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 .
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.
Priority
The instant application, filed 06/06/2023, is a 371 filing of PCT/CN2021/141311, filed 12/24/2021, and claims foreign priority to CN 202110022268.5, filed 01/08/2021.
Status of Application, Amendments, and/or Claims
Applicant’s response and the declaration of Dr. Yang Xu filed 04/17/2026 are acknowledged. Claims 79-80, 83-84, 87, 89, 91, and 95 are amended and claims 1-78, 81-82, and 102-105 are canceled. Claims 79-80, and 83-101 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/17/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Objections and Rejections
In the office action of 01/21/2026,
The drawings were objected to for containing colored figures without a petition. Applicant’s submission of black and white/grayscale drawings has overcome the objection and the objection is withdrawn.
Claim 79 was objected to. Applicant’s amendment from “comprising” to “comprises” has overcome the objection and the objection is withdrawn.
Claim 84 was objected to. Applicant’s amendment to the claim to add “and” between “(scFv)” and “the” has overcome the objection and the objection is withdrawn.
Claims 79-101 were rejected under 35 USC 112(b). Applicant’s amendment to claim 79, which has removed (e.g., TNFR2), has overcome the rejections and the rejections are withdrawn.
Claim 80 was rejected under 35 USC 112(b). Applicant’s amendment to the claim to remove “(e.g., CAR T monotherapy)” and the “and” between “PVR(CD155)” and “SIGLEC9 (CD329)” has overcome the rejection and the rejection is withdrawn.
Claims 82-83, 87, and 91 were rejected under 35 USC 112(b). Applicant’s amendment to claims 83, 87, and 91 to remove “or any functional forms thereof” has overcome the rejections and the rejections are withdrawn. The cancellation of claim 82 has rendered the rejection of claim 82 moot and the rejection is withdrawn.
Claim 84 was rejected under 35 USC 112(b). Applicant’s amendment to remove “(e.g., solid tumor surface marker)” has overcome the rejection and the rejection is withdrawn.
Claims 95-97 were rejected under 35 USC 112(b). Applicant’s amendment to claim 95 to change “the vector” to “a vector” has overcome the rejections and the rejections are withdrawn.
Claim 103 was rejected under 35 USC 112(b). The cancellation of the claim has rendered the rejection moot and the rejection is withdrawn.
Claims 82-83, 87, and 91 were rejected under 35 USC 112(d). Applicant’s amendment to claims 83, 87, and 91 to remove “or any functional forms thereof” has overcome the rejections and the rejections are withdrawn. The cancellation of claim 82 has rendered the rejection of claim 82 moot and the rejection is withdrawn.
Claims 102-105 were rejected under 35 USC 101. The cancelation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claims 79-80, 84-85, 88-95, and 97 were rejected under 35 USC 102(a)(1) and (a)(2) Over US’857. Applicant’s amendment to independent claim 79 to limit the cytoplasmic domain to including both Dectin-1 and FcγR has overcome the rejections and the rejections are withdrawn.
Claims 79-80, 84-87, 90-98, and 101 were rejected under 35 USC 102(a)(1) and (a)(2) over CN’246. Applicant’s amendment to independent claim 79 to limit the cytoplasmic domain to including both Dectin-1 and FcγR has overcome the rejections and the rejections are withdrawn.
Claims 79-80, 84-85, 92, and 94 were rejected under 35 USC 102(a)(1) and (a)(2) over US’748. Applicant’s amendment to independent claim 79 to limit the cytoplasmic domain to including both Dectin-1 and FcγR has overcome the rejections and the rejections are withdrawn.
Claims 79-85 and 92-101 were rejected under 35 USC 103 over Gill; claim 82 was rejected over US’748 and US’329; claims 82 and 86-91 were rejected over US’748 and Au’593; claims 102, 104, and 105 were rejected over US’748 and Capasso; claim 103 was rejected over US’748, Capasso, and Allen. The claims were also rejected on the grounds of nonstatutory double patenting. Applicant’s amendment to independent claim 79 to limit the cytoplasmic domain to including both the Dectin-1 and FcγR and the specific sequences recited has overcome the rejections and the rejections are withdrawn.
The following grounds of rejection are modified as necessitated by applicant’s amendment to the claims.
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.
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 79-80 and 83-101 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180244748 A1 (Gill, S., et al) 30 Aug 2018 in view of US 2024/0261329 A1 (Wang, W. and Y. Wei) 08 Aug 2024, effective filing date 13 Feb 2020 and AU 2018/227593 B2 (Suri, V., et al) 07 Sept 2018.
US’748 teaches methods and compositions for treating cancer, including solid tumors or hematologic malignancies. By expressing a chimeric antigen receptor in a monocyte, macrophage, or dendritic cell, the modified cell is recruited to the tumor microenvironment where it acts as a potent immune effector by infiltrating the tumor and killing the target cells. US’748 teaches a modified cell and a pharmaceutical composition comprising the modified cell for adoptive cell therapy and treating diseases or conditions associated with immunosuppression (abstract).
US’748 teaches that despite the high response rates demonstrated in hematopoietic malignancies, CAR T cell efficacy in solid tumors may be limited. Possible explanations for this include the potentially impaired ability of T cells to infiltrate solid tumors, poor trafficking, immunosuppressive tumor microenvironment, and expression of few tumor specific antigens on solid tumor cells (page 1, [0002]). US’748 teaches that, therefore, a need exists in the art for more effective compositions and methods that treat cancers by improving specificity for tumor cells and improving infiltration into tumor sites in both solid tumors and hematological malignancies and presents CAR modified cells to fulfill this need (page 1, [0003]).
US’748 teaches a modified cell comprising a CAR comprising an antigen binding domain, a transmembrane domain, and an intracellular signaling domain of a stimulatory and/or co-stimulatory molecule, and wherein the cell is a monocyte, macrophage, or dendritic cell that possesses targeted effector activity (page 1, [0005]).
US’748 further teaches that, in some embodiments, the CAR comprises dual signaling domains (page 1, [0009]).
US’748 teaches specific examples of CAR constructs in Fig. 1B, including CARMA-γ and CARMA-Dectin, which contain an antigen specific scFv, CD8 hinge, CD8 transmembrane, and FcεRI common γ subunit or the intracellular domain of dectin-1, respectively, and exemplified the CARs (page 2, [0023]; Figs. 10A-D; page 27, [0344]). US’748 demonstrates that the CARs are capable of killing CD19+ tumor cells in vitro luciferase-based specific lysis assays after coculture at various E:T ratios (Fig. 7; page 4, [0058]; Fig. 10; page 4, [0068]-[0069]).
US’748 further teaches polynucleotides encoding the CARs (page 1, [0006]; page 11, [0182]) and teaches both RNA and DNA for encoding the CAR polypeptide (page 1, [0013]; page 9, [0156]; page 17, [0244]).
US’748 further teaches that the antigen binding domain binds to a tumor antigen, such as an antigen that is specific for a tumor or cancer of interest. US’748 teaches tumor associated antigens including CD19, CD171, EGFRvIII, ganglioside G2 (GD2), mesothelin, Lewis Y antigen, Receptor tyrosine-protein kinase ERBB2 (Her2/Neu), fibroblast activation protein alpha (FAP), ephrin type-A receptor 2 (EphA2), and interleukin-13 receptor subunit alpha-2 (IL-13Ra2) (page 14, [0216]).
US’748 further teaches vectors for introducing the CAR into a monocyte, macrophage, or dendritic cell (page 17, [0241]-page 18, [0251]). The expression of natural or synthetic nucleic acids is typically achieved by operably linking a nucleic acid or portions thereof to a promoter and incorporating the construct into an expression vector. Typical vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence (page 17, [0245]), which meet the instant claim limitations of regulatory elements. US’748 teaches that, as used, ‘promoter/regulatory sequence’ means a nucleic acid sequence which is required for expression of a gene product operably linked to the promoter/regulatory sequence. In some instances, this sequence may be the core promoter and may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product (pages 11-12, [0185]).
US’748 teaches that the cells are phagocytic cells or a source of phagocytic cells, such as monocytes, macrophages, or dendritic cells, obtained from a subject. The cells can be obtained from a number of sources including peripheral blood mononuclear cells or bone marrow. In certain embodiments, any number of monocyte, macrophage, dendritic cells, or progenitor cell lines may be used (page 21, [0277]).
US’748 further teaches that the cells, or population of cells, comprising the monocytes, macrophages, or dendritic cells can also be cultured for expansion (page 22, [0285]-[0290]). The term “expand” refers to increasing the number of cells. In one embodiment, the cells are expanded ex vivo to increase the number relative to the number originally present in the culture. The term “ex vivo” refers to cells that have been removed from a living organism and propagated outside of the organism (page 9, [0159]).
The modified cells may be included in a composition for treatment of a subject. The composition can comprise the cells comprising the chimeric antigen receptors described. The composition may include a pharmaceutical composition and further include a pharmaceutically acceptable carrier. A therapeutically effective amount of the pharmaceutical composition comprising the modified cells may be administered (page 22, [0291]).
US’748 teaches a method of treating a disease or condition associated with a tumor or cancer in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the modified cells. In another aspect, US’748 includes a method of stimulating an immune response to a target tumor cell or a tumor tissue in a subject comprising administering a therapeutically effective amount of the pharmaceutical composition (page 22, [0292]). US’748 teaches that the cells have targeted effector activity against cells expressing the antigen target including phagocytosis, targeted cellular cytotoxicity, antigen presentation, and cytokine secretion (page 1, [0010]).
US’748 further teaches that the cells to be administered can be autologous or allogeneic with respect to the subject undergoing therapy (page 24, [0303]).
US’748 teaches that the cells can be administered as a pre-treatment or conditioning prior to treatment with an alternative anti-cancer immunotherapy, including, but not limited to, CAR-T cells (page 23, [0296]). US’748 also teaches that the cells may be administered in conjunction with, e.g., before, simultaneously, or following, any number of relevant treatment modalities, including use in combination with CAR T cell therapy (page 24, [0309]).
US’748; however, does not disclose that the cytoplasmic domain of Dectin-1 comprises SEQ ID NO: 1 and that the cytoplasmic domain of the FcεRI common γ comprises SEQ ID NO: 2.
US’329 teaches chimeric antigen receptors comprising an extracellular domain, a transmembrane domain, and an intracellular signaling domain. US’329 further teaches a costimulatory signaling domain comprising a full length or fragment of an amino acid sequence encoding a reverse dectin-1. Experiments prove that the CAR T cells are effective against a variety of solid tumors (abstract).
US’329 teaches the construct of plasmid encoding CARs. Anti-CD19 or anti-HER2 CARs include a single chain variable fragment (scFv) specific to CD19 (clone FMC63) or HER2 (clone 4D5). Four CAR sequences were constructed including hHD-DZ: comprising HER2 scFv-CD8α hinge + dectin-1 (TM+cytoplasm)-CD3ζ ICDs and h19D-DZ: comprising CD19 scFv-CD8α hinge + dectin-1 (TM+cytoplasm)- CD3ζ ICDs. Each CAR was constructed using double enzymes digestion with the PCLK lentiviral vector (page 3, [0051]). As US’329 teaches lentiviral vectors with the CAR constructs, an ordinarily skilled artisan would reasonably identify that US’329 used polynucleotide RNA to form the lentiviral vector. US’329 teaches that the amino acid sequence of the reverse dectin-1 intracellular signaling domain is SEQ ID NO: 1 (page 3, [0049]), which is identical to instant SEQ ID NO: 1, as shown in the ABSS alignment below:
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US’329 teaches that the use of reverse dectin-1 as a costimulatory signaling domain, and a CAR T cell prepared thereby, results in a CAR that influences T cell functions through dectin-1 costimulation, such as enhanced cytokine secretion and lytic capacity of a variety of cytokines including IFN-gamma, TNF-alpha, and IL-6, reduced exhaustion potential, increased cell expansion, and distinct antitumor activity. Results also demonstrate that the CAR T cells provided are effective against a variety of solid tumors and hematological malignancies (page 2, [0033]).
AU’593 teaches chimeric antigen receptors comprising an extracellular target moiety; a transmembrane domain; an intracellular signaling domain; and optionally, one or more co-stimulatory domains (page 4, [0016]).
AU’593 further teaches that examples of ITAM containing cytoplasmic signaling sequences include those derived from FcR gamma (page 5, [0021]; page 55, [00213]). AU’593 teaches intracellular domains of the Fc epsilon receptor I gamma chain that can be used in CAR production, including SEQ ID NOs: 371 and 373, both of which comprise instant SEQ ID NO: 2, as shown in the ABSS alignments below:
AU’593, SEQ ID NO: 371 aligned with instant SEQ ID NO: 2
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AU’593, SEQ ID NO: 373 aligned with instant SEQ ID NO: 2
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to include the cytoplasmic domain of both dectin-1 and FcεRI γ in the CAR intracellular signaling domain based on the teachings of US’748 as a whole. It would have further been obvious to substitute the dectin-1 in the polynucleotide disclosed by US’748 with the reverse dectin-1 sequence disclosed by US’329 and to use the FcεRI γ intracellular sequence disclosed by AU’593.
It would have been obvious to include both cytoplasmic domains as US’748 teaches that the CAR can comprise a dual signaling domain and also demonstrates efficacy of CARs comprising a dectin-1 or a FcεRI γ intracellular domain. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
One of ordinary skill in the art would have been motivated substitute the dectin-1 in the polynucleotide disclosed by US’748 with the reverse dectin-1 sequence disclosed by US’329 as US’329 teaches that the use of the reverse dectin-1 provides benefits including enhanced cytokine secretion and lytic capacity and distinct antitumor activity. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’748 and US’329 are teaching dectin-1 cytoplasmic domains as CAR intracellular domain sequences.
It would have been obvious to use the FcεRI γ intracellular sequences disclosed by AU’593 because AU’593 demonstrates that these were known and functional domains and sequences for use in CAR construction. An ordinarily skilled artisan would have had a reasonable expectation of success because US’748 teaches that the CAR can comprise a FcεRI γ intracellular domain.
It is noted that, while the applied references do not experimentally demonstrate that the CAR is capable of activating dendritic cells in an immunosuppressive tumor microenvironment, as recited in the claim, the CAR suggested by the combination of applied references would have been capable of performing the claimed function as evidenced by the instant disclosure which demonstrates that a CAR comprising a CD8 hinge, CD8 transmembrane domain, and the combination of a dectin-1 and FcεRI common γ subunit intracellular domain is capable of activating dendritic cells in an immunosuppressive tumor microenvironment. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.” In this case, because the CAR suggested by the combination of applied references would be capable of performing the recited function, the CAR meets the instant claim limitations.
Regarding claims 86-91, AU’593 further teaches inclusion of a signal peptide present at the N-terminus of synthesized proteins that are destined towards a particular location. For instance, signal sequences that direct the payload of interest to the surface membrane of a target call may be used. AU’593 teaches that the signal peptide may be a CD8α signal sequence, also referred to as a CD8α leader, and may comprise SEQ ID NO: 628 (page 127, [00271] and [00274]). AU’593, SEQ ID NO: 628 is identical to instant SEQ ID NO: 5 as shown in the ABSS alignment below:
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AU’593 further teaches that the CAR can also comprise a hinge region comprising a short sequence of amino acids that facilitates flexibility of the extracellular targeting domain and moves the target binding domain away from the effector cell surface to enable proper cell/cell contact, target binding, and effector cell activation. The hinge sequence may be derived from the extracellular regions of type 1 membrane proteins including CD8α (pages 63-64, [00222]). AU’593 teaches that the hinge connects the extracellular targeting domain to the transmembrane domain which traverses the cell membrane and connects to the intracellular signaling domain (page 49, [00199]). AU’593 also teaches sequences of CD8α hinges that can be used in CAR construction including SEQ ID NO: 439 (page 68, row 5), which is identical to instant SEQ ID NO: 7, as shown in the ABSS alignment below:
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AU’593 further teaches that the transmembrane domain of the CAR maybe derived from a molecule including CD8α (pages 5-6, [0025]) and teaches CD8α transmembrane domains for use in CARs including SEQ ID NO: 409 (page 66), which is identical to instant SEQ ID NO: 6, as shown in the ABSS alignment below:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the polynucleotide taught by the combination of US’748, US’329, and AU’593 by further including the CD8α signal peptide of AU’593, to use the CD8α hinge and transmembrane domains disclosed by AU’593 in place of the CD8 hinge and transmembrane domains taught by US’748. One of ordinary skill in the art would have been motivated to further include a signal peptide in order to direct the CAR to the surface membrane of the cell. It would have been obvious to use the CD8α signal peptide taught by AU’593 as AU’593 teaches the use of the signal peptide in CAR constructs. It would have further been obvious to use the CD8α hinge and transmembrane sequences disclosed by AU’593 because AU’593 demonstrates that these were known and functional domains and sequences for use in CAR construction. An ordinarily skilled artisan would have had a reasonable expectation of success because all of US’748, US’329, and AU’593 teach CAR constructs. Additionally, US’748 teaches the inclusion of CD8 hinge and transmembrane domains in the CARs disclosed.
Response to Arguments
Applicant’s arguments and the declaration of Dr. Yang Xu filed 04/17/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that the applied reference US’748 relates to modified monocytes/macrophages expressing CARs citing the examples of the reference. Applicant argues that a CAR with an intracellular signaling domain, such as that claimed, has not been applied to another type of cell, for example a dendritic cell, and that, without experimental verification, the effect is not predictable.
Although US’748 exemplifies CAR expression in monocytes/macrophages, US’748 teaches throughout the disclosure that the cell expressing the disclosed CARs can be a monocyte, macrophage, or dendritic cell. US’748 also teaches that the cell that expresses the CAR possesses targeted effector activity and specifically teaches that such activity can include antigen presentation and cytokine secretion, not just phagocytosis or targeted cytotoxicity (page 1, [0007] and [0010]). Additionally, the requirement of obviousness is a reasonable expectation of success, not conclusive proof of efficacy and the art is not required to experimentally demonstrate the claimed polynucleotide in order to establish a prima facie case of obviousness. See MPEP 2143.02 (I).
It is also noted that independent claim 79 is drawn to a product having the recited structure, which is a polynucleotide encoding a CAR comprising the recited elements where the polynucleotide is RNA or DNA. While the claim recites the limitation that the CAR is capable of activating dendritic cells in an immune suppressive tumor microenvironment, the claim does not require that the CAR be in a dendritic cell, only that the CAR be capable of performing the function recited. The only claim that actually requires that the cell be a dendritic cell is dependent claim 96 which limits the starting cell in the method of claim 95 to being a dendritic cell or a precursor or progenitor cell thereof.
Furthermore, the reason or motivation to modify the reference to arrive at the instantly claimed invention does not have to be for the same purpose as applicant’s. MPEP 2144 IV. states “[t]he reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.” As such, even if the combination of applied references suggested the claimed CAR for a different purpose, for instance for use in macrophages, such a use would still meet the limitations of claim 79 as the structure of the CAR would be the same and the structure would be one that is capable of performing the claimed function.
Applicant further argues that macrophages and DCs have different activation mechanisms and functions and cites a review article by Zanoni and Granucci as teaching that the same receptor has different activation functions in macrophages and DCs.
This argument; however, is not persuasive. As discussed in detail above and in the rejection, the combination of applied prior art, and in particularly the reference US’748 teaches monocytes, macrophages, or dendritic cells expressing the CARs disclosed. Even if the activation mechanisms and functions of naturally occurring macrophages and DCs are different, this alone does not discourage the construction or use of the CARs suggested by US’748, which are artificial receptors.
Applicant argues that the present inventors designed DC activating CAR molecules with intracellular domains composed of various DC-activating domains. As shown in the present application, CARs with traditional intracellular domains of 4-1BB, CD3ζ, TLR4, and TNFR2 cannot effectively activate DCs. After testing CARs with various combinations of DC activating domains, the inventors discovered that the cytoplasmic tails of dectin1 and FcRγ, specifically SEQ ID NOs: 1 and 2, can effectively activate DCs after they encounter a tumor immune suppressive microenvironment. Applicant references the CAR as CARDF-DC and states that the DC itself does not kill tumor cells. Applicant cites Fig. 1 of the instant disclosure which demonstrates that CARDF-DCs expressed higher levels of costimulatory molecules CD80 and CD86 compared to control DCs, which are DC activation markers. It is also shown that CARDF-DCs could induce more robust proliferation of allogeneic T cells than controls (Fig. 1E). Applicant further argues that the present application demonstrates that anti-CD19 CAR T cells conferred higher cytotoxicity to CD19+ H460 tumor cells in the presence of CARDF-DCs compared to controls and that CARDF can enhance activities of DCs to activate CAR-T cells, citing Fig. 1 H-J. Similar results were shown with anti-EphA2 CARDF-DCs (Fig. 2C). The results were also demonstrated with cells overexpressing CTLA4-Ig and PD-L1 to simulate the immunosuppressive microenvironment and increase the cytotoxicity of CAR T cells.
While it is appreciated that the present inventors have experimentally demonstrated DCs expressing CARs comprising the cytoplasmic tails of dectin1 and FcRγ, specifically SEQ ID NOs: 1 and 2, and their ability to activate DC and proliferate CAR T cells in immunosuppressive tumor models, conclusive proof of efficacy is not required in order to establish obviousness as discussed in detail above. As discussed in the rejection, US’748 teaches CARs that can be expressed in dendritic cells and exemplifies CARs comprising a dectin1 or a FcRγ intracellular signaling domain. US’748 also explicitly teaches that the CARs can comprise dual signaling domains suggesting the combination of dectin1 and FcRγ. While the combination of applied references does not conclusively demonstrate the CAR in a DC, experimental demonstration is not required in order to establish obviousness, only a reasonable expectation of success.
Additionally, applicant’s arguments and the results discussed in the response and disclosure, are not commensurate in scope with the claims. For instance, as discussed above, claim 79 is drawn to a product, which is a polynucleotide encoding the recited CAR wherein the polynucleotide is a RNA or DNA. While the claim recites a functional limitation that the CAR is capable of activating dendritic cells, the claim does not require that the polynucleotide or CAR be in a dendritic cell, only that it be capable of performing the claimed function.
Applicant further argues that the attached supplementary data in the declaration of Dr. Xu provides evidence of unexpected results. The results disclosed provide the CD86 expression (measure of activation) of wildtype DCs, CAR-DC-Dectin1-FcRγ, CAR-DC-dectin-1, and CAR-DC-FcRγ. Applicant argues that neither dectin1 alone nor FcRγ alone, when used as the intracellular signaling domain in the CAR, is capable of effectively activating the DCs. In contrast, the combination of Dectin-1 and FcRγ demonstrates a remarkable advantage in activating DCs compared to either alone. Applicant argues that the data indicates that using different signaling domains in different types of immune cells yields unpredictable activation effects. Specifically, applicant argues that CAR-T structures cannot effectively activate DC cells and, similarly, macrophage CARs, such as dectin-1 or FcRγ individually also cannot effectively activate DCs. Therefore, the effects of any structural combination and their function in different cells cannot be known by analogy and the results require experimental verification.
These results, however, are not sufficient to overcome the prima facie case of obviousness.
The results presented by applicant in the response do demonstrate a significant increase in DC activation when the combination of dectin-1 and FcRγ cytoplasmic domains are used (23.8%) compared to dectin-1 (8.18%) or FcRγ (12.9%) alone or WT DC (12.9%); however, it is not clear that these results are unexpected. Particularly as the CAR-DC-Dectin1-FcRγ has two signaling domains which would reasonably be expected to increase signaling compared to CARs with only a single signaling domain.
MPEP 716.02(a) states “a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).”
In this case, US’748 directly suggests the use of dual signaling domains. US’329 also teaches a dectin-1 cytoplasmic domain in combination with a CD3ζ ICD. These teachings demonstrate that the inclusion of two signaling domains was taught by the applied art. Applicant does not demonstrate that the results provided are greater than those that would have been expected from the prior art, when two signaling domains are used compared to one, but to an unobvious extent.
Furthermore, a comparison to a CAR with only a single signaling domain is not a comparison to the closest prior art, which directly suggests dual signaling domains.
MPEP 716.02 (b)(III) states “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.” MPEP 716.02 (e) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
In this case, while the comparison to dectin-1 or FcRγ alone is a comparison to the exemplified CARs in US’748, US’748 explicitly teaches that the intracellular domain of the CAR can comprise a dual signaling domain (page 31, claim 5), suggesting the combination of two intracellular signaling domains together. US’329 also teaches the use of a dectin-1 cytoplasmic domain in combination with a CD3ζ ICD, which has two signaling domains, further demonstrating the use of two signaling domains in the art. Applicant does not provide a comparison to any other combination of intracellular signaling domains (dual signaling domains) to demonstrate that the instantly claimed combination/sequences provide an unexpected result.
It is also noted that MPEP 716.02(e) II. states “Showing unexpected results over one of two equally close prior art references will not rebut prima facie obviousness unless the teachings of the prior art references are sufficiently similar to each other that the testing of one showing unexpected results would provide the same information as to the other.”
Additionally, the claims are not commensurate in scope with the results presented.
MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
As discussed in detail above, the claims do not require that the claimed polynucleotide/CAR be in a dendritic cell, which is the type of cell used in the experiments provided by the instant disclosure and the specification.
Furthermore, the independent claim encompasses any transmembrane domain and, in the broadest reasonable interpretation of the claim, the cytoplasmic domain of dectin-1 and the cytoplasmic domain of FcRγ could be included in the CAR in either order so long as both are included. The results discussed by applicant used a CAR comprising the structure shown in Fig. 1A, last row, which includes a CD8a hinge and TM domain followed by the cytoplasmic domain of dectin-1 then that of FcRγ. Applicant does not provide any evidence that the results provided would be maintained without a hinge, with any other TM domain, or if the FcRγ cytoplasmic domain was included before that of dectin-1.
Double Patenting
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
US 12,097,259 B2
Claims 79-80, 83-94, and 98 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,097,259 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
US’259 claims a vector for preparing a dendritic cell vaccine comprising a polynucleotide encoding a chimeric antigen receptor (CAR) capable of activating a dendritic cell, wherein the CAR comprises an extracellular antigen-binding domain comprising a single-chain scFv specific for a tumor surface marker, a transmembrane domain of CD8a, and an intracellular signaling domain comprising a cytoplasmic domain of dectin-1 and a cytoplasmic domain of FcγR, wherein the intracellular signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 3; and a polynucleotide encoding a tumor antigen.
US’259, SEQ ID NO: 3 is identical to instant SEQ ID NO: 3 as shown in the ABSS alignments below:
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207
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US’259 further claims that the intracellular signaling domain is encoded by SEQ ID NO: 4 and that the tumor surface marker is selected from a group consisting of surface markers that overlap with those of instant claim 85. US’259 claims that the CAR further comprises a signal peptide of CD8 alpha and SEQ ID NO: 5. US’259 further claims that the transmembrane domain of CD8a comprises SEQ ID NO: 6. US’259 claims that the extracellular antigen-binding domain is linked to the transmembrane domain by a hinge region, that is CD8a, with a sequence of SEQ ID NO:7. US’259 claims that the vector is DNA or RNA and that the polynucleotide is operatively linked to at least one regulatory polynucleotide element for expression of the CAR. US’259 further claims an engineered cell comprising the vector and that the cell is a dendritic cells or a precursor cell or progenitor cell thereof. US’259 claims a pharmaceutical composition comprising a population of the engineered cells and a pharmaceutically acceptable medium.
The claims of US’259 differ from the instant claims in that US’259 does not explicitly claim that the CAR is capable of activating dendritic cells in an immune suppressive tumor microenvironment. The capability of the claimed product to activate dendritic cells in an immunosuppressive tumor environment is inherent to the structure of the product. As the instantly claimed CAR is identical to that claimed in US’259, the CAR of US’259 would necessarily have this property. See MPEP 2112.01 I and MPEP 2145 II.
Thus, the claims of US’259 anticipate the instant claims.
Claims 95-97 and 99-101 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,097,259 B2 in view of US 20180244748 A1 (Gill, S., et al) 30 Aug 2018.
The claims of US’259 anticipate instant claim 79 as discussed in detail above.
The claims of US’259, however, do not teach a method of producing the engineered cells or the claimed methods of using the engineered cells.
The teachings of US’748 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’259 to include the claimed method of producing and methods of administering the engineered cells to improve efficacy of adoptive cell therapy, induce proliferation of immune cells, and treat diseases, based as taught by US’748 arriving at the instantly claimed invention. It would have been obvious to use the methods of US’748 for the production and application of the engineered cells of US’259 as US’748 is also teaching CAR engineered dendritic cells. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Response to Arguments
Applicant’s arguments and the declaration of Dr. Yang Xu filed 04/17/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
With regards to the nonstatutory double patenting rejection, applicant argues that DC expressing the instantly claimed CAR itself does not kill tumor cells, but that the CAR can activate DCs to resist tumor cell-induced immune suppression to effectively activate T cells. Applicant argues that the CARDF-DCs can be used in combinations such as with CAR-T cell therapies. Applicant argues that, in US’259, when the CAR and the tumor antigen are expressed in the DC cell, it is capable of decreasing the volume of a tumor comprising tumor cells expressing the tumor antigen and that the cells can be used as a single therapy.
These arguments; however, are not persuasive.
While the claims of US’259 comprise elements in addition to the CAR, and applicant’s intended use might be different, the CAR recited in US’259 is a species of the instantly claimed CAR.
Specifically, the instant claims recite a polynucleotide encoding a CAR comprising an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain comprising SEQ ID NO: 1 and SEQ ID NO: 2 where the polynucleotide is DNA or RNA and the CAR is capable of activating a dendritic cell in a immunosuppressive tumor microenvironment.
The claims of US’259 recite a vector that comprises a polynucleotide encoding a CAR capable of activating a dendritic cell, wherein the CAR comprises a scFv extracellular antigen binding domain specific for a tumor surface marker, a CD8a transmembrane domain, and an intracellular signaling domain comprising SEQ ID NO: 3, which is a combination of instant SEQ ID NOs: 1 and 2. US’259 also limits the vector to being DNA or RNA.
As such, the vaccine claimed in US’259 includes a CAR that is a species of the claimed CAR.
The instant claims are drawn to a product, specifically the recited polynucleotide, and; therefore, the CAR species recited in US’259 anticipates the instant claims, even if US’259 includes additional elements or would function differently if used in a particular method.
Applicant further argues that US’748 relates to modified monocytes/macrophages expressing CARs and does not teach how to activate DCs in an immune suppressive tumor microenvironment.
Applicant’s arguments concerning US’748; however, are not persuasive.
Contrary to applicant’s suggestion that US’748 relates only to modified monocytes /macrophages, US’748 also directly teaches that the CARs disclosed can be used in dendritic cells, as discussed in detail in the rejections. US’748 is applied in the nonstatutory double patenting rejection in order to demonstrate that methods of producing engineered cells and methods of using the engineered cells would have been obvious variations of the CAR recited in US’259 and would have been obvious in view of the prior art.
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 AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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