended. Claim 12-13, and 15-17 are cancelled by the applicant. Claims 19-23 are new. Claims 1-11, 14, and 18-23 are pending and under examination. Priority This application is a 371 of PCT/KDellamary023/000757, filed on 01/16/2023. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. KR-10-2022-0010141, filed on 01/24/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Information Disclosure Statement The information disclosure statements (IDS) submitted on 07/23/2024, 03/12/2025, and 04/04/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. Claim Objections 07-29-01 AIA Claim 18 is objected to because of the following informalities: Claim 18 is objected to for “An preparation…”, which needs to be “A preparation”. Claim 18 recites “a content of the compound Formula 2 is at least 95% based on…”. This is a grammatical error, as a suggested correct syntax is “a content of the compound of Formula 2 is at least 95% based on…” . Appropriate correction is required. Claim Rejections - 35 USC § 112 (b) 07-30-02 AIA The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. 07-34-01 Claim 18 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 18 recites “a second formulation having a pH of 7 to 11 buffer for dissolving…”. It is unclear as to whether the “pH of 7 to 11” is referring to the second formulation or the buffer portion of the second formulation. A suggested amendment is to change the claim language to “a second formulation having a pH of 7 to 11, comprising a buffer for dissolving…” or “a second formulation comprising a buffer having a pH of 7 to 11 for dissolving…” depending on the desired effect. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-103 AIA The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 1, 3-11, 14, and 18-21 are rejected under 35 U.S.C. 103 as being unpatentable over Shin et al. (US20080262032A1) in view of Dellamary (US20180133199A1) . Shin et al. discloses an invention relating to an isoxazoline derivative for use as caspase inhibitor, a process for preparing it, and a pharmaceutical composition comprising it [Abstract]. Shin et al. teaches the composition containing such compounds can be used to treat osteoarthritis [¶3], acting as an anti- inflammatory [¶¶2,23]. It is also used for “for treating dementia, cerebral stroke, brain impairment due to AIDS, diabetes, gastric ulcer, cerebral injury by hepatitis virus, hepatic diseases by hepatitis virus, acute hepatitis, fulminant hepatic failure, hepatocirrhosis, sepsis, organ trans-plantation rejection, rheumatoid arthritis, or cardiac cell necrosis due to ischemic cardiac diseases” (paragraph 118). Shin provides that administering prevents apoptosis (claim 26 of Shin). Shin et al. teaches that the composition may be formulated as an injection [¶122]. Shin teaches parenteral preparations with other ingredients including carrier, solubility aid, dispersing agent, wetting agent, or suspending agent (paragraph 124). Shin et al. teaches that the isoxazoline derivative of the invention is a compound with formula (1) [¶32]. Shin et al. teaches the following structure being the compound of formula (1) [¶32], wherein R 1 is preferably an isoquinolinyl and R 2 is an isopropyl [¶39, ¶53, ¶54]: PNG media_image1.png 341 528 media_image1.png Greyscale Shin et al. additionally teaches the following compounds of formula (15) and formula (16), wherein R 1 is alkyl or aryl and R 2 is an alkyl: PNG media_image2.png 416 1342 media_image2.png Greyscale Shin et al. teaches that when the mixture of the compounds of formula (15) and formula (16) are dissolved in an organic solvent, and when the seed of the compound of formula (1) is added (or mixed) to the solution, only the compound of formula (15) in the mixture is transformed into the compound of formula (1) to be isolated as solid [¶72]. In a single embodiment [¶79], Shin et al. also discloses the following species of formula (1), Formula (15), and formula (16): PNG media_image3.png 636 1022 media_image3.png Greyscale Shin et al. further elaborates that when the mixture of the compounds of formula (15) and formula (16) is treated with a catalytic amount of base together with a seed of formula (1), both the compound of formula (15) and the compound of formula (16) are transformed into the compound of formula (1), to produce the compound of formula (1) with higher yield, which also obviates the limitation of two separate formulations per present claim 1 and 18. However, Shin et al. fails to teach specific injectable formulation parameters and excipients, including phosphate buffer systems, surfactants, sodium hydroxide pH adjustment, physiologically acceptable pH osmolarity ranges, concentration of such excipients and active ingredients, and single-dose ready-to-use injectable formulation characteristics. Dellamary discloses single-dose, ready-to-use formulations and methods for preparing the formulations [abstract]. Dellamary teaches that the composition can be used to treat osteoarthritis [¶¶169, 172]. Dellamary teaches that the formulation may be used as an intra-articular injection [¶174], including hip joints and sacroiliac joints [¶169]. Dellamary teaches that supplementary active ingredients can also be incorporated into the formulations [¶60]. Dellamary teaches mixing slurry and aqueous solution to form a suspension where the mixing is done with any sterile diluent or solution for injection [paragraph 94). Dellamary teaches that the composition may include anti-inflammatory agents [¶171]. Dellamary teaches that the composition may include a surfactant such as polysorbate 80 [¶32]. Dellamary teaches that the composition may include tonicity agents such as sodium hydroxide [¶118]. Dellamary teaches that the composition may include buffer agents such as sodium phosphate dibasic heptahydrate and sodium phosphate monobasic monohydrate [¶110]. Dellamary teaches that the formulation can contain 0.001%-100% by weight of active ingredients and 0.005% to 100% by weight of the above excipients [¶116], thus overlapping with all of the claimed concentrations of the above ingredients stated in the present claims (e.g., in an aqueous solution/dispersion: 5-20 mg/mL of formula I ≈0.5-2% w/w per present claim 3; 100-130 mM of an equimolar mixture of sodium phosphate dibasic heptahydrate and sodium phosphate monobasic monohydrate ≈2.0-2.64% w/w per present claim 7; 0.2%-5.0% w/v of surfactant ≈0.2-5.0% w/w per present claim 10; 12-42 mM of NaOH ≈0.048-0.168% w/w per present claim 11). Dellamary teaches that the formulation of the composition can have a pH of about 6.0 to about 8.0 [¶115]. Dellamary teaches examples where such compositions have an osmolality of 307-308 mOsm/kg [¶379, table 37], overlapping with the osmotic pressure in present claim 5. It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to formulate the isoxazoline derivative of Shin et al., including the compound corresponding to formula 1 and its related formula 2/formula 3 species, as an injectable pharmaceutical preparation using the ready to use single-dose injectable formulation teachings of Dellamary, including phosphate buffer, polysorbate surfactant, sodium hydroxide/pH adjustment, physiologically acceptable pH, and suitable osmolarity concentration ranges. This is because Shin et al. teaches the same active compound class for anti-inflammatory treatment, including osteoarthritis, while Dellamary teaches conventional injectable formulation components and parameters useful for preparing stable, soluble, and administrable pharmaceutical compositions as well as mixing its slurries with solutions or sterile diluents to make injectable formulations. Shin et al. further elaborates that when the mixture of the compounds of formula (15) and (16) is treated with a catalytic amount of base together with a seed of formula (1), both compounds are transformed into the compound of formula (1) to produce the compound with higher yield, thereby evidencing that the related formula species and base-containing compositions were compatible and predictably inter-related under mixed formulation conditions. A person of ordinary skill in the art would therefore have reasonably expected success in providing the active-containing component and excipient-containing component as separate formulations for mixing prior to administration. Dellamary also recognizes the mixing of the separated agents (slurry and solution/diluent) to prepare the injectable formulation, thus, recognizing two components to prepare the formulation. Even though Dellamary is provided as ready-to-use, one of ordinary skill in the art would have reasoning based on the combination of the references to keep items separate until near time to use. Overall, A person of ordinary skill in the art would have thus been motivated to combine Shin et al. and Dellamary to provide an injectable formulation of Shin et al.’s active compound having acceptable solubility, stability, tonicity, pH, and administration properties, and would have had a reasonable expectation of success in doing so because selection and optimization of buffer, surfactant, pH, and osmolarity are routine result-effective variables of a formulation. Further, because Shin et al. teaches the formula 2/formula 3 related species and their conversion/inter-relationship under formulation conditions, the claimed post-mixing of over 95% formula 2 content would have been an expected result of using and optimizing the mixed two-formulation injectable system, rather than a patentably distinct structural feature of the claimed product . 07-21-aia AIA Claim 2, and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Shin et al. (US20080262032A1) in view of Dellamary (US20180133199A1) in further view Story et al. (US20170266221A1) . Shin et al. and Dellamary jointly teach all the limitations of claims 1, 3-11, 14, 18-21. However, Shin et al. and Dellamary fail to jointly teach the limitations of claims 2, and 22-23. Story et al. discloses compositions and methods for the treatment of osteoarthritis [abstract]. Story et al. teaches that the compositions can be injectable [¶8]. Story et al. teaches that the composition can include a multitude of components including anti-inflammatory agents [¶61]. Story et al. teaches that the composition can be in a variety of forms including liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, and powders [¶111]. Story et al. teaches that the composition can be administered via intra-articular injection [¶111], which is injection to the joint. Story et al. describes that in some embodiments, such compositions are provided in a kit for treating joints, which involves a first and second component that are injected after mixture, with an osmolarity of 330-750 mOSM [¶16, ¶¶130-133]. Story et al. teaches that in some embodiments, the components are combined approximately 30 minutes or less prior to injection [¶112]. It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to further modify the injectable formulation collectively taught by Shin et al. and Dellamary to provide the first formulation in powder form and to administer the resulting mixed formulation into a joint cavity within thirty minutes after mixing, as taught by Story et al. This is because Story et al. teaches injectable compositions for treating osteoarthritis that may be provided as powder/kit components, mixed before administration, and administered intra-articularly within about 30 minutes or less. A person of ordinary skill in the art would have been motivated to incorporate Story et al.’s powder, kit, intra-articular administration, and pre-injection mixing teachings to improve storage stability, enable convenient reconstitution, and provide localized joint treatment, with a reasonable expectation of success because such powder/reconstitution kits and intra-articular injection protocols were conventional and predictable pharmaceutical formulation administration techniques for osteoarthritis therapies. Double Patenting 08-33 AIA 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 1-3, 8-9, 14, 18-23 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over the following claims of co-pending application 18/849,729 (referred to as co-pending ‘729) ; 9 and 13 (for present claim 1); 9 (for present claim 2); 12 (for present claim 8); 14 (for present claim 3); 12 (for present claim 9); 17 (for present claim 14); 21 (for present claim 18); 15 (for present claim 19, 20); and 18 (for present claim 21); 19 (for present claim 22); 20 (for present claim 23)–– In view of Dellamary (US20180133199A1). Each of the above claims (or claim groups) of co-pending ‘729 teach all limitations of their corresponding claim(s) listed in the present application, except co-pending ‘729 does not teach the second formulation having a pH ranging from 7-11 per present claim 1. Dellamary remedies this deficiency by teaching that such injectable formulations for osteoarthritis treatment can have a pH that ranges from about 6.0 to about 8.0 [¶115], which overlaps with the presently claimed range. The variation of pH is an obvious variation that would have been optimized by one of ordinary skill in the art to provide a pharmaceutically acceptable injectable formulation with suitable stability, solubility, and tolerability characteristics. Accordingly, the present claims differ from the claims of co-pending ‘729 only by an obvious variation that does not impart a patentable distinction. This is a provisional non-statutory double patenting rejection because the patentably indistinct claims of co-pending ‘729 have not yet in fact been patented. Claims 1-7, 14, and 21-23 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over the following claims of co-pending application 18/839,166 (referred to as co-pending ‘166) ; 1 (for present claim 1, 2); 9 (for present claim 3); 7 (for present claim 4); 8 (for present claim 5); 2 (for present claim 6); 3, 13 (for present claim 7); 19 (for present claim 14); 20 (for present claim 21); 21 (for present claim 22); 22 (for present claim 23)–– In view of Dellamary (US20180133199A1). Each of the above claims (or claim groups) of co-pending ‘166 teach all limitations of their corresponding claim(s) listed in the present application, except co-pending ‘166 does not teach the second formulation having a phosphate buffer, or NaOH as the pH adjusting agent. Dellamary remedies this deficiency by teaching that polysorbate 80 [¶32], sodium phosphate dibasic heptahydrate and sodium phosphate monobasic monohydrate [¶110], and sodium hydroxide [¶118] can be included in such formulations. The addition of these components would have been optimized by one of ordinary skill in the art to provide a pharmaceutically acceptable injectable formulation with suitable stability, solubility, biocompatibility, and tolerability characteristics. Accordingly, the present claims differ from the claims of co-pending ‘166 only by an obvious variation that does not impart a patentable distinction. This is a provisional non-statutory double patenting rejection because the patentably indistinct claims of co-pending ‘166 have not yet in fact been patented. Conclusions No claim is found allowable. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARYA AHMADI BAZARGANI whose telephone number is (571)272-0211. The examiner can normally be reached Monday - Friday 9:00AM - 5:00 PM. 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, Brian-Yong Kwon can be reached at (571) 272-0581. 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. Arya A. Bazargani, Ph.D. Patent Examiner Art Unit 1613 /MARK V STEVENS/ Primary Examiner, Art Unit 1613 Application/Control Number: 18/832,464 Page 2 Art Unit: 1613 Application/Control Number: 18/832,464 Page 3 Art Unit: 1613 Application/Control Number: 18/832,464 Page 4 Art Unit: 1613 Application/Control Number: 18/832,464 Page 5 Art Unit: 1613 Application/Control Number: 18/832,464 Page 6 Art Unit: 1613 Application/Control Number: 18/832,464 Page 7 Art Unit: 1613 Application/Control Number: 18/832,464 Page 8 Art Unit: 1613 Application/Control Number: 18/832,464 Page 9 Art Unit: 1613 Application/Control Number: 18/832,464 Page 10 Art Unit: 1613 Application/Control Number: 18/832,464 Page 11 Art Unit: 1613 Application/Control Number: 18/832,464 Page 12 Art Unit: 1613
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