Office Action 2: Notice of Allowance (2025-02-20)

CLAIMS:
AMENDMENTS TO THE CLAIMS

Application No.: 18/807,825 Docket No.: 76161-20038.03

1\. (Currently Amended) A variant TACI-Fc fusion protein asset forth as the amino acid sequence in SEQ ID NO:167.

2\. (Currently Amended) A variant TACI-Fc fusion protein that is a homodimer comprising two identical copies of the variant TACI\-Fc fusion protein, wherein each polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID NO: 167 linked by a covalent disulfide bond.

3\. (Original) A pharmaceutical composition comprising the variant TACI-Fc fusion protein of claim 1 and a pharmaceutically acceptable excipient.

4\. (Currently Amended) A pharmaceutical composition comprising the homodimer of claim 2 and a pharmaceutically acceptable excipient.

5\. (New) A pharmaceutical composition comprising a variant TACI-Fc fusion protein homodimer and a pharmaceutically acceptable excipient, wherein each polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID NO. 167.2 sf-6215507

OFFICE ACTION:
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 .
Applicant’s response filed on 1/22/2025 is acknowledged and fully considered.
Status of Application, Amendments, And/Or Claims
The amendments of claims 1-2, and 4, and the addition of claim 5 have been made of record.
Claims 1-5 are pending and under consideration.
Information Disclosure Statement
The Information Disclosure Statement filed on 1/16/2025 has been considered.
EXAMINER’S COMMENT
Double Patenting--withdrawn
The rejection of claims 1-4 under 35 U.S.C. 101 as claiming the same invention as that of claims 18-19 and 29-30 of prior U.S. Patent No. 11,274,140. This is a statutory double patenting rejection is withdrawn in view of applicant’s amendments to claims 1-2 and 4 and the filing of a terminal disclosure on 1/22/2025 which was approved by the office on 1/23/2025.
The provisional rejection of claims 1-4 on the ground of nonstatutory double patenting as being unpatentable over claims 26-27 and 30 of copending Application No. 17346095 (17364095 was a typo) is withdrawn as the application No. 17/346,095 is now US Pat. No. 11,274,140 (see above). Applicants have filed a TD on 1/22/2025 to overcome with the rejection.
Conclusion
Claims 1-5 are allowed.

APPLICANT REBUTTAL: REMARKS
Status of the Claims
Claims 1 - 4 were pending in the application. By way of this amendment, claims 1, 2 and 4 are amended, and claim 5 is added. Claims 2 and 4 is are amended for clarity. After entry of the amendment, claims 1-5 will be pending and are under consideration. Support for the amendments and new claim 5 can be found throughout the application as filed. No new matter is added.
Amendment or cancellation of certain claims is not to be construed as a dedication to the public of any previously claimed subject matter. Applicant reserves the right to pursue any previously claimed subject matter in one or more future continuation and/or divisional applications.
Statutory Double Patenting
Claims 1-4 are rejected under 35 U.S.C. § 101 as purportedly claiming the same
invention as that of claims 18, 19, 29 and 30 of US Patent No. 11,274,140 (the '140 patent), which shares a priority claim with the present application.
The rejection of presently pending claims 1-4 for statutory double patenting is
respectfully traversed because claims 1-4 are not the same as the reference claims of the '140 Patent. New claim 5 also is not the same as any of the reference claims of the '140 patent.
Statutory double patenting under § 101 is proper where "the same invention is being claimed twice," and prevents two patents from issuing on "identical subject matter." MPEP § 804(II)(A) (emphasis added); 35 U.S.C. § 101. The MPEP provides that a "complete response to a statutory double patenting rejection" is "either a reply by applicant showing that the claims subject to the rejection are not the same as the reference claims, an amendment in response to the statutory double patenting rejection, or cancellation of the conflicting claims." MPEP §
804(I)(B)(2). Here, as explained below, the claims of the present application, as amended, and the claims of the '140 Patent do not recite identical subject matter.
Applicant submits that the claims of the two applications are not claiming the same identical invention, at least for the following reasons.
Claim 1
Applicant submits that claim 1 is not identical to any of the claims identified by the
Examiner, or any other claims of the '140 patent. Claim 1 of the present application ("present claim 1") recites:
1. A variant TACI-Fc fusion protein as set forth as the amino acid sequence in
SEQ ID NO:167.
Claims 18 and 29, and all other claims, of the '140 patent are directed to an immunomodulatory protein homodimer comprising two identical copies of a TACI-Fc fusion protein. Granted claims 1, 18 and 29 of the '140 patent recite:
1. An immunomodulatory protein homodimer comprising two identical copies
of a TACI-Fc fusion protein, wherein the TACI-Fc fusion protein comprises a
variant TACI polypeptide, an Fc region, and a linker between the variant TACI polypeptide and the Fc region, wherein the variant TACI polypeptide comprises
the amino acid substitutions K77E, F78Y, and Yl02D in the sequence set forth in SEQ ID NO: 13, wherein the numbering of positions corresponds to numbering of
positions set forth in SEQ ID NO:122.
18. The immunomodulatory protein homodimer of claim 1, wherein the TACI- Fc fusion protein is set forth in SEQ ID NO: 167.
29. An immunomodulatory protein that is a homodimer comprising two
identical copies of the TACI-Fc fusion protein set forth in SEQ ID NO: 167 or
SEQ ID NO: 168 linked by a covalent disulfide bond.
Claims 19 and 30 depend on claims 1 and 29, respectively.
It is plain from the above-highlighted language of the claims that present claim 1 is not the same as any of claims 1, 18 and 29 of the '140 patent. Applicant respectfully submits that a claim to a TACI-Fc fusion protein homodimer is not identical to a claim to a TACI-Fc fusion protein. As is known in the art, and described in the specification, Fe fusions of identical species can be dimerized to form Fe fusion homodimers (see e.g., paragraph [0126]). Also, as described in the specification, at paragraph [0295], "[i]n some embodiments, the immunomodulatory protein is a homodimer of two identical copies of the TACI-Fc fusion protein." A homodimer of a variant TACI-Fc fusion protein comprises two TACI Fe-fusion protein chains, whereas there is no such requirement in presently pending claim 1. Additionally, claim 29 of the '140 patent recites that the two copies of the TACI-Fc fusion protein are linked by a covalent disulfide bond, which is not recited in presently pending claim 1.
A reliable test for double patenting under 35 U.S.C. 101 is whether a claim in the application could be literally infringed without literally infringing a corresponding claim in the patent. In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970). If there is an embodiment of the invention that falls within the scope of one claim, but not the other then identical subject matter is not defined by both claims and statutory double patenting would not exist. See MPEP § 804(II)(A)(2). Here, a variant TACI-Fc fusion protein set forth as the amino acid sequence in SEQ ID NO: 167 would infringe present claim 1, but would not necessarily infringe an immunomodulatory protein homodimer of any of granted claims 1, 18 and 29 of the '140 patent if the variant TACI-Fc fusion is not a homodimer of two identical copies.
Applicant respectfully submits that claims 18 and 29 of the '140 patent are not identical to presently pending claim 1, and the scope of the claims is not identical. Similarly, claims 19 and 30 of the '140 patent, which are directed to a pharmaceutical composition comprising the immunomodulatory protein homodimer of claim 1 or claim 29 and a pharmaceutically acceptable excipient, respectively, also are not identical to presently pending claim 1, which is not directed to a pharmaceutical composition. Statutory double patenting thus does not exist with respect to claim 1 of the present application and the claims of the '140 Patent, because the claims are not the same. See MPEP §§ 804(II)(A), 804(I)(B)(2).
Claim 2
Applicant submits that claim 2 as presently amended is not identical to any of the claims identified by the Examiner, or any other claims of the '140 patent. The MPEP provides that "an amendment in response to the statutory double patenting rejection" is "a complete response to a double patenting rejection." MPEP § 804(I)(B)(2). Claim 2 of the present application ("present claim 2") as amended recites:
2.    A variant TACI-Fc fusion protein that is a homodimer comprising
two identical copies of the variant TACI-Fc fusion protein, wherein each
polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID
NO:167 linked by a covalent disulfide bond
Claims 18 and 29 of the '140 patent are reproduced above. Claims 18 and 29 of the '140 patent, which are referenced by the Examiner and are reproduced above, are directed to an immunomodulatory protein homodimer wherein the TACI-Fc fusion protein is set forth as the amino acid sequence in SEQ ID NO: 167, or the TACI-Fc fusion protein is set forth in SEQ ID NO: 167 or 168, respectively. Applicant respectfully submits that the scope of the immunomodulatory protein of claims 18 and 29 of the '140 patent is not identical to that of present claim 2.
Claims 19 and 30 of the '140 patent, which are referenced by the Examiner and are reproduced above, are directed to a pharmaceutical composition comprising an immunomodulatory protein and a pharmaceutically acceptable excipient. Applicant respectfully submits that the scope of the immunomodulatory protein in the pharmaceutical compositions of claims 19 and 30 of the '140 patent is not identical to that of present claim 2, which does not recite a pharmaceutical composition, nor does present claim 2 reference a pharmaceutically acceptable excipient. Thus, the scope of present claim 2 and claims 19 and 30, and any of the other claims of the '140 patent, is not identical.
Claim 18 of the '140 patent also is not identical to present claim 2. Claim 18 of the '140 patent, which is reproduced above, recites that the immunomodulatory protein is a homodimer wherein the TACI-Fc fusion protein is set forth in SEQ ID NO: 167. Present claim 2 recites that each polypeptide of the homodimer is set forth in SEQ ID NO:167 linked by a covalent disulfide bond. Claim 18 of the '140 patent does not recite that each polypeptide is linked by a covalent disulfide bond. Thus, an immunomodulatory protein of claim 18 of the '140 patent where the TACI-Fc fusion protein is set forth in SEQ ID NO:167 and is not linked by a covalent disulfide bond would infringe claim 18 of the '140 patent but would not infringe present claim 2. As noted above, if there is an embodiment of the invention that falls within the scope of one claim, but not the other then identical subject matter is not defined by both claims and statutory double patenting would not exist. See MPEP § 804(II)(A)(2). Thus, statutory double patenting thus does not exist here with respect to claim 2 of the present application and the claims of the '140 Patent, because the claims are not the same. See MPEP §§ 804(II)(A), 804(I)(B)(2).
Claim 29 of the '140 patent also is not identical to present claim 2. Claim 29 of the '140 patent, which is reproduced above, recites that the immunomodulatory protein is a homodimer comprising two identical copies of the TACI-Fc fusion protein set forth in SEQ ID NO:167 or SEQ ID NO: 168 linked by a covalent disulfide bond. Present claim 2 recites that each polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID NO: 167. Claim 29 of the '140 patent recites that the TACI-Fc fusion protein is set forth in SEQ ID NO:167 or SEQ ID NO: 168; claim 29 of the '140 patent includes that the TACI-Fc fusion protein is set forth in SEQ ID NO:168, whereas present claim 2 recites that each polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID NO: 167. Thus, an immunomodulatory protein of claim 29 of the '140 patent where the TACI-Fc fusion protein is set forth in SEQ ID NO:168 would infringe claim 29 but would not infringe present claim 2. Statutory double patenting thus does not exist here with respect to claim 2 of the present application and the claims of the '140 Patent, because the claims are not the same. See MPEP §§ 804(II)(A), 804(I)(B)(2).
Claim 3
Applicant submits that present claim 3 is not identical to any of the claims identified by the Examiner, nor any other claims of the '140 patent. Claim 3 of the present application ("present claim 3") recites:
3. A pharmaceutical composition comprising the variant TACI-Fc fusion
protein of claim 1 and a pharmaceutically acceptable excipient.
Claims 18 and 29 of the '140 patent are reproduced above. Claims 19 and 30 of the '140 patent are directed to a pharmaceutical composition comprising the immunomodulatory protein homodimer of claims 1 and 29, respectively. Granted claims 19 and 30 of the '140 patent recite:
19. A pharmaceutical composition comprising the immunomodulatory protein
homodimer of claim 1 and a pharmaceutically acceptable excipient.
30. A pharmaceutical composition comprising the immunomodulatory protein of
claim 29 and a pharmaceutically acceptable excipient.
Claim 30 of the '140 patent depends on claim 29, which is reproduced above, and claim 19 of the '140 patent depends on claim 1, which is reproduced above.
Present claim 3 is directed to a pharmaceutical composition comprising a variant TACI-Fc fusion protein of claim 1. As detailed above with respect to the rejection of present claim 1, present claim 3 does not recite that the TACI-Fc fusion protein is a homodimer. Conversely, claims 19 and 30 of the '140 patent are directed to a pharmaceutical composition comprising an immunomodulatory protein homodimer of claims 1 and 29, respectively. As detailed above, a TACI-Fc fusion protein is not identical to an immunomodulatory protein homodimer comprising a TACI-Fc fusion protein. Thus, a pharmaceutical composition of present claim 3, comprising a TACI-Fc fusion protein as recited in present claim 1, is not identical to a pharmaceutical composition comprising an immunomodulatory protein homodimer as recited in either of claims 19 and 30 of the '140 patent. With respect to claims 18 and 29 of the '140 patent,
the pharmaceutical composition of present claim 3, which comprises a TACI-Fc fusion protein as recited in present claim 1 is not identical to the immunomodulatory protein homodimer of claims 18 and 29 of the '140 patent for at least the reasons stated above. Statutory double patenting thus does not exist here with respect to claim 3 of the present application and the claims of the '140 Patent, because the claims are not the same. See IPEP §§ 804(II)(A), 804(I)(B)(2).
Claim 4
Applicant submits that claim 4 is not identical to any of the claims identified by the
Examiner, or any other claims of the '140 patent. Claim 4 of the present application ("present claim 4") recites:
A pharmaceutical composition comprising the homodimer of claim
2 and a pharmaceutically acceptable excipient.
Present claim 4 depends on present claim 2, as amended. Upon entry of the amendment to claim 2, claim 4 recites a
pharmaceutical composition
comprising a TACI-Fc fusion protein homodimer, wherein each polypeptide of the homodimer is set forth as the amino acid sequence in
SEQ ID NO: 167
linked by a covalent disulfide bond, and a pharmaceutically acceptable excipient. The subject matter of present claim 4 is not identical to any of the claims of the '140 Patent, including those noted by the Examiner.
Claims 18 and 29, which are referenced by the Examiner and are reproduced above, are directed to an immunomodulatory protein homodimer wherein the TACI-Fc fusion protein is set forth as the amino acid sequence in SEQ ID NO: 167, or the TACI-Fc fusion protein is set forth in SEQ ID NO: 167 or 168, respectively; neither of claims 18 and 29 are directed to a
pharmaceutical composition
comprising the homodimer
and a pharmaceutically acceptable excipient.
Applicant respectfully submits that the scope of the immunomodulatory protein of claims 18 and 29 of the '140 patent is not identical to the pharmaceutical composition of present claim 4.
Claims 19 and 30 of the '140 patent, which are referenced by the Examiner and are reproduced above, are directed to a pharmaceutical composition comprising an
immunomodulatory protein and a pharmaceutically acceptable excipient. Applicant respectfully submits that the scope of the immunomodulatory protein in the pharmaceutical compositions of claims 19 and 30 of the '140 patent is not identical to that of present claim 4.
For example, claim 19 is directed to a pharmaceutical composition comprising the immunomodulatory protein of claim 1; claim 1 of the '140 patent, which is reproduced above, recites that the TACI-Fc fusion protein in the homodimer comprises a variant TACI polypeptide, an Fc region, and a linker between the variant TACI polypeptide and the Fc region, wherein the variant TACI polypeptide
comprises
the amino acid substitutions K77E, F78Y, and Y102D in the sequence set forth in SEQ ID NO:13. Present claim 4 recites that each polypeptide of the homodimer
is set forth as the amino acid sequence in SEQ ID NO: 167
linked by a covalent disulfide bond. Claim 1 of the '140 patent recites that the variant TACI polypeptide comprises the amino acid substitutions K77E, F78Y and Y102D; this is open language, the variant TACI polypeptide comprises the amino acid substitutions K77E, F78Y and Y102D and also can comprise additional amino acid substitutions, whereas present claim 4 recites that each polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID NO: 167. As noted above, if there is an embodiment of the invention that falls within the scope of one claim, but not the other then identical subject matter is not defined by both claims and statutory double patenting would not exist. See MPEP § 804(II)(A)(2). Here, a pharmaceutical composition comprising the immunomodulatory protein of claim 1 of the '140 patent wherein the variant TACI polypeptide comprises K77E, F78Y and Y102D and one other amino acid substitution in the sequence set forth in SEQ ID NO: 13 would infringe claim 19 of the '140 patent but would not infringe present claim 4.
Claim 30 of the '140 patent also is not identical to present claim 4. Claim 30 of the '140 patent is directed to a pharmaceutical composition comprising the immunomodulatory protein of claim 29; claim 29 of the '140 patent, which is reproduced above, recites that the immunomodulatory protein is a homodimer comprising two identical copies of the TACI-Fc fusion protein set forth in SEQ ID NO:167 or SEQ ID NO: 168 linked by a covalent disulfide bond. Present claim 4 recites that each polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID NO: 167. Claim 29 of the '140 patent recites that the TACI-Fc fusion
protein is set forth in SEQ ID NO:167 or SEQ ID NO: 168; claim 29 of the '140 patent includes that the TACI-Fc fusion protein is set forth in SEQ ID NO:168, whereas present claim 4 recites that each polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID NO: 167. Thus, a pharmaceutical composition comprising the immunomodulatory protein of claim 29 of the '140 patent where the TACI-Fc fusion protein is set forth in SEQ ID NO:168 would infringe claim 29 but would not infringe present claim 4. Statutory double patenting thus does not exist here with respect to claim 4 of the present application and the claims of the '140 Patent, because the claims are not the same. See MPEP §§ 804(II)(A), 804(I)(B)(2).
Claim 5
Though not rejected, Applicant submits that new claim 5 also is not identical to any of the claims identified by the Examiner, nor any other claims of the '140 patent. Claim 5 of the present application ("present claim 5") recites:
5.    A pharmaceutical composition comprising a variant TACI-Fe fusion
protein homodimer and a pharmaceutically acceptable excipient, wherein each
polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID NO.
Present claim 5 is directed to a
pharmaceutical composition
comprising a variant TACI-Fc fusion protein homodimer, wherein each polypeptide of the homodimer is set forth as the amino acid sequence in
SEQ ID NO: 167.
The subject matter of present claim 5 is not identical to any of the claims of the '140 Patent.
For example, claims 18 and 29, which are referenced by the Examiner and are
reproduced above, are directed to an immunomodulatory protein homodimer wherein the TACI- Fc fusion protein is set forth as the amino acid sequence in SEQ ID NO: 167, or the TACI-Fc fusion protein is set forth in SEQ ID NO: 167 or 168, respectively; neither of claims 18 and 29 are directed to a
pharmaceutical composition
comprising the homodimer
and a pharmaceutically acceptable excipient.
Applicant respectfully submits that it is plain from the language of the claims that the scope of the immunomodulatory protein of claims 18 and 29 of the '140 patent is not identical to the pharmaceutical composition of present claim 5.
Claims 19 and 30 of the '140 patent, which are referenced by the Examiner and are reproduced above, are directed to a pharmaceutical composition comprising an immunomodulatory protein and a pharmaceutically acceptable excipient. Applicant respectfully submits that the scope of the immunomodulatory protein in the pharmaceutical compositions of claims 19 and 30 of the '140 patent is not identical to that of present claim 5.
Claim 19 of the '140 patent is directed to a pharmaceutical composition comprising the immunomodulatory protein of claim 1; claim 1 of the '140 patent, which is reproduced above, recites that the TACI-Fc fusion protein in the homodimer comprises a variant TACI polypeptide, an Fc region, and a linker between the variant TACI polypeptide and the Fc region, wherein the variant TACI polypeptide
comprises
the amino acid substitutions K77E, F78Y, and Y102D in the sequence set forth in SEQ ID NO:13. Thus, as described with respect to the rejection of present claim 4, there are embodiments that would infringe claim 19 of the '140 patent but would not infringe present claim 5, which recites that the pharmaceutical composition comprises a variant TACI-Fc fusion protein homodimer and a pharmaceutically acceptable excipient,
wherein each polypeptide of the homodimer is set forth as the amino acid se
q
uence in SEQ ID
NO. 167.
Claim 30 of the '140 patent also is not identical to present claim 5. Claim 30 of the '140 patent is directed to a pharmaceutical composition comprising the immunomodulatory protein of claim 29; claim 29 of the '140 patent, which is reproduced above, recites that the immunomodulatory protein is a homodimer comprising two identical copies of the TACI-Fc fusion protein set forth in SEQ ID NO:167 or SEQ ID NO: 168 linked by a covalent disulfide bond. Present claim 5 recites that each polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID NO: 167. As described above with respect to the patentability of present claim 4, claim 29 of the '140 patent recites that the TACI-Fc fusion protein is set forth in SEQ ID NO:167 or SEQ ID NO: 168; claim 29 of the '140 patent includes that the TACI-Fc fusion protein is set forth in SEQ ID NO:168, which is not identical to present claim 5, which recites that each polypeptide of the homodimer is set forth as the amino acid sequence in SEQ ID NO: 167. Present claim 5 also does not require that the immunomodulatory protein is a
homodimer comprising two identical copies of the TACI-Fc fusion protein
linked by a covalent disulfide bond,
as recited in claim 30 of the '140 patent. Statutory double patenting thus does not exist here with respect to claim 5 of the present application and the claims of the '140 Patent, because the claims are not the same. See MPEP §§ 804(II)(A), 804(I)(B)(2).
Summary
Applicant respectfully submits that statutory double patenting thus does not exist here with respect to any of the claims of the present application and the claims of the '140 Patent, because the claims are not the same. Applicant respectfully requests withdrawal of the rejection.
Non-Statutory Double Patenting
The Office Action also provisionally rejects claims 1-4 on the ground of non-statutory double patenting rejection over claims 26, 27 and 30 of the "copending" US Patent Application No. 17/364,095. As a provisional matter, Applicant respectfully submits that the Examiner intended to reference US Patent Application No. 17/346,095, which shares a priority claim with the present application, and submits that the "copending" application is issued as US Patent No. 11,274,140 (the '140 patent, discussed above). Claims 26, 27 and 30 of US Patent Application No. 17/346,095 prior to issuance correspond to claims 18, 19 and 30 as renumbered in the issued '140 patent.
Without conceding the propriety of the rejection, a terminal disclaimer over U.S. Patent No. 11,274,140 accompanies this response, thereby obviating this rejection. Applicant respectfully submits that this rejection should be withdrawn.
CONCLUSION


CITED REFERENCE SUMMARIES: Ref US11274140: Claims:
1. An immunomodulatory protein homodimer comprising two identical copies of a TACI-Fc fusion protein, wherein the TACI-Fc fusion protein comprises a variant TACI polypeptide, an Fc region, and a linker between the variant TACI polypeptide and the Fc region, wherein the variant TACI polypeptide comprises the amino acid substitutions K77E, F78Y, and Y102D in the sequence set forth in SEQ ID NO:13, wherein the numbering of positions corresponds to numbering of positions set forth in SEQ ID NO:122.
2. The immunomodulatory protein homodimer of claim 1, wherein the variant TACI polypeptide has increased binding affinity to one or both of APRIL and BAFF compared to the reference TACI polypeptide.
3. The immunomodulatory protein homodimer of claim 1, wherein the variant TACI polypeptide has at least 90% sequence identity to SEQ ID NO:13.
4. The immunomodulatory protein homodimer of claim 1, wherein the variant TACI polypeptide has at least 92% sequence identity to SEQ ID NO:13.
5. The immunomodulatory protein homodimer of claim 1, wherein the variant TACI polypeptide is set forth in SEQ ID NO: 26.
6. The immunomodulatory protein homodimer of claim 1, wherein the linker comprises a peptide linker and the peptide linker is selected from GSGGS (SEQ ID NO: 76), GGGGS (G45; SEQ ID NO: 77), GSGGGGS (SEQ ID NO: 74), GGGGSGGGGS (2×GGGGS; SEQ ID NO: 78), GGGGSGGGGSGGGGS (3×GGGGS; SEQ ID NO: 79), GGGGSGGGGSGGGGSGGGGS (4×GGGGS, SEQ ID NO:84), GGGGSGGGGSGGGGSGGGGSGGGGS (5×GGGGS, SEQ ID NO: 91), GGGGSSA (SEQ ID NO: 80), or GSGGGGSGGGGS (SEQ ID NO:194) or combinations thereof.
7. The immunomodulatory protein homodimer of claim 1, wherein the linker is GSGGGGS (SEQ ID NO: 74).
8. The immunomodulatory protein homodimer of claim 7, wherein the Fc region is an IgG1 Fc domain comprising the amino acid substitutions L234A, L235E an G237A by EU numbering.
9. The immunomodulatory protein homodimer of claim 8, wherein the Fc region is set forth in SEQ ID NO:73.
10. The immunomodulatory protein homodimer of claim 1, wherein the Fc region is an IgG1 Fc domain.
11. The immunomodulatory protein homodimer of claim 10, wherein the Fc region is set forth in SEQ ID NO:81.
12. The immunomodulatory protein homodimer of claim 1, wherein the Fc region is a variant IgG1 Fc domain that exhibits reduced effector function.
13. The immunomodulatory protein homodimer of claim 12, wherein the variant IgG1 Fc domain comprises the amino acid substitutions L234A, L235E, and G237A by EU numbering.
14. The immunomodulatory protein homodimer of claim 13, wherein the Fc region is set forth in SEQ ID NO:73.
15. The immunomodulatory protein homodimer of claim 1, wherein the Fc region is an Fc domain of IgG2.
16. The immunomodulatory protein homodimer of claim 1, wherein the Fc region is an Fc domain of IgG4 or is a variant IgG4 Fc domain containing the S228P mutation.
17. The immunomodulatory protein homodimer of claim 1, wherein the TACI-Fc fusion protein is set forth in SEQ ID NO: 168.
18. The immunomodulatory protein homodimer of claim 1, wherein the TACI-Fc fusion protein is set forth in SEQ ID NO: 167.
19. A pharmaceutical composition comprising the immunomodulatory protein homodimer of claim 1 and a pharmaceutically acceptable excipient.
20. An immunomodulatory protein homodimer comprising two identical copies of a TACI-Fc fusion protein of the formula TACI polypeptide (TACI)-Linker-Fc region, wherein the TACI polypeptide is a variant TACI polypeptide set forth in SEQ ID NO:26.
21. The immunomodulatory protein homodimer of claim 20, wherein the linker comprises a peptide linker and the peptide linker is selected from GSGGS (SEQ ID NO: 76), GGGGS (G45; SEQ ID NO: 77), GSGGGGS (SEQ ID NO: 74), GGGGSGGGGS (2×GGGGS; SEQ ID NO: 78), GGGGSGGGGSGGGGS (3×GGGGS; SEQ ID NO: 79), GGGGSGGGGSGGGGSGGGGS (4×GGGGS, SEQ ID NO:84), GGGGSGGGGSGGGGSGGGGSGGGGS (5×GGGGS, SEQ ID NO: 91), GGGGSSA (SEQ ID NO: 80), or GSGGGGSGGGGS (SEQ ID NO:194) or combinations thereof.
22. The immunomodulatory protein homodimer of claim 20, wherein the linker is GSGGGGS (SEQ ID NO: 74).
23. The immunomodulatory protein homodimer of claim 20, wherein the Fc region is an IgG1 Fc domain.
24. The immunomodulatory protein homodimer of claim 23, wherein the Fc region is set forth in SEQ ID NO:81.
25. The immunomodulatory protein homodimer of claim 20, wherein the Fc region is a variant IgG1 Fc domain that exhibits reduced effector function.
26. The immunomodulatory protein homodimer of claim 25, wherein the Fc region comprises the amino acid substitutions L234A, L235E, and G237A by EU numbering.
27. The immunomodulatory protein homodimer of claim 26, wherein the Fc region is set forth in SEQ ID NO:73.
28. A pharmaceutical composition comprising the immunomodulatory protein homodimer of claim 20 and a pharmaceutically acceptable excipient.
29. An immunomodulatory protein that is a homodimer comprising two identical copies of the TACI-Fc fusion protein set forth in SEQ ID NO:167 or SEQ ID NO: 168 linked by a covalent disulfide bond.
30. A pharmaceutical composition comprising the immunomodulatory protein of claim 29 and a pharmaceutically acceptable excipient.
Ref APP-17_346095: Claims:
An immunomodulatory protein homodimer comprising two identical copies of a TACI-Fc fusion protein, wherein the TACI-Fc fusion protein comprises a variant TACI polypeptide, an Fc region, and a linker between the variant TACI polypeptide and the Fc region, wherein the variant TACI polypeptide comprises the amino acid substitutions K77E, F78Y, and Y102D in the sequence set forth in SEQ ID NO:13, wherein the numbering of positions corresponds to numbering of positions set forth in SEQ ID NO:122.
The immunomodulatory protein homodimer of claim 1, wherein the variant TACI polypeptide has increased binding affinity to one or both of APRIL and BAFF compared to the reference TACI polypeptide.
The immunomodulatory protein homodimer of claim 1, wherein the variant TACI polypeptide has at least 90% sequence identity to SEQ ID NO:13.
The immunomodulatory protein homodimer of claim 1, wherein the variant TACI polypeptide has at least 92% sequence identity to SEQ ID NO:13.
The immunomodulatory protein homodimer of claim 1, wherein the variant TACI polypeptide is set forth in SEQ ID NO: 26.
The immunomodulatory protein homodimer of claim 1, wherein the linker comprises a peptide linker and the peptide linker is selected from GSGGS (SEQ ID NO: 76), GGGGS (G45; SEQ ID NO: 77), GSGGGGS (SEQ ID NO: 74), GGGGSGGGGS (2×GGGGS; SEQ ID NO: 78), GGGGSGGGGSGGGGS (3×GGGGS; SEQ ID NO: 79), GGGGSGGGGSGGGGSGGGGS (4×GGGGS, SEQ ID NO:84), GGGGSGGGGSGGGGSGGGGSGGGGS (5×GGGGS, SEQ ID NO: 91), GGGGSSA (SEQ ID NO: 80), or GSGGGGSGGGGS (SEQ ID NO:194) or combinations thereof.
The immunomodulatory protein homodimer of claim 1, wherein the linker is GSGGGGS (SEQ ID NO: 74).
The immunomodulatory protein homodimer of claim 7, wherein the Fc region is an IgG1 Fc domain comprising the amino acid substitutions L234A, L235E an G237A by EU numbering.
The immunomodulatory protein homodimer of claim 8, wherein the Fc region is set forth in SEQ ID NO:73.
The immunomodulatory protein homodimer of claim 1, wherein the Fc region is an IgG1 Fc domain.
The immunomodulatory protein homodimer of claim 10, wherein the Fc region is set forth in SEQ ID NO:81.
The immunomodulatory protein homodimer of claim 1, wherein the Fc region is a variant IgG1 Fc domain that exhibits reduced effector function.
The immunomodulatory protein homodimer of claim 12, wherein the variant IgG1 Fc domain comprises the amino acid substitutions L234A, L235E, and G237A by EU numbering.
The immunomodulatory protein homodimer of claim 13, wherein the Fc region is set forth in SEQ ID NO:73.
The immunomodulatory protein homodimer of claim 1, wherein the Fc region is an Fc domain of IgG2.
The immunomodulatory protein homodimer of claim 1, wherein the Fc region is an Fc domain of IgG4 or is a variant IgG4 Fc domain containing the S228P mutation.
The immunomodulatory protein homodimer of claim 1, wherein the TACI-Fc fusion protein is set forth in SEQ ID NO: 168.
The immunomodulatory protein homodimer of claim 1, wherein the TACI-Fc fusion protein is set forth in SEQ ID NO: 167.
A pharmaceutical composition comprising the immunomodulatory protein homodimer of claim 1 and a pharmaceutically acceptable excipient.
An immunomodulatory protein homodimer comprising two identical copies of a TACI-Fc fusion protein of the formula TACI polypeptide (TACI)-Linker-Fc region, wherein the TACI polypeptide is a variant TACI polypeptide set forth in SEQ ID NO:26.
The immunomodulatory protein homodimer of claim 20, wherein the linker comprises a peptide linker and the peptide linker is selected from GSGGS (SEQ ID NO: 76), GGGGS (G45; SEQ ID NO: 77), GSGGGGS (SEQ ID NO: 74), GGGGSGGGGS (2×GGGGS; SEQ ID NO: 78), GGGGSGGGGSGGGGS (3×GGGGS; SEQ ID NO: 79), GGGGSGGGGSGGGGSGGGGS (4×GGGGS, SEQ ID NO:84), GGGGSGGGGSGGGGSGGGGSGGGGS (5×GGGGS, SEQ ID NO: 91), GGGGSSA (SEQ ID NO: 80), or GSGGGGSGGGGS (SEQ ID NO:194) or combinations thereof.
The immunomodulatory protein homodimer of claim 20, wherein the linker is GSGGGGS (SEQ ID NO: 74).
The immunomodulatory protein homodimer of claim 20, wherein the Fc region is an IgG1 Fc domain.
The immunomodulatory protein homodimer of claim 23, wherein the Fc region is set forth in SEQ ID NO:81.
The immunomodulatory protein homodimer of claim 20, wherein the Fc region is a variant IgG1 Fc domain that exhibits reduced effector function.
The immunomodulatory protein homodimer of claim 25, wherein the Fc region comprises the amino acid substitutions L234A, L235E, and G237A by EU numbering.
The immunomodulatory protein homodimer of claim 26, wherein the Fc region is set forth in SEQ ID NO:73.
A pharmaceutical composition comprising the immunomodulatory protein homodimer of claim 20 and a pharmaceutically acceptable excipient.
An immunomodulatory protein that is a homodimer comprising two identical copies of the TACI-Fc fusion protein set forth in SEQ ID NO:167 or SEQ ID NO: 168 linked by a covalent disulfide bond.
A pharmaceutical composition comprising the immunomodulatory protein of claim 29 and a pharmaceutically acceptable excipient.