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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-4 and 9 in the reply filed on 03 June 2025 and 19 June 2025 are acknowledged. The office action mailed on 20 May 2025 required both restriction and election of species. The reply filed on 03 June 2025 consisted of the restriction election but no election of species. A telephone call was made to Andrew Cheng on 18 June 2025 to request an election of species over the phone. Applicant filed the species election without traverse on 19 June 2025. The claims amendments were filed by Applicant on 19 June 2025 which removed all non-elected species from the claims.
Claims 5-8 and 10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03 June 2025 and 19 June 2025.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 13 November 2019. It is noted, however, that applicant has not filed a certified copy of the CN201911106475.8 application as required by 37 CFR 1.55.
Should applicant desire 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 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.
Therefore, the current priority date is 30 September 2020 which corresponds to the filing date of PCT/CN2020/119322.
Claim Status
Claims 1 and 2 are currently amended, claims 5-8 and 10 are withdrawn from consideration as being drawn to a non-elected invention, and claims 1-4 and 9 have been considered on their merits.
Information Disclosure Statement
The information disclosure statement filed 05/12/2022 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
No English translations for the Chinese patent documents and no copies of the NPL documents were provided.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Interpretation
Claim 1 discloses the phrase “idiotype chimeric antigen receptors (CARs)” The term “idiotype” is defined by the specification (para. [0024]): “The concept of idiotype refers to the antigen specificity of an antibody molecule produced by each antibody-producing cell clone, which is determined by an amino acid sequence of a variable region of a light or the heavy chain of the antibody and thus is closely related to the antigen binding specificity of the antibody. The idiotype emphasizes the difference in the characteristic of antibody-antigen binding. A CAR also has an idiotype because the CAR recognizes an antigen based on its internal antibody structure.”
Therefore, the term idiotype regarding a CAR is a CAR having a specific antigen binding variable region, thus a CAR which binds to any specific antigen.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-4 and 9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
This is a new rejection, necessitated by applicants’ amendments to the claims.
Claim 1 recites the amended limitations:
“the one or more idiotype CARs each comprise an intracellular signaling domain, a transmembrane domain, and an extracellular recognition domain, and the extracellular recognition domain comprises an intact antibody, a heavy chain and light chain constituting an antibody, and an antibody fragment” and
“the antibody fragment comprises an antibody variable region, a single-chain fragment variable (scFV), a single-domain antibody, and an antigen-binding fragment (Fab)”
The instant disclosure supports the composition of the CARs to include the antibody fragment comprising these elements in the alternative, not where all of these elements are required for each CAR.
In amended cases, subject matter not disclosed in the original application is sometimes
added and a claim directed thereto. Such a claim is rejected on the ground that it recites elements
without support in the original disclosure under 35 U.S.C. 112, first paragraph, Waldemar Link,
GmbH & Co. v. Osteonics Corp. 32 F.3d 556, 559, 31 USPQ2d 1855, 1857 (Fed. Cir. 1994); In
re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). See MPEP § 2163.06 - § 2163.07(b) for a discussion of the relationship of new matter to 35 U.S.C. 112, first paragraph. New matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method. See MPEP § 608.04to § 608.04(c). See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) and MPEP § 2163.05 for guidance in determining whether the addition of specific percentages or compounds after a broader original disclosure constitutes new matter.
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.
Claim 1-4 and 9 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.
This is a new rejection, necessitated by applicants’ amendments to the claims.
Claim 1 recites the limitation "the one or more idiotype CARs" in the sixth line of the claim. There is insufficient antecedent basis for this limitation in the claim. The previous mention of CARs is directed to “more” CARs which would exclude one idiotype CAR.
It is unclear whether the one or more idiotype CARs in the beginning of the second paragraph of claim 1 are the same or different from the more idiotype CARs at the end of the second paragraph of claim 1.
Additionally, claim 1 now recites “…a plurality of first genetic elements encoding more idiotype chimeric antigen receptors (CARs)…”, in the first and third paragraph of the claim. It is unclear what constitutes “more” idiotype CARs.
The limitation “the more idiotype CARs at least three idiotype CARs are comprised” does not convey a clear meaning therefore, making the scope of this limitation unclear. The limitation appears to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors.
The limitation regarding the structure of the extracellular recognition domain including a
complete antibody, a heavy chain and light chain constituting an antibody, and an antibody fragment, makes the scope of the limitation unclear since a complete antibody could comprise the heavy chain, light chain, and an antibody fragment. The limitations are not presented in the alternative, therefore, it is unknown what is required by the claim a complete antibody or a fragment.
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.
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, 4, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Dai et al. (WO2020043152, published 05 March 2020) in view of Diaconu et al. (Molecular Therapy Vol. 25 No. 3, published March 2017, of record), and Lim et al. (WO2016/138034, published 01 September 2016, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims.
Regarding claim 1, the language of the newly amended claims is generally unclear; however, for the purposes of compact prosecution, the claim is interpreted as having [multiple] (more) idiotype CARs and the at least three idiotype CARs individually comprise different antibody fragment regions selected from the list of: an antibody variable region, a single-chain fragment variable (scFV), a single-domain antibody, and an antigen-binding fragment (Fab).
Dai et al. teach T cells engineered to express a CAR and uses thereof for treating certain cancers (para. [0012]). Dai et al. teach the antigen binding fragment comprises a Fab, a Fab', a F(ab')2, an Fv, a single-chain variable fragment (scFv), a minibody, a diabody, a single-domain antibody (sdAb), a light chain variable domain (VL), or a variable domain (VHH) of a camelid antibody (para. [0026]). Dai et al. teach an isolated antibody or antigen binding fragment comprising single domain antibody or a single chain variable fragment (para. [0052]). Dai et al. teach vectors comprising the polynucleotides of the invention, as well has host cells comprising the polynucleotides of the invention or the vectors of the invention (para. [0043]-[0044]). Dai et al. teach the coding sequences for the individual components of the CAR; e.g., scFv or sdAb, FSH fragment, CD3 epsilon, CD3 gamma or CD3 delta chain, or TCRα and TCRβ chains; can be separated by a sequence encoding a cleavage recognition sequence which allows the components of the construct to be expressed as a single fusion which undergoes intracellular cleavage to generate the two or more separate proteins (para. [00114]). Dai et al. teach the isolated polynucleotide encoding a protein of a modified TCR further comprises a second nucleotide sequence encoding a CAR, wherein the CAR comprises: (a) an extracellular domain comprising an antigen binding fragment that binds specifically to a tumor antigen (idiotype); (b) a transmembrane domain; and (c) an intracellular signaling domain (para. [00122]).
Dai et al. teach the term "chimeric antigen receptor" (CAR) refers to an artificial receptor that is engineered recombinantly to comprise at least an extracellular domain that binds specifically to an antigen or a target, a transmembrane domain and an intracellular T cell receptor-activating signaling domain (para. [00125]).
The isolated antibody of Dai et al. reads as an intact antibody (1), while the variations in the antigen binding fragment, scFv (2) or sdAb (3), read as two separate embodiments, therefore, the teachings of Dai et al. read as a vector assembly comprising at least three different idiotype CARs.
Dai et al. do not teach a vector assembly comprising an inducible protein and wherein the inducible protein is a suicide protein.
However, Diaconu et al. teach the inducible Capsase-9 (iC9) safety switch can eliminate CD19.CAR-Ts in a dose-dependent manner, allowing either a selective containment of CD19.CAR-T expansion in case of cytokine release syndrome (CRS) or complete deletion on demand allowing normal B cell reconstitution (Abstract). Diaconu et al. teach iC9 is based on a modified capsase-9 fused to the human FK506 binding protein (FKBP) to grant conditional dimerization using a chemical inducer of dimerization (CID) with consequent apoptosis of cells expressing the fusion protein (suicide protein) (p. 580, 2nd column). Therefore, Diaconu et al. teach the third genetic element, an inducible suicide protein.
Dai et al. in view of Diaconu et al. are silent to a genetic circuit which are pre-programmed and comprise a cis-regulatory factor and transcription factor wherein the activation of the idiotype CAR leads to an expression regulation effect on the inducible protein.
However, Lim et al. teach binding-triggered transcriptional switch polypeptides (Abstract). Transcriptional switch reads as “pre-programmed” as required by the claim. Lim et al. teach Notch receptor polypeptides and host cells genetically modified with the expression vector comprising the Notch receptor polypeptides wherein the host cell is genetically modified with a nucleic acid comprising a nucleotide sequence encoding a CAR and wherein the intracellular domain of the chimeric polypeptide is a transcriptional activator or wherein the nucleotide sequence encoding the CAR is operably linked to a transcriptional control element which is activated by the intracellular domain of the chimeric polypeptide (para. [0008]). Lim et al. teach SV40/UAS (cis-regulatory factor) reporter cells transduced with the anti-CD19 Chimeric Notch in which the intracellular domain is a fusion of the Gal4 DNA-binding domain with the transcriptional repressor domain KRAB (transcription factor) (Figure 33A, see Lim et al. FIG. 33A below). This embodiment of Lim et al. reads as a pre-programmed genetic circuit comprising a cis-regulatory factor and transcription factor, therefore, teaching the second genetic element.
PNG
media_image1.png
336
713
media_image1.png
Greyscale
It would have been obvious to one of ordinary skill in the art to combine the binding-triggered transcriptional switch polypeptides as taught by Lim et al. with the CAR as taught by Dai et al. and the inducible protein of Diaconu et al. with a reasonable expectation of success because Lim et al. teach their binding-triggered transcriptional switch polypeptides can be utilized in a host cell comprising a CAR comprising a genetic circuit operably linked to a transcriptional control element which is activated by the intracellular domain of the chimeric polypeptide, as seen in Figure 33A, above. One would be motivated to combine the binding-triggered transcriptional switch polypeptides as taught by Lim et al. with the CAR as taught by Dai et al. in view of Diaconu et al. because Diaconu et al. teach the inducible Capsase-9 (iC9) safety switch is extremely potent and specific in rapidly eliminating up to 90% of iC9-transduced T cells after the administration of a single dose of AP1903, which demonstrates the effectiveness of the iC9 at modulating T-cell activity.
Regarding claim 4 directed to a CAR cell library carrying the vector assembly according to claim 1, Dai et al. teach phage display library construction wherein VHs and VLs were amplified from mouse cDNA for generation of scFv phage library (para. [00426]), the constructed scFv phage library were panned against human mesothelin protein, output phage particles obtained via panning were used to infect exponentially growing E. coli TG1 cells to generate single clones for screening, and specific binders were selected and sequenced to identify unique anti-mesothelin scFv or sdAb clones (para. [00428]). Dai et al. teach three human sdAb variants were designed (para. [00430]). Dai et al. teach full CAR constructs were generated using a scFv or sdAb fragment with additional sequences to generate full CAR constructs (Figs 1A and 1B). Dai et al. teach the CAR fragment was then cloned into lentiviral vectors to create a full length CAR construct in a single coding frame (para. [00433]). This reads as a CAR cell library carrying the vector assembly according to claim 1.
Regarding claim 9, Dai et al. teach pharmaceutical compositions which can comprise a polynucleotide of the invention, a vector of the invention, a host cell of the invention, and/or an engineered immune cell of the invention and a pharmaceutically acceptable carrier (para. [0046]).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over Dai et al. (WO2020043152, published 05 March 2020) in view of Diaconu et al. (Molecular Therapy Vol. 25 No. 3, published March 2017, of record) and Lim et al. (WO2016/138034, published 01 September 2016, of record), as applied to claims 1, 4, and 9 above, and further in view of Finch-Edmondson et al. (Journal of Biological Chemistry, published 2 October 2015, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims.
Regarding claims 2 and 3, Dai et al. in view of Diaconu et al. and Lim et al. teach the fusion cis-acting factor is SV40/UAS and the transcription factor is Gal4-KRAB.
Lim et al. are silent to the SV40/UAS being 5xUAS, however, the combination of 5xUAS-SV40 is known in the art in mammalian expression vectors. Finch-Edmondson et al. teach a 4-hydroxytamoxifen (4HT) inducible lentiviral expression system wherein a constitutive expression of the GEV16 transcription factor (GEV16 TF) is driven by the ubiquitin promoter and following addition of 4HT, GEV16 TF translocates to the nucleus where its GAL4-DNA binding domain directs binding to GAL4 upstream activating sequences (5xUAS) to drive expression of mouse YAP or TAZ gene expression (Figure 1D and p. 27929, Plasmids and cDNAs 1st para.).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the 5xUAS of Finch-Edmondson et al. in the binding-triggered transcriptional switch polypeptides of Lim et al. with a reasonable expectation of success because Finch-Edmondson et al. demonstrate 5xUAS-SV40 in a mammalian cell system to regulate transcriptional coactivators YAP and TAX (Abstract). One would be motivated to utilize the 5xUAS of Finch-Edmondson et al. in the binding-triggered transcriptional switch polypeptides of Lim et al. because it is known in the art multiple UAS copies would enhance the binding of Gal4, resulting in a stronger and more reliable activation of the downstream gene compared to a single UAS.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 1, 4, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Cooper et al. (WO2015123642, published 20 August 2015, of record) in view of Diaconu et al. (Molecular Therapy Vol. 25 No. 3, published March 2017, of record) and Lim et al. (WO2016/138034, published 01 September 2016, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the new rejection below.
The language of the newly amended claims is generally unclear; however, for the purposes of compact prosecution, the claim is interpreted as having [multiple] (more) idiotype CARs and the at least three idiotype CARs individually comprise different antibody fragment regions selected from the list of: an antibody variable region, a single-chain fragment variable (scFV), a single-domain antibody, and an antigen-binding fragment (Fab).
Regarding claim 1, Cooper et al. teach methods for generating high throughput assembly of specific chimeric antigen receptor (CAR) molecules using triple site-specific recombination system (para. [0005] and [0008]). Cooper et al. teach a composition comprising a plurality of first vectors encoding one or more distinct antigen binding domains (extracellular recognition domain), a plurality of second vectors encoding one or more distinct hinge domains, and a plurality of third vectors encoding one or more distinct endodomains (intracellular domain); wherein the first, second, and third vectors comprise a plurality of two or more vectors encoding distinct antigen binding domains, hinge domains, and/or endodomains, and wherein the vectors comprise sites for homologous recombination to permit the generation of a fourth vector encoding a CAR (para. [0010]). Cooper et al. define “distinct” as domains having different polypeptide sequences (para. [0011]). Cooper et al. teach one or more of the first vectors encodes a scFv region and one or more of the second or third vector encodes a transmembrane domain (para. [0014]). Cooper et al. teach non-limiting examples of antigen binding domains, hinge regions, transmembrane domains, and endodomains do be used in the method of generating a CAR in Table 1 (para. [0021]). Therefore, Cooper et al. teach the first genetic element comprising an idiotype CAR which comprises an intracellular signaling domain, a transmembrane domain, and an extracellular recognition domain.
Regarding the interpretation of the second paragraph of claim 1, at least three idiotype CARs individually comprise different antibody fragment regions selected from the list of: an antibody variable region, a single-chain fragment variable (scFV), a single-domain antibody, and an antigen-binding fragment (Fab), Cooper et al. teach a vector comprising the antibody fragment scFV (para. [0008]). Cooper et al. teach a composition comprising a plurality of first vectors encoding one or more distinct antigen binding domains (para. [0010]). Cooper et al. teach the antigen binding regions or domain may comprise a fragment of the VH and VL chains of a single-chain variable fragment (scFV) (para. [0079]). Cooper et al. teach the arrangement of the antigen-binding domain of a CAR may be multimeric, such as diabody or multimers (para. [0080]). Therefore, the teachings of Cooper et al. suggests the utilization of other alternative antibody fragment regions.
It would have been obvious to one of ordinary skill in the art to utilize different portions of the antigen binding region to arrive at, at least three idiotype CARs, with a reasonable expectation of success because the teachings of Cooper et al. suggest the utilization of other alternative antibody fragment regions. One would be motivated to utilize different portions of the antigen binding region to arrive at, at least three idiotype CARs, because alternative antigen binding regions would offer enhanced stability, binding efficiency, and lower immunogenicity which could enable the precise tuning of CAR T cell behavior, resulting in safer, more effective, and more persistent immunotherapies.
Cooper et al. do not teach a vector assembly comprising an inducible protein and wherein the inducible protein is a suicide protein.
However, Diaconu et al. teach the inducible Capsase-9 (iC9) safety switch can eliminate CD19.CAR-Ts in a dose-dependent manner, allowing either a selective containment of CD19.CAR-T expansion in case of cytokine release syndrome (CRS) or complete deletion on demand allowing normal B cell reconstitution (Abstract). Diaconu et al. teach iC9 is based on a modified capsase-9 fused to the human FK506 binding protein (FKBP) to grant conditional dimerization using a chemical inducer of dimerization (CID) with consequent apoptosis of cells expressing the fusion protein (suicide protein) (p. 580, 2nd column). Therefore, Diaconu et al. teach the third genetic element, an inducible suicide protein.
Cooper et al. in view of Diaconu et al. are silent to a genetic circuit which are pre-programmed and comprise a cis-regulatory factor and transcription factor wherein the activation of the idiotype CAR leads to an expression regulation effect on the inducible protein.
However, Lim et al. teach binding-triggered transcriptional switch polypeptides (Abstract). Transcriptional switch reads as “pre-programmed” as required by the claim. Lim et al. teach Notch receptor polypeptides and host cells genetically modified with the expression vector comprising the Notch receptor polypeptides wherein the host cell is genetically modified with a nucleic acid comprising a nucleotide sequence encoding a CAR and wherein the intracellular domain of the chimeric polypeptide is a transcriptional activator or wherein the nucleotide sequence encoding the CAR is operably linked to a transcriptional control element which is activated by the intracellular domain of the chimeric polypeptide (para. [0008]). Lim et al. teach SV40/UAS (cis-regulatory factor) reporter cells transduced with the anti-CD19 Chimeric Notch in which the intracellular domain is a fusion of the Gal4 DNA-binding domain with the transcriptional repressor domain KRAB (transcription factor) (Figure 33A, see Lim et al. FIG. 33A below). This embodiment of Lim et al. reads as a pre-programmed genetic circuit comprising a cis-regulatory factor and transcription factor, therefore, teaching the second genetic element.
PNG
media_image1.png
336
713
media_image1.png
Greyscale
It would have been obvious to one of ordinary skill in the art to combine the binding-triggered transcriptional switch polypeptides as taught by Lim et al. with the CAR as taught by Cooper et al. and the inducible protein of Diaconu et al. with a reasonable expectation of success because Lim et al. teach their binding-triggered transcriptional switch polypeptides can be utilized in a host cell comprising a CAR comprising a genetic circuit operably linked to a transcriptional control element which is activated by the intracellular domain of the chimeric polypeptide, as seen in Figure 33A, above. One would be motivated to combine the binding-triggered transcriptional switch polypeptides as taught by Lim et al. with the CAR as taught by Cooper et al. in view of Diaconu et al. because Diaconu et al. teach the inducible Capsase-9 (iC9) safety switch is extremely potent and specific in rapidly eliminating up to 90% of iC9-transduced T cells after the administration of a single dose of AP1903, which demonstrates the effectiveness of the iC9 at modulating T-cell activity. Additionally, Cooper et al. teach safety features in clinical settings for CAR T-cells are known in the art (para. [0009]).
Regarding claim 4, Cooper et al. teach a composition comprising a library of different CAR encoding vectors (para. [0020]). Cooper et al. teach cloning vectors used to re-assemble CARs using three donor plasmids expressing (i) specific scFv, (ii) extracellular hinge and (iii) endodomains are adapted to generate panels of CARs that differ in hinge, transmembrane, and intracellular regions (para. [0031] and Figure 1). Cooper et al. teach a library of scFv and distinct scaffolds and signaling domains encoded in three donor plasmids (entry clones), are recombined in to the expression DNA vector to generated multiple CAR species in the format scFv-B-scaffold-C-signaling domains (para. [0031] and Figure 1). Cooper et al. teach libraries encoding a plurality of scFv regions, hinge/scaffold regions, transmembrane domains, and endodomains (signaling domains) may be generated by methods known to one of skill in the art (para [0074]).
Regarding claim 9 directed to a pharmaceutical composition comprising a pharmaceutically acceptable diluent or excipient, the vector assembly of claim 1 or the CAR cell library of claim 4, and a pharmaceutically acceptable carrier; Cooper et al. teach the transfected or transduced T cell is capable of expressing a CAR as a surface membrane protein with the desired regulation and at a desired level, the transduced T cells may be administered to the subject to activate anti-tumor responses in the subject (para. [0094]). Cooper et al. teach to facilitate administration, the transduced T cells may be made into a pharmaceutical composition or made into an implant appropriate for administration in vivo, with appropriate carriers or diluents, which are preferably pharmaceutically acceptable (para. [0094]).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments filed 27 September 2025 have been fully considered but they are not persuasive.
Applicant’s arguments at the top of page 7 of the remarks directed to Cooper not teaching the limitation "the more idiotype CARs at least three idiotype CARs are comprised". As pointed out in the 112(b) rejection above, the scope of this limitation is unclear, therefore the determination of whether or not this limitation is disclosed by Cooper cannot be ascertained.
Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections.
Regarding the arguments directed to Cooper individually, on page 7 of the response, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding the arguments pertaining to McGillis, it is noted for the record, the Examiner did not cite any reference McGillis.
Applicant’s arguments at the bottom of page 7 of the remarks directed to Cooper not teaching the limitation directed to the structure of the extracellular recognition domain, the extracellular recognition domain includes a complete antibody, a heavy chain and light chain constituting an antibody, and an antibody fragment. As pointed out in the 112(b) rejection above, the scope of this limitation is unclear, therefore the determination of whether or not this limitation is disclosed by Cooper cannot be ascertained.
Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections.
The arguments directed to Cooper on page 8 of the response, Applicant acknowledges Cooper discloses the CAR consists of a scFv region, but then states Cooper does not reveal the complete structure of the antibody fragment. However, the scFv region of the CAR of Cooper is in-fact a fragment of an antibody, therefore, this argument is not persuasive.
The argument directed to Cooper not disclosing the structure of the antibody fragment is not persuasive because the disclosed structure in the arguments is not commensurate in scope with the claims as the structural elements in the arguments are presented in the alternative.
Applicant did not present any arguments pertaining to the supporting references of the rejection.
Claims 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over Cooper et al. (WO2015123642, published 20 August 2015, IDS ref., of record) in view of Diaconu et al. (Molecular Therapy Vol. 25 No. 3, published March 2017, of record) and Lim et al. (WO2016/138034, published 01 September 2016, of record), as applied to claims 1, 4, and 9 above, and further in view of Finch-Edmondson et al. (Journal of Biological Chemistry, published 2 October 2015, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims.
Regarding claims 2 and 3, Cooper et al. in view of Diaconu et al. and Lim et al. teach the fusion cis-acting factor is SV40/UAS and the transcription factor is Gal4-KRAB.
Lim et al. are silent to the SV40/UAS being 5xUAS, however, the combination of 5xUAS-SV40 is known in the art in mammalian expression vectors. Finch-Edmondson et al. teach a 4-hydroxytamoxifen (4HT) inducible lentiviral expression system wherein a constitutive expression of the GEV16 transcription factor (GEV16 TF) is driven by the ubiquitin promoter and following addition of 4HT, GEV16 TF translocates to the nucleus where its GAL4-DNA binding domain directs binding to GAL4 upstream activating sequences (5xUAS) to drive expression of mouse YAP or TAZ gene expression (Figure 1D and p. 27929, Plasmids and cDNAs 1st para.).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the 5xUAS of Finch-Edmondson et al. in the binding-triggered transcriptional switch polypeptides of Lim et al. with a reasonable expectation of success because Finch-Edmondson et al. demonstrate 5xUAS-SV40 in a mammalian cell system to regulate transcriptional coactivators YAP and TAX (Abstract). One would be motivated to utilize the 5xUAS of Finch-Edmondson et al. in the binding-triggered transcriptional switch polypeptides of Lim et al. because it is known in the art multiple UAS copies would enhance the binding of Gal4, resulting in a stronger and more reliable activation of the downstream gene compared to a single UAS.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NICHOLAS A. HUMPHRIES whose telephone number is (703)756-5556. The examiner can normally be reached Monday - Friday, 7:30am - 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, James Schultz can be reached at 571-272-0763. 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.
/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631