DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Claim(s) 1-14 are pending and under examination
Claims 1-7 are amended. Claims 8-14 are new
The following Office Action is in response to Applicant's communication dated 06/30/2026.
Rejection(s) and/or objection(s) not reiterated from previous office actions are hereby withdrawn. The following rejection(s) and/or objection(s) are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Applicant’s arguments with respect to claim(s) 1-7 have been considered. Specifically, Applicant amended independent claim 1 to further require the peptide linker comprises 4 to 49 amino acid residues selected from the group consisting of alanine (A), praline (P), serine (S), and combinations thereof. This limitation was not in the previous claim set (Filed 07/21/2023). Hence narrowed the scope of claim 1 and required Examiner to conduct new prior art search directed to newly claimed subject matter. Ballinger et al. continue to be relied upon for the teachings discussed in the rejection, while Haupts et al. reference gas been included to address the newly added limitations regarding the peptide linker.
Modified Claim Rejections - 35 USC § 103-Neccessitated by Amendments
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Ballinger et al., Haupts et al., and Nakano et al.
Claim(s) 1-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ballinger et al. (US20040054131A1, EFD: September 9th 1999) in view of Haupts et al. (WO2017149002A1, EFD: March 1st 2017) and Nakano et al. (US20200032275A1, EFD: June 15th 2016).
Regarding claim 1, Ballinger discloses method for screening dimerized peptides, including steps:
(1B) providing a dimer of at least one, wherein the dimer includes: Including a cyclic peptide, a dimerization domain containing a cysteine residue and a leucine zipper region, and a peptide linker present between the cyclic peptide and the dimerization domain (e.g. polypeptide fusion containing FGF receptor binder cyclic peptide (. C19 clone with cysteines residues to permit intra-peptide and inter-peptide disulfide bonds, forming cyclic peptide [¶0072]), a linker (20 amino acid residues long and made of glycine and serine), and a cysteine containing leucine zipper (homodimerization domain is Jun’s C-leucine zipper [¶0080]) [Fig 1A shown below].)
(2) measuring activity based on binding of the dimer to a target molecule (e.g. the homodimers are evaluated for receptor associated activity as an FGFR agonist [¶0008])
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Ballinger does not disclose polypeptide obtained by synthesizing in a cell-free expression system and that the linker consisting of alanine, proline, serine, and combinations thereof.
Nakano discloses cell-free protein synthesis system using an E. coli-derived component for expressing target protein [¶0036] and explain that these systems are commercially available in the form of a kit, and can be used easily [¶0131].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to synthesize Ballinger’s polypeptide using Nakano’s cell-free protein synthesis system because Nakano expressly teaches the advantages of such system include: no maintenance of living cells (no need to keep cells alive, makes the system very easy to use and optimized), enable synthesize a toxic proteins toxic, enable synthesize many kinds of proteins simultaneously and rapidly (high-throughput), and enable synthesize a non-natural protein by, for example, incorporating a non-natural amino acid [¶0130].
Haupts discloses peptide linker linkers consisting of Ala, Pro, and Ser, including APS10 (SAPASPAPAA; 10 ammino acids), APS15 (ASPAAPAPASPAAPA; 15 ammino acids), APS20 (SAPAPSSAPAASAPPAAASA; 20 ammino acids), each suitable for spacing protein domains in fusion proteins [page 16, lines 18-35].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to substitute Ballinger’s flexible linker for known Haupts’ peptide linkers because Haupts expressly teaches such linkers form unstructured, random coils (reduce steric interference and provide enough spatial distance) and linkers are stable against proteases [page 15, lines 29-page 16 line 29]. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Regarding claim 2, Ballinger discloses step (1B), the at least one polypeptide includes comprises a plurality of different polypeptides expected to have binding affinity with the target molecule, and the step (2) further includes measuring the activity of dimers of the plurality of different polypeptides based on binding to the target molecule. (e.g. the subject peptidic compounds may exhibit one or more activities exhibited by a naturally occurring FGF, particularly bFGF. bFGF activities that may be exhibited by the subject peptidic compounds include: (1) binding to FGF receptor extracellular domain and FGF receptor over expressing cells with high affinity (IC50=8-37 nM); (3) stimulation of FGF receptor autophosphorylation in Swiss 3T3 cells; (4) stimulation of MAP kinase phosphorylation in FGF receptor expressing cells, as exemplified by 293 cells; (5) stimulation of BrdU incorporation or cell proliferation in Swiss 3T3 or endothelial cells; (6) induction of neurite outgrowth in PC12 cells [¶0023]).
Regarding claim 3, Ballinger discloses step (1B) further includes providing/creating a library including comprising a plurality of the at least one polypeptide or the dimer [column 5 line 65-column 9 line 39]
Regarding claim 4, Ballinger discloses C19 as preferred cyclic peptide and shows that C19-Jun exhibits potent FGFR agonist activity, including receptor activation, mitogenesis, cell proliferation, neurite outgrow, and FGFR specificity [¶0143-0151]. Ballinger further teaches preparing and screening mutants, fragments, and homologs of C19 to retain or improve biological activity [¶0068-0073]. Although Ballinger does not disclose the library includes comprises 8 or more kinds of polypeptides that differ in at least the cyclic peptide, it would have been prima facie obvious to a person of ordinary skill in the art to prepare a library comprising 8 or more C19-derived polynucleotides different in the cyclic peptide sequence as matter of routine optimization to identify variants with improved activity.
Regarding claim 7, Ballinger discloses method for obtaining dimerized cyclic peptides having activity based on binding to a target molecule by measuring the activity based on the binding to the target molecule by the method (e.g. C19 peptide with an intrapeptide disulfide bond was synthesized, purified by HPLC, and characterized by mass spectroscopy [¶0153]. Ballinger further discloses C19 as preferred cyclic peptide and shows that C19-Jun exhibits potent FGFR agonist activity, including receptor activation, mitogenesis, cell proliferation, neurite outgrow, and FGFR specificity [¶0143-0151])
Regarding claim 5, Ballinger discloses obtaining one or a plurality of polypeptides having binding affinity with a target molecule from a library including a plurality of displayed polypeptides, wherein the polypeptide includes a cyclic peptide, a dimerization domain containing a cysteine residue and a leucine zipper region, and a peptide linker present between the cyclic peptide and the dimerization domain (e.g. polypeptide fusion containing FGF receptor binder cyclic peptide (. C19 clone with cysteines residues to permit intra-peptide and inter-peptide disulfide bonds, forming cyclic peptide [¶0072]), a linker (20 amino acid residues long and made of glycine and serine), and a cysteine containing leucine zipper (homodimerization domain is Jun’s C-leucine zipper [¶0080]) [Fig 1A shown below]. Ballinger further discloses the peptides maybe chemically synthesized, using any convenient methodology. One may employ solid phase peptide synthesis techniques, where such techniques are known to those of skill in the art [¶0070 and ¶0087]).
Ballinger further discloses M13 phage displayed peptide libraries comprising randomized 12-mer and 18-mer peptides, contained zero, one, or two fixed cysteine residues, screening the displayed libraries against FGFR to identify binding peptides through iterative selection, amplification, and characterizing individual clones for their binding affinity toward the receptor [¶0132-0136].
Ballinger does not disclose that the linker consisting of alanine, proline, serine, and combinations thereof.
Haupts discloses peptide linker linkers consisting of Ala, Pro, and Ser, including APS10 (SAPASPAPAA; 10 ammino acids), APS15 (ASPAAPAPASPAAPA; 15 ammino acids), APS20 (SAPAPSSAPAASAPPAAASA; 20 ammino acids), each suitable for spacing protein domains in fusion proteins [page 16, lines 18-35].
The rationale for combining the Hindson and Kong references with respect to claim 5 is the same as set forth above for claim 1 and is incorporated herein by reference, as claim 5 does not introduce a limitation that would alter the motivation to combine or the predictable resulted achieved by the combination.
Regarding claim 6, Ballinger discloses creating an additional library based on one or a plurality of polypeptides obtained in (I') (e.g. C19 as preferred cyclic peptide and shows that C19-Jun exhibits potent FGFR agonist activity, including receptor activation, mitogenesis, cell proliferation, neurite outgrow, and FGFR specificity [¶0143-0151]. Ballinger further teaches preparing and screening mutants, fragments, and homologs of C19 to retain or improve biological activity [¶0068-0073]. )
Ballinger also discloses M13 phage displayed peptide libraries for screening the displayed libraries against FGFR to identify binding peptides through iterative selection[¶0132-0136].
Although Ballinger does not explicitly teach C19 mutant screening is done using phage display, it would have been prima facie obvious to a person of ordinary skill in the art to prepare additional phage display library consist of C19 variants to screen using the disclosed phage display method because of the successful identification of C19 scaffold using such technique. Also, Ballinger explicitly discloses preparing and screening mutants, fragments, and homologs of C19 to retain or improve biological activity [¶0068-0073]. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Ballinger et al., Haupts et al., Nakano et al., and Lindsley et al.
Claim(s) 8-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ballinger et al. (US6548634B1, EFD: September 9th 1999) in view of Haupts et al. (WO2017149002A1, EFD: March 1st 2017), Nakano et al. (US20200032275A1, EFD: June 15th 2016), and Lindsley et al. (Proc Natl Acad Sci U S A. 1996;93(7):2975-2980).
Regarding claim 8-14, Ballinger discloses dimerization domain has two cysteine residues instead of only one cysteine residue as claimed.
Lindsley discloses dimerization domain comprising a GCN4 leucine zipper followed by two glycines and a cysteine. Upon oxidation of the chimeric protein, a disulfide bond forms between the two cysteine leads to dimerization of the two protomers [Abstract and Fig. 1].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to modify Ballinger’s cysteine flank leucine zipper to containing single cysteine instead of two because both are known leucine zipper dimerization elements that associate two polypeptides and enable covalent stabilization of dimer through disulfide bond formation. Lindsley demonstrates that a single cysteine on each monomer predictably and successfully form disulfide bond while maintain a functional dimer [Abstract]. This modification represents simple substitution of one known leucine zipper dimerization element for another to obtain predictable result, which is formation of covalently stabilized dimer containing single cysteine in each dimerization domain. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143, B).
Conclusion
No claims are allowed
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/ Examiner, Art Unit 1684
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684
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