DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1, 3, 4-7, 9, 13-14, 16, 19, 22, 25, 27, 29, 31-33, and 37 are pending.
Claims 1, 3, 7, 9, and 13-14 are currently amended
Claims 2, 8, 10-12, 15, 17-18, 20-21, 23-24, 26, 28, 30, 34-36, and 38 are cancelled.
Claims 4-6, 16, 19, 22, 25, 27, 29, 31-33, and 37 are withdrawn.
Claims 1, 3, 7, 9, 13-14, and 25 (only fusion peptide) have been examined.
Priority
This application is a 371 of PCT/CN2021/129378 filed on 11/08/2021 and claims foreign priority of PCTCN2020129067 filed on 11/16/2020.
Withdrawn Rejection and Objection
The objection to claims 1-2 and 14 is withdrawn because the amendments to the claims overcome the objection.
The rejection of claims 2-3, 7, and 13 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn because the amendment to the claims overcomes the rejection of record.
Modified Rejection
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3, 7, 9, 13-14, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Alvarez et al. (WO 2013/184939 A2, cited in IDS) in view of Doyonnas et al. (The Journal of Immunology, 2000, 165: 840–851, cited in IDS), Chan et al. (J Biol Chem. (2001 Jan 19;276(3):2139-52, cited in IDS), Korf-Klingebiel et al. (Nat Med. 2015 Feb;21(2):140-9, cited in IDS), and Uniport MYDGF (https://www.uniprot.org/uniprotkb/ A0A2R9B4B0/entry#sequences. 2018-06-20).
Claim 1 is drawn to a fusion protein comprising (a) a peptide motif of SEQ ID NO: 2 and (b) a heterologous polypeptide of fibroblast growth factor 21 (FGF21), follicle-stimulating hormone (FSH), or myeloid-derived growth factor (MYDGF).
Alvarez et al. teach fusion polypeptides comprising a mucin-domain polypeptide covalently linked to an active protein to improve pharmacokinetic and/or physicochemical properties (Abstract). Alvarez et al. teach mucin-domain polypeptides may be linked to the active protein via either the N- and/or C-terminus of the active protein (p16, line 10-11; p17, line 3-10). Alvarez et al. teach a mucin domain polypeptide may also comprise all or a portion of a protein comprising a mucin domain of CD164 (p18, line 26; claim 10). Alvarez et al. teach a mucin domain polypeptide comprises domains of tandem amino acid repeats that are rich in Pro, Ser and Thr. In one aspect of this embodiment, the number of tandem repeat units within a mucin domain polypeptide of the invention is between 1 and 25 (p19, line 3-6; claim 11). Alvarez et al. teach the conjugated therapeutic proteins comprising recombinant follicle-stimulating hormone/rFSH (p38, line 14), parathyroid hormone (PTH) 1-84 (p38, line 31), or GLP-1 (p25, line 13) with short serum half-life.
Alvarez et al. teach a mucin domain polypeptide comprises domains of tandem amino acid repeats that are rich in Pro, Ser and Thr and the number of tandem repeat units within a mucin domain polypeptide of the invention is between 1 and 25, but does not specify a sequence from CD164.
Doyonnas et al. teach CD164 protein structure and protein sequence well known in the art as
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shown follows (p843, Fig 1A and 1B) and Mucin domain-2 of CD164 comprises a polypeptide sequence with 100% homology to the instant SEQ ID NO: 2. Similarly, Chan et al. is cited to show the transmembrane domain of CD164 starts at Ala 163 (mucin domain 2 ends at Asp 162) and the N-terminal Serine 110 linked to mucin domain 2 (Exon 4) is also a potential O-linked glycosylation site shown as follows (p2178, Fig 7A). Because both Doyonnas et al. and Chan et al. show CD164 polypeptide comprising multiple tandem amino acid repeats rich in Pro, Ser and Thr residues within the mucin domain 2, one of ordinary skill in the art would select the mucin domain 2 or both mucin domains 1 and 2 fusion to a short-life bioactive peptide to improve pharmacokinetic and/or physicochemical properties
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of the conjugated peptide.
Alvarez et al. in view of Doyonnas et al. and Chan et al. do not explicitly teach fusion of a mucin domain (e.g., mucin domain 2 of CD164) to MYDGF.
Korf-Klingebiel et al. teach Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction/MI (Title and Abstract). Korf-Klingebiel et al. teach Mydgf protects cardiac myocytes from cell death (p142, col 2, para 1; p142, Fig 2). Korf-Klingebiel et al. teach administration of Mydgf as a therapy for acute MI and elimination of Mydgf from plasma approximated a first-order kinetic with an estimated half-life of 15.3 min, suggesting Mydgf is a short half-life protein (p145, col 2, Mydgf protein therapy after MI). Because Korf-Klingebiel et al. teach Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction and Mydgf is a short half-life protein, one of ordinary skill in the art would have found it obvious to conjugate a mucin domain (e.g., mucin domain 2 of CD164) taught by Alvarez et al. in view of Doyonnas et al. and Chan et al. to Korf-Klingebiel’s Mydgf peptide.
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Uniport MYDGF is cited to show the protein sequence of MYDGF comprising the amino acids 1-31 as the signal peptide (p3). The full-length MYGDF is further shown as follows (p4).
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A sequence alignment of comparing the instant SEQ ID NO: 3 with the MYDGF protein fusion to with the mucin domain peptide taught by Alvarez et al. and evidenced by Fuleihan et al. in view of Doyonnas et al. and Chan et al. is shown as follows.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to combine (i) Alvarez et al. in view of Doyonnas et al. and Chan et al. and (ii) Korf-Klingebiel et al. in view of Uniport MYDGF because (a) Alvarez et al. in view of Doyonnas et al. and Chan et al. teach fusion of mucin domain 2 of CD164 to a short half-life bioactive peptide to improve pharmacokinetic and/or physicochemical properties (Alvarez’s Abstract), (b) Korf-Klingebiel et al. teach Mydgf with an estimated half-life of 15.3 min, suggesting Mydgf is a short half-life protein (p145, col 2, Mydgf protein therapy after MI), and (c) Uniport MYDGF is cited to show the protein sequence of MYDGF comprising the amino acids 1-31 as the signal peptide (p3) and the full-length MYGDF (p4). The combination would have reasonable expectation of success because Alvarez et al. suggest a mucin domain 2 of CD164) is expected to improve pharmacokinetic and/or physicochemical properties after fusion to the short-life MYDGF protein.
With respect to claim 3, Alvarez et al. teach mucin-domain polypeptides may be linked to the active protein via either the N- and/or C-terminus of the active protein (p16, line 10-11; p17, line 3-10).
With respect to claims 7, 9, and 13, one of ordinary skill in the art would expect a mucin domain 2 of CD164) fusion to the short-life MYDGF protein able to improve pharmacokinetic and/or physicochemical properties of the protein of MYDGF alone. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). See MPEP 2112.01(I).
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With respect to claim 14, a sequence alignment of comparing the instant SEQ ID NO: 3 with the MYDGF protein fusion to with the mucin domain peptide taught by Alvarez et al. and evidenced by Fuleihan et al. in view of Doyonnas et al. and Chan et al. is as shown above.
With respect to claim 25, Alvarez et al. teach a pharmaceutical composition comprising a fusion protein comprising a therapeutic active protein linked to a mucin-domain polypeptide and at least one pharmaceutically acceptable carrier (p45, line 25-27).
Applicant’s Arguments
The presently claimed invention successfully enhances solubilities, tissue distribution, and adsorptions by concerting the fusion protein to acidic forms and decreasing the isoelectric points (Pl) of the fusion protein through sialylation of the glycans. The prior art fails to teach how to obtain highly sialylated fusion proteins with decreased PI, suggesting that fusion of the CD164 mucin domain II (SEQ ID NO: 2) did not impact tissue distribution (Remarks, p7 to p8, para 1).
The prior art fails to teach how to obtain highly sialylated fusion proteins with decreased PI because (a) Alvarez et al. does not teach whether the CD 164 mucin domain can be sufficiently sialylated in a fusion protein (Remarks, p8, para 3-6), and (b) Doyonnas et al. and Chan et al. does not teach whether CD164 can be sufficiently sialylated in a fusion protein and induce effects such as decreased PI and improved tissue distribution (Remarks, p9, para 1-3).
Claims 1-3, 7, 9, 13-14, and 25 are not obvious over Alverez et al. and evidenced by Fuleihan et al. in view of Doyonnas et al., Chan et al. as applied to claims 1-3, 7, 9, and 25 and further in view of Korf-Klingebiel et al. and Uniprot MYDGF (Remarks, p9, 2nd last para).
Response to Arguments
Applicant's arguments filed 7/1/2026 have been fully considered but they are not persuasive for the reasons as follows.
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Applicant’s arguments (i) and (ii) are not persuasive because (a) CD164 is a member of the mucin-like receptor or sialomucin superfamily of glycoproteins known in the art evidenced by Saborio et al. (WO 2006/077266 A1, p3, last para), demonstrating CD164 inherently sialylated and (b) Sialic acid inherently has a carboxylic acid with a negative charge for reducing pI of sialomucin proteins (e.g., CD164) as evidenced by Li et al. (Protein Cell 2019, 10(8):550–565) as shown above (p551, Fig 1). The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. See MPEP 2144 (I). Furthermore, “Prima Facie Obviousness Is Not Rebutted by Merely Recognizing Additional Advantages or Latent Properties Present But Not Recognized in the Prior Art”. See MPEP 2145(II).
Applicant’s argument (iii) is not persuasive. See response to arguments above.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.L/Examiner, Art Unit 1658
29-August-2026
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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