CTNF 17/934,937 CTNF 80340 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. This is a second non-final rejection. Status of the claims Applicant filed a response on 9/17/2025. Claims 1-3, 7, 8, 10, 12, 13 are amended. Claims 4, 5 are canceled. Claims 1-3, 6-14 are under consideration Response to Amendment Claim objections Regarding the objection to claims 2, 5, 10, 12, 13 for misspelling “sialyl” as “sialy,” applicant has amended the claims. However, it is noted that the misspelling occurs in other claims. For example, in claim 1, “sialyated” should be “sialylated” and “sialytransferase” should be “sialyltransferase.” Claim rejections 112b: Applicant’s amendments to claims 1-3, 7, 8, 12 and 13 addressing phrases drawn to examples (“e.g.”) have been deleted. Applicant’s amendments have overcome the 112(b) rejections. The rejection is withdrawn . 102: The rejection of claims 1-3, 6 as being anticipated by Stuible et al. is withdrawn as applicant amended claim 1. However, the rejection of clam 9 remains . See below. 103: The rejection of claim 7 as being obvious over Stuible et al. is withdrawn as claim 1, which claim 7 depends on has been amended. The rejection of claims 2, 4, 4, 8, 19, 11 as being obvious over Stuible et al. and Perez et al. is withdrawn as claim 1 is amended. New or Maintained Rejections Claim Rejections - 35 USC § 112 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 1 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. Regarding claim 1, as stated in the applicant’s remark filed on September 17, 2025, original claims 4 and 5 are incorporated into claim 1, however, since there is no “and” or “or” between these additional limitations from original claims 4 and 5, the scope of the claim is not clearly defined. Based on the examiner’s interpretation, the amended claim 1 will be interpreted as “…. and wherein the sialyltransferase is ST3Gal1 or ST3Gal4.”. Therefore, the amended claim 1 comprises all limitations in the original claims 1, 4 and 5, and the instant application is examined accordingly. Claim Rejections - 35 USC § 112 07-30-01 AIA The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 07-31-01 Claim 2 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre- AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 2 recites the limitations, “inhibition of Siglec15 activity and/or expression” and “inhibition of M-CSF activity and/or expression.” However, based on the amendment to claim 1, there is no support for the agents in claim 1 that inhibit Siglec15 expression or M-CSF expression. According to the specification, page 15, sialylation is a process mediated by sialyltransferases (STs), which catalyze the transfer of a sialic acid (SA) moiety to various acceptors in different linkages. According to the art, a sialyldase is an enzyme that removes sialic acid from cell surface glycoconjugates (Takahashi et al., 2007, Bone, 41: 77-86 (cited in IDS of 8/5/2025) page 80, parag. under Most of the potential sialylation sites of accessible glycoconjugates on the osteoclast precursor surface are sialylated). Thus, according to the specification and the art, these two enzymes play a role either in transferring or removing sialic acid from glycoconjugates. While the art provides this teaching, neither the art nor the specification teaches that either of these enzymes have a role in regulating the expression levels of Siglic 15 or M-CSF. As such, the claims lack written description support for inhibition of Siglic 15 and M-CSF expression levels. Claim Rejection - 35 USC § 102 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. 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-15 AIA Claim 9 remains rejected under 35 U.S.C. 102 ( a)(1 ) as being anticipated by Stuible et al (2014) “Mechanism and function of monoclonal antibodies targeting siglec-15 for therapeutic inhibition of osteoclastic bone resorption.” J Biol Chem 2014 Mar 7; 289(10): 6498-6512 (cited in IDS of 8/5/2024) . Stuible et al. teach the use of monoclonal antibodies targeting Siglec-15 (sialic acid binding immunoglobulin-like lectin-15, pg 6498, column 2, paragraph 2) to inhibit differentiation of functional osteoclasts, and treatment of mice with these antibodies led to a marked increase in bone mineral density, consistent with the inhibitory effect on osteoclast activity (Abstract). Stuible et al further propose a model of the mechanism of action of Siglec-15 antibodies on inhibiting osteoclast activity: These antibodies block the binding of Siglec-15 to an “unidentified sialo-glycoprotein ligand”, which is required for normal differentiation of functional osteoclasts (page 6510, Figure 9). The fact that Siglec-15 antibody can inhibit osteoclast activity in a physiological context offer an exciting proof-of-principle for targeting Siglec 15 as a therapeutic strategy for bone loss such as osteoporosis (page 6510, column 2 , paragraph 1; page 6498, “Significance”). Therefore, this Siglec-15/sialylated ligand interaction blocking antibody anticipates the limitations in claim 9 . 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. 07-23-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. 07-21-aia AIA Claim s 1-7, 9-14 are newly rejected under 35 U.S.C. 103 as being unpatentable over Stuible et al (2014) “Mechanism and function of monoclonal antibodies targeting siglec-15 for therapeutic inhibition of osteoclastic bone resorption.” J Biol Chem 2014 Mar 7; 289(10): 6498-6512 (cited in IDS of 8/5/2024), in view of Takahata et al. "Sialylation of cell surface glycoconjugates is essential for osteoclastogenesis." Bone 41.1 (2007): 77-86 (cited in IDS of 8/5/2025) , Regarding claim 1, as discussed above, Stuible et al teach that anti-Siglec -15 antibody administered to mice increase their bone mineral density (BMD). While Stuible et al. teach blocking the interaction between Siglec-15 and its target results in increased BMD, they do not specifically teach that the inhibiting agent is a sialyldase agent. Takahata et al. teach SAase treatment inhibited osteoclast differentiation of osteoclast precursor cells treated with rhM-CSF and RANKL (Takahata et al., page 80, 2 nd col. Under Desialylation of osteoclast precursor cells inhibits RANKL-induced MNC formation during osteoclastogenesis). It would have been obvious for an artisan to substitute the anti-Siglic 15 antibody in Stuible et al. with the SAase taught by Takahata et al. One would have done so in order to arrive at mice with decreased number of osteoclasts and increased bone mineral density. There would have been reasonable expectation of success since both Stuible et al. and Takehata et al. teach reagents that block the development of osteoclasts. Regarding claims 1, 10-13 and the limitation of “sialyltransferase inhibiting agent,” while Stuible et al. teach blocking the interaction between Siglec15 and its target results in increased BMD, they do not specifically teach that the inhibiting agent is a sialyltransferase inhibiting agent. Takahata et al. teach the presence of alpha (2,3)-linked sialic acid stained with MAA lectin and alpha (2,6)-linked-sialic acid stained with SNA-I lectin in osteoclast precursor cells. Takahata et al. teach that after 3 days of culture with rhM-CSF and sRANKL, mononuclear cells undergoing cell fusion accumulated alpha (2,3)-linked-sialic acid and alpha (2,6)-linked sialic acid on the plasma membrane. In multinuclear giant cells with actin ring formation, alpha (2,3)-linked sialic acid was still expressed in the paranuclear area along the actin ring, whereas the expression of alpha (2,6)-linked-sialic acid was degraded in polykaryocytes. Takahata et al. also teach mRNA expression levels of sialyltransferases during osteoclastogenesis. All five beta-galactoside alpha(2,3)-sialyltranferases were expressed in BMMs and only ST6Gal-I (an alpha (2,6)-sialyltranferase) was expressed after RANKL expression (Takahata et al., page 79, under Expression of sialic acid in osteoclast precursor cells and osteoclasts, also Figures 1 and 2). From these results, Takahata et al. teach knockdown of ST6Gal-I mRNA with ST6Gal-I siRNA. Takahata et al. teach that TRAP-positive multinuclear cells (i.e. osteoclasts) were rarely observed when treated with ST6Gal-I siRNA treated cells (Takahata et al., page 81, 2 nd col. Under Knockdown of ST6Gal-I with siRNA and Figure 6). While Takahata et al. do not specifically teach siRNA against alpha (2,3)-sialyltransferases (such as ST3Gal1 or ST3Gal4), Takahata et al. teach in Figure 2 that these sialyltransferases are expressed in osteoclast precursor cells cultured with rHM-CSF and sRANKL. It would have been obvious for an artisan to make siRNA against any of ST3Gal1 to ST3Gal5 in order to block osteoclastogenesis in Stuible et al.’s osteoclast mouse model. Specifically, one would have substituted Stuible et al.’s anti-Siglic 15 antibody with siRNA against ST3Gal1 to ST3Gal5 to arrive at mice with increased bone mineral density. One would have been motivated to do so because Takahata et al. teach that removing (e.g. with SAase) or blocking the transfer of sialic acid (e.g. siRNA against ST6Gal-I) results in blocking osteoclastogenesis. One would have made siRNA against any of ST3Gal1 to ST3Gal5 in order to block transfer of alpha (2, 3)-linked sialic acid. It is noted that while claim 1 specifically recites ST3Gal1 and ST3Gal4, an artisan would have picked any of the 5 sialyltransferases and expected that siRNA against them would work. Regarding claims 2, 10-14, Takahara et al. teach that siRNA to a sialyltransferase would block RANKL stimulation. While Takehara et al. do not specifically indicate that TLR is the site of sialylation, treatment of precursor osteoclast cells with siRNA to a sialyltransferase would have resulted in that outcome. Regarding claims 3, 6, 7, Stuible et al. teach that Siglec 15 serves as a target of novel therapeutics for osteoporosis and cancer-associated bone loss (Stuible et al., page 6498, boxed section). While Stuible et al. teach a mouse model, it is understood that the Stuible et al.’s results translate to use in human patients . 07-21-aia AIA Claim s 1 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Stuible et al (2014) “Mechanism and function of monoclonal antibodies targeting siglec-15 for therapeutic inhibition of osteoclastic bone resorption.” J Biol Chem 2014 Mar 7; 289(10): 6498-6512 (cited in IDS of 8/5/2024), in view of Takahata et al. "Sialylation of cell surface glycoconjugates is essential for osteoclastogenesis." Bone 41.1 (2007): 77-86 (cited in IDS of 8/5/2025), and Huang et al., “Use of Alendornate Sodium (Fosamax) to Ameliorate Osteoporosis in Renal Transplant Patients: A Case-Control Study” PLOS ONE 7(11): (2012) e48481 . As indicated above in the rejection for claim 1, an artisan would have used SAase or siRNA against any of ST3Gal1 to ST3Gal5 to reduce osteoclastogenesis and to increase bone mineral density in bone patients, such as those with osteoporosis or cancer-associated bone loss. While Stuible et al. and Takehata et al. teach using SAase or an siRNA against any of ST3Gal1 to ST3Gal5, they do not teach using them in a patient who is already being treated for osteoporosis. Huang et al. teach renal transplant patients who experience osteoporosis as a result of steroid and immunosuppressive agents showed improvement in bone condition when treated with Fosamax (Huang et al., abstract). Huang et al. also teach that Fosamax treatment was more effective in men than in women (Huang et al, page 3, 2 nd col. Under Gender differences in the effect of Fosamax on bones). It would have been obvious for an artisan to supplement Huang et al.’s female patients treated with Fosamax with SAase or siRNA against any of ST3Gal1 to ST3Gal5 in order to improve their treatment of osteoporosis. One would have done so because Huang et al. teach that Fosamax treatment was less effective in women. Conclusion No claims allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOANNE HAMA whose telephone number is (571)272-2911. The examiner can normally be reached Monday-Thursday 8-4. 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, Bonnie Eyler can be reached at 571-272-1200 . 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647 Application/Control Number: 17/934,937 Page 2 Art Unit: 1647 Application/Control Number: 17/934,937 Page 3 Art Unit: 1647 Application/Control Number: 17/934,937 Page 4 Art Unit: 1647 Application/Control Number: 17/934,937 Page 5 Art Unit: 1647 Application/Control Number: 17/934,937 Page 6 Art Unit: 1647 Application/Control Number: 17/934,937 Page 7 Art Unit: 1647 Application/Control Number: 17/934,937 Page 8 Art Unit: 1647 Application/Control Number: 17/934,937 Page 9 Art Unit: 1647 Application/Control Number: 17/934,937 Page 10 Art Unit: 1647 Application/Control Number: 17/934,937 Page 11 Art Unit: 1647 Application/Control Number: 17/934,937 Page 12 Art Unit: 1647
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