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 .
Priority
This application is a U.S. national phase of International Application No. PCT/KR2021/001904, filed on 02/15/2021. This application claims priority to Republic of Korea Application No. KR10-2020-0018169, filed 02/14/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Applicant is notified that to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application KR10-2020-0018169 must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Claim Status
The amendment, filed on 08/12/2022, in which claims 5, 20, 22, 29, 38, 41-42, 68, and 70 are amended; and claims 6-19, 21, 24, 31, 34, 37, 44-67, 69, and 71 are canceled; and claim 72 is new, is acknowledged. Claims 1-5, 20, 22-23, 25-30, 32-33, 35-36, 38-43, 68, 70, and 72 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/12/2022, 12/16/2024, and 04/29/2025 have been considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
Page 5, Figure 49 brief description - “evalute” should read “evaluate”
Page 5, Figure 51 brief description; page 34, ¶ 4, line 1 - “cocytal” should read “cocrystal”
Page 6, Figure 76 brief description - “…potency of of…” should read “…potency of…”
Page 9, ¶ 5, line 9 - “activtiy” should read “activity”
Page 11, ¶ 2, line 8 - “domin” should read “domain”
Page 13, ¶ 1, line 5; and ¶ 2, line 5 - “varient” should read “variant”
Page 15, ¶ 7, line 7 - eponym “janus” should be capitalized
Page 16, ¶ 2, line 7 - “jun” should be capitalized
Page 22, ¶ 3, line 2 - “intracellular signal,region” should be corrected (unclear if region should be deleted)
Page 32, ¶ 6, last line - space missing between “cellswere”
Page 34, ¶ 4, last line - “phosphrylated" should read “phosphorylated”
Page 35, ¶ 1, last line - “effecacy" should read “efficacy”
Page 40, ¶ 3, line 4 - “aginst” should read “against”
Page 41, ¶ 1, line 2 - “superioty” should read “superiority”
Page 42, last ¶, line 2 - “during during the culture” should read “during culture”
Page 43, ¶ 7, line 2 - “malignacy" should read “malignancy”
Page 53, ¶ 5, line 4 - “theses” should read “these”
Page 85, ¶ 1, line 3 - “transuction” should read “transduction”
Appropriate correction is required.
The use of the terms:
“Dynabeads” (page 40, ¶ 7, line 2; page 42, last ¶, line 2; page 53, ¶ 3, line 3 and ¶ 4, line 5),
“IVIS” (page 43, ¶ 4, line 5; page 85, last ¶, lines 5 and 6; page 86, ¶ 1, line 3; ¶ 4, lines 5 and 6; ¶ 5, line 5; ¶ 8, lines 4 and 6; page 87, ¶ 1, line 5),
“Lenti-X” (page 53, ¶ 1, line 3),
“Alexa-Fluor” (page 81, ¶ 1, line 5 and ¶ 4, line 3),
“AffiniPure” (page 81, ¶ 1, line 5, ¶ 4, line 3, ¶ 2, line 2),
“CytoFLEX” (page 81, ¶ 3, line 3),
“CytExpert” (page 81, ¶ 3, line 4),
“ProLong” (page 81, ¶ 4, line 8),
“Optinity” (page 81, ¶ 5, line 4),
“PRO-PREP” (page 82, ¶ 2, line 2),
“XCell SureLock” (page 82, ¶ 3, line 2),
“XCell II” (page 82, ¶ 3, line 2),
“Nanodrop” (page 82, ¶ 5, line 3),
“SensiFAST” (page 82, ¶ 5, line 5),
“TaqMan” (page 82, ¶ 6, line 2; Table 37),
“DELFIA” (page 84, ¶ 4, lines 2 and 3; ¶ 7, line 3),
“SpectraMax” (page 84, ¶ 5, line 1; last ¶ , line 5),
which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Claim 3 is 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.
The instant claim recites “any one selected from the group consisting of…(a)-(e), and f) a combination thereof.” As written, it is unclear if the signaling pathway domain can be an embodiment of “one or more” of (a)-(e) or a combination of all (a)-(e). As the metes and bound of the claim are unclear the claim is deemed indefinite.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claim 70 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The specification, while being enabling for “treating” cancer, does not reasonably provide enablement for “preventing cancer.” The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Regarding the prevention of cancer, the America Cancer Society maintains that “There's no sure way to prevent cancer, but you can help reduce your risk by making healthy choices like eating right, staying active, and not smoking” (Cancer risk and prevention. American Cancer Society. Accessed January 22, 2025. https://www.cancer.org/cancer/risk-prevention.html. Internet – Wayback Machine). And, while analogous art of modified autologous human T-cells modified with nucleic acids encoding chimeric antigen receptors (CARs) have been shown effective in cancer treatment (see Tamada as cited below), there is no evidence in the prior art that administering immune cells transformed with a polynucleotide encoding a fusion protein according to instant claim 1 (i.e. multicistronic vector) to a subject enables cancer prevention without undue experimentation. See MPEP § 2146.01.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 20, 23, 26-27, 29-30, 33, 36, 38, 41-43, 68, 70 and 72 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 10,316,102 B2 (herein Tamada) as evidenced by You (Mol Cell Biol. 1999;19(3):2416-2424).
Regarding claims 1, 3, 20, 26-27, 29-30, 33, 36 and 38, Tamada teaches a CAR expression vector comprising a polynucleotide encoding a CAR (SEQ ID NO: 7) comprising (i) anti-FITC CAR consisting of anti-FITC scFv (positions 1-819), (ii) CD8 hinge and transmembrane domain (TMD) (positions 829-1074), and (iii) CD28-41BB-CD3ζ intracellular motifs (positions 1075-1197, 1198-1332, and 1333-1674, respectively; i.e. co-stimulatory domains derived from CD28 and 41BB and primary signaling domain derived from CD3ζ), and nucleic acids encoding T cell immune function-enhancing (i.e. T cell stimulation pathway) factors IL-7 and CCL19 (SEQ ID NO: 9), wherein the T cell immune function enhancing factors are linked via self-cleaving peptide (e.g. F2A peptides) (i.e. instant structural formula (I) N’-X-L1-Y-C’, wherein X is IL-7, L1 is F2A, and Y is CCL19) (Claims 1-2; Figures 1-2; column 13, ¶ 4).
Regarding claim 2, the instant specification defines a spacer to include CD8α hinge (page 22-23 spanning ¶), which is disclosed in the CAR sequence as discussed above.
Regarding claims 4-5, Tamada further discloses CAR expression vectors comprising sequences for CD20 CAR fused via 2A self-cleaving peptides to SHP2 dominant negative mutant (SHP2DN) (Figure 29) comprising an N-terminal SH2 domain (SEQ ID NO: 6; see alignment below) which inhibits the effects of endogenous SHP2 (a negative regulator of the Jak/STAT pathway as evidenced by You; Abstract) by competing for interactions with cytoplasmic YVKM motifs as disclosed in the instant specification (page 10, ¶ 5).
N-terminal domain of SHP2 (Instant SEQ ID NO:28; Query) aligned with Tamada SEQ ID NO:6
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Regarding claim 23, Tamada teaches an anti-CD20 CAR comprising the format as described above except that the sequence of the anti-FITC scFv is replaced with an anti-CD20 scFv sequence (column 14, lines 35-44).
Regarding claims 41-43, Tamada teaches polynucleotide containing the various receptors described above were expressed in T cells using retroviral vector (e.g. pMSGV) (column 14, ¶ 3-4).
Regarding claim 68, Tamada teaches an anticancer agent comprising disclosed isolated CAR-T cells and a pharmaceutically acceptable additive (i.e. pharmaceutical composition) (claims 12-16).
Regarding claim 70, Tamada teaches administration of anti-human CD20 CAR-IL-7/CCL-19 expressing T cells decreased tumor volume and improved overall survival in mouse tumor model using P815 mastocytoma cells genetically recombined to express human CD20 (Example 8; Figures 20-21).
Regarding claim 72, Tamada teaches that while practical examples utilize P815 cells, the anticancer agent (i.e. disclosed CAR-T cells) can be used to treat cancers including a list of species overlapping with the instant claim (column 11-12 spanning ¶).
Claims 1-3, 5, 23, 26-27, 29-30, 32-33, 35-36, 38-43, 68, 70, and 72 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 12,291,560 B2 (herein Jarjour; filed 12/13/2019).
The instant claims are drawn to a polynucleotide encoding a fusion protein comprising various elements (i)-(v). Claim 1 uses inclusive or open-ended language to define the scope of the claim. Specifically, the term “comprising” is inclusive and does not exclude additional, unrecited elements or method steps (see MPEP 2111.03). Therefore, it is not necessary for a reference to explicitly recite N- to C-terminal embodiments as disclosed in the instant specification, nor are additional domains excluded from the claims.
Regarding claims 1-3, 5, 23, 26-27, 29-30, 32-33, 35-36, and 38-43, Jarjour teaches lentiviral plasmids containing polynucleotides encoding dimerizing agent regulated immunoreceptor complexes (DARICs) fused to a CAR (CD33 DARIC) transduced into T cells (Column 73, Example 1; Figure 1). The CD33 DARIC comprises a CD8α signal peptide, a FRB domain variant, a CD8α derived transmembrane domain, a 4-1BB costimulatory domain (identical to instant SEQ ID NO:7), and a CD3ζ signaling domain (identical to instant SEQ ID NO: 9), a P2A sequence, a lg-derived signal peptide, one of two anti-CD33 scFvs (SEQ ID NOs: 2-3), a FKBP12 domain, and a CD4 derived transmembrane and truncated intracellular domain (SEQ ID NOs: 4 and 5) (Column 73, lines 10-20).
Regarding claims 68, 70, and 72, Jarjour further teaches a pharmaceutical composition comprising cells comprising CD33 DARIC (Claim 10) and demonstrate that co-cultures with CD33+ THP-1 or CD33+ Molm-1 leukemia cells lines showed increased cytokine production in the presence of rapamycin, suggesting use of transduced cells as a method of cancer treatment (Column 74, Example 2; Column 56, lines 41-45).
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.
Claims 22, 25, 28, 32, 35, 39, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Tamada as applied to claim 1, 29, and 38 above, and further in view of WO 2018/161017 A1 (herein Suri).
Regarding claim 22, Tamada teaches claim 1 as discussed above.
However, while Tamada discloses a polynucleotide containing a SHP2 derived signaling pathway modulator, Tamada does not teach additional FKBP12 and cyclophilin A domains
Suri teaches that biocircuit systems can include destabilizing domains (DDs) including FK506 binding protein (FKBP) (Uniprot ID: P62942; also known as FKBP12) (Table 1) and teaches a CD19 CAR with C-terminal FKBP (Table 10b, OT-CD19c-007; SEQ ID NO: 641 and 707). While Suri explicitly teaches a construct with a GS based linker
Regarding claims 25, 28, 32, 35, 39, and 40 Tamada teaches claim 1, 29 and 38 as discussed above.
Tamada further teaches antigen binding domain can be a surface antigen expressed on a cancer cell including CD19 (column 6, line 26).
However, Tamada teaches mouse specific nucleic acid sequences (column 13, lines 18-27) and does not explicitly teach human specific amino acid sequences SEQ ID NO: 3 (CD19 scFv), SEQ ID NO: 5 (CD8α hinge-TMD), SEQ ID NO: 7 (4-1BB co-stimulatory domain), and SEQ ID NO: 9 (CD3ζ intracellular signaling domain) as instantly claimed, nor does Tamada teach a signal peptide inserted prior to the antigen binding domain of the fusion peptide.
Suri teaches sequence for a CD19 CAR (amino acid sequence SEQ ID NO:635 and corresponding nucleic acid SEQ ID NO:701) with domains identical to instant sequences claimed in all but one residue of the CD3ζ domain. This sequence further comprises a signal peptides preceding antigen binding domain (scFv) (e.g. identical to instant SEQ ID NO:1) (alignment shown below). Regarding the single amino acid difference, Suri also teaches additional known alternative intracellular domain sequences that can be used within their constructs (Table 6), including CD3ζ variant (SEQ ID NO:323) identical to instant SEQ ID NO: 9.
Fusion of Instant SEQ ID NOs: 1, 3, 5, 7, and 9 aligned with Suri CD19 CAR (SEQ ID NO:635)
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Instant SEQ ID NO:9 (CD3ζ domain) aligned with Suri SEQ ID NO:323
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It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the various domains of the mouse construct as taught by Tamada for the domains as taught by Suri for use in human cancers. An ordinarily skilled artisan would have had a reasonable expectation of success, because Suri teaches these viable alternative CAR domains can be interchangeably used in CAR construction.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Tamada as applied to claim 1 above, and further in view of WO 2014/127261 A1 (herein Wu).
Tamada teaches claim 1 as discussed above.
While Tamada teaches a CAR with SHP2 protein, Tamada does not teach the combination of SHP2, FKBP12 (or a fragment thereof), and cyclophilin A.
Wu teaches CARs with dimerization binding pairs to generate conditionally activatable CARs that be controlled pharmacologically (¶ [0004]) and teaches suitable dimers to include FKBP and cyclophilin (¶ [00117]). Wu further teaches amino acid sequences that correspond to FKBP12 (SEQ ID NO:12; ¶ [00119]) and cyclophilin A (SEQ ID NO:72; ¶ [00121]). Through this pharmacological “On-switch” cytotoxic activity toward target cells can be titrated (¶ [00282]; Figure 15).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine the CAR-SHP2DN as taught by Tamada with a dimerization pair (FKBP12 and cyclophilin) as taught by Wu to allow for finer control of targeted cytotoxicity by adding a specific “On-switch” to a CAR-T cell already expressing inhibitor for negative feedback inhibition (SHP2DN) as a means to reduce potential off-target cytotoxicity in the absence of the dimerizing agent.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647