M6PR CELL SURFACE RECEPTOR BINDING COMPOUNDS AND CONJUGATES

§102 §103 §112 §DP

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 . 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. This office action is a response to applicant’s communication submitted September 3, 2024, wherein claims 1, 3, 5, 7, 18, 21-22, 24, 29-30, 39, 41, 45, 48, 50, 53, 55, 57, 61-63, 65, 68, 70, 73, 119, 123 and 128 were preliminarily amended, and claims 2, 4, 6, 18-17, 19-20, 25-28, 32-38, 42-44, 46-47, 49, 51-52, 56, 58-60, 64, 66-67, 69, 71-72, 74-118, 120-122, 124-126 were canceled. This application is a 371 of PCT/US2022/037196 filed 07/14/2022 and claims benefit to US provisional 63/221,915 filed 07/14/2021. Claims 1, 3, 5, 7, 18, 21-24, 29-31, 39-41, 45, 48, 50, 53-55, 57,61-63, 65, 68, 70, 73, 119, 123 and 128 are pending in this application. Claim Objections Claim 63 is objected to because of the following informalities: Claim 63 has a parenthesis beginning in in the phrase “(C10-20-alkylene….” Which should be deleted. Appropriate correction is required. Claim Interpretation The phrase “a moiety of interest” is not particularly limiting. The broadest reasonable interpretation includes any atom or group of atoms. According to the instant specification, in certain cases, one, two, three, four, five or more, ten or more, or even more carbon atoms of a linker backbone may be optionally substituted with heteroatoms, e.g., sulfur, nitrogen or oxygen heteroatom (pg. 44, para. 0168). Thus the phrase “an optionally substituted alkylene” includes wherein a carbon is replaced with a heteroatom, such as oxygen. Claim Rejections - 35 USC § 112 (b) 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. Claims 1, 3, 5, 7, 18, 21-24, 29-31, 39-41, 45, 48, 50, 53-55, 57,61-63, 65, 68, 70, 73, 119, 123 and 128 are 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 claims 1, 3, 5, 7, 18, 21-24, 29-31, 39-41, 45, 48, 50, 53-55, 57,61-63, 65, 68, 70, 73, 119, 123 and 128: In claims 1, 21-22, 30, 39, 41, 55, 57, 62-63 the phrase “(e.g.,…)” or “such as” renders the claims and dependent claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Regarding claim 53: In claim 53 variables n and X are not defined. Additionally there is an n variable defined in claim 1 for a separate moiety. The multiple n values leads to a lack in clarity of scope. Thus a person of ordinary skill would be unable to ascertain the metes and bounds of the invention. Dependent claims 54-55, 57, 61-63, 65 are similarly rejected. Regarding claim 62: In claim 62 variable Z4 is not defined. Thus a person of ordinary skill would be unable to ascertain the metes and bounds of the invention. Additionally, Claim 62 recites the limitation "the branching atom". There is insufficient antecedent basis for this limitation in the claim Regarding claims 119, 123, 128: Claims 119, 123, 128 recite the limitation "conjugate". There is insufficient antecedent basis for this limitation in the claim as claim 1 is directed towards compounds. 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. Claims 1, 3, 5, 7, 18, 21-24, 29-31, 39-41, 45, 48, 50, 53-55, 57,61-63, 65, 68, 70, 73, 119 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Aivazian (WO 2021/263061, IDS filed January 10, 2024). The applied reference has a common Applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. Regarding claims 1, 5, 7, 18, 21, 22, 24, 30, 39-41, 45, 48, 50, 53-55, 57, 61-63, 65, 68, 70, 73: Aivazian teaches compositions and methods for delivering a viral composition to cells (abstract). Aivazian teaches PNG media_image1.png 500 523 media_image1.png Greyscale (pg. 12, para. 0067). Aivazian teaches exemplary M6PR binding ligands PNG media_image2.png 141 161 media_image2.png Greyscale (pg. 34, table 1, X2), PNG media_image3.png 144 425 media_image3.png Greyscale (pg. 35, table 1, X3), PNG media_image4.png 138 212 media_image4.png Greyscale (pg. 37, X11). Aivazian teaches Y can be a protein (i.e. a biomolecule) (pg. 101, para. 0368). Aivazian teaches the following compounds to be conjugated PNG media_image5.png 98 517 media_image5.png Greyscale (pg. 117, compound 557) PNG media_image6.png 171 449 media_image6.png Greyscale PNG media_image7.png 230 460 media_image7.png Greyscale (pg. 129, compound 702 and 705) PNG media_image8.png 234 465 media_image8.png Greyscale (pg. 130, compound 707) PNG media_image9.png 259 466 media_image9.png Greyscale (pg. 132, compound 711). Regarding claim 119: Aivazian teaches binding of a viral particle (e.g. AAV) to a bridging composition followed by cell surface mediated internalization of the viral particle into the target cell (abstract, pg. 2, 0012, figure 1). Aivazian modified viral compositions and methods for reducing levels or titers of neutralizing antibodies in a subject in need of viral therapy, e.g., gene therapy, are provided (abstract). Claims 1, 3, 5, 7, 18, 21-24, 29-31, 39-41, 45, 48, 50, 53-55, 57,61-63, 65, 68, 70, 73, 119 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Aivazian (WO 2021/263060, IDS filed January 10, 2024). The applied reference has a common Applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. Regarding claims 1, 3, 5, 7, 18, 21-24, 29-31, 39-41, 45, 48, 50, 53-55, 57,61-63, 65, 68, 70, 73: Aivazian teaches compositions and methods for delivering a viral composition to cells (abstract). Aivazian teaches PNG media_image10.png 430 524 media_image10.png Greyscale (pgs. 12-13, para. 0078). Aivazian teaches exemplary M6PR binding ligands PNG media_image2.png 141 161 media_image2.png Greyscale (pg. 34, table 1, X2), PNG media_image3.png 144 425 media_image3.png Greyscale (pg. 35, table 1, X3), PNG media_image4.png 138 212 media_image4.png Greyscale (pg. 37, X11). Aivazian teaches Y can be a polypeptide (i.e. a biomolecule) (pg. 88, para. 0318). Aivazian teaches the following compounds to be conjugated PNG media_image5.png 98 517 media_image5.png Greyscale (pg. 123, compound 557) PNG media_image6.png 171 449 media_image6.png Greyscale PNG media_image7.png 230 460 media_image7.png Greyscale (pgs. 136-137, compound 70 and 705) PNG media_image8.png 234 465 media_image8.png Greyscale (pg. 138, compound 707) PNG media_image9.png 259 466 media_image9.png Greyscale (pg. 140, compound 711). Regarding claim 119: Aivazian teaches binding of a viral particle (e.g. AAV) to a bridging composition followed by cell surface mediated internalization of the viral particle into the target cell (abstract, pg. 2, 0012, figure 1). Aivazian modified viral compositions and methods for reducing levels or titers of neutralizing antibodies in a subject in need of viral therapy, e.g., gene therapy, are provided (abstract).. Claims 1, 5, 7, 21-22, 24, 39, 41, 48, 53-55, 62-63, 65, 70, 73 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kinzel (J. Peptide Science, 2003, cited on PTO-892). Regarding claims 1, 5, 7, 21-22, 24, 39, 41, 48, 53-55, 62-63, 65, 70, 73: Kinzel teaches conjugate 13 which is produced by combination of target cluster mannoside 2 with peptide 10 (see Figure 2; Figure 4; Scheme 3, 13 (conjugate 2 + 10); page 380 Conjugate 13, to a solution of 10… was added mannoside 2; mannoside 2 and peptide 10 pictured below) PNG media_image11.png 453 462 media_image11.png Greyscale . This conjugate meets the structural limitations as recited by 1, 5, 7, 21, 24, 39, 41, 48, 53-55, 62-63, 65, 70, 73. Claims 1, 5, 7, 21, 24, 39-41, 45, 48, 53-54, 68, 73 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Barragan (Chem. Commun., 2001, IDS filed January 10, 2024). Regarding claims 1, 5, 7, 21, 24, 39-41, 45, 48, 53-54, 68, 73: Barragan teaches a hydrolytically stable sugar phosphonate coupled to a steroid (i.e. a biomolecule) via a long and semi-rigid spacer (synthesized via a 12-step sequence) binds both to the mannose-6-phosphonate receptors of certain cancer cells and to the lipid bilayer of vesicles, thereby serving as a multivalent adhesive between cell and vesicle surfaces (abstract). Barragan teaches the compound 14 has the following structure PNG media_image12.png 90 311 media_image12.png Greyscale wherein R = H, R’ = Na+ (pg. 85, scheme 1, compound 14). Barragan teaches compound 14 binds to cancer cells and vesicles and serves as an adhesive between living and chemical systems (pg. 85, col. 1, para. 3). Claims 1, 3, 7, 21, 24, 39, 48, 53, 57, 68 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Janetka (WO 2017/165619, cited on PTO-892). Regarding claims 1, 3, 7, 21, 24, 39, 48, 53, 57, 68: Janetka teaches the following compound: PNG media_image13.png 90 231 media_image13.png Greyscale (pg. 61, para. 0307, example 28). Claims 1, 3, 7, 21, 24, 29, 39, 48, 53, 68 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mydock-Mcgrane (J. Med. Chem., 2016, cited on PTO-892). Regarding claims 1, 3, 7, 21, 24, 29, 39, 48, 53, 68: Mydock-Mcgrane teaches the following compounds PNG media_image14.png 145 329 media_image14.png Greyscale . 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. Claims 1, 5, 7, 21-22, 24, 29, 39-41, 45, 48, 53, 61, 70, 73, and 128 are rejected under 35 U.S.C. 103 as being unpatentable over Hamdaoui (Bull Soc. Chim. Fr., 1994, cited on PTO-892) in view of Barragan (Chem. Commun., 2001, IDS filed January 10, 2024). The English translation relied upon was provided by the Examiner. Regarding claims 1, 5, 7, 21-22, 24, 29, 39-41, 45, 48, 53, 61, 70, 73, and 128: Hamdaoui teaches bioconjugates of pepstatin A (a pseudopeptide inhibitor of cathepsin d, i.e. a biomolecule) and mannose-6-phosphate, which are recognized by specific mannose-6-phosphate membrane receptors, were synthesized and evaluated in vitro (abstract). These hybrids exhibit the inhibition and recognition activities of their precursors. Moreover, the bifunctional Pep(M6P)2 shows an antiproliferative activity on breast-cancer cell strains (abstract). Hamdaoui teaches the following compound 17 PNG media_image15.png 126 271 media_image15.png Greyscale (pg. 855, col. 2, figure 3). Hamdaoui teaches the compound inhibits Cath-D and binds to M6P receptors (English translation, pg.2, col. 1, para. 3). Hamdaoui tested the ability of the compound to inhibit the proliferation of human breast cancer cells and verified the activity (English translation, pg.2, col. 1, para. 4, pg. 7, cols. 1-2, bridging para). Thus it would have been obvious to administer the compound for the treatment of breast cancer. The compound of Hamdaoui encompasses the structural formulas as recited by instant claims 1, 5, 7, 21-22, 24, 29-30, 39-41, 45, 48, 53, 61, 70, 73, 119, and 128 except wherein W is a non-hydrolyzable hydrophilic head group. However, Barragan teaches a hydrolytically stable sugar phosphonate coupled to a steroid (i.e. a biomolecule) via a long and semi-rigid spacer (synthesized via a 12-step sequence) binds both to the mannose-6-phosphonate receptors of certain cancer cells and to the lipid bilayer of vesicles, thereby serving as a multivalent adhesive between cell and vesicle surfaces (abstract). Barragan teaches the use of mannose-6-phosphate moieties to target bioactive molecules is not as attractive as it might seem (pg. 1, col. 1, para. 2). The problem lies in the susceptibility of sugar phosphates to hydrolysis by various phosphatase enzymes (pg. 1, col. 1, para. 2). To circumvent this problem, we have recently developed synthetic routes to two phosphonate analogs of mannose-6-phosphate (M6-P); one is isosteric with the phosphate moiety while the other is not. Both, however, are hydrolytically stable (pg. 1, col. 1, para. 2). Upon submitting the analogs for biological testing, it was found that the isostere (but not the non-isostere) binds to M6-P receptors as effectively as does M6-P itself (pg. 1, col. 1, para. 2).. Barragan teaches the compound 14 has the following structure PNG media_image12.png 90 311 media_image12.png Greyscale wherein R = H, R’ = Na+ (pg. 85, scheme 1, compound 14). Barragan teaches compound 14 binds to cancer cells and vesicles and serves as an adhesive between living and chemical systems (pg. 85, col. 1, para. 3). Taken together it would have been prima facie obvious to modify the compound of Hamdaoui such that the phosphate moiety is replaced with a hydrolytically stable phosphonate as suggested by Barragan. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order to improve hydrolytic stability of the compound while maintaining the compounds ability to bind M6-P receptors. Claims 119 and 123 rejected under 35 U.S.C. 103 as being unpatentable over Hamdaoui (Bull Soc. Chim. Fr., 1994, cited on PTO-892) and Barragan (Chem. Commun., 2001, IDS filed January 10, 2024) as applied to claims 1, 5, 7, 21-22, 24, 29, 39-41, 45, 48, 53, 61, 70, 73, and 128 above in view of Bertozzi (WO 2020132100, IDS filed September 5, 2024). The English translation relied upon was provided by the Examiner. Regarding claims 119 and 123: As discussed above the prior art render obvious a compound according to claim 1. They do not teach a method of internalizing/reducing levels of a target protein in a biological system/cell wherein the compound binds the target protein, facilitates cellular uptake and degradation of the target protein. However, Bertozzi teaches bifunctional molecules that include a first moiety that specifically binds a cell surface molecule or extracellular molecule, and a second moiety that specifically binds a lysosomal targeting molecule. The bifunctional molecules find use e.g., for targeted degradation of cell surface and extracellular molecules (e.g., proteins) via the endosomal/lysosomal pathway (abstract). Bertozzi teaches comparable isothiocyanate M6P binding groups can be conjugated to proteins used in the invention (pg. 2, lines 24-28, drawings pg. 7, figure 7). Bertozzi teaches the bifunctional molecules internalize a target protein and degrade the target protein (drawings, pg. 1, figure 1). Bertozzi teaches poly(M6Pn) labeled antibodies, such as with cetuximab, can shuttle their binding partner EGFR for degradation (pg. 38, lines 24-25). Taken together it would have been prima facie obvious to modify the compound of Hamdaoui and Barragan such that pepstatin is replaced with a cetuximab moiety that binds a target protein (EGFR) to facilitate its uptake and degradation as suggested by Bertozzi. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art recognizes M6P conjugates can shuttle binding partners to lysosomes for degradation and would recognize the compound of Hamdaoui and Barragen serving this purpose. Claims 18, 23, and 30-31 rejected under 35 U.S.C. 103 as being unpatentable over Hamdaoui (Bull Soc. Chim. Fr., 1994, cited on PTO-892), Barragan (Chem. Commun., 2001, IDS filed January 10, 2024), and Bertozzi (WO 2020/132100, IDS filed September 5, 2024) as applied to claims 1, 5, 7, 21-22, 24, 29-30, 39-41, 45, 48, 53, 61, 70, 73, 119, 123, and 128 above in view of Garcia (US 8,962,573, IDS filed September 5, 2024). The English translation relied upon was provided by the Examiner. Regarding claims 18, 23, and 31. As discussed above, the prior art render obvious the compound of claim 1 for shuttling binding partners to lysosomes. They do not teach a compound wherein the linking group is PNG media_image16.png 93 159 media_image16.png Greyscale wherein the phenyl can be substituted with an alcohol group. However, Garcia teaches comparable compounds that target the mannose 6-phosphate receptor with a high affinity PNG media_image17.png 119 236 media_image17.png Greyscale for enzyme replacement therapies (abstract). Garcia teaches comparable compounds to be conjugates PNG media_image18.png 192 534 media_image18.png Greyscale (drawings pg. 7, figure 7C). Garcia teaches the mannose group can be connected to the linker with an S atom (col. 3, lines 40-67). Garcia teaches the linker L is a substituted or not, linear or branched alkyl or alkenyl chain, particularly a substituted or not, linear or branched C-C alkyl or alkenyl chain, wherein one or more carbon atom of said chain are optionally replaced by a chemical group selected from the group consisting of ether, amine, thioether, amide urea, carbamate, and cyclic or hetero cyclic systems, said cyclic or heterocyclic systems being saturated or not and substituted or not, provided that said chain separates the A and the Y moieties by at least 4 consecutive atoms (col 5, lines 27-39). Garcia teaches the cyclic or heterocyclic system may be substituted by functional groups such as an alcohol (col. 5, lines 61-66). Garcia teaches modifications to linker can affect steric hindrance around M6P binding sights and affect overall binding affinity (col. 4, lines 52-57). Taken together it would have been prima facie obvious to further modify the compound of Hamdaoui, Barragan and Bertozzi by substituting the oxophenylthiourea group with a sulfophenylurea group that can be substituted with an alcohol group as taught by Garcia. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as these are known tolerable linking groups in order to optimize steric hindrance of the M6P binding sites and overall binding affinity. Optimization of linking groups in mannose conjugation is a known technique in the art. Claims 1, 5, 7, 21-22, 24, 39-41, 45, 48, 53-54, 62, 73 are rejected under 35 U.S.C. 103 as being unpatentable over Ye (Biochemistry, 2005, cited on PTO-892) in view of Barragan (Chem. Commun., 2001, IDS filed January 10, 2024). The English translation relied upon was provided by the Examiner. Regarding claims 1, 5, 7, 21-22, 24, 39-41, 45, 48, 53-54, 62, 73: Ye teaches triplex-forming oligonucleotide to BSA-(M6P)20 conjugates (abstract). Ye teaches M6P is a ligand for the M6P/IGF II receptor which is upregulated in HSCs (pg. 4474, col. 1, para. 2). Ye teaches the M6P-BSA conjugate enhances uptake (pg. 4474, col. 2, para. 3). Ye teaches the conjugate has the following structure: PNG media_image19.png 56 180 media_image19.png Greyscale wherein M6P-BSA has the following structure PNG media_image20.png 80 191 media_image20.png Greyscale (pg. 4467, figure 1). BSA is a protein and thus has many consecutive atoms as well as branching groups. The compound of Ye encompasses the structural formulas as recited by instant claims 1, 5, 7, 21-22, 24, 29-30, 39-41, 45, 48, 53, 61, 70, 73, 119, and 128 except wherein W is a non-hydrolyzable hydrophilic head group. However, Barragan teaches a hydrolytically stable sugar phosphonate coupled to a steroid (i.e. a biomolecule) via a long and semi-rigid spacer (synthesized via a 12-step sequence) binds both to the mannose-6-phosphonate receptors of certain cancer cells and to the lipid bilayer of vesicles, thereby serving as a multivalent adhesive between cell and vesicle surfaces (abstract). Barragan teaches the use of mannose-6-phosphate moieties to target bioactive molecules is not as attractive as it might seem (pg. 1, col. 1, para. 2). The problem lies in the susceptibility of sugar phosphates to hydrolysis by various phosphatase enzymes (pg. 1, col. 1, para. 2). To circumvent this problem, we have recently developed synthetic routes to two phosphonate analogs of mannose-6-phosphate (M6-P); one is isosteric with the phosphate moiety while the other is not.5 Both, however, are hydrolytically stable (pg. 1, col. 1, para. 2). Upon submitting the analogs for biological testing, it was found that the isostere (but not the non-isostere) binds to M6-P receptors as effectively as does M6-P itself (pg. 1, col. 1, para. 2).. Barragan teaches the compound 14 has the following structure PNG media_image12.png 90 311 media_image12.png Greyscale wherein R = H, R’ = Na+ (pg. 85, scheme 1, compound 14). Barragan teaches compound 14 binds to cancer cells and vesicles and serves as an adhesive between living and chemical systems (pg. 85, col. 1, para. 3). Taken together it would have been prima facie obvious to modify the compound of Ye such that the phosphate moiety is replaced with a hydrolytically stable phosphonate as suggested by Barragan. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order to improve hydrolytic stability of the compound while maintaining the compounds ability to bind M6-P receptors. 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, 3, 5, 7, 18, 21-24, 29-31, 39-41, 45, 48, 50, 53-55, 57, 61-63, 65, 68, 70, 73, are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of patented copending application 17/792,027 (US 2023/0158155, cited on PTO-892, allowance mailed July 7, 2026). Although the claims at issue are not identical, they are not patentably distinct from each other because: The patented claims teach PNG media_image21.png 651 589 media_image21.png Greyscale PNG media_image22.png 446 585 media_image22.png Greyscale (claim 142). The patented claims further teach wherein PNG media_image23.png 576 686 media_image23.png Greyscale (claim 151). These formulae encompasses the claimed compounds. Claims 119, 123, and 128 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of patented copending application 17/792,027 (US 2023/0158155, cited on PTO-892, allowance mailed July 7, 2026) as applied to claims 1, 3, 5, 7, 18, 21-24, 29-31, 39-41, 45, 48, 50, 53-55, 57, 61-63, 65, 68, 70, 73 above in view of Bertozzi (WO 2020/132100, IDS filed September 5, 2024). Although the claims at issue are not identical, they are not patentably distinct from each other because: Regarding claims 119, 123, and 128: As discussed above, the patented claims teach a cell surface mannose-6-phosphate receptor (M6PR) binding compound comprising an antibody or antibody fragment that specifically binds a target protein. They do not teach methods of internalizing the target protein in a cell to facilitate cellular uptake and degradation of the target protein or wherein the compound binds a target protein in order to treat a disease associated with a target protein. However, Bertozzi teaches bifunctional molecules that include a first moiety that specifically binds a cell surface molecule or extracellular molecule, and a second moiety that specifically binds a lysosomal targeting molecule. The bifunctional molecules find use e.g., for targeted degradation of cell surface and extracellular molecules (e.g., proteins) via the endosomal/lysosomal pathway (abstract). Bertozzi teaches comparable isothiocyanate M6P binding groups can be conjugated to proteins used in the invention (pg. 2, lines 24-28, drawings pg. 7, figure 7). Bertozzi teaches the bifunctional molecules internalize a target protein and degrade the target protein (drawings, pg. 1, figure 1). Bertozzi teaches poly(M6Pn) labeled antibodies, such as with cetuximab, can shuttle their binding partner EGFR for degradation (pg. 38, lines 24-25). Bertozzi teaches EGFR is known to induce proliferation and angiogenesis in hepatocellular carcinoma (pg. 40, lines 10-14).Bertozzi teaches the bifunctional compounds can be used to treat cancer (pg. 24, lines 26-30). Taken together it would have been prima facie obvious to modify the compound of patenting claims such that the antibody is cetuximab moiety that binds a target protein (EGFR) to facilitate its uptake and degradation for the treatment of cancer as suggested by Bertozzi. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art recognizes M6P conjugates can shuttle binding partners to lysosomes for degradation and would recognize the compound of patented claims comprising an antibody and M6Pr surface binding molecule serving this purpose. Conclusion No claims are allowed in this action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 AM - 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, Scarlett Y Goon can be reached at 571-270-5241. 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. /SAMUEL L GALSTER/Examiner, Art Unit 1693