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
Amendments
In the reply filed on 08/12/2026, Applicant has amended claims 17-18 and 20-22, and has cancelled claim 19.
Claim Status
Claims 17-18 and 20-23 are pending and are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/12/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
Withdrawn Claim Objections
The prior objection to claims 17-18 and 22 because of minor informalities is withdrawn in light of Applicant’s amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 17-23 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for insufficient antecedent basis is withdrawn in light of Applicant’s amendment to claim 17 to replace “the transcriptional regulator” with “the transcriptional activator”.
Maintained 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.
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.
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.
Claims 17-18 and 20-23 stand rejected under 35 U.S.C. 103 as being unpatentable over Lim et al., (US 2016/0264665 A1, cited in IDS 03/02/2026) in view of Gudas et al. (US 8,013,128 B2, prior art of record) and Wayne et al., (J Control Release. 2016;223:215-223, prior art of record).
Regarding the newly recited limitation in claim 17, Applicant is reminded that instant claims are directed to a synthetic notch receptor polypeptide, a nucleic acid encoding the synNotch receptor polypeptide, and a recombinant vector comprising the nucleic acid. However, the newly recited limitation “wherein release of the intracellular domain induces expression of an anti-PSMA chimeric antigen receptor in a cell that expresses the synNotch receptor polypeptide” is directed to an anti-PSMA chimeric antigen receptor (CAR) whose expression is induced by the released intracellular domain of the synNotch receptor. There is no evidence or disclosure in the claims demonstrating that the anti-PSMA CAR engineering or expression would provide any structure to the claimed anti-PSCA synNotch receptor polypeptide, to the claimed nucleic acid, or to the claimed recombinant vector. Since there is no clear structural limitation given by the newly recited wherein clause, the newly recited limitation does not provide any patentable weight in determining patentability of the claimed synNotch receptor polypeptide, the nucleic acid, or the recombinant vector. Therefore, the prior rejection of the claims set forth in the prior Office action mailed on 05/15/2026 is maintained and cited below.
With respect to claim 17, Lim teaches “a chimeric polypeptide (also referred to herein as a “chimeric Notch receptor polypeptide”) (i.e., equivalent to the claimed synthetic notch (synNotch) receptor polypeptide), comprising, from N-terminal to C-terminal and in covalent linkage: a) an extracellular domain comprising a first member of a specific binding pair (i.e., equivalent to the claimed extracellular binding domain); b) a Notch receptor polypeptide (i.e., equivalent to the claimed Notch core domain), wherein the Notch receptor polypeptide … comprises one or more ligand-inducible proteolytic cleavage sites; and c) an intracellular domain, …wherein binding of the first member of the specific binding pair to a second member of the specific binding pair induces cleavage of the Notch receptor polypeptide at the one or more ligand-inducible proteolytic cleavage sites, thereby releasing the intracellular domain” (e.g., [0007]). Lim teaches the intracellular domain is a transcriptional activator (e.g., [0007]), and in some cases, the transcriptional activator is GAL4-VP64 (e.g., [0404], [0490], [0661]), thus teaches the transcriptional activator comprises a DNA binding domain (e.g., a GAL4 DNA binding domain, e.g., [0728]) and a transactivation domain (e.g., a VP64 transactivation domain, e.g., [0404]).
Lim teaches the SynNotch polypeptide is a binding-triggered transcriptional switch polypeptide (e.g., [0043]) and teaches the binding of the extracellular first member to the second member induces production of a therapeutic gene product (e.g., [0416]), such as an apoptosis inducer TRAIL (e.g., section “SynNotch Driven T Cell Delivery of Custom Therapeutics - TRAIL Production”, [0709]-[0712] teaches synNotch T cells are engineered to produce cell surface-anchored TRAIL upon binding to target, also see Fig 106E). Lim teaches the first member of the specific binding pair (i.e., the extracellular binding domain) is an antibody that specifically binds a tumor antigen (e.g., [0007]) and the antigen includes, e.g., tumor antigens or cancer cell-associated antigens such as PSCA (e.g., [0472]), thus suggests a SynNotch receptor polypeptide comprising an extracellular antibody domain specifically binding PSCA.
However, Lim does not specifically teach the extracellular domain comprises an anti-PSCA antibody in the working examples that is recited in claim 17 or the CDR sequences of the anti-PSCA antibody recited in claim 18.
In regard to an anti-PSCA antibody, Gudas teaches antibodies that bind to PSCA protein and the sequences of the antibodies (e.g., abstract). Gudas teaches one PSCA monoclonal antibody clone 4.121 has high affinity to PSCA (see affinity analysis on Fig 10) and inhibits growth of human prostate cancer xenografts, prolongs survival and inhibits metastasis (see e.g., Figs 20-22 and 26). The PSCA monoclonal antibody clone 4.121 has the VH sequence (reference SEQ ID NO: 19) and the c.26 VL sequence (reference SEQ ID NO: 21) (e.g., see col. 9, para 1). The VH sequence of reference SEQ ID NO: 19 comprises the instantly claimed HCDR1 – SEQ ID NO: 153, HCDR2 – SEQ ID NO: 156 and HCDR3 – SEQ ID NO: 159 in claim 18 (see below, bolded and underlined for HCDR1, HCDR2 and HCDR3, respectively):
GLQCVAAPRWVLSQVQLQQWGAGLLKPSETLSLTCAVYGGSFSGNYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGSYNYFDYWGQGTLVTVSSASTKGPSVK
The c.26 VL sequence of reference SEQ ID NO: 21 comprises the instantly claimed LCDR1 – SEQ ID NO: 164, LCDR2 – SEQ ID NO: 167, and LCDR3 – SEQ ID NO: 170 in claim 18 (see below, bolded and underlined for LCDR1, LCDR2 and LCDR3, respectively):
MRLPAQLLGLLMLWVSGSSGDIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLVWYLQKPGQSPQLLIYLGSIRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQPLQTPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Thus, Gudas reduces to practice a PSCA monoclonal antibody comprising the claimed sequences in claim 18 that has high affinity to PSCA and is highly functional.
In regard to the reason to engineer PSCA-specific synNotch T cells to produce cell surface-anchored TRAIL upon binding to PSCA-positive prostate cancer cells, Wayne teaches TRAIL-coated T cells rapidly clear prostate cancer cells from circulating blood thus prevents metastasis, and suggests use of circulating T cells as a carrier for the anti-cancer protein TRAIL could be an effective tool to directly target circulating tumor cells for the prevention of prostate cancer metastasis (e.g., abstract). It is noted that one of ordinary skill in the art would have immediately acknowledged that the prostate cancer cell line DU145 cells used in Wayne express PSCA.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the synNotch receptor polypeptide engineered in T cells to produce cell surface-anchored TRAIL upon binding to target disclosed by Lim, by choosing a PSCA monoclonal antibody taught by Gudas as the extracellular binding domain as suggested by Lim with a reasonable expectation of success. Since Lim suggests a synNotch polypeptide comprising an extracellular antibody domain specifically binding PSCA (e.g., [0007] and [0472]) and teaches a SynNotch-driven T cell delivery of cell membrane-anchored TRAIL (e.g., [0709]-[0712]), since Gudas reduces to practice a PSCA monoclonal antibody sequence that has high affinity to PSCA and is highly functional (see e.g., Figs 10, 22-22 and 26), and since Wayne teaches TRAIL-coated T cells rapidly clear prostate cancer cells from circulating blood and suggests use of circulating T cells as a carrier for TRAIL to directly target circulating tumor cells for the prevention of prostate cancer metastasis (e.g., abstract), one of ordinary skill in the art would have had a reason to choose the PSCA monoclonal antibody taught by Gudas to make a PSCA-specific synNotch polypeptide in order to engineer T cells to produce cell surface-anchored TRAIL upon binding to PSCA-positive prostate cancer cells to directly target circulating prostate cancer cells for the prevention of prostate cancer metastasis (Wayne, abstract).
Therefore, one of ordinary skill in the art would have acknowledged that the anti-PSCA synNotch receptor polypeptide itself, as suggested by Lim in view of Gudas and Wayne, that comprises an extracellular anti-PSCA binding domain, a Notch core domain and an intracellular domain comprising a transcription activator wherein binding of the extracellular anti-PSCA binding domain to PSCA induces cleavage of the Notch core domain to release the intracellular transcription activator domain, makes obvious the claimed synNotch receptor polypeptide in claim 17.
With respect to claim 20 directed to GAL4, and claim 21 directed to a transactivation domain of VP64, as stated supra, Lim teaches the intracellular domain is a transcriptional activator such as GAL4-VP64 (e.g., [0404], [0490], [0661]), thus teaches the transcriptional activator comprises a GAL4 DNA binding domain (e.g., [0728]) and a transactivation domain VP64 (e.g., [0404]).
With respect to claim 22 directed to a nucleic acid encoding the synNotch receptor polypeptide, Lim teaches nucleic acids comprising nucleotide sequences encoding the binding-triggered transcriptional switch polypeptides (e.g., abstract).
With respect to claim 23 directed to a recombinant vector comprising the nucleic acid, Lim teaches a recombinant expression vector comprising a nucleotide sequence encoding a chimeric Notch receptor polypeptide (e.g., [0008]).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 08/12/2026 are acknowledged.
Applicant argues that (1) the prior rejection does not address the anti-PSMA chimeric antigen receptor limitation now recited in claim 17 since the prior rejection is built entirely on a TRAIL payload (Remarks, p. 7. Para 2), and (2) there is no direction in the cited art to the recited PSCA/PSMA antigen pairing. Lim only identifies PSCA and PSMA as two names among many dozens of candidate antigens listed together in [0472] (Remarks, p. 7, last para).
Applicant’s arguments have been fully considered but they are not persuasive.
As stated supra, instant claims are directed to an anti-PSCA synNotch receptor polypeptide, a nucleic acid encoding the polypeptide, and a recombinant vector comprising the nucleic acid. However, the amendment indicates that an anti-PSMA CAR is co-engineered with the synNotch receptor in a cell and the expression of the anti-PSMA CAR is induced when the intracellular domain of the synNotch receptor is released upon PSCA binding. There is no evidence or disclosure in the claims demonstrating that the anti-PSMA CAR engineering or expression would provide any structure to the claimed anti-PSCA synNotch receptor polypeptide, to the claimed nucleic acid, or to the claimed recombinant vector. In other words, even though prior art Lim in view of Gudas and Wayne suggest an anti-PSCA synNotch receptor that is co-engineered with a surface-anchored TRAIL in a T cell and the expression of the TRAIL is induced when the intracellular domain of the synNotch receptor is released upon PSCA binding, the claimed anti-PSCA synNotch receptor polypeptide itself is obvious from the anti-PSCA synNotch receptor polypeptide of the prior art.
Applicant argues that (3) the PSCA status of a given prostate carcinoma cell line was not a matter of common knowledge. Although Examiner has alleged that "one of ordinary skill in the art would have immediately acknowledged that the prostate cancer cell line DU145 cells used in Wayne express PSCA”, no reference of record supports it. Wayne does not mention PSCA and has no reason to assay or report it. Gudas demonstrates antibody binding by using recombinant cell lines such as PC3-PSCA and 3T3-PSCA and by comparing PC3-PSCA against PC3 parental cells. Applicant states that “Had the PSCA positivity of prostate carcinoma lines been a fact the skilled artisan would have "immediately acknowledged," the very reference relied upon for the anti-PSCA antibody would have had no need to construct PSCA-transduced lines in order to demonstrate binding” (Remarks, p. 8).
Applicant’s arguments have been fully considered but they are not persuasive.
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As a first matter, regarding the PSCA status of a given prostate carcinoma cell line, e.g., the DU145 cell line used in Wayne, in order to complete the art of record and rebut Applicant's arguments, prior art Zhang et al., (Exp Ther Med. 2017;14(2):1795-1801) regarding PSCA expression in DU145 cells has been attached. Zhang evidences that it was well known before the filing date of the claimed invention that PSCA is expressed in DU145 cells (see Fig 4B attached for western blot and Fig 4A for mRNA expression). Therefore, one of ordinary skill in the art would have immediately acknowledged that the prostate cancer cell line DU145 cells used in Wayne express PSCA.
Furthermore, regarding Applicant’s argument that since Gudas constructs PSCA-transduced lines to exogenously express PSCA, Gudas must have no knowledge on the PSCA positivity of prostate carcinoma lines (Remarks, p. 8), Gudas does indeed acknowledge the PSCA positivity of various cancer cell lines, including prostate carcinoma line LAPC-9, human pancreatic cancer cell line HPAC and human bladder tumor cell line SW780, and use these PSCA-positive cancer cell lines to demonstrate the inhibition effect of the anti-PSCA antibodies (see e.g., Figs 18-23 for LAPC-9, Figs 24-25 for HPAC, and Fig 27 for SW780, and see Table I in col. 128 for cancers expressing PSCA). The fact that Gudas additionally uses PSCA-transduced lines and compares them to their parent lines, does not demonstrate that the skilled artisan would not have had knowledge on PSCA positivity of prostate carcinoma lines. For example, since the only difference between the PSCA-transduced lines and their parent lines is the presence or absence of PSCA expression, the skilled artisan would have had a reason to construct and compare those lines in order to obtain a clean comparison in the anti-PSCA antibody binding assay. Applicant is additionally reminded that the instant rejection is based on Lim in view of Gudas and Wayne as discussed above, but does not rely solely on 'common knowledge' in the art.
In conclusion, Applicant’s arguments are not persuasive and the prior rejection over Lim in view of Gudas and Wayne is therefore maintained.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
