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 .
Claim 2 has been canceled. Claim 1 has been amended. Claims 16-21 have been added. Claims 1 and 3-21 are pending and under consideration.
Benefit of an earlier filing date is not extended to the ‘437 application for the reasons set forth in the prior Office action.
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 17 and 19 are rejected and claims 1 and 3-15 remain 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.
(A) Claims 1 and 17 recite “a peptide moiety having SEQ ID NO: 8 or an Fc variant thereof having 95% sequence identity to SEQ ID NO: 8, wherein the Fc variant has the same numbering as SEQ ID NO: 8, and then further recites “wherein one disulfide bridge links the cysteine residues located in position 11 of SEQ ID NO:8 of each moiety, and wherein the other disulfide bridge links cysteine residues located in position 14 of SEQ ID NO:8 of each moiety”. It is unclear if this requirement for the disulfide bridges between Cys 11 and Cys 11, and between Cys 14 and Cys 14 of SEQ ID NO:8 pertains to the sequence having 95% sequence identity to SEQ ID NO:8 as opposed to SEQ ID NO: 8.
(B) Claim 14 recites “wherein the lysine residue of “C” is located in position 31 or position 33 of SEQ ID NO:8. It is unclear if this limitation pertains to a sequence having 95% sequence identity to SEQ ID NO:8 as opposed to SEQ ID NO: 8.
(C) Claim 15 recites “wherein the cysteine residues in positions 46 and 106 of SEQ ID NO: 8 are connected to form a disulfide bridge and wherein the cysteine residues in positions 152 and 210 of SEQ ID NO: 8 are connected to form a disulfide bridge. It is unclear if this limitation pertains to a sequence having 95% sequence identity to SEQ ID NO:8 as opposed to SEQ ID NO: 8.
Applicant has amended claim 1 to state that “wheein the Fc variant amino acid sequence has the same numbering as SEQ ID NO:8”, this fails to clarify if the one disulfide bridge links the cysteine residues located in position 11 of the Fc variant of each moiety, and wherein the other disulfide bridge links cysteine residues located in position 14 of the Fc variant of each moiety in claim 1; if the lysine residue of “C” is located in position 31 or position 33 of the Fc variant in claim 14; and if the cysteine residues in positions 46 and 106 and positions 152 and 210 of the Fc variant are connected to form a disulfide bridge in claim 15.
The rejection of claims 1 and 3-15 are 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 is withdrawn in light of applicant’s amendment. Specifically claim 1 has been amended to state (a) that “A” is a moiety comprising SEQ ID NO: 7 and (b) that the Fc variant having 95% sequence identity to SEQ ID NO:8 differs from SEQ ID NO:8 only by conservative amino acid substitutions and said variant is capable of binding to another Fc variant by two disulfide bridges.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 6-11, 14, 15, 17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Lindhout et al (WO2024/155750, reference of the IDS filed 10/5/2025) in view of Shih et al (WO2025/148785) as evidenced by Zhu et al (U.S. 2022/0098242) and Liu and May (mAbs, 2012, Vol. 4, pp. 17-23).
Lindhout et al teach lysosomal targeting bifunctional molecules that target disease-causing extracellular proteins such as autoantibodies for degradation, wherein he bifunctional molecules include a ligand moiety that specifically bind to asialoglycoprotein receptor (paragraph [0024]). Lindhout et al teach a ligand moiety that specifically binds to asialoglycoprotein receptor as
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(page 13) which meets the requirement of “E” comprising formula (II) in instant claims 1 and 17. Lindhout et al teach linkers for conjugation to the moiety which binds to the ASGRP cell surface receptor, and “Y” wherein the linker is capable of binding to a lysine amino group on the polypeptide “Y” by means of an amine reactive group such as an active ester (pages 64-65, bridging sentence). Lindhout et al teach that the linkers encompass branching structures such as
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, which meets the limitations of multiple “E” groups connected to “D” which is connected to the lysine side chain of “C” and
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in claim 6. Lindhout et al teach examples of ASGRP binding compounds-linkers such as compound 1235:
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which fulfills the requirement of claim 7 for
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; the requirement of claims 8 and 9 for
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, wherein m=3 an n=1; the requirement of claim 10 for
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, wherein n=2. Lindhout et al teach the ASGPR binding compounds include “11-1”
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(page 124, Table 14, which meets the limitations of formula (IIa) in claim 11
Lindhout et al teach that the extracellular target binding moieties include Y-B, wherein “B” is the polypeptide that specifically binds to the extracellular target moiety, such as the autoantibody, and Y is a carrier polypeptide, and that in some embodiments the carrier polypeptide is fused directly to “B”, or fused indirectly via a spacer (page 225, paragraph [0524]). Lindhout et al teach that the carrier peptide is a Fc fragment such as an Fc dimer, and that in some embodiment the Fc is conjugated to an antigen in the format of an Fc-antigen-fusion (paragraph [0525] and [0557]). Lindhout et al teach that attaching to the carrier, Y, imparts one or more desirable properties onto the resulting bifunctional molecule, such as increase of in vivo stability and/or half-life and also provides for conjugation sites to a ligand-linker moiety without disrupting the autoantibody binding properties of the target binding polypeptide, B (paragraph [0527]). Lindhout et al teach that in some embodiments the Fc fragment is conjugated to an antigen to form an Fc fusion (pages 225-226, bridging sentence). Lindhout et al teaches that the Fc fragments contain the CH2 and CH3 region and part of the hinge region held together by one or more disulfides (paragraph [0558]).
Lindhout et al teach that the polypeptide B that specifically binds to a target antibody or target autoantibody is an antigen or autoantigen (paragraph [0559]). Lindhout et al teach that the target autoantibody includes thyroid autoantibodies such as autoantibodies (paragraph [0560]). Lindhout et al teach that the autoantibody is associated with Grave’s disease (paragraph [0561]).
Lindhout et al teach that the bifunctional molecule is a conjugate of formula (Ia) wherein the Z of formula Ia is a residual moiety resulting from the covalent linkage of an amine-active chemo selective ligation group to one or more lysine residues of Y-B, wherein Y-B is the chimeric fusion protein including a carrier polypeptide and a polypeptide that specifically binds the target autoantibody (paragraphs [0497]-[0498]). Lindhout et al teach that in certain embodiments, the linker is bonded to an amide bond (Z) to a lysine residue of the polypeptide (paragraph [0500]). Lindhout et al teach that the loading of a ligand-linker moiety with respect to the protein construct Y-B refers to the number of discreet or average number of ligand-linker moieties attached per molecule of polypeptide or protein conjugate (page 220, paragraph [0503]).
Lindhout et al teach that Y-B is a chimeric fusion protein including the carrier polypeptide and a polypeptide that specifically binds to the target autoantibody (page 219, paragraph [0498]) which meets the limitation of claim 1 as a “means for” connecting A and C, and claim 3 wherein B is a single chemical bond.
Lindhout et al teach a construct comprising the TSHR of SEQ ID NO:15, which is identical to the instant SEQ ID NO: 7 fused to human Fc of SEQ ID NO: 3
ALIGNMENTS
RESULT 1
BPQ89769
ID BPQ89769 standard; protein; 239 AA.
XX
AC BPQ89769;
XX
DT 19-SEP-2024 (first entry)
XX
DE TSHR ECD M22-L260 JMG55 (H63C/R112P/D143P/DI51E/V169R/I253R), SEQ: 15.
XX
KW TSH receptor; TSHR protein; autoantibody; degradation; mutein;
KW protein degradation.
XX
OS Synthetic.
OS Unidentified.
XX
CC PN WO2024155750-A1.
XX
CC PD 25-JUL-2024.
XX
CC PF 17-JAN-2024; 2024WO-US011901.
XX
PR 18-JAN-2023; 2023US-0480509P.
PR 09-AUG-2023; 2023US-0518537P.
XX
CC PA (LYCI-) LYCIA THERAPEUTICS INC.
XX
CC PI Lindhout DA, Chen T, Glynne R, Iwig J, Lewis JG, Li D, Lind N;
CC PI Shurtleff M, Staben S, Totten SM, Turtle ED;
XX
DR WPI; 2024-76725C/064.
XX
CC PT New extracellular target binding conjugates useful for reducing levels of
CC PT extracellular target molecule in biological system.
XX
CC PS Example 2; SEQ ID NO 15; 324pp; English.
XX
CC The present invention relates to a novel extracellular target binding
CC conjugate (I) useful for reducing levels of extracellular target
CC molecules in biological systems. The invention further discloses a method
CC for reducing levels of an extracellular target molecule in a biological
CC system, comprising contacting the biological system with a conjugate,
CC where the compound specifically binds the extracellular target molecule
CC and specifically binds a lysosomal targeting molecule of cells in the
CC biological system to facilitate cellular uptake and degradation of the
CC extracellular target molecule. The extracellular target binding
CC conjugates (I) are useful for reducing levels of an extracellular target
CC molecule in a biological system and treating depletion of pathogenic
CC autoantibodies by degradation through the lysosomal pathway. The
CC extracellular target binding conjugates (I) include a moiety that targets
CC a lysosomal targeting molecule, a linker, and a polypeptide that
CC specifically binds an extracellular target molecule e.g. an antibody that
CC is targeted for degradation; and provides sequestering and degrading of a
CC target molecule in the cell's lysosome.
XX
SQ Sequence 239 AA;
Query Match 100.0%; Score 1255; Length 239;
Best Local Similarity 100.0%;
Matches 239; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETCLRTIPSHAFSNLPNISRI 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETCLRTIPSHAFSNLPNISRI 60
Qy 61 YVSIDVTLQQLESHSFYNLSKVTHIEIRNTPNLTYIDPDALKELPLLKFLGIFNTGLKMF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YVSIDVTLQQLESHSFYNLSKVTHIEIRNTPNLTYIDPDALKELPLLKFLGIFNTGLKMF 120
Qy 121 PPLTKVYSTEIFFILEITDNPYMTSIPRNAFQGLCNETLTLKLYNNGFTSVQGYAFNGTK 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PPLTKVYSTEIFFILEITDNPYMTSIPRNAFQGLCNETLTLKLYNNGFTSVQGYAFNGTK 180
Qy 181 LDAVYLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELRARNTWTL 239
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LDAVYLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELRARNTWTL 239
Lindout et al further teach that the TSHR-Fc fusion is further linked to compound 1209:
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Thus, Lindhout et al teach the embodiments of claims 1, 3, 4, 6-11 with the exceptions of (a1)the requirement that the “C” moieties are linked together by two sulfide bridges wherein one disulfide bridge links the cys at position 11 of each moiety and the other disulfide bridge links the cys at position 14; (a2) the lysine residue of “C” is located at position 31 or 33; (a3)the cysteine residues at positions 46 and 106 are connected to form a disulfide bridge and wherein the cysteine residues in positions 152 and 210 are connected to form a disulfide bridge; and (b)”C” is a peptide moiety comprising a Fc variant of SEQ ID NO: 8 having having at least 95% sequence identity to SEQ ID NO:8, wherein the difference in sequence is due to only conservative amino acid substitutions.
Regarding the Fc variant of SEQ ID NO: 8, Shih et al (WO2025/148785) teach a protein construct comprising a human IgG1 hinge and Fc region of SEQ ID NO: 69 which is identical to the instant SEQ ID NO: 8 with the exception of a conservative amino acid substitution at position 5:
GenCore version 6.5.2
Copyright (c) 1993 - 2026 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: March 7, 2026, 20:42:51 ; Search time 1 Seconds
(without alignments)
0.054 Million cell updates/sec
Title: AASEQ1_03072026_204249
Perfect score: 1255
Sequence: 1 EPKSSDKTHTCPPCPAPEAA..........MHEALHNHYTQKSLSLSPGK 232
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 232 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 1 summaries
Database : US-19-253-824-8.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 1252 99.8 232 1 US-19-253-824-8 BIFUNCTIONAL DEGRA
ALIGNMENTS
RESULT 1
US-19-253-824-8
Query Match 99.8%; Score 1252; DB 1; Length 232;
Best Local Similarity 99.6%;
Matches 231; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF 60
||||:|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EPKSADKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF 60
Qy 61 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKT 120
Qy 121 ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP 180
Qy 181 PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 232
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 232
It would have been prima facie obvious to substitute the Fc of Shih et al for the Fc of Lindhout et al. One of skill in the art would have been motivated to do so because both Fcs are used in fusion constructs. The Fc of Shih et al is thus an art recognized alternative for the Fc of Lindout et al.
Regarding (a1)the requirement that the “C” moieties are linked together by two disulfide bridges wherein one disulfide bridge links the cys at position 11 of each moiety and the other disulfide bridge links the Cys at position 14; (a2) the lysine residue of “C” is located at position 31 or 33; (a3)the cysteine residues at positions 46 and 106 are connected to form a disulfide bridge and wherein the cysteine residues in positions 152 and 210 are connected to form a disulfide bridge, Zhu et al teach that the two cysteine residues at positions 11 and 14 in the Fc help retain the ability for dimer formation (paragraph [0124]). Liu and May teach that presumably, all cysteine residues in IgG are in the disulfide-bonded state (page 18, lines 1-2 under the heading “Free Sufhydryls”). Thus, it would be inherent in the fusion protein of Shih et al that the two cysteine moieties in positions 11 and 14 were connected to the two cysteine moieties of the second chain by disulfide bond formation; and the cysteine residues at positions 46 and 106 of SEQ ID NO:69 and positions 152 and 210 of SEQ ID NO:69 of Shih et al were connected to form a disulfide bridge because (i) Zhu et al teach that the two cysteine residues at positions 11 and 14 in the Fc help retain the ability for dimer formation and (ii) Liu and May teach that presumably, all cysteine residues in IgG are in the disulfide-bonded state. Thus, the cystines at positions 11 and 14 would be presumed to be disulfides in the dimer and the two cysteine moieties of the second chain by disulfide bond formation; and the cysteine residues at positions 46 and 106 of SEQ ID NO:69 and positions 152 and 210 of SEQ ID NO:69 due to proximity of the cysteines in the three-dimensional structure which puts said cysteines into bonding distance.
Claim 1, 3, 4, 6-11, 14, 15, 17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Lindhout et al (WO2024/155750) in view of Shih et al (WO2025/148785) as evidenced by Zhu et al (U.S. 2022/0098242) and Liu and May (mAbs, 2012, Vol. 4, pp. 17-23). as applied to claims 1, 3, 6-11, 14, 15, 17 and 19 above, and further in view of Alvarez et al (U.S. 2016/0175458).
Claim 4 requires that “B” comprises the sequence of SEQ ID NO:9.
The combined teachings of Lindhout et al and Shih et al render obvious a dimeric fusion protein of a moiety having at the TSHR sequence of SEQ ID NO:7 fused to SEQ ID NO:69 of Shih et al based on the teachings of Lindhout et al that Y-B is the chimeric fusion protein including a carrier polypeptide and a polypeptide that specifically binds the target autoantibody, wherein the carrier polypeptide is an Fc region. Lindhout et al do not specifically address the presence or absence of a peptide between Y and B in the chimeric fusion protein.
Alvarez et al teach single chain Fc fusion proteins which form a dimer through disulfide bond formation between free cysteines in the hinge region of the two monomeric Fc fusion proteins (abstract). Alvarez et al teach that an scFc fusion protein can be arranged such that X, the soluble protein is linked to Hinge-Fc through a linker L1, which includes L3 and optionally L2 and L4 (paragraph [0059]-[0066]). Alvarez et al teach that L2, L3 and L4 include artificial flexible domains comprising Gly and Ser which is preferably SEQ ID NO: 22 (paragraphs [0070]-[0071] which is identical to the instant SEQ ID NO:9.
It would have been prima facie obvious at the time prior to the effective filing date to make the chimeric fusion protein rendered obvious by the combined teachings of Lindhout et al, and Shih et al by including SEQ ID NO:22 of Alvarez et al between Y and B, wherein Y is the Fc and B is the TSHR for targeting TSHR autoantigens in patients. One of skill in the art would be motivated to provide a flexible linker connecting the TSHR and the Fc such that the presence of the Fc did not hinder the binding of the TSHR to the anti-TSHR autoantibodies.
Claim 1, 3, 6-12, 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Lindhout et al, and Shih et al, as evidenced by Zhu et al, and Liu and May as applied to claims 1, 3, 6-11, 14 and 15 above, and further in view of Liu (WO2018/075308).
Lindhout et al teach the compound
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which meets the limitations of claim 12 wherein ZB is -C(=O)(CH2)IM, wherein IM is 2, with the exception that the portion of the molecule corresponding to “E” comprises –(O-(CH2)2)4- rather than –(O-(CH2)2)3.
Liu teaches multi-arm polymer moieties having the formula
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, wherein B serves as the core linking multiple polymeric arms (page 11, lines 12-15), wherein L1 and L2 can comprise –(CH2)aO(CH2CH2O)c- and wherein c is an integer from 0-25 (page 12, lines 25-31).
It would have been prima facie obvious to delete a (CH2CH2O) unit from the above compound to arrive at the compound of claim 12. One of skill in the art would have been motivated to do so by the teachings of Liu et al wherein PEG moieties used as linker in branching constructs, (CH2CH2O), can be varied over a wide range.
All other rejections and/or objections as set forth in the prior Office action are withdrawn.
Allowable Subject Matter
Claims 16, 18, and 20-22 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/ Primary Examiner, Art Unit 1643