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 .
1. Claims 6, 9, 10, 12, 19-22, 24, 25, 27, and 31-38 have been cancelled. Claims 2, 11, 13-17, 26, and 28-30 have been amended.
Claims 1-5, 7, 8, 11, 13-18, 23, 26, and 28-30 are pending and under examination.
2. All objections/rejections pertaining to claim 12 are moot because the claim was cancelled with the reply filed on 10/29/2025.
The objections to claims 2, 11, 13-15, 26, 29, and 30 are withdrawn in response to the amendments filed on 10/29/2025.
Specification
3. The claim listing is objected to because claim 17 has not been amended, and thus, the correct identified for this claim is “original”, not “currently amended”.
Claim Objections
4. Claims 4 and 17 are objected to because of the recitations “a truncated MyD88”, and “a CD40”. Appropriate correction to “the truncated MyD88”, and “the CD40” is required.
5. As previously indicated, claim 28 should be amended to recite:
b) after a), administering an effective amount of a rapamycin or a rapalog that binds to the FRB polypeptide or FRB variant region of the chimeric costimulating polypeptide to reduce the number of the target cells in the subject.
Double Patenting
6. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
7. Claims 1-5, 7, 8, 16-18, 23, 26, and 28-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,934,346, in view of both Clackson (Chemical Biology. From Small Molecules to System Biology and Drug Design, 2007, Chapter 4.2, pp. 227-249) and Di Stasi et al. (N. Eng. J. Med., 2012, 365: 1-16). Clackson and Di Stasi et al. are of record in the parent applications 17/219,116 and 15/377,776.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass a modified T-cell comprising a polynucleotide encoding a CAR and a polynucleotide encoding a chimeric stimulatory polypeptide comprising MyD88 lacking TIR and the cytoplasmic domain of CD40. The specific species of MyD88-CD40 recited in the patent claims anticipate the genus of MyD88-CD40 recited in the instant claims. As evidenced by the sequence alignment of record in the parent application 17/219,116, SEQ ID NO: 11 recited in the patent claims encodes FKBP12v36. Although the patent claims do not recite a nucleic acid as recited in the instant claims 4 and 5, one of skill in the art would have reasonably concluded that obtaining the modified cell entails possession of the nucleic acid. Thus, one of skill in the art would have reasonably considered further claiming the nucleic acid as an obvious variation.
The patent claims do not recite a chimeric pro-apoptotic polypeptide. Di Stasi et al. teach using iCas9 lacking CARD to enhance safety for cell CAR T-cell therapy, where iCas9 comprises Cas9 linked to the dimerization FKBP12v36 domain (see the full paper). Based on these teachings, one of skill in the art would have found obvious to modify the patent claims by further including a nucleic acid encoding the iCas9 of Di Stasi et al. to achieve the predictable result of obtaining T-cells expressing an inducible safety switch. By doing so, one of skill in the art would have obtained a T-cell where both stimulatory and death signals are under the control of the same ligand, i.e., AP1903 which is specific for FKBP12v36 (see Clackson, p. 233, first and second full paragraphs). However, one of skill in the art would have readily understood that stimulation and death via apoptosis are events that should be separately controlled. Modifying either one of the chimeric stimulatory polypeptide and chimeric pro-apoptotic polypeptide by replacing FKBP12v36 with dimerization domains capable of binding ligands other than AP1903 would have been obvious to one of skill in the art as such domains were routinely used in the prior art. For example, Clarkson teaches that polypeptides bearing FRB and FKBP12 domains could be dimerized by rapamycin because rapamycin simultaneously binds FRB and FKBP12 (see p. 227; p. 229, second paragraph; paragraph bridging p. 230 and 231; p. 231, first full paragraph; paragraph bridging p. 240 and 241; p. 241, first full paragraph). Clarkson also discloses specific concentrations at which AP1903 binds FKBP12v but not FKBP12 (see Fig. 5). Based on these teachings, one of skill in the art would have reasonably concluded that rapamycin and AP1903 could be used to separately control the death and stimulatory signals as needed. Thus, replacing AP1903-FKBP12v in any one of the chimeric polypeptides with rapamycin-FRB/FKBP12 would have been obvious to one of skill in the art
Thus, the instant claims and the patent claims are obvious variants.
8. Claims 1-5, 7, 8, 11, 13-18, 23, 26, and 28-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 7-10, 12, 13, 39, and 41 of copending Application No. 17/353,587 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to (1) a modified cell comprising a first polynucleotide encoding the same chimeric pro-apoptotic caspase-9 polypeptide, a second the polynucleotide encoding the same chimeric stimulatory polypeptide comprising MyD88 lacking TIR and the cytoplasmic domain of CD40, and a third polynucleotide encoding a CAR; (2) a nucleic acid comprising the first and second polynucleotides; and (3) the same methods for controlling the survival of the modified cell and treating a disease associated with elevated expression of a target antigen by transplanting the modified cell and administering a ligand. Although the application claims do not recite stimulating a cellular immune response, as recited in the instant claims 11 and 26, treating a disease associated with elevated expression of a target antigen as recited in the application claim 13 would necessarily result in stimulating a cellular immune response. The application specification discloses that the disease associated with elevated expression of a target antigen could be cancer (see p. 388-389, embodiments F1-F5 and F13-F14). The specific CAR recognizing Her2/Neu recited in the application claim 39 anticipate the genus of CARs recited in the instant claim 3. The application specification discloses that caspase-9 lacks the caspase recruitment domain (CARD) (see p. 17, first paragraph). The instant specification discloses that the FRB variant is FRBL, as recited in the application claim 41 (see p. 5). Thus, the instant claims and the application claims are obvious variants.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
9. Claims 1-5, 7, 8, 11, 13-18, 23, 26, and 28-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-18 of U.S. Patent No. 12,410,231 (filed as Application No. 17/053,275). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass (1) a modified NK cell comprising the same polynucleotide encoding the same chimeric pro-apoptotic polypeptide, the same polynucleotide encoding the same chimeric stimulatory polypeptide comprising MyD88 lacking TIR and the cytoplasmic domain of CD40, and a polynucleotide encoding a CAR; and (2) the same methods for stimulating an immune response, treating cancer, and controlling the survival of the modified NK-cell. The specific CAR species recited in the patent claim 4 anticipate the genus of CARs recited in the instant claim 3. The specific SEQ ID NOs recited in the patent claims 11 and 12 anticipate the genus of truncated MyD88 lacking TIR recited in the instant claims. The specific diseases recited in the patent claim 16 anticipate the genus of diseases associated with an elevated expression level of a target antigen recited in the instant claim 13. Although the patent claims do not recite a nucleic acid as recited in the instant claims 4 and 5, one of skill in the art would have reasonably concluded that obtaining the modified cell entails possession of the nucleic acid. One of skill in the art would have reasonably considered further claiming the nucleic acid as an obvious variant. Thus, the instant claims and the patent claims are obvious variants.
Claim Rejections - 35 USC § 103
10. 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 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.
11. Claims 1-5, 7, 8, 11, 14-18, 23, 26, 29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Budde et al. (PLOS One, 2013, 8: 1-10), in view of all Clackson (Chemical Biology. From Small Molecules to System Biology and Drug Design, 2007, Chapter 4.2, pp. 227-249), Bourgeois et al. (Science, 2002, 297: 2060-2063), Geng et al. (Blood, 2010, 116: 3494-3504), and Narayanan et al. (J. Clin. Invest., 2011, 121: 1524-1534). All references are of record in the parent application 15/377,776.
Budde et al. teach modified T-cells comprising a polynucleotide encoding a chimeric antigen receptor (CAR) and a polynucleotide encoding a chimeric pro-apoptotic polypeptide comprising caspase 9 (Cas9) linked to a mutated FKBP12 dimerization domain (i.e., FKBP12v) mediating dimerization in the presence of AP1903. Budde et al. teach expressing the CAR- and Cas9-encoding polynucleotides are from the same expression vector (claims 1, 3, 8, 18, and 23) (see Abstract; p. 2; p. 3, Fig. 1 and column 2, last two paragraphs; p. 5, column 2; p. 6, column 2, last paragraph). Since AP1903 is specific for FKBP12v36 (see Clackson, p. 233, first and second full paragraphs), the FKBPv taught by Budde et al. is FKBP12v36. Although Budde et al. do not specifically teach that T-cells comprise Cas9 lacking the CARD domain, they do teach that iCas9 lacking CARD is suitable as an inducible safety switch (see p. 2, column 1, first full paragraph). Thus, using an iCas9 lacking CARD in the T-cell of Budde et al. would have been obvious to one of skill in the art (claim 7).
Budde et al. also teach a method for inducing a cellular immune response and reducing tumor size in vivo by administering the modified T-cells to subjects affected by cancer (see Abstract; paragraph bridging p. 4 and 5; p. 7, Fig. 5). Budde et al. teach a method for eliminating 90% of transplanted modified T-cells in subjects by administering AP1903; Budde et al. teach the need for killing the transplanted modified T-cells to eliminate the adverse effects resulting from their prolonged proliferation (see p. 2, column 1, first full paragraph; p. 6; p. 8, Fig. 7). Budde et al. also teach that CAR T-cells are useful for treating human cancer (see Abstract).
Budde et al. do not teach a polynucleotide encoding a costimulatory polypeptide comprising two FKBP12v36 dimerization domains, MyD88, and the CD40 cytoplasmic region, wherein MyD88 lacks the TIR domain (claims 1, 2, and 17). Bourgeois et al. teach that activating CD40 signaling pathway in T-cells is required for rapid proliferation and high cytokine secretion and that such activation has therapeutic value (see Abstract; p. 2062, column 3; p. 2063). Geng et al. teach that activating TLR2-MyD88 signaling in T-cells increases their activation and cytotoxicity; Geng et al. suggest improving the efficacy of T-cell-based therapies by targeting TLR2-MyD88 signaling within T-cells (see Abstract; p. 3494; paragraph bridging p. 3500 and 3501; p. 3502, column 2, first full paragraph; p. 3503, column 1). Based on these combined teachings, one of skill in the art would have reasonably concluded that providing stimulatory signals via activating both CD40 and MyD88 signaling pathways in the CAR T-cells of Budde et al. would result in cells exhibiting enhanced therapeutic potential. Furthermore, nucleic acids providing the MyD88 and CD40 stimulatory signals were known and used in the prior art. For example, Narayanan et al. teach that nucleic acids encoding a chimeric polypeptide comprising two FKBP12v36 dimerization regions, MyD88 lacking TIR, and the CD40 cytoplasmic region are suitable to provide regulatable and synergistic MyD88 and CD40 stimulatory signals to immune cells upon the administration of AP1903 (see Abstract; p. 1524, paragraph bridging columns 1 and 2; p. 1525, column 2, first full paragraph. 1526, Fig. 1A; p. 1531, column 2). One of skill in the art would have found obvious to modify the T-cell of Budde et al. by further including the polynucleotide of Narayanan et al. in the expression vector to achieve the predictable result of obtaining a T-cell exhibiting enhanced therapeutic potential (claims 4 and 5).
By doing so, one of skill in the art would have obtained a T-cell where both stimulatory and death signals are under the control of the same ligand, i.e., AP1903 which is specific for FKBP12v36 (see Clackson, p. 233, first and second full paragraphs). However, one of skill in the art would have readily understood that stimulation and death via apoptosis are events that should be separately controlled. Modifying either one of the chimeric stimulatory polypeptide and chimeric pro-apoptotic polypeptide by replacing FKBP12v36 with dimerization domains capable of binding ligands other than AP1903 would have been obvious to one of skill in the art as such domains were routinely used in the prior art. For example, Clarkson teaches that polypeptides bearing FRB and FKBP12 domains could be dimerized by rapamycin because rapamycin simultaneously binds FRB and FKBP12 (see p. 227; p. 229, second paragraph; paragraph bridging p. 230 and 231; p. 231, first full paragraph; paragraph bridging p. 240 and 241; p. 241, first full paragraph). Clarkson also discloses specific concentrations at which AP1903 binds FKBP12v but not FKBP12 (see Fig. 5). Based on these teachings, one of skill in the art would have reasonably concluded that rapamycin and AP1903 could be used to separately control the death and stimulatory signals as needed. Thus, replacing AP1903-FKBP12v in any one of the chimeric polypeptides with rapamycin-FRB/FKBP12 would have been obvious to one of skill in the art (claims 1 and 16). Furthermore, one of skill in the art would have found obvious to administer the resultant modified T-cells to subjects (including human subjects) affected by cancer followed by the administration of either AP1903 or rapamycin, with the reasonable expectation that doing so would induce a cellular immune response and reduce tumor size in the subjects (claims 11, 14, 26, and 29).
One of skill in the art would have also found obvious to further administer either rapamycin (claim 15) or AP1903 (claim 30) in an amount effective to kill at least 90% of modified T-cells when needed, to achieve the predictable result of preventing or mitigating the adverse effects associated with the prolonged proliferation of these cells.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
12. Claims 1-5, 7, 8, 11, 13-18, 23, 26, and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Budde et al. taken with all Clackson, Bourgeois et al., Geng et al., and Narayanan et al., in further view of Mardiros et al. (Blood, September 2013, 122: 3138-3148).
The teachings of Budde et al., Clackson, Bourgeois et al., Geng et al., and Narayanan et al. are applied as above for claims 1-5, 7, 8, 11, 14-18, 23, 26, 29, and 30. Budde et al., Clackson, Bourgeois et al., Geng et al., and Narayanan et al. do not specifically teach treating a cancer associated with elevated expression of a target antigen (claims 13 and 28). However, the prior art teaches that CAR T-cells are suitable to treat cancer overexpressing target antigens. For example, Mardiros et al. teach treating CD123-overxpressing AML by using CD123 CAR T-cells (see Abstract; paragraph bridging p. 3142 and 3143). Thus, one of skill in the art would have found obvious to modify the teachings of Budde et al., Clackson, Bourgeois et al., Geng et al., and Narayanan et al. by using an anti-CD123 scFv as the CAR extracellular domain and further administering the resultant CD123 CAR T-cells to subjects affected by AML followed by administration of AP1903 (claim 13) or rapamycin (claim 28) to achieve the predictable result of treating the AML in these subjects.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
13. The arguments addressing the references individually are not found persuasive because none of the references has to teach every claim limitation. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In this case, the combination of the cited references suggests arriving at the claimed invention.
The argument that the claims require specific pairings not disclosed by the prior art as being used together in the same cell is not found persuasive.
The T-cell expressing a CAR) and a chimeric pro-apoptotic polypeptide comprising Cas9 linked to a dimerization domain responsive to AP1903 is already taught by Budde. The secondary references provide a strong motivation to further express Narayanan’s chimeric polypeptide. While using Narayanan’s chimeric polypeptide would have resulted in a T-cell with both stimulatory and death signals under the control of AP1903, one of skill in the art would have readily understood that T-cell stimulation and death via apoptosis are events that should be separately controlled. The step of modifying either one of the chimeric polypeptides by using dimerization domains capable of binding ligands other than AP1903 would have been the logical result of applying common sense reasoning. MPEP 2141.03 states:
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
PNG
media_image1.png
18
19
media_image1.png
Greyscale
The "hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art." Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
14. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILEANA POPA whose telephone number is (571)272-5546. The examiner can normally be reached 8:00 am to 4:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ILEANA POPA/Primary Examiner, Art Unit 1633