Any 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 .
Election/Restrictions
Applicant’s election of Group I, claims 1-3, 7-20, 22-24, 30, 33, and 40 in the reply filed on 11/12/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
In response to species election, applicant elected species for both A and B subunit sequences as C10A/K15A/L17D in SEQ ID NO: 1 and both C and D are C10A/K15A/V121R in SEQ ID NO: 1, reading on claims 1-3, 7-8, 16-17, 20, 22-24, 30, 33, and 40. Any claim does not explicitly show a mutation of C10A/K15A/L17D and C10A/K15A/V121R are considered non-elected species and withdrawn.
Claim Status
Claims 1-3, 7-20, 22-24, 30, 33, and 40 are pending.
Claims 4-6, 21, 25-29, 31-32, 34-39, and 41-48 are cancelled.
Claims 18-19 are withdrawn as being directed to a non-elected species, the election having been made on 11/12/2025.
Claims 1-3, 7-17, 20 22-24, 30, 33, and 40 have been examined.
Priority
This application is a 371 of PCT/US2020/040873 07/06/2020
PCT/US2020/040873 has PRO 62/871,247 07/08/2019
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/1/2023, 10/12/2023, 4/29/2025, 11/12/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 USC § 112
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 3, 7-13, and 33 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.
With respect to claim 3, the phrase “amino acids positions selected from the list comprising:” at line 3 is an improper Markush grouping. A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. See MPEP 2173.05(h).
With respect to claim 7, similar to claim 3, the phrase “amino acids positions selected from the list comprising:” at line 2-3 is an improper Markush grouping.
With respect to claim 8, similar to claim 3, the phrase “amino acids positions selected from the list comprising:” at line 2-3 is an improper Markush grouping.
With respect to claim 9, similar to claim 3, the phrase “amino acids positions selected from the list comprising:” at line 2-3 and 5-6 is an improper Markush grouping.
With respect to claim 10, similar to claim 3, the phrase “said mutations is selected from the list comprising:” at line 2-3 is an improper Markush grouping.
With respect to claim 11, similar to claim 3, the phrase “said mutations is selected from the list comprising:” at line 2-3 is an improper Markush grouping.
With respect to claim 12, similar to claim 3, the phrase “said mutations selected from the list comprising:” at line 2-3 is an improper Markush grouping.
With respect to claim 13, similar to claim 3, the phrase “said mutations selected from the list comprising:” at line 2-3 is an improper Markush grouping.
With respect to claim 33, the phrase “said linker is selected from the list comprising:” is an improper Markush grouping.
Appropriate correction is required
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 20, 22-24, and 40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Walker et al. (US 8,633,153 B2, cited in IDS 9/1/2023) and evidenced by (i) Neumann et al. (Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1313-9) and (ii) evidenced by Tomar et al. (PLoS One. 2012;7(9):e43522).
Claim 1 is drawn to a recombinant tetramer transthyretin (TTR) protein complex; wherein, each subunit of SEQ ID NO: 1 (A, B, C, and D) contains at least one mutation in favor over the formation of ABAB tetramer or CDCD tetramer.
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Walker et al. teach a wild-type monomer polypeptide sequence of Transthyretin (TTR) as SEQ ID NO: 1 (col 7, line 47-61). Walker et al. teach a recombinant TTR tetramer complex of PTH-TTR(C10A/K15A/G83C) comprising a mutation of K15 by A15 (col 23, Example 8, line 40-41). Neumann et al. is cited as evidenced to show Lys15 not only involved in ligand binding but also inherent for tetramer stabilization of Transthyretin known in in art (p1314, col 2, para 1 and Fig 1-2) and consistent with applicant’s admission of C10A/K15A mutation of TTR favor ABAB or CDCD tetramer formation in claims 1-3. Tomar et al. is further cited to show amino acids in the dimer-dimer interphase of units A and C involved in ligand binding and/or stability of the wild-type tetramer comprising Lys15, Leu 17, Thr106, and V121 (p5, Fig 2; p2, col 2, para 1).
With respect to claim 20, Walker et al. teach any number of peptide can be conjugated to the recombinant TTR tetramer complex including cytotoxic T-lymphocyte antigen 4/CTLA4, an immune checkpoint receptor (col 5, line 1-2 and 7-8), or TTR-GLP-1 fusion protein capable of binding to a GLP-1 receptor (col 13, line 50-55), reading on an antigen binding proteins as receptors themselves are antigens. A conjugated cellular receptor or ligand reads on an antigen because it can induce immune response.
With respect to claims 22-23, Walker et al. teach a peptide can be fused to either the C-terminus or N-terminus of a TTR variant protein (col 3, line 1-8; col 23, Example 8/line 25-26 and Example 9/line50-51). Walker et al. teach fusing a peptide to either the C-terminus or N-terminus of PTH-TTR(C10A/K15A/G83C) does not have a significant impact on its oligomeric structure (col 23, line25-27).
With respect to claim 24, Walker et al. teach the use of a linker or spacer between each of the domain of the fusion protein such as TTR-GLP-1 fusion protein or a recombinant TTR tetramer complex fusion to a cytotoxic T-lymphocyte antigen 4/CTLA4 described in rejection of claim 20. Walker et al. teach a linker can be introduced to make chimeric TTR fusion polypeptide via recombinant DNA technology (col 12, line 8-21).
With respect to claim 40, Walker et al. teach a pharmaceutical composition comprising the recombinant TTR tetramer complex (col 2, line 29-32; col 16, line 4-20).
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)(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, 20, 23-24, and 40 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Walker et al. (WO 2019/070901 A1, previously cited 9/1/2023) and (i) evidenced by Neumann et al. (Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1313-9) and (ii) evidenced by Tomar et al. (PLoS One. 2012;7(9):e43522)..
Walker et al. show transthyretin (TTR) fusion proteins for dimerization and tetramerization of antibodies (Abstract; Fig 1a-1c shown as follows). Walker et al. teach transthyretin (TTR) fusion protein comprising SEQ ID NO: 1 (100% identity to the instant SEQ
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ID NO: 1) or its variants present as a tetramer [0095]. Walker et al. teach a TTR variant of SEQ ID NO: 1 comprising K15A and C10A mutations [00120]. Neumann et al. is cited as evidenced to show Lys15 not only involved in ligand binding but also inherent for tetramer stabilization of Transthyretin known in in art (p1314, col 2, para 1 and Fig 1-2) and consistent with applicant’s admission of C10A/K15A mutation of TTR favor ABAGB or CDCD tetramer formation in claims 1-3. Tomar et al. is further cited to show amino acids in the dimer-dimer interphase of units A and C involved in ligand binding and/or stability of the wild-type tetramer comprising Lys15, Leu 17, Thr106, and V121 (p5, Fig 2; p2, col 2, para 1).
With respect to claims 20 and 24, Walker et al. teach homotetramer fusion proteins comprising four antigen binding proteins (e.g., a Fab tetramer) or eight antigen binding proteins (e.g., an Ab tetramer). Walker et al. teach the homotetramer fusion proteins comprising antigen binding proteins linked to a TTR protein complex, wherein the TTR protein complex is a TTR tetramer [00108]. Walker et al. show transthyretin (TTR) fusion proteins for dimerization and tetramerization of antibodies via a linker [0008, Fig 1a-1c, 0176-0178].
With respect to claim 23, Walker et al. teach the C-terminus of the antigen binding protein is directly fused to an N-terminus present in the TTR protein complex [0008].
With respect to claim 40, Walker et al. teach a pharmaceutical composition comprising the recombinant TTR tetramer complex [00132].
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
1. Claims 1-3, 20, 22-24, 30, 33, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Walker et al. (WO 2019/070901 A1) and evidenced by (i) Neumann et al. (Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1313-9) and (ii) evidenced by Tomar et al. (PLoS One. 2012;7(9):e43522)as applied to 1-3, 20, 23-24, and 40 and further in view of Walker et al. (US 8,633,153 B2, referred to the ‘153 patent) and Long et al. (J. Biol. Chem. (2018) 293(23) 9030–9040).
Claim 33 is drawn to antigen binding protein or peptide is attached to the TTR protein complex at the C-terminus of a TTR subunit.
Walker et al. and evidenced by Neumann et al. and Tomar et al. teach transthyretin (TTR) fusion proteins for dimerization and tetramerization of antibodies (Abstract; Fig 1a-1c) comprising a poly-glycine linker [0087].
Walker et al. and evidenced by Neumann et al. and Tomar et al. do not specify antigen binding protein or peptide is attached to the TTR protein complex at the C-terminus of a TTR subunit.
The ‘153 patent teach a peptide can be fused to either the C-terminus or N-terminus of a TTR variant protein (col 3, line 1-8; col 23, Example 8/line 25-26 and Example 9/line50-51). Walker et al. teach fusing a peptide to either the C-terminus or N-terminus of a TTR variant tetramer without a significant impact on its oligomeric structure (col 23, line25-27), further reading on claims 22-23.
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Walker et al. and evidenced by Neumann et al., evidenced by Tomar et al. and in view of the ‘153 patent do not specify a glycine linker as a single glycine residue or a homopolymer of glycine.
Long et al. teach optimizing the length and amino acid sequence of a peptide linker to improve binding, stability, and other biophysical properties of recombinant antibody constructs (Abstract). Long et al. teach a peptide linker can be optimized from 1 to 25 amino acids and can be either a single glycine or a homopolymer of glycine as well as a mixture of glycine and serine shown as follows (p9032, Fig 1A), reading on G, GG, GGG, GGGG or a homopolymer comprising up to 25 glycine residues, reading on claims 30 and 33.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Walker et al. and evidenced by Neumann et al. and Tomar et al. with (ii) the ‘153 patent and (iii) Long’s peptide linker because (a) Walker et al. and evidenced by Neumann et al. and Tomar et al. teach a chimeric transthyretin (TTR) fusion proteins (Abstract; Fig 1a-1c) comprising a poly-glycine linker [0087], (b) the ‘153 patent teach a peptide can be fused to either the C-terminus or N-terminus of a TTR variant protein (col 3, line 1-8; col 23, Example 8/line 25-26 and Example 9/line50-51) without a significant impact on its oligomeric structure (col 23, line25-27), and (c) Long et al. teach a peptide linker can be optimized with either a single glycine or a homopolymer of glycine as well as a mixture of glycine and serine for engineering a recombinant antibody (p9032, Fig 1A). The combination would have reasonable expectation of success because all Walker et al., the ‘153 patent, and Long et al. teach the use of a glycine-rich linker for engineering a recombinant antibody construct.
2. Claims 1-3, 7-17, 20, 22-24, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Walker et al. (WO 2019/070901 A1, cited in IDS dated 9/1/2023) in view of Neumann et al. (Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1313-9) and Walker et al. (US 8,633,153 B2, referred to the ‘153 patent) as applied to 1-3, 20, 22-24, and 40 and further in view of Tomar et al. (PLoS One. 2012;7(9):e43522), Prapunpoj et al. (FEBS Journal 276 (2009) 5330–5341), and Isom et al. (PNAS. 2010; 107 (37):16096-16100).
Claims 7-13 are drawn to one or more mutation site of subunits A, B, C, and D.
Walker et al. in view of Neumann et al. and the ‘153 patent teach Lys15 of TTR not only involved in ligand binding but also inherent for tetramer stabilization of Transthyretin known in in art (see Neumann et al. p1314, col 2, para 1 and Fig 1-2).
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Walker et al. in view of Neumann et al. dis not teach further mutation of other amino acid residues in the dimer-dimer interphase of destabilized wild type tetramer but favor ABAB tetramer or CDCD tetramer formation.
Tomar et al. teach ligand bound wt TTR complex and amino acids in the dimer-dimer interphase of unit A and C involved in ligand binding and/or stability of the wild-type tetramer comprising Lys15, Leu 17, Thr106, and V121 (p5, Fig 2; p2, col 2, para 1).
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Prapunpoj et al. is cited to show that a common knowledge of a person with ordinary skill in the art knows the primary polypeptide sequence and secondary structures of TTR monomer shown as follows (p5331, Fig 1) and the interaction of force of hydrogen bonding and hydrophobic interactions for dimer-dimer contact (p5332, Fig 2; p5332, col 2, para 1). K15A was known to destroy hydrogen bonding to destabilize a wild-type TTR tetramer. Prapunpoj et al. show multiple sequence alignment of Leu 17 residue in a ligand binding site and between unit A and C as taught by Tomar et al. (p5, Fig 2) is conserved across multiple species, suggesting mutation of L17 may destabilize hydrophobic interaction of the wild type tetramer. Isom et al. teach charges are inherently incompatible with hydrophobic environment known in the art (Abstract) and Isom et al. suggest substitution of a hydrophobic leucine inside a folded protein with a negatively charged amino acid (reading on aspartic acid or functionally similar variant of glutamic acid in an example of Fig 2). Thus, one of ordinary skill in the art would have found it obvious to introduce L17D or L17E mutation into the mutant C10A/K15A of TTR to further destabilize wild type tetramer in favor of ABAB or CDCD tetramer formation.
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Furthermore, Prapunpoj et al. show multiple sequence alignment of the conserved Val 121 residue in a ligand binding site shown as follows (p5331, Fig 1), between unit A and C as taught by Tomar et al. (p5, Fig 2) across multiple animal species, suggesting mutation of Val 121 may destabilize hydrophobic interaction of the wild type tetramer. Tomar et al. show Prapunpoj’s Val 121 in the boundary of β-strand (p5, Fig 2) for the interaction with a ligand and/or other hydrophobic residues. Isom et al. teach charges are inherently incompatible with hydrophobic environment known in the art (Abstract). One of ordinary skill in the art would at once envisage (i) to avoid substitution of V121 by a hydrophobic amino acid and (ii) introduce a charged amino acid to destroy the hydrophobic interaction. Although the cited refences did not explicitly teach a specific charged amino acid to substitute Val 121, the charged amino acid residues are known to be limited to (a) positively charged Arg (R), Lys(K), and His (H) or (b) negatively charged Glu (E) and Asp (D), reading on both C and D are C10A/K15A/V121R in SEQ ID NO: 1.
For the combined teachings described above, one of ordinary skill in the art would mutate C10A, K15A, L17[DE] in favor of ABAB tetramer and C10A,K15A,Val121[KRH] for CDCD tetramer, reading on claims 7-17 and including the elected species C10A/K15A/L17D and C10A/K15A/V121R mutants of a TTR tetramer in claims 16-17. See MPEP 2144. The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). Also see MPEP 2141.03 (I). A person of ordinary skill in the art is well defined as a person of ordinary creativity able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at ___, 82 USPQ2d at 1396.
One of ordinary skill in the art before the effective fining date of this invention would have found it obvious to combine (i) Walker et al. (WO 2019/070901 A1) in view of Neumann et al. and (ii) Tomar et al. in view of Prapunpoj et al. because (A) Walker et al. in view of Neumann et al. teach mutations of C10A/K15A of transthyretin (TTR) fusion proteins for dimerization and tetramerization of antibodies (Walker et al. Abstract; Fig 1a-1c) and Lys15 not only involved in ligand binding but also inherent for tetramer stabilization of Transthyretin known in in art (Neumann et al. p1314, col 2, para 1 and Fig 1-2), (B) Tomar et al. teach ligand bound wt TTR complex and amino acids in the dimer-dimer interphase of unit A and C involved in ligand binding and/or stability of the wild-type tetramer comprising Lys15, Leu 17, Thr106, and V121 (p5, Fig 2; p2, col 2, para 1), and (C) Prapunpoj et al. is cited to show that a common knowledge of a person with ordinary skill in the art knows the primary polypeptide sequence and secondary structures of TTR monomer (p5331, Fig 1) and the interaction of force of hydrogen bonding and hydrophobic interactions for dimer-dimer contact (p5332, Fig 2; p5332, col 2, para 1). The combination would have reasonable expectation of success because all references either explicitly teach or suggest potential amino acid mutations in the dimer-dimer interface to destabilize a wild-type TTR tetramer.
One of ordinary skill in the art before the effective fining date of this invention would have found it obvious to combine (i) Walker et al. in view of Neumann et al., Tomar et al. and Prapunpoj et al. and (ii) Isom’s teaching charged amino acids in hydrophobic environment because (A) Walker et al. in view of Neumann et al., Tomar et al. and Prapunpoj et al. teach hydrophobic and conserved amino acid residues of Leu 17 and Val 121 across various animal species are involved in ligand-binding and/or stability of wild-type TTR tetramer and (B) Isom et al. teach charges are inherently incompatible with hydrophobic environment known in the art (Abstract); namely, it is obvious for one of ordinary skill in the art to substitute a hydrophobic amino acid within a hydrophobic environment by a charged amino acid (either positively or negatively charged amino acid) to destabilize hydrophobic interaction force of a wild-type TTR tetramer in favor of engineered ABAB or CDCD tetramer formation. The combination would have reasonable expectation of success because substitution of a hydrophobic amino acid by a charged amino acid incompatible with hydrophobic environment in a protein is expected to destabilize the original protein folding structure.
Additional reference
Blake et al. Protein-DNA and protein-hormone interactions in prealbumin: a model of the thyroid hormone nuclear receptor? Nature. 1977 Jul 14;268(5616):115-20. Blake et al. teach various potential amino acid residues involved in ligand binding and/or stability of the wild-type TTR tetramer.
Ciccone et al. Transthyretin complexes with curcumin and bromo-estradiol: evaluation of solubilizing multicomponent mixtures. N Biotechnol. 2015 Jan 25;32(1):54-64. Ciccone et al. also teach various potential amino acid residues involved in ligand binding and/or stability of the wild-type TTR tetramer.
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, 7-17, 20, 23-24, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 8,633,153 B2 (the ‘153 patent, cited in IDS) in view of Walker et al. (WO 2019/070901 A1, cited in IDS), Neumann et al. (Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1313-9), Tomar et al. (PLoS One. 2012;7(9):e43522), Prapunpoj et al. (FEBS Journal 276 (2009) 5330–5341), and Isom et al. (PNAS. 2010; 107 (37):16096-16100).
Claim 1 of the ‘153 patent disclosed a transthyretin (TTR) variant comprising mutation at Cysteine 10 and Lysine 15.
Claim 2 of the ‘153 patent disclosed C10A mutation.
Claims 1-2 of the ‘153 patent did not disclosed the use of the TTR variant comprising C10A and K15A with other mutations to form a chimeric TTR tetramer.
The relevancy of Walker et al. in view of Neumann et al., Tomar et al., Prapunpoj et al., and Isom et al. as applied to claims 1-3, 7-17, 20, 23-24, and 40 above not repeated here.
Because Walker et al. in view of Neumann et al., Tomar et al., Prapunpoj et al., and Isom et al. teach beneficial modification of a TTR variant comprising C10A and K15A mutations with additional mutations for dimerization and tetramerization of antibodies, one of ordinary skill in the art would have found it obvious to combine claims 1-2 of the ‘153 patent with Walker et al. in view of Neumann et al., Tomar et al., Prapunpoj et al., and Isom et al. to generate a chimeric TTR variant tetramer as claimed.
Thus, claims 1-2 of the ‘153 patent in view of Walker et al., Neumann et al., Tomar et al., Prapunpoj et al., and Isom et al. are obvious to the instant claims 1-3, 7-17, 20, 23-24, and 40.
Claims 1-3, 7-17, 20, 22-24, and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 12,269,898 B2 (the ‘898 patent) in view of Walker et al. (WO 2019/070901 A1, cited in IDS), Neumann et al. (Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1313-9), Walker et al. (US 8,633,153 B2, cited in IDS, referred to the ‘153 patent), Tomar et al. (PLoS One. 2012;7(9):e43522), Prapunpoj et al. (FEBS Journal 276 (2009) 5330–5341), and Isom et al. (PNAS. 2010; 107 (37):16096-16100).
Claim 1 of the ‘898 patent disclosed a transthyretin (TTR) variant tetramer complex.
Claim 2 of the ‘898 patent disclosed a transthyretin (TTR) variant tetramer complex comprising C10A and K15A mutations.
Claims 1-2 of the ‘898 patent did not disclosed the use of the TTR variant further comprising an additional mutation.
The relevancy of Walker et al. in view of Neumann et al., the ‘153 patent, Tomar et al., Prapunpoj et al., and Isom et al. as applied to claims 1-3, 7-17, 20, 22-24, and 40 above not repeated here.
Because Walker et al. in view of Neumann et al., the ‘153 patent, Tomar et al., Prapunpoj et al., and Isom et al. teach beneficial modification of a TTR variant comprising C10A and K15A mutations for dimerization and tetramerization of antibodies, one of ordinary skill in the art would have found it obvious to combine claims 1-2 of the ‘898 patent with Walker et al. in view of Neumann et al., the ‘153 patent, Tomar et al., Prapunpoj et al., and Isom et al. to generate a TTR variant tetramer as claimed.
Thus, claims 1-2 of the ‘898 patent in view of Walker et al., the ‘153 patent, Neumann et al., the ‘153 patent, Tomar et al., Prapunpoj et al., and Isom et al. are obvious to the instant claims 1-3, 7-17, 20, 22-24, and 40.
Conclusion
No claim is allowed.
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/J.L/Examiner, Art Unit 1658
23-January-2026
/LI N KOMATSU/ Primary Examiner, Art Unit 1658