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 .
Status of Application, Amendments and/or Claims
The amendment of 30 March 2026 has been entered in full. Claims 1-164 are cancelled. Claims 165-198 are added.
Claims 165-198 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 165-194 (which correspond to the previously pending claims of Group I drawn to an immunomodulatory protein) in the reply filed on 30 March 2026 is acknowledged.
New claims 195-198, which correspond to the previously pending claims of Group IV, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 30 March 2026.
Claims 165-194 are under consideration in the instant application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 30 March 2026 (5) and 05 April 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
1. Claims 165, 181, 190, 192, and 193 are objected to because of the following informalities:
1a. Claim 165, 181, 192, and 193 recite the acronym “CRD2” without first defining what it represents. While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym and/or in each independent claim.
1b. In claims 181 and 192, subparts (1)-(2) should be renumbered utilizing “(a)-(b)” or “(i)-(ii)” so as to prevent confusion with claim numbering.
1c. Applicant is advised that should claim 169 be found allowable, claim 190 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Please note that this issue could be overcome by amending claim 190 to depend from claim 181.
Appropriate correction is required.
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.
2. Claims 165-180, 190, 193, and 194 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.
2a. Claims 165-180, 190 are rejected as being indefinite because claim 165 recites the limitation "variant TACI extracellular domain polypeptide" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 1, at lines 1-3 and 5, recites a “variant TACI polypeptide” and does not include the phrase “extracellular domain”. Therefore, this issue could be overcome by amending line 2 of claim 165 to delete “extracellular domain” ("variant TACI extracellular domain polypeptide").
If Applicant deletes “extracellular domain” from claim 165, please also see claim 171, lines 1-3; claim 172, line 2; claim 173, line 2; claim 177, lines 2-4 which recite “variant TACI extracellular domain polypeptide”.
2b. Claims 193 and 194 are rejected as being indefinite because claim 193 depends from itself (claim 193). Therefore, it is not clear what claim claim 193 is intended to depend from. For instance, it is not clear if claim 193 is intended to depend from claim 181 or claim 192 (or one of their dependents) because both independent claims 181 and 192 are directed to an immunomodulatory protein comprising CTLA-4 and TACI regions.
Claim Rejections - 35 USC § 102
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 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.
3. Claims 165-173 and 177-179 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ruben et al. (U.S. Patent 6,969,519).
Ruben et al. teach a protein, named “TR17”, that comprises an amino acid sequence that is 100% identical to the TACI amino acid sequence of SEQ ID NO: 709 of the instant claims, meeting the limitations of instant claim 166 (see SEQ ID NO: 2 and Figure 1 of Ruben et al.; see sequence alignment set forth below).
Qy= instant SEQ ID NO: 709
Db= SEQ ID NO: 2 of Ruben et al.
Sequence 2, US/09961376
Patent No. 6969519
GENERAL INFORMATION
APPLICANT: Ruben et al.
TITLE OF INVENTION: Human Tumor Necrosis Factor Receptor TR17
FILE REFERENCE: PF524P1
CURRENT APPLICATION NUMBER: US/09/961,376
CURRENT FILING DATE: 2001-09-25
PRIOR APPLICATION NUMBER: 60/254,874
PRIOR FILING DATE: 2000-12-13
PRIOR APPLICATION NUMBER: 60/235,991
PRIOR FILING DATE: 2000-09-26
PRIOR APPLICATION NUMBER: 09/533,822
PRIOR FILING DATE: 2000-03-24
PRIOR APPLICATION NUMBER: 60/188,208
PRIOR FILING DATE: 2000-03-10
NUMBER OF SEQ ID NOS: 7
SEQ ID NO 2
LENGTH: 293
TYPE: PRT
ORGANISM: Homo sapiens
Query Match 100.0%; Score 909; Length 293;
Best Local Similarity 100.0%;
Matches 166; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQR 60
Qy 61 TCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRR 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRR 120
Qy 121 QRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKLSADQVALVYST 166
||||||||||||||||||||||||||||||||||||||||||||||
Db 121 QRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKLSADQVALVYST 166
Ruben et al. state that TR17 is a member of the TNF receptor superfamily that binds APRIL and Neutrokine-alpha (abstract; column 123, lines 55-56; column 7, lines 45-61; column 9, lines 35-38). It is noted that Neutrokine-alpha is also well-known in the art as BAFF, Blys, and TNFSF13B (see for instance Rixon et al., US 2003/0103986, page 1, [0007] (cited on the IDS of 30 March 2026). Ruben et al. disclose that the amino acid sequence may comprise, for example, 1-3 or 1-2 substitutions, additions, or deletions (column 46, lines 58-64). In reference to SEQ ID NO: 2 of Ruben et al., Ruben et al. teach that amino acid Q75 may be replaced with N, D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C, meeting the limitations of instant claims 165 and 167-170 (column 47, lines 1-2, 39; column 49, lines 46-49; column 50, lines 65-67). Ruben et al. also indicate that amino acid R84 may be replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C, meeting the limitations of instant claims 165 and 167-170 (column 47, line 44; column 51, lines 10-11).
Ruben et al. teach that the polypeptide of SEQ ID NO: 2 (or its derivative, fragment, or analog) may be fused with a human IgG1 Fc, meeting the limitations of instant claims 172 and 173 (column 19, lines 45-47; column 45, lines 60-67 through column 46, line 8; column 71, lines 55-60; column 196, Example 6; column 208, Example 14). Ruben et al. disclose two or more TR17 polypeptides of the invention, including homodimers, are joined through synthetic linkers, meeting the limitations of instant claims 177-179 (column 34, lines 1-16, 34-35; column 35, lines 2-10; column 71, lines 55-60).
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.
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.
Ruben et al. and Gross et al.
4. Claims 165-175 and 177-179 are rejected under 35 U.S.C. 103 as being unpatentable over Ruben et al. (U.S. Patent 6,969,519) and Gross et al. (Immunity 15: 289-302, 2001; cited on the IDS of 05 April 2024).
The teachings of Ruben et al. are set forth above.
Ruben et al. do not teach a TACI polypeptide fused with an IgG Fc, wherein the IgG1 Fc comprises one or more amino acid substitutions selected from L234A, L234V, L235A, L235E, G237A, S267K, R292C, N297G, and V302C.
Gross et al. teach the generation of soluble TACI-Ig by fusing the signal sequence derived human tissue plasminogen activator, the extracellular domain of human TACI (amino acids 1-154), and a mutated Fc region from the human IgG1 heavy chain (page 299, column 2, 3rd full paragraph). Gross et al. disclose that to create the mutated Fc region, amino acid substitutions L234A, L235E, and G237A are introduced into IgG1 Fc to reduce binding to FcγRI, FcγRIIa, and FcγRIII (page 299, column 2, 3rd full paragraph).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the TACI polypeptide fused with an IgG Fc as taught by Ruben et al., by utilizing an IgG Fc with amino acid substitutions L234A, L235E, and G237A as taught by Gross et al. The person of ordinary skill in the art would have been motivated to make that modification to reduce binding to FcγRI, FcγRIIa, and FcγRIII and thus, decrease unwanted cell activation/responses and increase the serum half-life of the TACI-Fc fusion protein (see Gross et al., page 299, column 2, 3rd full paragraph). The person of ordinary skill in the art would have expected success because the amino acid substitutions L234A, L235E, and G237A in an IgG1 Fc (and fusion proteins therewith) were already being successfully made at the time the invention was made. Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Ruben et al. and Evans et al.
5. Claims 165-180 and 190 are rejected under 35 U.S.C. 103 as being unpatentable over Ruben et al. (U.S. Patent 6,969,519) and Evans et al. (WO 2019/074983; published 18 April 2019; cited on the IDS of 05 April 2024).
The teachings of Ruben et al. are set forth above.
Ruben et al. do not teach a TACI polypeptide fused with an IgG Fc, wherein the IgG1 Fc comprises one or more amino acid substitutions selected from L234A, L234V, L235A, L235E, G237A, S267K, R292C, N297G, and V302C and wherein the Fc region comprises the amino acid sequence set forth in any one of SEQ ID NOs: 589, 591, 598, 599, 722, 723, 724, or 725.
Evans et al. teach immunomodulatory proteins comprising a variant CTLA-4 protein attached to an immunoglobulin Fc (page 103, [0255-0256]). Evans et al. disclose the variant CTLA-4-Fc fusions comprise an Fc region that exhibits reduced effector functions, making it desirable for applications in which the half-life of the CTLA-4-Fc variant fusion in vivo is important yet certain effector functions (such as CDC and ADCC) are unnecessary or deleterious (page 104, [0259]; pages 16-17, [0046]). Evans et al. state that the Fc region of CTLA-4-Fc variant fusions has an Fc region in which any one or more of amino acids at positions 234, 235, 236, 237, 238, 239, 270, 297, 298, 325, and 329 (indicated by EU numbering) are substituted with different amino acids compared to the native Fc region (page 105, [0263]). Evans et al. also discuss other substitutions, including S267K, R292C, N297G, and V302C (page 17, [0046]; page 105, [0263]; page 107, [0269-0270]). Evans et al. indicate that such alterations of the Fc region include alterations such as deglycosylated chains (N297A and N297Q), IgGl-N297G, IgGl-L234A/L235A, IgGl-L234A/L235E/G237A, IgGl-A325/A330S/P331S, IgG l-C226S/C229S, IgGl-C226S/C229S/E233P/L234V/L235A, IgG l-E233P/L234V/L235A/G236del/S267K, IgGl-L234F/L235E/P331S, and IgGl-S267E/L328F (page 105, [0263]; pages 106-107, [0267-0272]). Evans et al. teach that Fc mutations that reduce effector activity include L234A, L235E, and G237A (page 106, [0267]). It is noted that the Fc region amino acid sequences of SEQ ID NOs: 438-441 and 524-527 of Evans et al. are 100% identical to the Fc region amino acid sequences of SEQ ID NOs: 589, 591, 598, 599, 722, 723, 724, and 725, respectively, of the instant claims. For example, please see sequence alignment, below, between SEQ ID NO: 439 of Evans et al. and SEQ ID NO: 591 of the instant application.
Qy= instant SEQ ID NO: 591
Db=SEQ ID NO: 439 of Evans et al.
DE Immunoglobulin Fc (homodimeric) polypeptide SEQ: 439.
XX
KW Immunoglobulin; antibacterial; antiinflammatory; autoimmune disease;
KW bacterial infection; cancer; cardiovascular disease; cardiovascular-gen.;
KW cytostatic; dermatological; dermatological disease; endocrine disease;
KW endocrine-gen.; gastrointestinal disease; gastrointestinal-gen.;
KW genitourinary disease; hematological disease; hematological-gen.;
KW immune disorder; immune modulation; immunomodulator; immunomodulatory;
KW immunosuppressive; inflammatory disease; metabolic disorder;
KW metabolic-gen.; musculoskeletal disease; musculoskeletal-gen.;
KW neurological disease; neuroprotective; ocular disease; ophthalmological;
KW protein engineering; protein production; protein therapy;
KW respiratory disease; respiratory-gen.; therapeutic; uropathic;
KW viral infection; virucide.
XX
OS Unidentified.
XX
CC PN WO2019074983-A1.
XX
CC PD 18-APR-2019.
XX
CC PF 09-OCT-2018; 2018WO-US055095.
XX
PR 10-OCT-2017; 2017US-0570619P.
PR 03-JAN-2018; 2018US-0613379P.
PR 19-SEP-2018; 2018US-0733615P.
XX
CC PA (ALPI-) ALPINE IMMUNE SCI INC.
XX
CC PI Evans L, Kuijper JL, Swanson R;
XX
DR WPI; 2019-36378P/35.
XX
CC PT New variant cytotoxic T-lymphocyte-associated antigen 4 polypeptide
CC PT useful in pharmaceutical composition for treating disease or condition,
CC PT preferably inflammatory or autoimmune disease or condition in human.
XX
XX
SQ Sequence 232 AA;
Query Match 100.0%; Score 1257; Length 232;
Best Local Similarity 100.0%;
Matches 232; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EPKSSDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EPKSSDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF 60
Qy 61 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT 120
Qy 121 ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP 180
Qy 181 PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 232
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 232
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the TACI polypeptide fused with an IgG Fc as taught by Ruben et al., by utilizing (i) an IgG Fc with one or more amino acid substitutions selected from L234A, L234V, L235A, L235E, G237A, S267K, R292C, N297G, and V302C or (ii) an Fc region comprising the amino acid sequence set forth in any one of SEQ ID NOs: 438-441 and 524-527 as taught by Evans et al. The person of ordinary skill in the art would have been motivated to make that modification to utilize an Fc region that exhibits reduced effector functions, making it desirable for applications in which the half-life of the TACI-Fc variant fusion is important yet certain effector functions (such as CDC and ADCC) are unnecessary or deleterious (see Evans et al., page 104, [0259]; pages 16-17, [0046]). The person of ordinary skill in the art would have expected success because amino acid substitutions in IgG1 Fc (and fusion proteins therewith) were already being successfully made at the time the invention was made. Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Yin and Ruben et al.
6. Claims 181-183 and 186-191 are rejected under 35 U.S.C. 103 as being unpatentable over Yin, Y. (CN 103232542; 13 May 2015) and Ruben et al. (U.S. Patent 6,969,519). Please see the attached English translation of CN 103232542 provided by the USPTO. The citations below refer to the English translation document.
Yin teaches a double target chimeric protein comprising the extracellular region of CTLA-4 (that binds CD80 or CD86), the extracellular region of TACI, and an immunoglobulin Fc fragment (abstract; [0011-0016]; Figure 1; SEQ ID NOs: 29-32). Yin indicates that the combination containing the fusion protein reduces B cell and T cell number, reduces immunoglobulin levels, and reduces tissue structure damage caused by inflammation ([0037]). Yin et al. discloses a CTLA-4 region comprising the amino acid sequence of SEQ ID NO: 29 ([0016]). It is noted that the amino acid sequence of SEQ ID NO: 29 of Yin is 97.7% identical to the amino acid sequence of SEQ ID NO: 1 of the instant application, meeting the limitations of instant claims 182 and 183 (see sequence alignment, below). The amino acid sequence of SEQ ID NO: 29 of Yin also comprises an IgV domain, as required by instant claim 186 (see bolded/underlined residues in the sequence alignment, below, showing the IgV domain; see also Table 3 of the instant application disclosing SEQ ID NO: 191 as wild-type IgV domain).
Qy= instant SEQ ID NO: 1
Db= SEQ ID NO: 29 of Yin
Query Match 97.7%; Score 643; DB 1; Length 126;
Best Local Similarity 99.2%;
Matches 124; Conservative 0; Mismatches 1; Indels 0;
Qy 2 AMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELT 61
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELT 60
Qy 62 FLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEP 121
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEP 120
Qy 122 CPDSD 126
||||
Db 121 SPDSD 125
Yin does not teach a variant TACI extracellular domain polypeptide, wherein the variant TACI extracellular domain polypeptide comprises amino acid substitutions at positions Q75 and R84, wherein the positions correspond to numbering of positions set forth in SEQ ID NO: 709.
Ruben et al. teach a protein, named “TR17”, that comprises an amino acid sequence that is 100% identical to the TACI amino acid sequence of SEQ ID NO: 709 of the instant claims, meeting the limitations of instant claims 181 and 187 (see SEQ ID NO: 2 and Figure 1 of Ruben et al.; see sequence alignment set forth below). It is noted that amino acids 29-114 of the amino acid sequence of Ruben et al. are 100% identical to the TACI amino acid sequence of SEQ ID NO: 30 of Yin.
Qy= instant SEQ ID NO: 709
Db= SEQ ID NO: 2 of Ruben et al.
Sequence 2, US/09961376
Patent No. 6969519
GENERAL INFORMATION
APPLICANT: Ruben et al.
TITLE OF INVENTION: Human Tumor Necrosis Factor Receptor TR17
FILE REFERENCE: PF524P1
CURRENT APPLICATION NUMBER: US/09/961,376
CURRENT FILING DATE: 2001-09-25
PRIOR APPLICATION NUMBER: 60/254,874
PRIOR FILING DATE: 2000-12-13
PRIOR APPLICATION NUMBER: 60/235,991
PRIOR FILING DATE: 2000-09-26
PRIOR APPLICATION NUMBER: 09/533,822
PRIOR FILING DATE: 2000-03-24
PRIOR APPLICATION NUMBER: 60/188,208
PRIOR FILING DATE: 2000-03-10
NUMBER OF SEQ ID NOS: 7
SEQ ID NO 2
LENGTH: 293
TYPE: PRT
ORGANISM: Homo sapiens
Query Match 100.0%; Score 909; Length 293;
Best Local Similarity 100.0%;
Matches 166; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQR 60
Qy 61 TCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRR 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRR 120
Qy 121 QRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKLSADQVALVYST 166
||||||||||||||||||||||||||||||||||||||||||||||
Db 121 QRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKLSADQVALVYST 166
Ruben et al. state that TR17 is a member of the TNF receptor superfamily that binds APRIL and Neutrokine-alpha (abstract; column 123, lines 55-56; column 7, lines 45-61; column 9, lines 35-38). It is noted that Neutrokine-alpha is also well-known in the art as BAFF, Blys, and TNFSF13B (see for instance Rixon et al., US 2003/0103986, page 1, [0007] (cited on the IDS of 30 March 2026). Ruben et al. disclose that the amino acid sequence may comprise 1-3 or 1-2 substitutions, additions, or deletions (column 46, lines 58-64). In reference to SEQ ID NO: 2 of Ruben et al., Ruben et al. teach that amino acid Q75 may be replaced with N, D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C, meeting the limitations of instant claims 188-191 (column 47, lines 1-2, 39; column 49, lines 46-49; column 50, lines 65-67). Ruben et al. also indicate that amino acid R84 may be replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C, meeting the limitations of instant claims 188-191 (column 47, line 44; column 51, lines 10-11).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the double target chimeric protein comprising the extracellular region of CTLA-4, the extracellular region of TACI, and an immunoglobulin Fc fragment as taught by Yin by substituting the TACI region of Yin for the variant TR17/TACI amino acid sequences of Ruben et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because the variant TR17/TACI amino acid sequences of Ruben et al. are also known TR17/TACI sequences and the simple substitution of one known equivalent element for another obtains predictable results (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Yin, Ruben et al., and Evans et al.
7. Claims 184, 185, 193, and 194 are rejected under 35 U.S.C. 103 as being unpatentable over Yin, Y. (CN 103232542; 13 May 2015; abstract cited on the IDS of 30 March 2026) and Ruben et al. (U.S. Patent 6,969,519) as applied to claims 181-183 and 186-191 above, and further in view of Evans et al. (WO 2019/074983; published 18 April 2019; cited on the IDS of 05 April 2024).
Applicant is reminded that claims 193 and 194 are included in this rejection in view of the rejection of claims 193 and 194 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, set forth above.
The teachings of Yin and Ruben et al. are set forth above.
Yin and Ruben et al. do not teach that the extracellular region of CTLA-4 in the double target chimeric protein comprising the extracellular region of CTLA-4, the extracellular region of TACI, and an immunoglobulin Fc fragment comprises one or more amino acid substitutions selected from L12F, R16H, G29W, T53S, M56T, N58S, L63P, L98Q, Y105L relative to the amino acid sequence of SEQ ID NO:1.
Evans et al. teach immunomodulatory proteins comprising variant CTLA-4 proteins (page 1, [0003]; page 2, [0005]). Evans et al. disclose that the variant CLTA-4 polypeptide contains one or more amino acid modifications, including L12F, R16H, G29W, T53S, M56T, N58S, L63P, L98Q, Y105L (page 3, [0015]; pages 214-216, Examples 8, 9; Table 9). Evans et al. disclose that a CTLA-4 variant containing mutations L12F/R16H/G29W/M56T/L98Q/Y105L is associated with enhanced binding to CD80, CD86, and ICOSL and suppression of interferon-gamma (page 214, [0503]; page 215, [0504], Table 9). The amino acid sequence of SEQ ID NO: 599 of Evans et al. comprises a human CTLA-4 extracellular domain (ECD) polypeptide (residues 36-161) variant (G29W/L98Q/Y105L) and is 100% identical to the CTLA-4 amino acid sequence of SEQ ID NO: 186 of the instant application, meeting the limitations of instant claim 194 (see sequence alignment, below) (see also Evans et al. page 90, Table 2; page 215, Table 9).
Qy= instant SEQ ID NO: 186
Db= SEQ ID NO: 599 of Evans et al.
AC BGF65695;
XX
DT 13-JUN-2019 (first entry)
XX
DE CTLA-4 ECD variant G29W/L98Q/Y105L SEQ: 599.
XX
KW CD152 protein; CTLA-4 protein; Cytotoxic T-lymphocyte protein-4;
KW antibacterial; antiinflammatory; autoimmune disease; bacterial infection;
KW cancer; cardiovascular disease; cardiovascular-gen.;
KW cluster of differentiation 152; cytostatic;
KW cytotoxic T-lymphocyte-associated protein 4; dermatological;
KW dermatological disease; endocrine disease; endocrine-gen.;
KW gastrointestinal disease; gastrointestinal-gen.; genitourinary disease;
KW hematological disease; hematological-gen.; immune disorder;
KW immune modulation; immunomodulator; immunomodulatory; immunosuppressive;
KW inflammatory disease; metabolic disorder; metabolic-gen.;
KW musculoskeletal disease; musculoskeletal-gen.; mutein;
KW neurological disease; neuroprotective; ocular disease; ophthalmological;
KW protein engineering; protein production; protein therapy;
KW respiratory disease; respiratory-gen.; therapeutic; uropathic;
KW viral infection; virucide.
XX
OS Homo sapiens.
OS Synthetic.
XX
CC PN WO2019074983-A1.
XX
CC PD 18-APR-2019.
XX
CC PF 09-OCT-2018; 2018WO-US055095.
XX
PR 10-OCT-2017; 2017US-0570619P.
PR 03-JAN-2018; 2018US-0613379P.
PR 19-SEP-2018; 2018US-0733615P.
XX
CC PA (ALPI-) ALPINE IMMUNE SCI INC.
XX
CC PI Evans L, Kuijper JL, Swanson R;
XX
DR WPI; 2019-36378P/35.
XX
CC PT New variant cytotoxic T-lymphocyte-associated antigen 4 polypeptide
CC PT useful in pharmaceutical composition for treating disease or condition,
CC PT preferably inflammatory or autoimmune disease or condition in human.
XX
CC PS Claim 17; SEQ ID NO 599; 262pp; English.
XX
CC The present sequence represents a human CTLA-4
CC extracellular domain (ECD) polypeptide (residues 36-161) variant
CC (G29W/L98Q/Y105L) sequence useful in treating the above-mentioned
CC diseases. Note: This sequence is a mutant of the parent sequence shown in
CC SEQ ID NO: 2 (see BGF65098).
XX
SQ Sequence 126 AA;
Query Match 100.0%; Score 661; Length 126;
Best Local Similarity 100.0%;
Matches 126; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 KAMHVAQPAVVLASSRGIASFVCEYASPWKATEVRVTVLRQADSQVTEVCAATYMMGNEL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 KAMHVAQPAVVLASSRGIASFVCEYASPWKATEVRVTVLRQADSQVTEVCAATYMMGNEL 60
Qy 61 TFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVEQMYPPPYLLGIGNGTQIYVIDPE 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVEQMYPPPYLLGIGNGTQIYVIDPE 120
Qy 121 PCPDSD 126
||||||
Db 121 PCPDSD 126
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the double target chimeric protein comprising the extracellular region of CTLA-4, the extracellular region of TACI, and an immunoglobulin Fc fragment as taught by Yin and Ruben et al. by substituting the CTLA-4 region of Yin for a variant CTLA-4 extracellular domain amino acid sequence comprising one or more amino acid modifications, including G29W, L98Q, and Y105L (among others) as taught by Evans et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because the variant CTLA-4 extracellular domain sequences of Evans et al. enhance binding to CD80, CD86, and ICOSL and suppress interferon-gamma (page 214, [0503]). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
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 165-180 and 190 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,202,882. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite an immunomodulatory protein comprising at least one variant TACI polypeptide.
Claim 165 of the instant application is directed to an immunomodulatory protein comprising at least one variant TACI polypeptide, wherein the at least one variant TACI extracellular domain polypeptide comprises a TACI extracellular domain (ECD) or a fragment thereof comprising a TACI CRD2 domain, wherein the variant TACI polypeptide comprises amino acid substitutions at positions Q75 and R84, wherein the positions correspond to numbering of positions set forth in SEQ ID NO: 709.
Meanwhile, claim 1 of the ‘882 patent recites an immunomodulatory protein comprising at least one variant TACI polypeptide, wherein the at least one variant TACI polypeptide comprises one or more amino acid substitutions relative to the sequence of the extracellular domain (ECD) of a reference TACI polypeptide, wherein the one or more amino acid substitutions comprise a substitution at position 77 that is K77E and a substitution at position 78 that is F78Y, corresponding to numbering of positions set forth in SEQ ID NO:122.
Claim 12 of the ‘882 patent recites the immunomodulatory protein of claim 1, wherein the one or more amino acid substitutions comprise a substitution are selected from W40R, Q59R, R60G, T61P E74V, Q75E, Q75R, G76S, Y79F, L82H, L82P, L83S, R84G, R84L, R84Q, D85E, D85V, C86Y, I87L, I87M, S88N, I92V, Q95R, P97S, K98T, Q99E, A101D, Y102D, F103S, F103V, F103Y, or a conservative amino acid substitution thereof, in addition to the substitution at positions 77 and 78.
It is noted that the amino acid sequence of SEQ ID NO: 122 of the ‘882 patent is 100% identical to the amino acid sequence of SEQ ID NO: 709 of the instant claims. The claims of the ‘882 patent clearly recite the same amino acid substitutions as those recited in claims 165-170 of the instant application (see underlined/bolded residues above).
Furthermore, claims 172-173 of the instant application and claims 2-3 of the ‘882 patent recite that the variant TACI polypeptide is linked to an Fc domain.
Instant claim 177 and claim 2 of the ‘882 patent recite a variant TACI-Fc fusion protein comprising the at least one variant TACI polypeptide, an Fc region, and a linker between one of the at least one variant TACI polypeptide and the Fc region.
Instant claim 178 and claim 4 of the ‘882 patent recite that the immunomodulatory protein is a homodimer comprising two identical copies of the variant TACI-Fc fusion protein.
Instant claim 179 and claim 7 of the ‘882 patent recite that the TACI-Fc fusion protein comprises the structure: (TACI)-Linker-Fc region-Linker-(TACI) or the structure: (TACI)-Linker-(TACI)-Linker-Fc region. Claim 8 of the ‘882 patent recites that the Fc region is set forth in SEQ ID NO: 73. It is also noted that the amino acid sequence of SEQ ID NO: 73 of claim 8 of the ‘882 patent claim is 100% identical to the amino acid sequence of SEQ ID NO: 589 of instant claims 176 and 180 (see sequence alignment below). The sequence listing for SEQ ID NO: 73 in the ‘882 patent states in the “other information” line that SEQ ID NO: 73 is “Fc C220S/L234A/L235E/G237A/K447del” and therefore, meets the limitations of instant claims 172-175.
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 1252 100.0 231 1 US-17-315-168-73 APRIL AND BAFF INH
RESULT 1
US-17-315-168-73
Query Match 100.0%; Score 1252; DB 1; Length 231;
Best Local Similarity 100.0%;
Matches 231; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EPKSSDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EPKSSDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF 60
Qy 61 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT 120
Qy 121 ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP 180
Qy 181 PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 231
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 231
9. Claims 165-191, 193, and 194 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,202,882 in view of Yin, Y. (CN 103232542; 13 May 2015; abstract cited on the IDS of 30 March 2026) and Evans et al. (WO 2019/074983; published 18 April 2019; cited on the IDS of 05 April 2024). Please see the attached English translation of CN 103232542 provided by the USPTO. The citations below refer to the English translation document.
The claim limitations of the ‘882 patent are set forth above.
The ‘882 patent claims do not recite that the immunomodulatory protein comprising at least one variant TACI polypeptide also comprises a CTLA-4 extracellular domain polypeptide or that such CTLA-4 polypeptide comprises one or more amino acid substitutions selected from L12F, R16H, G29W, T53S, M56T, N58S, L63P, L98Q, Y105L relative to the amino acid sequence of SEQ ID NO:1.
Yin teaches a double target chimeric protein comprising the extracellular region of CTLA-4 (that binds CD80 or CD86), the extracellular region of TACI, and an immunoglobulin Fc fragment (abstract; [0011-0016]; Figure 1; SEQ ID NOs: 29-32). Yin indicates that the combination containing the fusion protein reduces B cell and T cell number, reduces immunoglobulin levels, and reduces tissue structure damage caused by inflammation ([0037]). Yin et al. discloses a CTLA-4 region comprising the amino acid sequence of SEQ ID NO: 29 ([0016]). It is noted that the amino acid sequence of SEQ ID NO: 29 of Yin is 97.7% identical to the amino acid sequence of SEQ ID NO: 1 of the instant application, meeting the limitations of instant claims 182 and 183 (see sequence alignment, below). The amino acid sequence of SEQ ID NO: 29 of Yin also comprises an IgV domain, as required by instant claim 186 (see bolded/underlined residues in the sequence alignment, below, showing the IgV domain; see also Table 3 of the instant application disclosing SEQ ID NO: 191 as wild-type IgV domain).
Qy= instant SEQ ID NO: 1
Db= SEQ ID NO: 29 of Yin
Query Match 97.7%; Score 643; DB 1; Length 126;
Best Local Similarity 99.2%;
Matches 124; Conservative 0; Mismatches 1; Indels 0;
Qy 2 AMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELT 61
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELT 60
Qy 62 FLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEP 121
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEP 120
Qy 122 CPDSD 126
||||
Db 121 SPDSD 125
Additionally, Evans et al. teach immunomodulatory proteins comprising variant CTLA-4 proteins (page 1, [0003]; page 2, [0005]). Evans et al. disclose that the variant CLTA-4 polypeptide contains one or more amino acid modifications, including L12F, R16H, G29W, T53S, M56T, N58S, L63P, L98Q, Y105L (page 3, [0015]; pages 214-216, Examples 8, 9; Table 9). Evans et al. disclose that a CTLA-4 variant containing mutations L12F/R16H/G29W/M56T/L98Q/Y105L is associated with enhanced binding to CD80, CD86, and ICOSL and suppression of interferon-gamma (page 214, [0503]; page 215, [0504], Table 9). The amino acid sequence of SEQ ID NO: 599 of Evans et al. comprises a human CTLA-4 extracellular domain (ECD) polypeptide (residues 36-161) variant (G29W/L98Q/Y105L) and is 100% identical to the CTLA-4 amino acid sequence of SEQ ID NO: 186 of the instant application, meeting the limitations of instant claim 194 (see Evans et al. page 90, Table 2; page 215, Table 9).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the immunomodulatory protein comprising at least one variant TACI polypeptide of the ‘882 patent claims by utilizing the protein in a double target chimeric protein comprising the extracellular region of CTLA-4, an extracellular region of TACI, and an immunoglobulin Fc fragment as taught by Yin. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because the simple substitution of one known equivalent TACI polypeptide sequence for another obtains predictable results (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
Furthermore, it would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the double target chimeric protein comprising the extracellular region of CTLA-4, the extracellular region of TACI, and an immunoglobulin Fc fragment as taught by Yin and the ‘882 patent claims by substituting the CTLA-4 region of Yin for a variant CTLA-4 extracellular domain amino acid sequence comprising one or more amino acid modifications, including G29W, L98Q, and Y105L (among others) as taught by Evans et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because the variant CTLA-4 extracellular domain sequences of Evans et al. enhance binding to CD80, CD86, and ICOSL and suppress interferon-gamma (page 214, [0503]). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
10. Claims 165-180 and 190 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of copending Application No. 18/895,187. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite an immunomodulatory protein comprising at least one variant TACI polypeptide.
Claim 165 of the instant application is directed to an immunomodulatory protein comprising at least one variant TACI polypeptide, wherein the at least one variant TACI extracellular domain polypeptide comprises a TACI extracellular domain (ECD) or a fragment thereof comprising a TACI CRD2 domain, wherein the variant TACI polypeptide comprises amino acid substitutions at positions Q75 and R84, wherein the positions correspond to numbering of positions set forth in SEQ ID NO: 709.
Meanwhile, claim 1 of the ‘187 application recites an immunomodulatory protein comprising at least one variant TACI polypeptide, wherein the at least one variant TACI polypeptide comprises one or more amino acid substitutions relative to the sequence of the extracellular domain (ECD) of a reference TACI polypeptide at positions selected from among 40, 59, 60, 61, 74, 75, 76, 79, 82, 83, 84, 85, 86, 87, 88, 92, 95, 97, 98, 99, 101, 102, and 103, corresponding to numbering of positions set forth in SEQ ID NO:122.
Claim 167 of the instant application recites that the amino acid substitutions are Q75E and R84Q. Claim 6 of the ‘187 application recites that the one or more amino acid substitutions are selected from W40R, Q59R, R60G, T61P, E74V, Q75E, Q74R, G76S, Y79F, L82H, L82P, L83S, R84G, R84L, R84Q, D85E, D85V, C86Y, I87L, I87M, S88N, I92V, Q95R, P97S, K98T, Q99E, A101D, Y102D, F103S, F103V, or F103Y, or a conservative amino acid substitution thereof (emphasis added by the Examiner).
It is noted that the amino acid sequence of SEQ ID NO: 122 of the ‘187 application is 100% identical to the amino acid sequence of SEQ ID NO: 709 of the instant claims. The claims of the ‘187 application clearly recite the same amino acid substitutions as those recited in claims 165-170 of the instant application (see underlined/bolded residues above).
Furthermore, claims 172-173 of the instant application and claims 2 of the ‘187 application recite that the variant TACI polypeptide is linked to an Fc domain.
Instant claim 177 and claim 2 of the ‘187 application recite a variant TACI-Fc fusion protein comprising the at least one variant TACI polypeptide, an Fc region, and a linker between one of the at least one variant TACI polypeptide and the Fc region.
Instant claim 178 and claim 17 of the ‘187 application recite that the immunomodulatory protein is a homodimer comprising two identical copies of the variant TACI-Fc fusion protein.
Instant claim 179 and claim 18 of the ‘187 application recite that the variant TACI-Fc fusion protein comprises the structure: (TACI)-Linker-Fc region-Linker-(TACI) or the structure (TACI)-Linke-(TACI)-Linker-Fc region.
Claim 174 of the instant application and claim 13 of the ‘187 application recite that the Fc region is a variant IgG1 Fc domain comprising one or more amino acid substitutions selected from L234A, L234V, L235A, L235E, G237A, S267K, R292C, N297G, and V302C, by EU numbering.
Instant claim 175 and claim 14 of the ‘187 application recite that the Fc region comprises the amino acid substitutions L234A, L235E and G237A by EU numbering 15.
Instant claims 176 and 180 and claim 15 of the ‘187 application recite specific Fc region amino acid sequences. is set forth in SEQ ID NO: 73. It is also noted that the amino acid sequences of SEQ ID NO: 73, 75, 83, and 724 of claim 15 of the ‘187 application are 100% identical to the amino acid sequences of SEQ ID NO: 589, 591, 599, and 724, respectively, of instant claims 176 and 180.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
11. Claims 165-191, 193, and 194 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of copending Application No. 18/895,187 in view of Yin, Y. (CN 103232542; 13 May 2015; abstract cited on the IDS of 30 March 2026) and Evans et al. (WO 2019/074983; published 18 April 2019; cited on the IDS of 05 April 2024). Please see the attached English translation of CN 103232542 provided by the USPTO. The citations below refer to the English translation document.
The claim limitations of the ‘187 patent application are set forth above.
The ‘187 application claims do not recite that the immunomodulatory protein comprising at least one variant TACI polypeptide also comprises a CTLA-4 extracellular domain polypeptide or that such CTLA-4 polypeptide comprises one or more amino acid substitutions selected from L12F, R16H, G29W, T53S, M56T, N58S, L63P, L98Q, Y105L relative to the amino acid sequence of SEQ ID NO:1.
Yin teaches a double target chimeric protein comprising the extracellular region of CTLA-4 (that binds CD80 or CD86), the extracellular region of TACI, and an immunoglobulin Fc fragment (abstract; [0011-0016]; Figure 1; SEQ ID NOs: 29-32). Yin indicates that the combination containing the fusion protein reduces B cell and T cell number, reduces immunoglobulin levels, and reduces tissue structure damage caused by inflammation ([0037]). Yin et al. discloses a CTLA-4 region comprising the amino acid sequence of SEQ ID NO: 29 ([0016]). It is noted that the amino acid sequence of SEQ ID NO: 29 of Yin is 97.7% identical to the amino acid sequence of SEQ ID NO: 1 of the instant application, meeting the limitations of instant claims 182 and 183 (see sequence alignment, below). The amino acid sequence of SEQ ID NO: 29 of Yin also comprises an IgV domain, as required by instant claim 186 (see bolded/underlined residues in the sequence alignment, below, showing the IgV domain; see also Table 3 of the instant application disclosing SEQ ID NO: 191 as wild-type IgV domain).
Qy= instant SEQ ID NO: 1
Db= SEQ ID NO: 29 of Yin
Query Match 97.7%; Score 643; DB 1; Length 126;
Best Local Similarity 99.2%;
Matches 124; Conservative 0; Mismatches 1; Indels 0;
Qy 2 AMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELT 61
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELT 60
Qy 62 FLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEP 121
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEP 120
Qy 122 CPDSD 126
||||
Db 121 SPDSD 125
Additionally, Evans et al. teach immunomodulatory proteins comprising variant CTLA-4 proteins (page 1, [0003]; page 2, [0005]). Evans et al. disclose that the variant CLTA-4 polypeptide contains one or more amino acid modifications, including L12F, R16H, G29W, T53S, M56T, N58S, L63P, L98Q, Y105L (page 3, [0015]; pages 214-216, Examples 8, 9; Table 9). Evans et al. disclose that a CTLA-4 variant containing mutations L12F/R16H/G29W/M56T/L98Q/Y105L is associated with enhanced binding to CD80, CD86, and ICOSL and suppression of interferon-gamma (page 214, [0503]; page 215, [0504], Table 9). The amino acid sequence of SEQ ID NO: 599 of Evans et al. comprises a human CTLA-4 extracellular domain (ECD) polypeptide (residues 36-161) variant (G29W/L98Q/Y105L) and is 100% identical to the CTLA-4 amino acid sequence of SEQ ID NO: 186 of the instant application, meeting the limitations of instant claim 194 (see Evans et al. page 90, Table 2; page 215, Table 9).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the immunomodulatory protein comprising at least one variant TACI polypeptide of the ‘187 application claims by utilizing the protein in a double target chimeric protein comprising the extracellular region of CTLA-4, an extracellular region of TACI, and an immunoglobulin Fc fragment as taught by Yin. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because the simple substitution of one known equivalent TACI polypeptide sequence for another obtains predictable results (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
Furthermore, it would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the double target chimeric protein comprising the extracellular region of CTLA-4, the extracellular region of TACI, and an immunoglobulin Fc fragment as taught by Yin and the ‘187 application claims by substituting the CTLA-4 region of Yin for a variant CTLA-4 extracellular domain amino acid sequence comprising one or more amino acid modifications, including G29W, L98Q, and Y105L (among others) as taught by Evans et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because the variant CTLA-4 extracellular domain sequences of Evans et al. enhance binding to CD80, CD86, and ICOSL and suppress interferon-gamma (page 214, [0503]). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Conclusion
Claims 165-191, 193, and 194 are rejected. Claim 192 is objected.
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BEB
Art Unit 1647
05 June 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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