DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 05, 2025 has been entered.
2. Claim 232 has been amended. Claims 232-234, 236-238, 242 and 243 are currently being examined as drawn to the elected species.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
3. Claims 232-234, 236-238, 242 and 243 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US 2005/0027109 A1 (Mezo et al. Feb. 3, 2005), “Mezo” in view of WO 2013/00355 (Ploegh et al. Jan. 03, 2013, IDS), “Ploegh” for the reasons of record.
Mezo teaches producing chimeras comprising biologically active molecules, including polypeptides, and the immunoglobulin Fc region and portions thereof that bind the Fc receptor, wherein a) the portion of an immunoglobulin constant region comprises an N terminus cysteine and b) the biologically active molecule comprises a functional group capable of reacting with an N terminus cysteine to form a bond. See claims 1-13.
The bond formed in the chimeric protein is a native peptide bond formed by native ligation via a thioester functional groups. See ¶¶ 0006-0009, 0014, 0039 and Figs. 1 and 4.
Mezo teaches the chimeric protein can comprise linkers such as polyethylene glycol (PEG) or peptides. See ¶¶ 0155-0166. Mezo teaches that the linker can be linked to the Fc cysteine by native peptide ligation. See ¶¶ 0162-0163.
The N-terminal cysteine sequence includes CPPCP. See Figs. 2 and 4.
Mezo teaches that the chimeric proteins can bind to FcRn via the Fc domain thereby increasing the half-life of the protein. See ¶¶ 0096, 0104 and 0146-0148 and claims 12 and 13.
Mezo does not teach a chemical structure with a reactive terminal azide or alkyne linked to the Fc domain.
Ploegh teaches a method of installing click chemistry handles to the N- or C-terminus of a target protein with a sortase to generate protein conjugates. See abstract, [0005-0015]. claims 1 and 3, and Figs. 1 and 2.
Ploegh teaches that the click chemistry handles including azide, cyclooctyne, dibenzoazacyclooctyne (DIBAC). See ¶¶ [0065], [0238-0242], and [0260-0262], Figs. 1, 12, 13 and claims 11, 18, and 61.
Ploegh teaches the key advantages of using a sortase transacylation strategy to modify a target protein are the ease of synthesis, and execution of the reaction on native proteins under physiological conditions. ¶¶ [0085] and [0204]. Ploegh also teaches that the method allows for N to N and C to C proteins fusions to allow optimal protein activity. See ¶¶ [0202-0203]
Ploegh teaches adding detectable labels, including fluorescent proteins, and PEG to extend the half-life of the proteins with the sortase method. See ¶¶ [0068-0069] and[0211-0212] and claims 43-45.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Mezo and Ploegh and use the method of Ploegh to add click chemistry handles including azide, cyclooctyne, dibenzoazacyclooctyne (DIBAC) to the chimeric Fc proteins of Mezo to add detectable labels for detection or PEG to extend the half-life of the chimeric Fc proteins as taught by Ploegh. One would have been motivated to use the method of Ploegh to add click chemistry handles including azide, cyclooctyne, dibenzoazacyclooctyne (DIBAC) to the chimeric Fc proteins of Mezo because Ploegh teaches the key advantages of using a sortase transacylation strategy to modify a target protein are the ease of synthesis, and execution of the reaction on native proteins under physiological conditions and that the method allows for various orientation of the conjugates to optimize the activity of the fusion proteins.
4. Claims 232-234, 236-238, 242 and 243 are alternatively rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US 2005/0027109 (Mezo et al. Feb. 3, 2005), “Mezo” in view of WO 2013/003555 (Ploegh et al. Jan. 03, 2013, IDS), “Ploegh” as applied to claims 232-241 above, and further in view of WO 99/02711 (Strom et al. Jan. 21, 1999), “Strom” for the reasons of record.
Mezo and Ploegh teach as set forth above.
Mezo additionally teaches that the chimeric proteins can contain a hinge region of an immunoglobulin. See ¶¶ [0140, 0144, and 0145].
Mezo and Ploegh teach as set forth above, but do not teach EPKSCDKTHTCPPCP (SEQ ID NO: 135) in the chimeric Fc proteins.
Strom teaches making fusion proteins with immunoglobulin hinge linker regions. See abstract, claims 1-23, and Table on p. 8.
Strom teaches that the proteins can be attached to the hinge region by the amino or carboxyl terminus of the proteins. Strom teaches that this is advantageous in that allows the carboxyl terminus of the protein to interact or bind ligands. See p. 2-line 23-30.
Strom teaches that the hinge regions are flexible and allows freedom of movement. See p. 6-lines 17-22.
Strom teaches that the IgG1 hinge peptide comprises EPKSCDKTHTCPPCP. See Table p. 8.
It would have been prima facie obvious at the time the invention was made given that the level of skill in the art was high to combine the teachings of Mezo, Ploegh and Strom and use a hinge at the N-terminus of a Fc chimera using the hinge peptide linkers of Strom because Mezo teaches that the chimeric proteins can contain a hinge region of an immunoglobulin and Strom teaches that the hinge regions are flexible and allow freedom of movement and allow the carboxyl terminus of the protein to interact or bind ligands. Thus one would have been motivated to use the hinge peptide linkers of Strom to provide flexibility to the conjugates of Mezo and Ploegh so that their activity could be maintained.
Response to Arguments
5.
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Applicant’s arguments have been considered, but have not been found.
Regarding (1) and the amendment to include the structures of J, J includes a bond, an amide, and an amino acids. These structures are not particularly limited and include peptides like the LPXTG sortase recognition motif. Thus, this limitation does not differentiate the claims from the prior art.
Regarding (2), a peptide bond does not exclude peptides like LPXTG that contains peptide bonds. Thus, this limitation does not differentiate the claims from the prior art.
Regarding (3), although the claims no longer recite an organic acid residues, the amended claims do not exclude peptides like LPXTG as set forth above. Additionally, The N-terminal cysteine sequence includes CPPCP of Mezo includes a stretch of amino acids found in at least SEQ ID NO: 135.
Regarding the examples of structures in Figures 3 and 4, the claims are not limited to the structures therein . Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Thus, Applicant’s arguments are not found persuasive for the reasons previously set forth and above and the rejections are maintained for the reasons of record.
New Claim Rejections - 35 USC § 103
6. Claims 232, 233, 242 and 243 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over WO 2007/048127 A2 (Barbas III, C. l. 26 April 2007, IDS), “Barbas” in view of WO 99/02711 (Strom et al. Jan. 21, 1999), “Strom”.
Barbas teaches a method for labeling a protein molecule that includes therein the Fc portion of an antibody molecule comprising the steps of: (1 ) providing a protein molecule that includes therein the Fc portion of an antibody molecule, the protein molecule having a reactive amino acid residue selected from the group consisting of an azide-substituted amino acid residue and an alkyne-substituted amino acid residue; (2) providing a targeting molecule, the targeting molecule having a reactive residue selected from the group consisting of an azide and an alkyne such that the protein molecule and the targeting molecule, taken together, have an azide modification and an alkyne modification; and (3) reacting the protein molecule with the targeting molecule by azide-alkyne [3 + 2] cycloaddition to produce a labeled protein molecule such that the targeting molecule solely directs the targeting of the labeled protein molecule to a target that is a soluble molecule or a cell-surface molecule. See ¶ [0010] and claim 3 and Figs. 1 and 12a.
Barbas teaches that an aldehyde-containing Fc protein is reacted with a hydroxylamine bearing an azide functionality to provide an azide-Fc. See ¶¶ 0044, 0112, 0113 and Fig. 12a.
Barbas teaches that the amino terminus can be mutated to a reactive cysteine. See ¶¶ 0066, 0114, 0165, 0166, 0172, 0188, 0203, and 0204 and claims 26 and 90.
Barbas teaches that the Fc fragment can include the hinge region. See ¶¶ 0064 and 0179 and claims 19-21.
Barbas teaches using linker molecules like polyethylene glycol (PEG). See abstract, ¶¶ 0019, 0023, 0068, 0069, 0191, 0201 and claims 27, 67 and 68.
Barbas teaches as set forth above, but does not teach EPKSCDKTHTCPPCP (SEQ ID NO: 135) in the chimeric Fc proteins.
Strom teaches as set forth above.
It would have been prima facie obvious at the time the invention was made given that the level of skill in the art was high to combine the teachings of Barbas and Strom and use a hinge at the N-terminus of the labeled Fc proteins using the hinge peptide linkers of Strom because Barbas teaches that the labeled Fc proteins can contain a hinge region of an immunoglobulin and Strom teaches that the hinge regions are flexible and allow freedom of movement and allow the carboxyl terminus of the protein to interact or bind ligands. Thus one would have been motivated to use the hinge peptide linkers of Strom to provide flexibility to the labeled Fc proteins of Barbas so that their activity could be maintained.
7. Claims 234 and 236-238 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over WO 2007/048127 A2 (Barbas III, C. l. 26 April 2007, IDS), “Barbas” in view of WO 99/02711 (Strom et al. Jan. 21, 1999), “Strom” as applied to claims 232, 233, 242 and 243 above, and further in view of Debets et al. (Chem. Commun. 2010 46: 97-99, of record), “Debets”.
Barbas and Strom teach as set forth above, but do not teach using a cycloalkyne or cyclooctyne.
Debets teaches that the Huisgen cycloaddition “click” reaction is a powerful method in the field of bio-conjugation because it is selective, fast, and high-yielding. See p. 97-left column.
Debets teaches an improvement to the reaction using a functionalized aza-cyclooctyne that eliminates the need for copper, which can interfere in subsequent uses and is toxic to cells. See abstract and p. 97.
Debets teaches the hybrid cyclooctyne structure aza-dibenzocyclooctyne (DIBAC), for performing the copper free click reaction. See p. 97 and Fig. 1-structure E and Scheme 1.
Debets teaches linking DIBAC and DIBC to PEG2000 and azide-containing CalB (AHA-CalB) or HRP. See pp. 98-99 and scheme 2.
Debets teaches that the DIBCs show fast and efficient modification, with DIBAC, in particular, being a highly efficient and versatile for copper free cycloaddition reactions. See p. 99-last two paragraphs.
It would have been prima facie obvious at the time the invention was made given that the level of skill in the art was high to combine the teachings of the Barbas and Strom and Debets to use the DIBCs, particularly DIBAC, of Debets as the alkyne of the method of Barbas and Strom because Debets teaches that the DIBCs show fast and efficient modification, with DIBAC, in particular, being a highly efficient and versatile for copper free cycloaddition reactions. One would have been motivated to use the reagents of Debets for copper free cycloaddition reactions given their efficiency and the elimination of copper reduces the potential for unwanted effects such as toxicity to cells.
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.
8. Claims 232, 233, 242, and 243 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-29 of U.S. Patent No. 11,220,556 (Capon D., Jan. 11, 2022) for the reasons of record.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘556 claims are drawn to:
27. A process for producing a compound having the structure:
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wherein A is a first polypeptide component of the compound; wherein C is a second polypeptide component of the compound, which polypeptide component has at its N-terminus a sequence selected from the group consisting of a cysteine, selenocysteine, CP, CPXCP (where X=P, R, or S) (SEQ ID NOs: 128-130), CDKTHTCPPCP (SEQ ID NO: 131), CVECPPCP (SEQ ID NO: 132), CCVECPPCP (SEQ ID NO: 133) and CDTPPPCPRCP (SEQ ID NO: 134) and comprises consecutive amino acids which (i) are identical to a stretch of consecutive amino acids present in a chain of an Fc domain of an antibody; and (ii) bind to an Fc receptor, wherein B is (a) an organic acid residue or (b) a stretch of consecutive amino acid residues which is, or is present in any of the following sequences: EPKSCDKTHTCPPCP (SEQ ID NO: 135), ERKCCVECPPCP (SEQ ID NO: 136), ELKTPLGDTTHTCPRCP(EPKSCDTPPPCPRCP)3 (SEQ ID NO: 137), or ESKYGPPCPSC (SEQ ID NO: 138); wherein the dashed line between B and C represents a peptidyl linkage between B and the N-terminus of C; wherein the solid line between A and B represents a nonpeptidyl linkage comprising the structure:
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wherein R1 is part of a cyclic structure, R2 is an organic structure which is connected to A, and R4 is an organic structure which is connected to B, wherein the cyclic structure comprises: the carbon attached to R2, R1, and may also comprise (a) R2, or (b) a derivative of A, and a first terminal reactive group which is an alkyne; b) obtaining a B′ which comprises B or a derivative of B, a second terminal reactive group and a third terminal reactive group, wherein the second terminal reactive group is an azide capable of reacting with the first terminal reactive group to form a non-peptidyl linkage, and the third reactive group is a thioester; c) obtaining a C′ which comprises C or a derivative of C, and a fourth terminal reactive group, wherein the fourth terminal reactive group is an amino acid or amino acid derivative capable of reacting with the third terminal reactive group to form a peptidyl linkage; and d) reacting A′, B′ and C′ in any order to produce the compound.
28. The process according to claim 27, wherein the fourth reactive group is cysteine, selenocysteine, homocysteine, or homoselenosysteine, or a derivative of cysteine, selenocysteine, homocysteine, or homoselenosysteine.
Thus B′ of the ‘556 claims has all of the properties of the currently claimed B’’ and is linked to an Fc protein with an N-terminal cysteine by a peptidyl linkage. The alkyne and azide could be used on either A or B′ to facilitate the optimal reaction to produce the claimed compound
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.
9. Claims 234 and 236-238 are rejected on the ground of nonstatutory double patenting as being unpatentable over 27-29 of U.S. Patent No. 11,220,556 (Capon D., Jan. 11, 2022), as applied to claims 232, 233, 242, and 243 above in view of Debets et al. (Chem. Commun. 2010 46: 97-99), “Debets” for the reasons of record.
The ‘556 claims teach as set forth above, but do not teach using a cycloalkyne or cyclooctyne.
Debets teaches that the Huisgen cycloaddition “click” reaction is a powerful method in the field of bio-conjugation because it is selective, fast, and high-yielding. See p. 97-left column.
Debets teaches an improvement to the reaction using a functionalized aza-cyclooctyne that eliminates the need for copper, which can interfere in subsequent uses and is toxic to cells. See abstract and p. 97.
Debets teaches the hybrid cyclooctyne structure aza-dibenzocyclooctyne (DIBAC), for performing the copper free click reaction. See p. 97 and Fig. 1-structure E and Scheme 1.
Debets teaches linking DIBAC and DIBC to PEG2000 and azide-containing CalB (AHA-CalB) or HRP. See pp. 98-99 and scheme 2.
Debets teaches that the DIBCs show fast and efficient modification, with DIBAC, in particular, being a highly efficient and versatile for copper free cycloaddition reactions. See p. 99-last two paragraphs.
It would have been prima facie obvious at the time the invention was made given that the level of skill in the art was high to combine the teachings of the ‘556 claims and Debets to use the DIBCs, particularly DIBAC, of Debets as the alkyne of the method of the ‘556 claims on either A or B′ because Debets teaches that the DIBCs show fast and efficient modification, with DIBAC, in particular, being a highly efficient and versatile for copper free cycloaddition reactions. One would have been motivated to use the reagents of Debets for copper free cycloaddition reactions given their efficiency and the elimination of copper reduces the potential for unwanted effects such as toxicity to cells.
Response to Arguments
10. Applicant argues that the filed terminal disclaimer filed November 5, 2025 explicitly states that the Applicant, Biomolecular Holdings LLC, has 100% interest in the referenced patents and the terminal disclaimer complies with all of the requirements of 37 CFR 1.321(c).
Applicant’s arguments have been considered, but have not been found persuasive because the terminal disclaimer has been disapproved. The terminal disclaimer was disapproved because the 1st page, paragraph 3, line 4 should read “full” statutory term. See Terminal Disclaimer review decision of November 09, 2025. Thus, given that the terminal disclaimer was disapproved the rejections are maintained for the reasons of record.
Conclusion
11. No claims allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
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/PETER J REDDIG/ Primary Examiner, Art Unit 1646