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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/17/2025 has been entered.
Claims 1, 7-8, 11-12, 15, 18, 23, 27, 30, and 32-35 are currently being pending. Claims 1, 8, 12, 15, and 18 have been amended. Claims 1, 7-8, 11-12, 15, 18, 23, 27, 30, and 32-35 are currently under prosecution
New Rejection
(Necessitated by Amendments)
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7-8, 11-12, 15, 18, 23, 27, 30, and 32-35 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.
Claim 1 (i)-(iv) are drawn to non-cytolytic IgG1 Fc fragments comprising a sequence or a variant thereof with three mutations. It is unclear what location these mutations are referring to. The sequences have only 250 amino acids, and the locations of the mutations are in positions greater than 250. The numbering system of the mutations needs to be defined. The amendments to the specific substitutions will not be taken into consideration as the claim is indefinite, the metes and bounds cannot be determined.
Maintained Rejections
(Arguments Addressed)
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 7-8, 11-12, 15, 18, 23, 27-30, and 32-35 remain 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a Fc fusion protein, wherein said Fc fusion protein is a homodimer of two polypeptides, each comprising (i) an immunoglobulin IgG Fc domain and (ii) a human IL-10 or a variant thereof comprising a conservative substitution of 1, 2, 3, amino acid residues, wherein the human IL-10 polypeptide is covalently linked to the N-terminus or the C-terminus of the Fc domain by a peptide linker and the two polypeptides of the homodimer, and wherein the Fc domain comprises an Fc fragment selected from the group consisting of either non-cytolytic IgG1, IgG2, IgG3, or IgG2 comprising the sequences of SEQ ID NO: 2, 5, 8, 11, or variants thereof, respectively and that the Fc fusion protein comprises the sequences of SEQ ID NO: 4, 7, 10, or 13, or variants of the sequences. The claims recite that the variant thereof comprises substitutions of 1, 2, or 3 amino acid residues, or at least 1, 2, or 3 substitutions in the IgG Fc fragments. These claims provide partial sequence structure, wherein they comprise sequences with variants anywhere in the sequences.The variants are not defined and can have sequence discrepancy anywhere in the sequences critical to the Fc fusion protein.
The instant specification recites that the Fc fusion protein may comprise SEQ ID NO: 4, 7, 11, or 13, and that the IgG1-4 may comprise SEQ ID Nos: 2, 5, 8, or 11, or variants thereof. The instant specification defines variant that has at least one amino acid different than the reference sequences. The specification fails to disclose any other representative structure sequences of the Fc fusion proteins of the IgG domains required to make the Fc fusion protein and function, as claimed. The specification fails to disclose any other representative variants comprising less than 100% of the sequences listed above that function as claimed.
To provide adequate written description and evidence of possession of the claimed Fc fusion protein, the instant specification can structurally describe representative Fc fusion protein that function as stated above, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
With regards to variants having unlimited sequence discrepancies from the sequences of the Fc fusion protein, Applicants have not established any reasonable structure-function correlation with regards to the sequences in Fc fusion protein or IgG1-4 domains that can be altered and maintain function. The instant claims attempt to claim every Fc fusion protein and every IgG1-4 domain that would achieve a desired result, wherein the instant specification does not describe sufficient representative examples to support the full scope of the claims. The skilled artisan would not have been in possession of the vast repertoire of Fc fusion proteins or variants of the instantly claimed sequences encompassed by the Fc fusion proteins. Therefore, one could not readily envision members of the broadly claimed genus.
The instant claims attempt to claim every Fc fusion protein that would achieve the desired result, wherein the instant specification does not describe representative number of species to support the full scope of the claimed genus because the instant specification discloses only the sequences as recited above. Applicants have not established any reasonable structure-function correlation with regards to the sequences that can be altered and maintain function. The instant claims attempt to claim every Fc fusion protein that would achieve a desired result, wherein the instant specification dose not describe representative examples to support the full scope of the claims.
Given the lack of representative examples to support the full scope of the claimed Fc fusion protein and lack of reasonable structure correlation with regards to the unknown sequences, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of the Fc fusion protein that is required to practice the claimed invention.
Response to Arguments
Applicants amend the claims to remove “deletion” and remove “4 or 5” conservative amino acid substitutions for both SEQ ID NO: 1 and the IgG1, IgG2, IgG3, and IgG4 Fc fragments. Applicants note that each variant recited in claim 1 now only have 1, 2, or 3 conservative amino acid substitutions. Applicant’s argue that the crystal structure of IL-10 was well characterized, as well as the interaction between IL-10 and the specific receptor. Applicant argues there is a clear structure-function correlation that exists.
Applicant’s arguments have been considered but are not persuasive. The written description is directed to the “variants” of the instantly claimed sequences. The claims are drawn to variants of the sequences of up to 3 amino acid residues anywhere in the sequence. It is well known in the art that mutations or changes in peptides can alter specificity and change or even abolish antigen binding. (see Herold et al (Sci Rep. 2017 Sep 25;7(1):12276; of record) Rudikoff et al (Proc Natl Acad Sci U S A. 1982 Mar;79(6):1979-83; of record) also demonstrates that even a single amino acid substitution is capable of completely altering antigen-binding specificity. [pg 1982] Rabia et al (Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility. Biochemical engineering journal, 137, 365–374, 2018) and Vajdos et al (Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis. Journal of molecular biology, 320(2), 415–428, 2022) teaches that changes to amino acid sequence are unpredictable in terms of affinity, specificity, and solubility, (see Rabia whole documents), and teaches that even minute changes to the can impact binding affinities. (see Figure 2, effects of CDR mutations on binding affinity), respectively. Thus, although IL-10 polymorphisms are known as asserted by the Applicant, changes in the structure up to 3 amino acid sequences, may have an effect on the structure of the amino acid sequence.
Maintained Rejection
(Amendments and Arguments Addressed)
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.
Claim(s) 1, 7, 8, 11-12, 15, 18, 23, 28, 34 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Moustakas et al (US20170368144 A1, Published 12/28/2017; of record), in view of Czajkoswky et al (Fc-fusion proteins: new developments and future perspectives, EMBO Mol Med. 2012 Jul 26;4(10):1015–1028; of record), Zheng et al (A noncytolytic IL-10/Fc fusion protein prevents diabetes, blocks autoimmunity, and promotes suppressor phenomena in NOD mice; J Immunol (1997) 158 (9): 4507–4513; of record), Sun et al (US7250493 B2; Published 7/31/2007; of record), Lazar et al (WO2011103584 A2, Published 8/25/2011; of record), and Ciaramella et al (WO2011064758 A2; Published 6/3/2011; of record).
Regarding claim 1: Moustakas teaches a Fc fusion protein, wherein said Fc fusion protein linked to a Fc fragment. [0007] Moustakas teaches that the Fc fusion protein is a homodimer of two polypeptides, each comprising (i) an immunoglobulin IgG Fc domain [0033] and (ii) a heterologous polypeptide a comprising a sequence of a human IL-10 or a variant thereof, wherein the heterologous polypeptide is covalently linked to the N-terminus or the C-terminus of the Fc domain by a polypeptide linker and the two heterologous polypeptides are non-covalently assembled in a homodimer. [0010, 0031, 0042, 0044, 0068, 0099, 00121, 0127] Moustakas teaches that IL-10 is a potent anti-inflammatory cytokine that inhibits the production of inflammatory mediators, as well as immunostimulatory properties on CD4+, CD8+ T-cells, and/or N cells. Moustakas teaches that IL-10 induces cytotoxic activity and tumor promoting inflammation, as it increases the infiltration of CD8+ T-cells to a tumor. Moustakas teaches that a drawback of using IL-10 is short serum half-life, and one way to increase serum half-life is to attach the protein to an Fc domain of an antibody. Moustakas teaches Fc domains are capable of forming homodimers. [0002-0006]
Moustakas teaches that the Fc fusion protein comprises the sequence of human IL-10, wherein the sequence of the human IL-10 is SEQ ID NO: 42, which matches 100% to the instantly claimed SEQ ID NO: 1. [see sequence alignment below]
Moustakas teaches wherein the sequence of said Fc fusion protein comprises the sequence of an IgG1 Fc fragment. [0033, 0074, 0075, 0080, 0081]
Regarding claims 8, 12, 15, and 18: Moustakas teaches the sequence of said Fc fusion protein comprises:
SEQ ID NO: 13, which matches 98.9% to SEQ ID NO: 4;
SEQ ID NO: 15, which matches 94.3% to SEQ ID NO: 7;
SEQ ID NO: 52, which matches 83.2% to SEQ ID NO: 10;
SEQ ID NO: 14, which matches 94.5% to SEQ ID NO: 13;
Regarding claims 23, 27, 28, 34, and 35: Moustakas teaches a pharmaceutical composition comprising at least one Fc fusion protein as noted above, and a pharmaceutically acceptable carrier, diluent, or excipient. [0144, 0150] Moustakas teaches that the fusion protein may be administered with one or more additional agents. [0151] Moustakas teaches that the fusion protein may be used to treat cancer, such as cancer of the uterus or melanoma. [0128, 0141, 0142, 0143]
Sequence Result for SEQ ID NO: 1
RESULT 12
US-15-630-341-45
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
Sequence 45, US/15630341
Patent No. 10335459
GENERAL INFORMATION
APPLICANT: ALKERMES, INC.
TITLE OF INVENTION: COMPOSITIONS AND METHODS FOR MODULATING IL-10 IMMUNOSTIMULATORY
TITLE OF INVENTION: AND ANTI-INFLAMMATORY PROPERTIES
FILE REFERENCE: 4000.3071 US1
CURRENT APPLICATION NUMBER: US/15/630,341
CURRENT FILING DATE: 2017-06-22
PRIOR APPLICATION NUMBER: 62/353,478
PRIOR FILING DATE: 2016-06-22
NUMBER OF SEQ ID NOS: 54
SEQ ID NO 45
LENGTH: 325
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 100.0%; Score 836; Length 325;
Best Local Similarity 100.0%;
Matches 160; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 166 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYL 225
Qy 61 GCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 226 GCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 285
Qy 121 VEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN 160
||||||||||||||||||||||||||||||||||||||||
Db 286 VEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN 325
Sequence Result for SEQ ID NO: 4
RESULT 1
US-15-630-341-13
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
Sequence 13, US/15630341
Patent No. 10335459
GENERAL INFORMATION
APPLICANT: ALKERMES, INC.
TITLE OF INVENTION: COMPOSITIONS AND METHODS FOR MODULATING IL-10 IMMUNOSTIMULATORY
TITLE OF INVENTION: AND ANTI-INFLAMMATORY PROPERTIES
FILE REFERENCE: 4000.3071 US1
CURRENT APPLICATION NUMBER: US/15/630,341
CURRENT FILING DATE: 2017-06-22
PRIOR APPLICATION NUMBER: 62/353,478
PRIOR FILING DATE: 2016-06-22
NUMBER OF SEQ ID NOS: 54
SEQ ID NO 13
LENGTH: 557
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 98.9%; Score 2073; Length 557;
Best Local Similarity 99.0%;
Matches 388; Conservative 1; Mismatches 3; Indels 0; Gaps 0;
Qy 1 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 166 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYL 225
Qy 61 GCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 226 GCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 285
Qy 121 VEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNEPKSCDKTHTCPPCPAPEVA 180
|||||||||||||||||||||||||||||||||||||||||||| |||||||||||||:
Db 286 VEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNEPKSSDKTHTCPPCPAPELL 345
Qy 181 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 346 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 405
Qy 241 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSR 300
||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||
Db 406 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 465
Qy 301 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 466 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 525
Qy 361 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 392
||||||||||||||||||||||||||||||||
Db 526 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 557
Sequence Result for SEQ ID NO: 7
RESULT 45
US-15-630-341-15
(NOTE: this sequence has 3 duplicates in the database searched.
See complete list at the end of this report)
Sequence 15, US/15630341
Patent No. 10335459
GENERAL INFORMATION
APPLICANT: ALKERMES, INC.
TITLE OF INVENTION: COMPOSITIONS AND METHODS FOR MODULATING IL-10 IMMUNOSTIMULATORY
TITLE OF INVENTION: AND ANTI-INFLAMMATORY PROPERTIES
FILE REFERENCE: 4000.3071 US1
CURRENT APPLICATION NUMBER: US/15/630,341
CURRENT FILING DATE: 2017-06-22
PRIOR APPLICATION NUMBER: 62/353,478
PRIOR FILING DATE: 2016-06-22
NUMBER OF SEQ ID NOS: 54
SEQ ID NO 15
LENGTH: 550
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 94.3%; Score 1959.5; Length 550;
Best Local Similarity 94.9%;
Matches 369; Conservative 7; Mismatches 8; Indels 5; Gaps 2;
Qy 1 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 166 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYL 225
Qy 61 GCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 226 GCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 285
Qy 121 VEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNERKCCVECPPCPAPP-VAGP 179
|||||||||||||||||||||||||||||||||||||||| ||||||| : ||
Db 286 VEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNTH----TCPPCPAPELLGGP 341
Qy 180 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNS 239
|||||||||||||||||||||||||||||||||||:|||||||||||||||||||||:||
Db 342 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 401
Qy 240 TFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEM 299
|:||||||||:||||||||||||||||| ||: ||||||| |||||||||||||||||||
Db 402 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM 461
Qy 300 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ 359
||||||||||||||||||||||||||||||||||||||:|||||||||||||||||||||
Db 462 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 521
Qy 360 QGNVFSCSVMHEALHNHYTQKSLSLSPGK 388
|||||||||||||||||||||||||||||
Db 522 QGNVFSCSVMHEALHNHYTQKSLSLSPGK 550
Sequence Result for SEQ ID NO: 10
RESULT 1
US-15-630-341-52
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
Sequence 52, US/15630341
Patent No. 10335459
GENERAL INFORMATION
APPLICANT: ALKERMES, INC.
TITLE OF INVENTION: COMPOSITIONS AND METHODS FOR MODULATING IL-10 IMMUNOSTIMULATORY
TITLE OF INVENTION: AND ANTI-INFLAMMATORY PROPERTIES
FILE REFERENCE: 4000.3071 US1
CURRENT APPLICATION NUMBER: US/15/630,341
CURRENT FILING DATE: 2017-06-22
PRIOR APPLICATION NUMBER: 62/353,478
PRIOR FILING DATE: 2016-06-22
NUMBER OF SEQ ID NOS: 54
SEQ ID NO 52
LENGTH: 622
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 83.2%; Score 1992; Length 622;
Best Local Similarity 86.4%;
Matches 382; Conservative 10; Mismatches 42; Indels 8; Gaps 2;
Qy 1 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 186 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYL 245
Qy 61 GCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 246 GCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 305
Qy 121 VEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNELKTPLGDTTHTCPRCPEPK 180
|||||||||||||||||||||||||||||||||||||||| : | |
Db 306 VEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNSGSGGASSESSASSDGPHPV 365
Qy 181 SCDTPPPCPRCPEPKSCDTPPPCP---RCPEPKSCDTPPPCPRCPAPELLGGPSVFLFPP 237
:: | | : | | |||| | || |||||||||||||||||
Db 366 ITES-----RASSESSASSDGPHPVITESREPKSSDKTHTCPPCPAPELLGGPSVFLFPP 420
Qy 238 KPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSV 297
||||||||||||||||||||||||||||:| |||||||||||||||||||||||:|||||
Db 421 KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV 480
Qy 298 LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSL 357
||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||
Db 481 LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 540
Qy 358 TCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSC 417
||||||||||||||||||:||||||| ||||:||||||||||||||||||||||||:|||
Db 541 TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 600
Qy 418 SVMHEALHNRFTQKSLSLSPGK 439
||||||||| :|||||||||||
Db 601 SVMHEALHNHYTQKSLSLSPGK 622
Sequence Result for SEQ ID NO: 13
RESULT 7
US-15-630-341-14
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
Sequence 14, US/15630341
Patent No. 10335459
GENERAL INFORMATION
APPLICANT: ALKERMES, INC.
TITLE OF INVENTION: COMPOSITIONS AND METHODS FOR MODULATING IL-10 IMMUNOSTIMULATORY
TITLE OF INVENTION: AND ANTI-INFLAMMATORY PROPERTIES
FILE REFERENCE: 4000.3071 US1
CURRENT APPLICATION NUMBER: US/15/630,341
CURRENT FILING DATE: 2017-06-22
PRIOR APPLICATION NUMBER: 62/353,478
PRIOR FILING DATE: 2016-06-22
NUMBER OF SEQ ID NOS: 54
SEQ ID NO 14
LENGTH: 553
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Description of Artificial Sequence: Synthetic
polypeptide
Query Match 94.5%; Score 1933.5; Length 553;
Best Local Similarity 94.1%;
Matches 366; Conservative 6; Mismatches 16; Indels 1; Gaps 1;
Qy 1 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 166 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYL 225
Qy 61 GCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 226 GCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 285
Qy 121 VEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNESKYGPPCPPCPAPEFLGGP 180
|||||||||||||||||||||||||||||||||||||||| | |||||||| ||||
Db 286 VEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNSDK-THTCPPCPAPELLGGP 344
Qy 181 SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS 240
||||||||||||||||||||||||||||| |||||:|||||||||||||||||||||:||
Db 345 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 404
Qy 241 TYRVVSVLTVLHQDWLXGKEYKCKVSXKGLGSSIEKTISXAXGQPREPQVYTLPPSQEEM 300
|||||||||||||||| ||||||||| | | : |||||| | ||||||||||||||:|||
Db 405 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM 464
Qy 301 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSXWQ 360
||||||||||||||||||||||||||||||||||||||||||||||||||:|||||| ||
Db 465 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 524
Qy 361 EGNVFSCSVMHEALHNHYTQKSLSLSLGK 389
:||||||||||||||||||||||||| ||
Db 525 QGNVFSCSVMHEALHNHYTQKSLSLSPGK 553
However, Moustakas does not explicitly teach: (1) that the IgG Fc fusion comprises a “noncytolytic” IgG Fc domain, do not teach the sequences of the IgG1, IgG3, or IgG4 Fc fragments (SEQ ID Nos: 2, 8, or 11, respectively), or a variant thereof, or (2) the sequences of the flexible hinges (SEQ ID NO: 3 and SEQ ID NO: 6),
Czajkowsky teaches various structures of Fc-based fusion proteins, which are composed of an immunoglobulin Fc domain directly linked to another peptide. See Figure 1(A) below: Czajkowsky demonstrates an Fc fusion protein, wherein the fusion protein comprises an immunoglobulin Fc domain and a heterologous polypeptide, wherein they are assembled in a homodimer.
PNG
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405
711
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Greyscale
Zheng teaches that IL-10 has a very short circulating half-life (20 minutes) and that administration of IL-10 produces potent but short-lived therapeutic effects. Zheng teaches an Fc fusion protein comprising a noncytolytic Il-10 fusion protein that allows for longer therapeutic effects. [pg 4507; 2nd column]
Sun teaches constructs of an Fc fusion protein and teach the known sequences of utilizing an IgG1 Fc fragment, comprising the sequence of SEQ ID NO: 22, which matches 99.5% to SEQ ID NO: 2 (a variant) (see sequence alignment below)
Sequence Result for SEQ ID NO: 2
US-11-017-185-22
Filing date in PALM: 2004-12-17
Sequence 22, US/11017185
Patent No. 7250493
GENERAL INFORMATION
APPLICANT: Sun, Lee-Hwei K
APPLICANT: Sun, Bill N
APPLICANT: Sun, Cecily R
TITLE OF INVENTION: Fc fusion proteins of human erythropoietin with increased biological
TITLE OF INVENTION: activities
FILE REFERENCE: 02SUN2001D2
CURRENT APPLICATION NUMBER: US/11/017,185
CURRENT FILING DATE: 2004-12-17
PRIOR APPLICATION NUMBER: US 09/932,812
PRIOR FILING DATE: 2001-08-17
NUMBER OF SEQ ID NOS: 28
SEQ ID NO 22
LENGTH: 435
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: HuEPO-L-vFc gamma1 with a 27-amino acid leader peptide (Figure 2C
)
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
2 1156 99.5 435 US-09-932-812A-22 2001-08-17 2 Fc fusion proteins of human erythropoietin with increased biological activities
ALIGNMENT:
Query Match 99.5%; Score 1156; Length 435;
Best Local Similarity 99.1%;
Matches 215; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APEVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 219 APEVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 278
Qy 61 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 279 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYT 338
Qy 121 LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 180
|||||:|:||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 339 LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 398
Qy 181 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 217
|||||||||||||||||||||||||||||||||||||
Db 399 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 435
Lazar teaches constructs of an Fc fusion protein and teach the known sequences of utilizing an IgG3 or IgG4 Fc fragments, comprising the sequences of SEQ ID NO: 6 and 7, which match 100% and 98.9% to SEQ ID Nos: 8 and 11, respectively. [see sequence alignments below)
Sequence Result for SEQ ID NO: 8
RESULT 2
AZM53723
(NOTE: this sequence has 27 duplicates in the database searched.
See complete list at the end of this report)
ID AZM53723 standard; protein; 218 AA.
XX
AC AZM53723;
XX
DT 27-OCT-2011 (first entry)
XX
DE Human immunoglobulin G3 (IgG3) heavy chain Fc region, SEQ ID 6.
XX
KW IgG 3; Immunoglobulin G3; antiarthritic; antiinflammatory;
KW antimicrobial-gen.; antipsoriatic; cardiovascular disease;
KW cardiovascular-gen.; crohns disease; cytostatic; dermatological;
KW dermatological disease; endocrine disease; endocrine-gen.;
KW gastrointestinal-gen.; heavy chain constant region; immune disorder;
KW immunoadhesin; immunomodulator; immunosuppressive; infection;
KW kidney transplant rejection; liver transplant rejection; lupus nephritis;
KW metabolic disorder; metabolic-gen.; mouth disease;
KW musculoskeletal disease; musculoskeletal-gen.; neoplasm; nephrotropic;
KW neurological disease; neuroprotective; oral-dental-gen.;
KW pancreas transplant rejection; prophylactic to disease;
KW protein interaction; protein therapy; psoriasis; psoriatic arthritis;
KW rheumatoid arthritis; systemic lupus erythematosus; therapeutic;
KW transplant rejection; ulcerative colitis.
XX
OS Homo sapiens.
XX
CC PN WO2011103584-A2.
XX
CC PD 25-AUG-2011.
XX
CC PF 22-FEB-2011; 2011WO-US025747.
XX
PR 19-FEB-2010; 2010US-0306311P.
PR 14-MAY-2010; 2010US-0334806P.
PR 10-NOV-2010; 2010US-0412309P.
XX
CC PA (XENC-) XENCOR INC.
XX
CC PI Lazar GA, Bernett MJ;
XX
DR WPI; 2011-K92752/58.
XX
CC PT Immunoadhesin useful for treating a patient with an immune related
CC PT disorder, e.g. Crohn's disease and systemic lupus erythematosus,
CC PT comprises a first domain comprising a variant cytotoxic T-lymphocyte
CC PT associated antigen 4.
XX
CC PS Example 1; SEQ ID NO 6; 78pp; English.
XX
CC The present invention relates to an immunoadhesin comprising a first
CC domain which comprises a variant cytotoxic T-lymphocyte associated
CC antigen 4 (CTLA4) AZM53719 binds with high affinity to human B7-1 (CD80)
CC and B7-2 (CD86) and a second domain which comprises an immunoglobulin G
CC (IgG) Fc region bind to one or more Fc receptors or Fc ligands. The CTLA4
CC -lg immunoadhesin helps to inhibit interactions between antigen
CC presenting cells (APCs) and T cells. The invention also includes: (1) a
CC method for treating a patient with an immune related disorder; (2) a
CC nucleic acid encoding the immunoadhesin; and (3) a method for making an
CC immunoadhesin. The immunoadhesin and method of the invention are useful
CC for treating a patient with an immune related disorder (Crohn's disease,
CC systemic lupus erythematosus (SLE), lupus nephritis, psoriatic arthritis,
CC psoriasis, rheumatoid arthritis, ulcerative colitis, and transplant
CC rejection (including kidney transplant, liver transplant, and pancreatic
CC transplant)). The CTLA4 immunoadhesin also useful for treating or
CC preventing neoplasm, infectious diseases, autoimmune diseases,
CC inflammatory disorders, cardiovascular disease, dermatological disease,
CC musculoskeletal disease, mouth disease, endocrine disease, metabolic
CC disorder, neurological disease. The present sequence is a human
CC immunoglobulin G3 (IgG3) heavy chain Fc region which is defined as
CC position 230 to the C-terminus (230-447) based on the EU numbering scheme
CC and used to bind with one or more Fc receptors or Fc ligands for
CC producing CTLA4-Ig immunoadhesin.
XX
SQ Sequence 218 AA;
Query Match 100.0%; Score 1160; Length 218;
Best Local Similarity 100.0%;
Matches 217; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTK 61
Qy 61 PREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 62 PREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYT 121
Qy 121 LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 122 LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL 181
Qy 181 TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK 217
|||||||||||||||||||||||||||||||||||||
Db 182 TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK 218
Sequence Result for SEQ ID NO: 11
ZM53724
ID AZM53724 standard; protein; 218 AA.
XX
AC AZM53724;
XX
DT 27-OCT-2011 (first entry)
XX
DE Human immunoglobulin G4 (IgG4) heavy chain Fc region, SEQ ID 7.
XX
KW IgG 4; Immunoglobulin G4; antiarthritic; antiinflammatory;
KW antimicrobial-gen.; antipsoriatic; cardiovascular disease;
KW cardiovascular-gen.; crohns disease; cytostatic; dermatological;
KW dermatological disease; endocrine disease; endocrine-gen.;
KW gastrointestinal-gen.; heavy chain constant region; immune disorder;
KW immunoadhesin; immunomodulator; immunosuppressive; infection;
KW kidney transplant rejection; liver transplant rejection; lupus nephritis;
KW metabolic disorder; metabolic-gen.; mouth disease;
KW musculoskeletal disease; musculoskeletal-gen.; neoplasm; nephrotropic;
KW neurological disease; neuroprotective; oral-dental-gen.;
KW pancreas transplant rejection; prophylactic to disease;
KW protein interaction; protein therapy; psoriasis; psoriatic arthritis;
KW rheumatoid arthritis; systemic lupus erythematosus; therapeutic;
KW transplant rejection; ulcerative colitis.
XX
OS Homo sapiens.
XX
CC PN WO2011103584-A2.
XX
CC PD 25-AUG-2011.
XX
CC PF 22-FEB-2011; 2011WO-US025747.
XX
PR 19-FEB-2010; 2010US-0306311P.
PR 14-MAY-2010; 2010US-0334806P.
PR 10-NOV-2010; 2010US-0412309P.
XX
CC PA (XENC-) XENCOR INC.
XX
CC PI Lazar GA, Bernett MJ;
XX
DR WPI; 2011-K92752/58.
XX
CC PT Immunoadhesin useful for treating a patient with an immune related
CC PT disorder, e.g. Crohn's disease and systemic lupus erythematosus,
CC PT comprises a first domain comprising a variant cytotoxic T-lymphocyte
CC PT associated antigen 4.
XX
CC PS Example 1; SEQ ID NO 7; 78pp; English.
XX
CC The present invention relates to an immunoadhesin comprising a first
CC domain which comprises a variant cytotoxic T-lymphocyte associated
CC antigen 4 (CTLA4) AZM53719 binds with high affinity to human B7-1 (CD80)
CC and B7-2 (CD86) and a second domain which comprises an immunoglobulin G
CC (IgG) Fc region bind to one or more Fc receptors or Fc ligands. The CTLA4
CC -lg immunoadhesin helps to inhibit interactions between antigen
CC presenting cells (APCs) and T cells. The invention also includes: (1) a
CC method for treating a patient with an immune related disorder; (2) a
CC nucleic acid encoding the immunoadhesin; and (3) a method for making an
CC immunoadhesin. The immunoadhesin and method of the invention are useful
CC for treating a patient with an immune related disorder (Crohn's disease,
CC systemic lupus erythematosus (SLE), lupus nephritis, psoriatic arthritis,
CC psoriasis, rheumatoid arthritis, ulcerative colitis, and transplant
CC rejection (including kidney transplant, liver transplant, and pancreatic
CC transplant)). The CTLA4 immunoadhesin also useful for treating or
CC preventing neoplasm, infectious diseases, autoimmune diseases,
CC inflammatory disorders, cardiovascular disease, dermatological disease,
CC musculoskeletal disease, mouth disease, endocrine disease, metabolic
CC disorder, neurological disease. The present sequence is a human
CC immunoglobulin G4 (IgG4) heavy chain Fc region which is defined as
CC position 230 to the C-terminus (230-447) based on the EU numbering scheme
CC and used to bind with one or more Fc receptors or Fc ligands for
CC producing CTLA4-Ig immunoadhesin.
XX
SQ Sequence 218 AA;
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
44 1118 98.9 218 AEG04971 -- 52 Human IgG4.
ALIGNMENT:
Query Match 98.9%; Score 1118; Length 218;
Best Local Similarity 97.2%;
Matches 211; Conservative 0; Mismatches 6; Indels 0; Gaps 0;
Qy 1 APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK 61
Qy 61 PREEQFNSTYRVVSVLTVLHQDWLXGKEYKCKVSXKGLGSSIEKTISXAXGQPREPQVYT 120
|||||||||||||||||||||||| ||||||||| ||| |||||||| | ||||||||||
Db 62 PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT 121
Qy 121 LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 122 LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL 181
Qy 181 TVDKSXWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 217
||||| |||||||||||||||||||||||||||||||
Db 182 TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 218
Regarding claims 7, 10 and 14: Ciaramella teaches immunoglobulin Fc fusion proteins comprising an immunoglobulin Fc region, wherein the Fc fusion protein comprises the sequence of a flexible hinge selected from SEQ ID NO: 3 or SEQ ID NO: 5, which match 100% to the instantly claimed SEQ ID NO: s 3 and 6, respectively. Ciaramella teaches the sequences of an IgG2 Fc fragment comprising the sequence of SEQ ID NO: 1, which matches 100% to SEQ ID NO: 5. [see sequence alignments below]
Sequence Result for SEQ ID NO: 3
RESULT 7
AZI68741
(NOTE: this sequence has 15 duplicates in the database searched.
See complete list at the end of this report)
ID AZI68741 standard; peptide; 16 AA.
XX
AC AZI68741;
XX
DT 21-JUL-2011 (first entry)
XX
DE Human Immunoglobulin G1/IgG 1 full hinge region, SEQ ID:3.
XX
KW IgG 1 protein; Immunoglobulin G1; antiinflammatory; antimicrobial-gen.;
KW gastrointestinal-gen.; gene expression; hepatitis c virus infection;
KW hepatotropic; liver disease; protein engineering; protein production;
KW therapeutic; virucide.
XX
OS Homo sapiens.
XX
CC PN WO2011064758-A2.
XX
CC PD 03-JUN-2011.
XX
CC PF 29-NOV-2010; 2010WO-IB055474.
XX
PR 30-NOV-2009; 2009US-0265001P.
XX
CC PA (PFIZ ) PFIZER LTD.
XX
CC PI Ciaramella G, Flores MV, Horscroft NJ, Katragadda M, Wu Y;
XX
DR WPI; 2011-G25805/37.
XX
CC PT New fusion protein useful for treating conditions associated with
CC PT administration of interferon-alpha (IFN-alpha) for treating liver
CC PT disorder, preferably hepatitis C, comprises immunoglobulin Fc region and
CC PT IFN-alpha.
XX
CC PS Disclosure; SEQ ID NO 3; 42pp; English.
XX
CC The present invention relates to novel fusion protein useful for treating
CC conditions associated with administration of interferon-alpha (IFN-alpha)
CC for treating liver disorder, preferably hepatitis C. The fusion protein
CC comprises immunoglobulin Fc region and an IFN-alpha protein. The
CC invention provides a method of recombinant production of the fusion
CC protein using host cells transfected with expression vector comprising
CC the nucleic acid molecule encoding the protein. The present sequence
CC corresponds to the human Immunoglobulin G1/IgG 1 full hinge region which
CC is used in the invention for producing fusion proteins that are used for
CC treating liver disorders including hepatitis C.
XX
SQ Sequence 16 AA;
Query Match 100.0%; Score 98; Length 16;
Best Local Similarity 100.0%;
Matches 15; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EPKSCDKTHTCPPCP 15
|||||||||||||||
Db 1 EPKSCDKTHTCPPCP 15
Sequence Result for SEQ ID NO: 6
RESULT 4
AZI68743
(NOTE: this sequence has 18 duplicates in the database searched.
See complete list at the end of this report)
ID AZI68743 standard; peptide; 14 AA.
XX
AC AZI68743;
XX
DT 21-JUL-2011 (first entry)
XX
DE Human Immunoglobulin G2/IgG 2 full hinge region, SEQ ID:5.
XX
KW IgG 2 protein; Immunoglobulin G2; antiinflammatory; antimicrobial-gen.;
KW gastrointestinal-gen.; gene expression; hepatitis c virus infection;
KW hepatotropic; liver disease; protein engineering; protein production;
KW therapeutic; virucide.
XX
OS Homo sapiens.
XX
CC PN WO2011064758-A2.
XX
CC PD 03-JUN-2011.
XX
CC PF 29-NOV-2010; 2010WO-IB055474.
XX
PR 30-NOV-2009; 2009US-0265001P.
XX
CC PA (PFIZ ) PFIZER LTD.
XX
CC PI Ciaramella G, Flores MV, Horscroft NJ, Katragadda M, Wu Y;
XX
DR WPI; 2011-G25805/37.
XX
CC PT New fusion protein useful for treating conditions associated with
CC PT administration of interferon-alpha (IFN-alpha) for treating liver
CC PT disorder, preferably hepatitis C, comprises immunoglobulin Fc region and
CC PT IFN-alpha.
XX
CC PS Disclosure; SEQ ID NO 5; 42pp; English.
XX
CC The present invention relates to novel fusion protein useful for treating
CC conditions associated with administration of interferon-alpha (IFN-alpha)
CC for treating liver disorder, preferably hepatitis C. The fusion protein
CC comprises immunoglobulin Fc region and an IFN-alpha protein. The
CC invention provides a method of recombinant production of the fusion
CC protein using host cells transfected with expression vector comprising
CC the nucleic acid molecule encoding the protein. The present sequence
CC corresponds to the human Immunoglobulin G2/IgG 2 full hinge region which
CC is used in the invention for producing fusion proteins that are used for
CC treating liver disorders including hepatitis C.
XX
SQ Sequence 14 AA;
Query Match 100.0%; Score 81; Length 14;
Best Local Similarity 100.0%;
Matches 12; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ERKCCVECPPCP 12
||||||||||||
Db 1 ERKCCVECPPCP 12
Sequence Result for SEQ ID NO: 5
RESULT 1
AZI68739
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
ID AZI68739 standard; protein; 216 AA.
XX
AC AZI68739;
XX
DT 21-JUL-2011 (first entry)
XX
DE Human Immunoglobulin G2/IgG 2 Fc region, SEQ ID:1.
XX
KW IgG 2 protein; Immunoglobulin G2; antiinflammatory; antimicrobial-gen.;
KW gastrointestinal-gen.; gene expression; hepatitis c virus infection;
KW hepatotropic; liver disease; protein engineering; protein production;
KW therapeutic; virucide.
XX
OS Homo sapiens.
XX
CC PN WO2011064758-A2.
XX
CC PD 03-JUN-2011.
XX
CC PF 29-NOV-2010; 2010WO-IB055474.
XX
PR 30-NOV-2009; 2009US-0265001P.
XX
CC PA (PFIZ ) PFIZER LTD.
XX
CC PI Ciaramella G, Flores MV, Horscroft NJ, Katragadda M, Wu Y;
XX
DR WPI; 2011-G25805/37.
XX
CC PT New fusion protein useful for treating conditions associated with
CC PT administration of interferon-alpha (IFN-alpha) for treating liver
CC PT disorder, preferably hepatitis C, comprises immunoglobulin Fc region and
CC PT IFN-alpha.
XX
CC PS Claim 12; SEQ ID NO 1; 42pp; English.
XX
CC The present invention relates to novel fusion protein useful for treating
CC conditions associated with administration of interferon-alpha (IFN-alpha)
CC for treating liver disorder, preferably hepatitis C. The fusion protein
CC comprises immunoglobulin Fc region and an IFN-alpha protein. The
CC invention provides a method of recombinant production of the fusion
CC protein using host cells transfected with expression vector comprising
CC the nucleic acid molecule encoding the protein. The present sequence
CC corresponds to the human Immunoglobulin G2/IgG 2 Fc region which is used
CC in the invention for producing fusion proteins that are used for treating
CC liver disorders including hepatitis C.
XX
SQ Sequence 216 AA;
Query Match 100.0%; Score 1160; Length 216;
Best Local Similarity 100.0%;
Matches 216; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKP 60
Qy 61 REEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 REEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTL 120
Qy 121 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT 180
Qy 181 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 216
||||||||||||||||||||||||||||||||||||
Db 181 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 216
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to construct the Fc fusion protein of Moustakas, comprising non-cytolytic IL-10 fusion proteins, with the instantly claimed sequences of the IgG1, IgG2, IgG3, and IgG4 sequences. One would have been motivated to, and have a reasonable expectation of success, because: (1) Moustakas teaches that the Fc fusion protein comprises a homodimer of two polypeptides, comprising (a) an immunoglobulin IgG Fc domains, and (b) a heterologous polypeptide comprising a sequence of human Il-10, (2) Moustakas teaches the Fe fusion proteins comprising domains consisting of either IgG1, IgG3, or lgG4 domains, (3) Czajkowsky teaches various ways of construction and utilizing Fc fusion proteins, including linking the heterologous polypeptide to the N-terminus or the C-terminus of the Fc domain by a peptide linker, and that they are assembled in a homodimer, (4) Zheng teaches construction of Fc fusion proteins comprising the use of noncytolytic, and (5) Sun, Lazar, and Ciaramella teach constructs of known Fc fusion protein sequences. Given the known methods of constructing Fc fusion proteins, known methods of utilizing non-cytolytic IgG’s as demonstrated by the prior art , and given the known sequences of the IgG Fc fragments, one of skill in the art could have constructed the Fc fusion protein of Moustakas with the instantly claimed sequences of the IgG1, IgG3, or IgG4 Fe fragments and non- cytolytic IgGs, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to construct the Fc fusion protein of Moustakas with the instantly claimed sequences of the flexible hinge. One would have been motivated to, and have a reasonable expectation of success, because: (1) Moustakas and Czajkowsky both teach the Fc fusion proteins comprising sequences of a flexible hinge and (2) Ciaramella teaches the construct of an Fc fusion protein comprising utilizing the instantly claimed sequences of the flexible hinge. Given the known methods of constructing Fc fusion proteins, and given the known sequences of the flexible hinge regions, one of skill in the art could have constructed the Fc fusion protein of Moustakas with the instantly claimed sequences of the hinge regions, with a reasonable expectation of success.
Claim(s) 27, 29, 30, 32, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Moustakas et al (US20170368144 A1, Published 12/28/2017; of record), Czajkoswky et al (Fc-fusion proteins: new developments and future perspectives, EMBO Mol Med. 2012 Jul 26;4(10):1015–1028; of record), Zheng et al (A noncytolytic IL-10/Fc fusion protein prevents diabetes, blocks autoimmunity, and promotes suppressor phenomena in NOD mice; J Immunol (1997) 158 (9): 4507–4513; of record), Sun et al (US7250493 B2; Published 7/31/2007; of record), Lazar et al (WO2011103584 A2, Published 8/25/2011; of record), and Ciaramella et al (WO2011064758 A2; Published 6/3/2011; of record), as applied to claims 1, 7, 8, 11-12, 15, 18, 23, 28, 34 and 35 above, and further in view of Baeuerle et al (WO2018067993 A1; Published 4/12/2018; of record) and Cogwell et al (US20150125463 A1; Published 5/7/2015; of record).
The teachings of the combined references are cited above. However, they do not teach the Fc fusion protein is administered with an anti-cancer immunotherapy, such as immune checkpoint blockade therapy or ACT therapy.
Baeuerle teaches a method of treating cancer, melanoma, comprising administering ACT therapy, such as TCR-T. [Abstract, 00158-00160]
Cogwell teaches a method of treating cancer, melanoma, comprising administering an immune checkpoint inhibitor. [0014] Cogwell teaches that the immune checkpoint inhibitor can be administered with other agents to promote reduction in tumor growth or size. [0059, 00153-0156]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine the instantly claimed Fc fusion protein with either an immune checkpoint blocker or an ACT. One would have been motivated to, and have a reasonable expectation of success, because: (1) Moustakas teaches that the fusion protein may be administered with one or more additional agents, (2) Moustakas teaches that the fusion protein may be used to treat cancer, such as melanoma, (3) Baeuerle teaches a method of treating melanoma, comprising admisntering an ACT therapy, and (4) Cogwell teaches a method of treating melanoma comprising admisntering an immune checkpoint inhibitor, and this can be combined with other agents that treat cancer.
Those of skill in the art recognize that the agents are all known both known to successfully, pharmaceutically treat cancer, such as melanoma, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat melanoma and have additive effects through the combination of the agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective at treating cancer, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of treating cancer, such as melanoma.
Response to Arguments
Applicant argues:
No teaching or suggestion of claim 1 as a whole: Applicant argues that a piecemeal approach of looking at individual elements fails to appreciate the inventive step of combining them. Applicant argues that the art is too generic and that the cited art gives no direction as to which of many possible choices is likely to be successful with IL-10, and moreover, with an IL-10 homodimer.
No reasonable expectation of success: Applicant argues that there is nothing in the 6-way combination of art that would lead one skilled in the art to reasonably expect the claimed fusion protein comprising the claimed noncytolytic IgG Fc fragments would be successful at treating cancer and inducing immunity or having any of the properties as discussed prior.
Applicant's arguments have been fully considered but they are not persuasive. Although Applicants argue that they are not arguing individual references, they have failed to consider the teachings as a whole. In the instant case, Applicants have continued to argue the Ciaramella, Sun and Lazar reference individually and failed to consider the combined teaching with all the references to render the invention obvious.
The primary reference, Moustakas teaches that the Fc fusion protein is a homodimer of two polypeptides, each comprising (i) an immunoglobulin IgG Fc domain [0033] and (ii) a heterologous polypeptide a comprising a sequence of a human IL-10 or a variant thereof, wherein the heterologous polypeptide is covalently linked to the N-terminus or the C-terminus of the Fc domain by a polypeptide linker and the two heterologous polypeptides are non-covalently assembled in a homodimer, and teaches the use of these agents for the treatment of cancer. Furthermore, Moustakas teaches Moustakas teaches that IL-10 is a potent anti-inflammatory cytokine that inhibits the production of inflammatory mediators, as well as immunostimulatory properties on CD4+, CD8+ T-cells, and/or N cells. Moustakas teaches that IL-10 induces cytotoxic activity and tumor promoting inflammation, as it increases the infiltration of CD8+ T-cells to a tumor. Moustakas teaches that a drawback of using IL-10 is short serum half-life, and one way to increase serum half-life is to attach the protein to an Fc domain of an antibody. Thus, Moustakas provides motivation and reasonable expectation of success to formulate Fc fusion proteins comprising the instantly claimed structure. However, as noted above, Moustakas does not teach the instantly claimed sequences and the Examiner relied on secondary references to render the invention obvious. The purpose of the secondary references was to demonstrate the known sequences of the IgG sequences: 2, 5, 8, and 11 and to construct the Fc fusion protein of Moustakas comprising these known sequences. The teachings of Sun, Lazar, and Ciaramella all teach known sequences of these IgG sequences. Thus, given known methods of Fc fusion proteins, known methods of utilizing non-cytolytic IgG’s as demonstrated by the prior art, and given the known sequences of the IgG Fc fragments, one of skill in the art could have constructed the Fc fusion protein of Moustakas with the instantly claimed sequences of the IgG1, IgG3, or IgG4 Fe fragments and non- cytolytic IgGs, with a reasonable expectation of success. Applicants note that the amended claim include combination therapy that includes ACT therapy and immune checkpoint blockade. This was addressed in the 103 further in view above.
Conclusion
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/SARAH A ALSOMAIRY/ Examiner, Art Unit 1646
/Zachariah Lucas/ Supervisory Patent Examiner, Art Unit 1600