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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August 6, 2026 has been entered.
Claim Status
Claims 1, 5, and 16-17 have been amended.
Claims 2-4 and 7 have been canceled.
Claims 1, 5-6, and 8-23 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/US21/35110 filed 6/1/2021, which claims the benefit of U.S. Provisional Application No. 63/033,385 filed 6/2/2020.
Claims 1, 5-6, and 8-23 have an earliest effective filing date of 6/2/2020, corresponding to Provisional Application No. 63/033,385.
Information Disclosure Statement
The information disclosure statement (IDS) submitted 12/1/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities.
Page 132 (lines 28-30) of the specification contains miscellaneous text:
PNG
media_image1.png
106
654
media_image1.png
Greyscale
Appropriate correction is required.
Claim Objections
Claims 1, 9, 14, 17, and 21 are objected to for the following informalities.
Claims 1, 9, and 17 – “co-stimulatory” should read “costimulatory” to be consistent with the other claims and the specification.
Claim 9 (line 11) – should read “wherein the dash (“–“) represents a bivalent linker.
Claim 14 (lines 2-3) – recite “a Natural Killer (NK) cells, a Natural Killer T (NKT) cell…”, however, the claim should read ““a natural killer (NK) cell, a natural killer T (NKT) cell…”.
Claim 17 – the term “polypeptide” should be added throughout the claim as follows:
An immune effector cell genetically modified to express a first chimeric antigen receptor (CAR) polypeptide and a second CAR polypeptide, wherein the first CAR polypeptide comprises an octreotide-derived SSTR-binding domain and an incomplete ectodomain, and wherein the second CAR polypeptide comprises a synaptophysin, CXCR4 or CD56-binding domain and an incomplete ectodomain, wherein if the first CAR polypeptide comprises an intracellular signaling domain, the second CAR polypeptide comprises an intracellular signaling domain but the first CAR polypeptide does not, and wherein if the first CAR polypeptide comprises a co-stimulatory signaling region, the second CAR polypeptide comprises a co-stimulatory signaling region but the first CAR polypeptide does not.
Claim 21 – “up-regulation” should read “upregulation”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1 and 8-23 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites the term “octreotide-derived peptide”. The specification provides examples of “octreotide-derived peptides”, however, does not disclose any amino acid sequence for “octreotide”, or provide any definition for an “octreotide-derived peptide”. Accordingly, one of ordinary skill in the art would not know what qualifies as a derivative of octreotide. For the purpose of examination, the term “octreotide-derived peptide” is interpreted as being derived from the structure Octreotide: FCFWKXCX X, DL-Threonine (SEQ ID NO: 48) as taught by Bonnet et al. (US 2019/0328887).
Claims 8-23 are included in the rejection because they depend from or otherwise require all the limitations of the rejected claim but fail to clarify the issue.
Claim 17 (lines 6-9) recites a) wherein if the first CAR comprises an intracellular signaling domain, the second CAR comprises an intracellular signaling domain but the first CAR does not; and b) wherein if the first CAR comprises a costimulatory signaling region, the second CAR comprises a co-stimulatory signaling region but the first CAR does not”.
The claim as written does not make sense. If the first CAR comprises an intracellular signaling domain (or a costimulatory signaling region) and the second CAR comprises an intracellular signaling domain (or a costimulatory signaling region), how can the first CAR not when the first part of the claim requires them?
It is suggested that the claim be simplified to read, “wherein the first CAR polypeptide or the second CAR polypeptide comprises an intracellular signaling domain, and wherein the first CAR polypeptide or the second CAR polypeptide comprises a costimulatory signaling region”.
Or alternatively the claim can be amended to read, “wherein if the first CAR polypeptide comprises an intracellular signaling domain, the second CAR polypeptide does not, or if the first CAR polypeptide does not comprise an intracellular signaling domain, the second CAR polypeptide does; and wherein if the first CAR polypeptide comprises a costimulatory signaling region, the second CAR polypeptide does not, or if the first CAR polypeptide does not comprise a costimulatory signaling region, the second CAR polypeptide does”.
Claim 18 recites a method of providing an anti-cancer immunity in a subject with a SSTR-expressing cancer, the method comprising administering to the subject an effective amount of the immune effector cell of claim 15, thereby providing an anti-tumor immunity in the subject.
The preamble of the claim recites a method for providing anti-cancer immunity, however, the body of the claim recites providing an anti-tumor immunity, which does not have antecedent basis in the claim. It is suggested that the claim preamble be amended to recite “a method of providing anti-tumor immunity”.
Claims 19-23 are included in the rejection because they depend from or otherwise require all the limitations of the rejected claim but fails to clarify the issue.
Appropriate correction is required.
Claim Rejections - 35 USC § 102 – Withdrawn
The previous rejection of claim(s) 1-2, 8-21, and 23 under 35 U.S.C. 102(a)(1) as being anticipated by Mule et al. (WO 2019/241334) has been withdrawn in view of Applicant’s claim amendments, including specifying that the SSTR binding domain is an octreotide-derived peptide, and Applicant’s arguments in reference to the Declaration of Daniel Abate-Daga under 37 C.F.R. § 1.132.
Of note, the previous anticipation rejection under 35 U.S.C. 102(a)(1) should have been a rejection under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2), as Mule qualifies as prior art under both 35 U.S.C. 102(a)(1) and 102(a)(2).
Applicant’s Arguments
Mule discloses chimeric antigen receptor lymphocytes (CAR-T cells), wherein SSTR2 is one of many antigens listed as targets for the CAR disclosed by Mule. Mule does not teach or suggest a CAR comprising an octreotide-derived peptide. Applicant provides further evidence that the present invention is not anticipated by Mule in the Declaration of Daniel Abate-Daga under 37 C.F.R. § 1.132, submitted with the reply received August 6, 2026.
Response to Arguments
Applicant’s arguments were carefully considered and were found persuasive. Specifically, as presented in the Declaration of Daniel Abate-Daga, an octreotide is a chemically synthesized drug substance. It is not a ribosomally produced polypeptide. It is manufactured by solid-phase peptide synthesis, and the resulting molecule contains D-configuration amino acid residues together with further chemical modifications (i.e., alcohol derivative of threonine) that are introduced during synthesis and that cannot be produced by a cell. A CAR is a genetically encoded polypeptide. The nucleic acid encoding the CAR is introduced into the immune effector cell, and the CAR is translated by that cell's own ribosomal machinery. Ribosomal translation incorporates only the standard L-amino acids. A CAR expressed by a T cell therefore cannot contain D-amino acid residues, and cannot carry the synthetic chemical modifications present in octreotide. It follows that the SSTR-binding moiety expressed as part of a CAR is a chemically distinct molecule from the octreotide drug, and the affinity for SSTR2 depends on the three-dimensional conformation of the cyclic peptide core, wherein the non-natural residues and chemical modifications present in octreotide contribute to constraining that conformation and to the molecule's receptor affinity and metabolic stability. Importantly Abate-Daga discloses, ribosomal expression removes the non-natural residues, and it could not be predicted that the peptide would be able to adopt a conformation capable of engaging SSTR2 on a tumor cell, and whether such engagement would be productive enough to trigger T cell activation.
Therefore, it would not be anticipated that an octreotide-derived, genetically encoded SSTR-binding domain would recognize SSTR2 when used in place of a traditional CAR encoding an scFv based on the teachings of Mule that merely lists SSTR2 as one of many possible targets. Therefore, the previous rejection has been withdrawn.
Claim Rejections - 35 USC § 103 – Withdrawn
The previous rejection under 35 U.S.C. 103 as being unpatentable over Mule et al. (WO 2019/241334), in view of Moore et al. (US 2018/0118827) and Bonnet et al. (US 2019/0328887) have been withdrawn in view of Applicant’s claim amendments specifying that the SSTR binding domain is an octreotide-derived peptide and the Declaration of Daniel Abate-Daga under 37 C.F.R. § 1.132 for the reasons set forth above.
Claim Rejections - 35 USC § 103 - New
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.
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 1 and 8-23 are rejected under 35 U.S.C. 103 as being unpatentable over Mandriani et al. (Pancreas, 2020; 49(3):479, Presented October 3-5, 2019) (“Mandriani”), in view of Mule et al. (WO 2019/241334) (“Mule”).
Regarding claims 1 and 8 – Mandriani teaches second generation chimeric antigen receptor (CAR) T cells directed against somatostatin receptors (SSTRs) containing two molecules of octreotide in the extracellular moiety and CD28 as costimulatory module.
Regarding claims 11-14 – Mandriani teaches the CAR construct was cloned in a pMSGV1-28Z retroviral vector and then transduced in CD8+ T cells (i.e., cytotoxic T cells) from a healthy donor.
Regarding claims 15, 18, 21 and 23 – Mandriani teaches anti-SSTR CAR T exhibit antitumor activity against neuroendocrine tumor (NET) cell lines that overexpress SSTRs.
Mandriani teaches a second generation anti-SSRT CAR comprising two molecules of octreotide, however, does not teach the CAR comprises a transmembrane domain or an intracellular signaling domain, or the immune effector cell is further engineered to secrete cytokine(s) upon activation, or further comprising administering to the subject a checkpoint inhibitor, or a bispecific antibody.
These deficiencies are remedied by Mule.
Regarding claims 1 and 10 – Mule teaches chimeric antigen receptor (CAR) T cells comprising an intracellular signaling domain derived from CD3 zeta (CD3z) and a transmembrane domain [pg. 7, lines 30-31; pg. 8, line 16].
Regarding claim 9 – Mule teaches the CAR can include a signal peptide (SP), a binding domain (i.e., SSTR), a hinge domain (HG), a transmembrane domain (TM), a costimulatory domain (CSR), and intracellular signaling domain (ISD), and bivalent linkers intended to separate the linking molecule and a compound by a specific distance [pg. 9, lines 15-25; pg. 24, lines 9-13].
Regarding claim 16 – Mule teaches T cells can be engineered to co-express a CAR and an antitumor cytokine that is induced by T cell activation. Targeted by CAR specificity, localized production of pro-inflammatory cytokines recruits endogenous immune cells to tumor sites and may potentiate an antitumor response [pg. 3, lines 33-35 to pg. 4, lines 1-2].
Regarding claims 17 and 22 – Mule teaches the CAR comprises a second CAR, wherein the CAR can have incomplete ectodomains requiring the second CAR for activation [pg. 3, lines 18-20]. A dual CAR T cell expresses two separate CARs with different ligand binding targets (i.e., bispecific); one CAR includes only the CD3z domain and the other CAR includes only the co-stimulatory domain(s) [pg. 4, lines 33-35]. Antigens that can be targeted using a CAR include SSTR2 and CD56 [pg. 5, lines 13-19].
Regarding claims 19-20 – Mule teaches the CAR T cells can be used in combination with a checkpoint inhibitor. Checkpoint inhibitors include, but are not limited to antibodies that block PD-1, PD-L1, PD-L2, and CTLA-4 [pg. 16, lines 25-26, 35-36; pg. 17, lines 1-4].
Mandriani teaches a second generation anti-SSRT CAR comprising two molecules of octreotide for the treatment of neuroendocrine tumors, however, does not teach specific details regarding the structure of the CAR construct. It would have been obvious to one of ordinary skill to combine the methods of Mandriani with those of Mule, given that Mule teaches second generation bispecific CAR constructs with the ability to target multiple tumor antigens, including SSTR2. The skilled artisan would have a reasonable expectation of success in incorporating octreotide peptide(s) as an antigen targeting domain because Mandriani teaches such a CAR comprising 2 copies of an octreotide peptide that successfully inhibits neuroendocrine tumors.
Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Mandriani et al. (Pancreas, 2020; 49(3):479, Presented October 3-5, 2019) (“Mandriani”) in view of Mule et al. (WO 2019/241334) (“Mule”), as applied to claims 1 and 8-23 above, and in further view of Bonnet et al. (US 2019/0328887) (“Bonnet”).
The teachings of Mandriani and Mule have been set forth above.
Specifically, Mandriani teaches a second generation anti-SSTR CAR comprising 2 copies of an octreotide peptide. However, Mandriani or Mule do not teach any amino acid sequence(s) the SSTR antigen binding domain (i.e., octreotide peptide(s)).
Bonnet remedies this deficiency.
Regarding claim 5 – Bonnet teaches octreotide peptides have the general structure FCFWKXCX X, DL-Threonine (SEQ ID NO: 48). Bonnet teaches several octreotide derived polypeptides, including octreotide acetate comprising the amino acid sequence FCFWKTCT (SEQ ID NO: 49) [0066].
The octreotide derived peptide amino acid sequence FCFWKTCT (SEQ ID NO: 49) taught by Bonnet is 100% identical to the presently claimed SSTR antigen binding domain comprising SEQ ID NO: 1 as recited in claim 5.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Mandriani and Mule with those of Bonnet to arrive at a CAR capable of binding SSTR comprising instant SEQ ID NO: 1. One of ordinary skill in the art would be motivated to do so, because Mandriani teaches a second generation anti-SSTR CAR wherein the antigen binding comprises 2 copies of an octreotide peptide, while Mule provides additional details regarding second generation CAR constructs. Furthermore, one of ordinary skill in the art would be motivated to use the octreotide peptide amino acid sequences taught by Bonnet that are capable of binding SSTR for use in an anti-SSTR CAR. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Prior Art
The following pertinent prior art reference was found during examination but was not relied upon as grounds of rejection.
Mandriani et al., (B06) Development of Anti-SSTR CART Cells for Future Treatment of NETs, Neuroendocrinology, 2020;110(suppl 1):1-312.
Allowable Subject Matter
Claim 6 is objected to as being dependent upon a rejected independent claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
Claim 6 is drawn to a chimeric antigen receptor (CAR) comprising an SSTR antigen binding domain comprising the amino acid sequence FCFWKTCTGGGGSGGGGSGGGGSFCFWKTCT (SEQ ID NO: 9).
There is no prior art that teaches or suggests an engineered nuclease and the specific sequences with greater than 85% identity are free of prior art.
There is no prior art that teaches or suggests an SSTR antigen binding domain comprising the amino acid sequence FCFWKTCTGGGGSGGGGSGGGGSFCFWKTCT (SEQ ID NO: 9).
The closest prior art, Bonnet et al. (US 2019/0328887) teaches several octreotide polypeptides derived from the base octreotide structure amino acid sequence FCFWKXCX X, DL-Threonine (SEQ ID NO: 48),however, does not teach or suggest the presently claimed method with the specific SSTR antigen binding domain amino acid sequence of FCFWKTCTGGGGSGGGGSGGGGSFCFWKTCT (SEQ ID NO: 9).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571)270-0730. The examiner can normally be reached Monday through Friday.
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, Samira Jean-Louis can be reached on (571) 270-3503. 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.
/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1644
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
