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 Claims
Claims 1, 5, 20-21, 25-27, 29-31, 33, 38-39, 60, and 133 are currently pending.
Claim 1 is amended.
Claims 21 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 2-4, 6-19, 22-24, 28, 32, 34-37, 40-59, 61-132, 134-279 are cancelled.
Claims 1, 5, 20, 25-27, 29-31, 33, 38-39, 60, and 133 have been considered on the merits.
Withdrawn Rejections
The rejection made under 35 U.S.C. 112(b) onto claim 1 is withdrawn in light of the amendments submitted on 08/19/2025.
New and Maintained Rejections Necessitated by Amendment
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, 5, 20, 25-27, 29-31, 33, 38-39, 60, 133, and 279 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 contains the phrase “wherein the modified PSMA comprises a deletion of residues 2-10 compared to wild-type” in lines 3-4 which is indefinite. It is unclear whether or not the “residues 2-10” is meant to be any 2-10 residues, residues 2-10 of the N-terminal end of the sequence, or residues 2-10 of the C-terminal end of the sequence. Therefore, the phrase is indefinite. Claims 5, 20, 25-27, 29-31, 33, 38-39, 60, and 133 depend from claim 1 and are therefore included in this rejection.
Claim Rejections - 35 USC § 103
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.
Claims 1, 5, 20, 25-27, 29-31, 33, 38-39, 60, and 133 are rejected under 35 U.S.C. 103 as being unpatentable over Pomper et al (US20170218464A1), reference of record.
With regards to claim 1, Pomper teaches an engineered cell comprising a modified prostate-specific membrane antigen (PSMA) where in the modified PSMA comprises a deletion of the first 11 N-terminal amino acids, which covers the claim limitation of deletion of the as compared to wild type as required by claims 1 and 133 ([0040]). Pomper teaches the sequence of SEQ ID NO: 5 which is 100% identical to the instantly claimed SEQ ID NO: 23 as required by claim 1 (see SEQ ID NO: 23 Alignment below). The modifications can comprise deletions and substitutions as required by claim 1 ([0040]). Pomper teaches that the functional modifications employed alter the PSMA enzymatic activity, ligand binding ability, and cellular internalization as required by claim 1 ([0042]). Pomper also teaches the inclusion of a recombinant antigen receptor (coxsackie adenovirus receptor) in the engineered cell (PC3 prostate cancer cell) as required by claim 1 ([0093]). Pomper teaches that the modified PSMA can be recognized by a targeting molecule as required by claim 5 ([0084]). The targeting molecule is taught to be a small molecule, ligand, anti-PSMA antibody, or peptide as required by claims 25, 26, and 29 ([0084]/[0088]). The small molecule targeting molecule is taught to be YC-VI-11, DCFPyL, DCFBC, or ASP dyes as required by claim 27 ([0088]/[0060]). The anti-PSMA antibody is taught to be J591 as required by claim 30 ([0088]). Pomper also teaches the wild type PSMA sequence which has a 100% identity to the elected SEQ ID NO: 52 and that the modifications to the wild type can be a substitution of the AA in the second position (i.e. over 85% identity to SEQ ID NO: 52 and the MET start codon at the first position remains untouched) as required by claim 20 ([0040], see SEQ ID NO 52 sequence alignment below).
With regards to claims 5, 29-31, 33, 38-39, and 60, the modified PSMA of Pomper has a 100% identity to the claimed modified PSMA, therefore the modified PSMA of Pomper would inherently “be capable” of being recognized by a PSMA-targeting molecule of any of claims 5, 29-31, 33, 38-39, and 60.
Pomper does not teach that the deletion comprises a deletion of only residues 2-10, i.e. maintaining residue 1.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007)): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
In the present situation, rationales A, B, C, D, and E are applicable. The claims merely require the combining of known prior art cell taught by Pomper with the teaching of Pomper that N-terminal truncations of the PSMA protein, such as truncation of the first 11 amino acids, still allow the N-terminally modified PSMA to successfully localize to the cell membrane and centrosome ([0040]). The combination of Pomper with the teachings that deletion of up to the first 11 residues of the PSMA would result in a PSMA which remains functional to localize to the cell membrane and therefore would lead to a predictable result absent results to the contrary. Therefore, one of ordinary skill in the art would find it obvious to complete any truncation between 1-11 N-terminal amino acids based on the disclosure of Pomper as required by claim 1 and 279. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, Pomper renders the claims obvious.
Claims 1 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Pomper et al (US20170218464A1), as applied to claims 1, 5, 20, 25-27, 29-31, 33, 38-39, 60, and 133 above, and in further view of Lupold et al (Am J Clin Exp Urol, 04/01/2018) all of which are references of record.
With regards to claim 31, Pomper teaches the limitations of the independent claim above. Pomper does not teach that the PSMA targeting molecule is an aptamer selected from A9, A10, A10g, A10-3.2 and SZT101 as required by claim 31.
However, Lupold teaches a review of PSMA aptamer for use in tumor-selective targeting and drug delivery. Lupold teaches about the development of both A9 and A10 aptamers as well as their smaller isoforms including A10-3.2 which bind PSMA as required by claim 31 (abstract). Further, Lupold teaches that A9 aptamers can be conjugated to nanoparticles to enhance detection of PSMA positive cells through imaging (pg. 82, column 2, para 1).
One of ordinary skill in the art would find it obvious prior to the effective filling date of the instant invention to combine the engineered cell of Pomper with the PSMA targeting aptamers taught by Lupold to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Lupold teaches that A9 aptamers can be conjugated to nanoparticles to enhance detection of PSMA positive cells through imaging (pg. 82, column 2, para 1). One of ordinary skill in the art would have a reasonable expectation of success when combining Pomper with Lupold because the A9 and A10 aptamers taught by Lupold were produced to be a selective PSMA targeting molecule.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1 and 33, 38-39, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Pomper et al (US20170218464A1), as applied to claims 1, 5, 20, 25-27, 29-31, 33, 38-39, 60, and 133 above, and in further view of Stephan et al (US20160145348A1), all of which are references of record.
With regards to claim 33, Pomper teaches the limitations of the independent claim above. Pomper does not teach that the recombinant antigen receptor is capable of binding to a target antigen that is associated with or expressed on a cell or tissue of a disease, disorder, or condition as required by claim 33. Pomper does not teach that the recombinant antigen receptor is a T cell receptor (TCR) or an antigen binding fragment thereof as required by claim 38. Pomper does not teach that that the recombinant antigen receptor is a chimeric antigen receptor (CAR) as required by claim 39. Pomper does not each that the engineered cell is a T cell, NK cell or iPSC as required by claim 60.
However, Stephan teaches compositions and methods of selectively modifying immune cells for therapeutic objectives. Stephan teaches the use of TCR genes (i.e. fragments thereof as required by claim 38) loaded into T cells along with a CAR including a fragment of PSMA as required by claims 38, 39, and 60 ([0287]). The specific CAR T cell is able to be activated to bind to PSMA which is highly expressed on prostate cancer cells (i.e. a tissue of disease nature) as required by claim 33 ([0287]). Further, the CAR system is employed in cells which have previously undergone gene transfer to incorporate a fluorescent recombinant PSMA protein as the reporter for the CAR T cell ([0299]).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the engineered cell taught by Pomper with the recombinant antigen receptor modified immune cells taught by Stephan to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Stephan teaches that the CAR system is employed in cells which have previously undergone gene transfer to incorporate a fluorescent recombinant PSMA protein as the reporter for the CAR T cell. Specifically, the method of employing PSMA as a fluorescent reporter is an alternative method of using a PSMA protein for detection similar to the PSMA small molecule and antibody labelling taught by Pomper and would therefore motivate one of ordinary skill in the art to employ the alternative recombinant antigen receptors taught by Stephan. One of ordinary skill in the art would have a reasonable expectation of success when combining Pomper with Stephan because both Pomper and Stephan employ recombinant antigen receptors along with modified PSMA labelling techniques.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
SEQ ID NO: 52 Alignment
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SEQ ID NO: 23 Alignment
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590
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Response to Arguments
Applicant's arguments filed 08/19/2025 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 7-8) that Pomper fails to provide any motivation to modify the N-11 PSMA to arrive at the claimed N9del PSMA with a reasonable expectation of success because “Pomper fails to teach or suggest any alternative modifications to PSMA that would (not could) lead a person of ordinary skill in the art to N9del”.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, the combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007)): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
In the present situations, rationales A, B, C, D, and E are applicable.
Specifically in reference to the truncation starting at residue 2 and not truncating beginning at residue 1, rationale E is applicable. One of ordinary skill in the art would recognize that the first residue is a methionine which signals a start. Therefore, it would be obvious to try a truncation which retains the start codon and therefore begins at residue 2 of the N terminal end. Pomper also teaches an alternatively modified PSMA protein which contains only a modified amino acid residue at residue 2, which was also able to localize in the manner expected with the N-11 deletion of the N-terminal residues. Pomper confirms that any C-terminally truncated PSMA was unable to localize to the plasma membrane indicating importance of the C-terminal end over the N-terminal end in localization ([0105]).
With reference to the truncation ending at residue 10 and not a full N-11 truncation, rationales A, B, C, D, and E are applicable. The claims merely require the combining of known prior art cell taught by Pomper with the teaching of Pomper that N-terminal truncations of the PSMA protein, such as truncation of the first 11 amino acids, still allow the N-terminally modified PSMA to successfully localize to the cell membrane and centrosome ([0040]). The combination of Pomper with the teachings that deletion of up to the first 11 residues of the PSMA would result in a PSMA which remains functional to localize to the cell membrane and therefore would lead to a predictable result absent results to the contrary. Therefore, one of ordinary skill in the art would find it obvious to complete any truncation between 1-11 N-terminal amino acids based on the disclosure of Pomper as required by claim 1 and 279. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR. Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 9-10) that the instant invention, including the N9del working examples, demonstrated unexpected results in that the claimed N9del PSMA has increased cell surface expression compared to a wild-type PSMA and that the N9del performs better than full-length, wild-type PSMA.
In response to this argument, these results do not appear to be unexpected based on Figure 10 of Pomper. Figure 10 displays results of a cellular uptake assay which demonstrates the surface expression of PSMA based on the uptake of a specific PSMA targeted molecule. The results demonstrate that the wild-type and the truncated PSMA are both expressed, however the modified PSMA displayed and increased uptake, demonstrating higher expression of the truncated PSMA molecule.
Therefore, this argument is not found persuasive.
Applicant argues (Remarks, pg. 12) that Lupold and Stephan do not remedy the alleged deficiencies of Pomper. These alleged deficiencies have been addressed at points 17 and 18, therefore the arguments are not found persuasive.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632