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 Claims/Application
Applicant’s preliminary amendment of 06/06/2023 is acknowledged. Claims 1-78 are canceled and claims 79-105 are new. Claims 79-105 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/06/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Drawings
The drawings filed 06/06/2023 are objected to for containing colored figures without the filing of an appropriate petition under 37 CFR 1.84(a)(2). Applicant is required to filed an appropriate petition for colored drawings or black and white/grayscale replacement figures.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claim 79 is objected to because of the following informality: the claim currently recites “wherein the CAR comprising (1)…” the word “comprising” should be corrected to “comprises”. Appropriate correction is required.
Claim 84 is objected to because of the following informality: the claim recites “the extracellular antigen-binding domain comprises a single-chain variable fragment (scFv), the scFv is specific for a tumor surface marker”. The claim is missing a word between “(scFv),” and “the” for instance “wherein” or “and”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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.
Claims 79-101, 103, and 105 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.
Claim 79, line 6 recites the limitation “TNFR (e.g., TNFR2)”. The recitation of “e.g., TNFR2” and the use of parentheticals renders the claim indefinite as it is unclear if the limitations following “e.g.” and within the parentheticals, which are a narrower embodiment of the preceding limitation, are part of the claimed invention or an exemplary embodiment. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 79 recites the broad recitation “TNFR”, and the claim also recites “(e.g., TNFR2)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
Claims 80-101 are rejected by virtue of their dependency on claim 79 as they do not resolve the ambiguity discussed above.
Claim 80, lines 2-3, recite the limitation “monotherapy of adoptive cell therapy (e.g., CAR-T cell monotherapy)”. The recitation of “e.g., CAR-T cell monotherapy” and the use of parentheticals renders the claim indefinite as it is unclear if the limitations following “e.g.” and within the parentheticals, which are a narrower embodiment of the preceding limitation, are part of the claimed invention or an exemplary embodiment. See MPEP § 2173.05(c). In the present instance, claim 80 recites the broad recitation “monotherapy of adoptive cell therapy”, and the claim also recites “(e.g., CAR-T cell monotherapy)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Additionally, lines 6-10 recite a list of immune inhibitory molecules and, on line 8, recites “PVR(CD155) and SIGLEC9 (CD329)”. Based on the use of “and” between these two molecules, and at the end of the list on line 10, it is unclear if both PVR(CD155) and SIGLEC9 (CD329) are required together as alternative immune inhibitory molecules or if one of PVR(CD155) or SIGLEC9 (CD329) would meet the claim limitation.
Appropriate correction is required.
Claims 82-83, 87, and 91 all narrow a specific domain of the CAR and recite that the domain comprises the recited amino acid or nucleic acid sequences “or any functional forms thereof”. It is unclear if the recitation of “or any functional forms thereof” applies to the domain type or the recited sequences rendering the metes and bounds of the claims indefinite. For instance, claim 82 recites “wherein the cytoplasmic domain of Dectin-1 comprises an amino acid sequence set forth in SEQ ID NO: 1, or any functional forms thereof”. It is unclear if any functional form of the cytoplasmic domain of Dectin-1 would meet the limitation or if the domain must have some commonality to SEQ ID NO: 1.
Appropriate correction is required.
In the instant office action, the claims are interpreted as encompassing any functional form of the recited domain, even those that do not comprise the recited amino acid or nucleic acids. This interpretation is supported by the definition of “functional forms” in the instant specification which states that “The term ‘functional forms’ as used herein, refers to different forms (such as variants, fragments, fusions, derivatives and mimetics) of the parent molecule which, despite of having difference in amino acid sequences or in chemical structures, still retains substantial biological activity of the parent molecule.” (instant specification, page 16, [00116]).
Claim 84, lines 2-3, recite the limitation “tumor surface marker (e.g., solid tumor surface marker).” The recitation of “e.g., solid tumor surface marker” and the use of parentheticals renders the claim indefinite as it is unclear if the limitations following “e.g.” and within the parentheticals, which are a narrower embodiment of the preceding limitation, are part of the claimed invention or an exemplary embodiment. In the present instance, claim 84 recites the broad recitation “tumor surface marker”, and the claim also recites “(e.g., solid tumor surface marker)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
Claim 95 recites the limitation "the vector comprising the polynucleotide of claim 79" in line 3. There is insufficient antecedent basis for this limitation in the claim. Neither of claims 79 or 95 recite a vector comprising the polynucleotide of claim 79 that could be being referenced by the claim.
Appropriate correction is required.
Claims 96-97 are rejected by virtue of their dependency on claim 95 as they do not resolve the ambiguity discussed above.
Claim 103, lines 2-3, recite the limitation “autologous human hematopoietic stem cells (e.g., human CD34+ hematopoietic stem cells).” The recitation of “e.g., human CD34+ hematopoietic stem cells” and the use of parentheticals renders the claim indefinite as it is unclear if the limitations following “e.g.” and within the parentheticals, which are a narrower embodiment of the preceding limitation, are part of the claimed invention or an exemplary embodiment. In the present instance, claim 103 recites the broad recitation “human hematopoietic stem cells”, and the claim also recites “(e.g., human CD34+ hematopoietic stem cells)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Additionally, lines 1-2 of the claim recite “non-human animal comprises… autologous human hematopoietic stem cells”. The instant specification defines autologous as referring to “any cells derived from the same subject into which they are later to be re-introduced.” (page 15, [00110]). It is unclear who the autologous human hematopoietic stem cells are derived from, rendering the metes and bounds of the claim indefinite. This is particularly the case as neither claim 103, nor claim 102 on which it depends, recites a human to which the cells are taken from and reimplanted in. Additionally, the cells cannot be autologous to the non-human animal as they would not be human.
Appropriate correction is required.
In the instant office action, the limitation is interpreted as requiring that the non-human animal be implanted with human hematopoietic stem cells.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 82-83, 87, and 91 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Each of claims 82-83, 87, and 91 recite an amino acid sequence “or any functional forms thereof”. As discussed above, this limitation is interpreted as encompassing any form of the recited intracellular signaling domains, signal peptides, hinges, or transmembrane domains. Under this interpretation, the claims encompass embodiments that do not act to further limit the claims upon which they depend.
For instance, claim 82 depends on claim 81. Claim 81 recites that the intracellular signaling domain comprises the cytoplasmic domain of dectin-1 and the cytoplasmic domain of Fc gamma R. Claim 82 encompasses an embodiment where the dectin-1 and Fc gamma R cytoplasmic domains are in any functional form, which does not act to further limit the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 102-105 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception, specifically an abstract idea, without significantly more. The claims are evaluated below using the “Subject Matter Eligibility Test for Products and Processes” flow chart as shown in MPEP § 2106 III.
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Yes. The claims are drawn to a process (method).
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes. Claim 102 recites the abstract idea of “selecting” the candidate CAR as a CAR capable of activating dendritic cells.
In the broadest reasonable interpretation of the claim, “selecting” the candidate CAR is a mental process that can be performed in the human mind, which is an abstract idea. See MPEP 2106.04(a)(2)III which states “the "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions.”
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No. The claims do not recite additional elements that integrate the judicial exception into a practical application.
The method of claim 102 ends with the abstract idea of the selection of the candidate CAR as a CAR capable of activating dendritic cells. The claim does not recite any additional steps that integrate the judicial exception into a practical application, for instance, through the administration of the CAR to a person. See MPEP 2106.04(d).
Claims 103 and 104 act to further limit the non-human animal that the CAR is tested in. The claims also do not integrate the judicial exception into a practical application.
Claim 105 further limits the immune cell for which activation is detected in the method of claim 102. The claim also does not integrate the judicial exception into a practical application.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. The claims do not recite additional elements that amount to significantly more than the judicial exception.
While claim 102 recites administering a dendritic cell to the non-human animal and the detection of a maker for the dendritic cell activation, testing in non-human animals and the detection of activation markers is well-understood, routine, and conventional activities known in the art. Additionally, these are considered to be insignificant extra-solution activity and are data gathering steps required in order to implement the judicial exception. See MPEP 2106.05.
Claims 103 and 104 act to further limit the non-human animal that the CAR is tested in. The claims also do not recite additional elements that amount to significantly more than the judicial exception, particularly as the use of non-human animals in testing is well-understood, routine, and conventional.
Claim 105 further limits the immune cell for which activation is detected in the method of claim 102. The claims also do not recite additional elements that amount to significantly more than the judicial exception, particularly as the detection of activation of the immune cells is well-understood, routine, and conventional.
As the instant claims recite judicial exceptions that are not integrated into a practical application and recite no elements that amount to significantly more than the judicial exceptions, the claims were found to not be drawn to eligible subject matter under 35 USC 101.
Claim Rejections - 35 USC § 102
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 79-80, 84-85, 88-95 and 97 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2016/0058857 A1 (Spencer, D., et al) 03 MAR 2016.
US’857 teaches methods for activating T cells and other cells resulting in an immune response against a target cell. US’857 further teaches therapeutic cells that express chimeric antigen receptors, wherein the chimeric antigen receptors have an endodomain that includes MyD88- and CD40-derived polypeptides, and methods for treating patients using the modified therapeutic cells (abstract).
US’857 teaches a HER2 targeting CAR comprising the following construct in Figure 18A:
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Which comprises an extracellular antigen binding domain scFv targeting HER2, a CD8 stalk and transmembrane domain, and an intracellular domain that comprises a cytoplasmic domain of MyD88, CD40, and the intracellular signaling domain of CD3ζ. US’857 teaches similar constructs in which the scFv is specific for PSCA (Figure 4A) and CD19 (Fig 26C).
US’857 teaches that examples presented evaluating the utility of MCD88/CD40 (MC) costimulation in CAR T cells focused on including the MyD88/CD40 polypeptide within the CAR, in the conventional location for costimulatory domains, such as CD28 or OX40, for example. The polynucleotide encoding the MyD88/CD40 polypeptide was placed between the CD8 transmembrane region and CD3 (Fig. 26). This CAR design, designated MC.ζ, demonstrated significantly higher cytokine production, including IL-2 and IL-6, enhanced T cell survival and proliferation, and provided superior tumor killing during in vitro coculture assays (page 90, [0683] and [0689]).
US’857 teaches that, in the examples, the T cells were transduced with a nucleic acid comprising a polynucleotide encoding the CAR molecule (page 56, [0516]) and teaches the use of retroviruses comprising the CAR constructs using a synthetic DNA approach (page 62, [0546]; page 61, [0533]).
US’857 further teaches the sequences used in the CAR constructs (pages 76-78, Example 15) which disclose that the CARs comprise a CD8 alpha transmembrane region of SEQ ID NO: 167, which comprises instant SEQ ID NO: 6, a CD8 alpha stalk of SEQ ID NO: 165, which comprises a functional fragment of instant SEQ ID NO: 7, and the CD40 cytoplasmic domain of SEQ ID NO: 173. US’857 further teaches that the retroviral vectors comprise promoters and enhancer sequences (page 31, [0336]), which meet the instant claim limitations of a regulatory polynucleotide element.
While US’857 does not experimentally demonstrate that the CAR is capable of activating dendritic cells in an immune suppressive tumor environment as claimed, the capability of the claimed product to activate dendritic cells in an immunosuppressive tumor environment is inherent to the structure of the product. MPEP 2112.01 I states “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established.” Additionally, 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.”
Thus, US’857 anticipates the instant claims.
Claims 79-80, 84-87, 90-98, and 101 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by CN 107286246 (Fan, K. and G. Tongtong) 24 OCT 2017 (English translation from Espacenet obtained from https://worldwide.espacenet.com/patent/search/family/060095928/publication/
CN107286246A?q=CN107286246, on 12/09/2025).
CN’246 teaches that, given that dendritic cells (DCs) are the most important antigen-presenting cells in the human body, DCs were transduced with CAR structures enabling them to more effectively recognize and present tumor antigens. Tumor-targeting CAR-DCs can effectively present multiple antigens from the same tumor to the effector T cells, thereby overcoming the single-target recognition and killing effect of CAR T cells. CN’246 teaches the design of a novel DC cell therapy strategy for tumors using a lentiviral system to fuse the CD40 signaling domain with a tumor-associated chimeric antigen receptor with an anti-EGFRvIII scfv, transducing DC cells, and constructing EGFRvIII CAR-DCs. It activates DCs by binding to glioma cells through its tumor associated chimeric antigen receptor, while simultaneously presenting tumor antigens and stimulating T cell activation, thereby achieving an anti-tumor effect (page 5, [0008]).
CN’246 provides a schematic of the CAR in Fig. 1, which consists of a CD8α signal peptide (CD8αSP), EGFRvIII antibody light chain variable region (EGFRvIII scFv-VL), linker region, EGFRvIII heavy chain variable region (EGFRvIII scFv-VH), CD8α hinge region, CD40 transmembrane region (CD40 TM), and CD40 intracellular region. A control structure was also designed, which has no CD40 intracellular signal region (pages 8-9, [0024]).
CN’246 teaches a DNA polynucleotide encoding the EGFRvIIICAR (SEQ ID NO: 2; page 34, [0159]). The complete sequence was synthesized and an Xba I restriction site was added to its 5’ end and an EcoR I restriction site was added to the 3’ end (page 15, [0054]). The CAR was cloned into the pCDH lentiviral expression vector to construct a pCDH-EGFRvIIICAR plasmid (page 16, [0056]-[0057]).
The EGFRvIIICAR of CN’246, SEQ ID NO: 2 comprises a CD8α signal peptide that is identical to instant SEQ ID NO: 5, as shown in the ABSS alignment below:
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The CAR also comprises a CD8α hinge region that is identical to instant SEQ ID NO: 7, as shown in the ABSS alignment below:
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CN’246 further provides information of the pCDH-EGFRvIIICAR lentiviral expression vector plasmid in Figure 2, which is shown to include a CMV promoter, which is a regulatory element.
CN’246 teaches in vitro culture, infection, and expansion of dendritic cells and teaches that CD14+ cells were sorted from PBMCs using a dendritic cell sorting kit. Cells were resuspended in medium with GM-CSF and differentiated into dendritic cells. CAR virus concentrate was added to dendritic cells and cultured. EGFRvIIICAR-DC were obtained (page 21, [0075]-[0079]).
CN’246 further teaches a pCDH-EGFRvIIICAR lentiviral expression vector plasmid (page 9, [0025]; Fig. 2) and teaches that, which cultured in vivo with tumor cells, EGFRvIIICAR-DC cells achieved a higher degree of activation and maturation in vitro when stimulated with EGFRvIII+ cells (page 9, [0026]). CN’246 further teaches that in a mouse glioma model, tumors in mice injected with EGFRvIII CAR-DC cells + T cells were significantly inhibited and the tumor volume shrank significantly until it disappeared over time (page 10, [0028]). As CN’246 teaches injection of the EGFRvIII CAR DC cells in animal models, the cells would necessarily have been in a pharmaceutically acceptable medium.
While CN’246 does not experimentally demonstrate that the CAR is capable of activating dendritic cells in an immune suppressive tumor environment as claimed, the capability of the claimed product to activate dendritic cells in an immunosuppressive tumor environment is inherent to the structure of the product. See MPEP 2112.01 I and MPEP 2145 II.
Thus, CN’246 anticipates the instant claims.
Claims 79-80, 84-85, 92, and 94 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by US 2018/0244748 A1 (Gill, S., et al) 30 Aug 2018.
US’748 teaches CAR constructs with an FcεRI common γ subunit intracellular domain, CAR19γ, CARMA19γ, and teaches that the CARs were packaged into lentivirus vectors and used to transduce THRP-1 myeloid cells in a three-fold serial viral dilution. CAR19y was expressed on THP-1 macrophages (page 27, [0344]; Fig 7A). Figure 1B demonstrates that the CAR construct was a polynucleotide comprising a scFv, a CD8 hinge, a CD8 transmembrane domain, and a FcεRI γ intracellular signaling domain.
US’748 further teaches CAR constructs comprising a Dectin-1 intracellular signaling domain. The constructs were packaged into lentivirus and used to transduce THP-1 myeloid cells in a three-fold serial dilution of lentiviral titers (page 28, [0353]; Figure 10A). Figure 10A demonstrates that the CAR construct was a polynucleotide comprising a CD19 scFv binding domain, a CD8 hinge, either a Dectin TM or a CD8 TM, and a Dectin-1 intracellular signaling domain.
US’748 teaches that ‘lentivirus’ refers to a genus of the retroviridae family and can be used to deliver a significant amount of genetic information into the DNA of the host cell (page 11, [0174]), demonstrating that the polynucleotide was a DNA.
US’748 also experimentally 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]).
While US’748 does not experimentally demonstrate that the CAR is capable of activating dendritic cells in an immune suppressive tumor environment as claimed, the capability of the claimed product to activate dendritic cells in an immunosuppressive tumor environment is inherent to the structure of the product. See MPEP 2112.01 I and MPEP 2145 II.
Thus, US’748 anticipates the instant 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 79-85 and 92-101 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180244748 A1 (Gill, S., et al) 30 Aug 2018.
The teachings of US’748 are as discussed above.
US’748 further 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 (page 2, [0023]).
US’748 also exemplified CD19 CARs that comprises a Dectin-1 cytoplasmic domain (Figs. 10A-D) or CAR constructs with an FcεRI common γ subunit (page 27, [0344]) and 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 alternative intracellular signaling domains including CD86, CD40, TLR4, TNFR2, and CD36 (page 15, [0228]-[0229]).
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 and a source of phagocytic cells, such as monocytes, macrophages, or dendritic cells, is 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]).
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 arrive at the instantly claimed polynucleotide and methods based on the teachings of US’748 which teaches polynucleotides encoding CARs according to the instant claims as well as methods of producing engineered cells expressing the CARs, and methods of treatment comprising administration of pharmaceutical compositions comprising the CAR expressing cells. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
While US’748 does not experimentally demonstrate that the CAR is capable of activating dendritic cells in an immune suppressive tumor environment as claimed, the capability of the claimed product to activate dendritic cells in an immunosuppressive tumor environment is inherent to the structure of the product. See MPEP 2112.01 I and MPEP 2145 II. Furthermore, US’748 teaches that the disclosed CARs can improve specificity for tumor cells and improve infiltration into tumor sites in solid tumors where CAR T cells have been impaired due to poor trafficking, immunosuppressive tumor microenvironments, and expression of few tumor specific antigens on solid tumor cells, suggesting that the cells would be capable of activation in the immune suppressive tumor microenvironment.
Regarding claims 81-83, 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 domains based on the teachings of US’748 as a whole. 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.
As US’748 demonstrates CARs comprising cytoplasmic signaling domains of Dectin-1 and FcεRI γ, an ordinarily skilled artisan would reasonably recognize that the domains comprise functional forms of the cytoplasmic signaling domains, meeting the limitations of instant claims 82 and 83.
Claim 82 is rejected under 35 U.S.C. 103 as being unpatentable over US 20180244748 A1 (Gill, S., et al) 30 Aug 2018 as applied to claims 79 and 81 above, and in further view of US 2024/0261329 A1 (Wang, W. and Y. Wei) 08 Aug 2024, effective filing date 13 Feb 2020.
It is noted that claim 82 was rejected above under 35 USC 103 over US’748. The claim is further rejected here to demonstrate that a cytoplasmic domain comprising SEQ ID NO: 1 would have been obvious in view of the teachings of the prior art.
US’748 teaches the polynucleotide of claim 81 as discussed in detail above.
US’748, however, does not disclose that the intracellular sequence of dectin-1 comprises SEQ ID NO: 1.
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]).
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 substitute the dectin-1 in the polynucleotide disclosed by US’748 with the reverse dectin-1 sequence disclosed by US’329. One of ordinary skill in the art would have been motivated to make this substitution 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.
Claims 82 and 86-91 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180244748 A1 (Gill, S., et al) 30 Aug 2018 as applied to claims 79 and 81 above, and in further view of AU 2018/227593 B2 (Suri, V., et al) 07 Sept 2018.
It is noted that claim 82 was rejected above under 35 USC 103 over US’748. The claim is further rejected here to demonstrate that a cytoplasmic domain of FcγR comprising SEQ ID NO: 2 would have been obvious in view of the teachings of the prior art.
US’748 teaches the polynucleotide of claim 79 as discussed in detail above.
As discussed above, US’748 teaches that the CARs comprise a CD8 hinge and CD8 transmembrane domain.
US’748, however, does not teach that the CAR further comprises a signal peptide of CD8 alpha or the sequence thereof. Additionally, US’748 does not specifically disclose that the CD8 hinge and transmembrane domains are from CD8 alpha or the sequences thereof. US’748 also does not teach the that the FcγR cytoplasmic domain comprises an amino acid sequence of SEQ ID NO:2.
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 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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AU’593 further teaches that the intracellular signaling domain may be selected from a cell surface molecule including FcR gamma and also teaches co-stimulatory domains including CD40 (page 5, [0021]). Examples of ITAM containing cytoplasmic signaling sequences include those derived from FcR gamma, (page 55, [00213]). AU’593 further 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 modify the polynucleotide of US’748 to further include 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, and to use the FcεRI γ intracellular sequence disclosed by AU’593. 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 and 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, like US’748, AU’593 teaches CAR construction. Additionally, US’748 and AU’593 teach overlapping domains including CD8 hinge and transmembrane domains and FcεRI γ intracellular domains, demonstrating a further nexus among the art.
Claims 102, 104, and 105 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 Capasso, A., et al (2019) Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts Journal for ImmunoTherapy of cancer 7(37); 1-16.
The teachings of US’748 are as discussed above.
As discussed above, US’748 teaches cells possessing targeted effector activity, including monocytes, macrophages, or dendritic cells, expressing the CARs (page 13, [0211]; page 19, [0252]). US’748 also teaches that the intracellular signaling domain is responsible for activation of the cell in which the CAR is expressed (page 15, [0225]). US’748 further teaches that the endogenous immune system is typically non-reactive to malignant cells, or can be actively immunosuppressive with respect to the body’s reaction to the presence of malignant cells. One way to enhance treatment of tumors is to force tumor recognition by the immune system through engineered leukocytes. However, the immunosuppressive tumor microenvironment has potentially impaired the ability of T cells to infiltrate solid tumors (page 1, [0002]). US’748 teaches that 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 (abstract).
US’748 further teaches that the effector activity is selected from phagocytosis, targeted cellular cytotoxicity, antigen presentation, and cytokine secretion (page 31, claim 7). US’748 teaches that TCRs are complexes on the membrane of T cells that activate T cells in response to the presentation of an antigen. The TCR is responsible for recognizing antigens bound to MHC complex molecules. US’748 also teaches that cells comprising TCRs include T cells and NKT cells (pages 12-13, [0200]).
US’748 teaches in vivo assays for testing CAR transduced human macrophages (page 26, [0329]). In the studies, NSGS mice were used as human xenograft models. Mice were engrafted with CBG-luciferase positive human SKOV3 ovarian cancer cells and treated with either controls, without CAR transduction, or CAR transduced macrophages. Serial bioluminescent imaging was performed to monitor tumor burden. Organs and tumor were harvested upon sacrifice for FACS analysis. Overall survival was monitored and compared using Kaplan Meier analysis (page 26, [0329]). US’748 uses the models to determine that CAR monocytes and macrophages had activity in the first 24 hours compared to controls (page 28, [0361]).
US’748, however, does not exemplify the in vivo assay for testing dendritic cells or that the assays comprised mice with an immune suppressive tumor microenvironment as claimed.
Capasso teaches that conventional murine xenograft models have been hampered by their immune-compromised status and, thus, developed a hematopoietic humanized mouse model, hu-CB-BRGS, and used it to study anti-tumor human immune responses to triple negative breast cancer cell lines and patient derived colorectal cancer xenografts (abstract, background). BRGS pups were humanized through transplantation of cord blood (CB) derived CD34+ cells (abstract, method).
Capasso teaches that the testing of immunotherapies has been hampered by a lack of dynamic interactions between the tumor, tumor microenvironment (TME), and the immune system and an inability to investigate in vivo conditions that may influence the tumor-immune system interaction. Similarly, the use of syngeneic murine-derived cancer models in immune-competent mice presents significant limitations because of the inconsistencies between murine and human immune systems (HIS) and limit the repertoire of available syngeneic models. Thus, better in vivo preclinical models, which harbor a HIS and are capable of growing more diverse patient-derived human tumors, are needed to test immunotherapeutic approaches. Capasso teaches that the hematopoietic humanized mice are generated by intravenous injection of human CD34+ stem cells derived from umbilical cord blood (CB) into immunodeficient mice lacking T, B, and NK cells. These mice have been shown to accept and grow tumor cells from patient derived xenografts (page 2, left column, paragraph 2).
Capasso teaches that the T cells of hu-CB-BRGS express high levels of PD-1, suggesting an immunosuppressed, exhausted phenotype. This is validated by vigorous engraftment of non-HLA matched human tumors (page 2, paragraph bridging columns).
Capasso concludes that the studies disclosed provide evidence that the hu-CB-BRGS mice are suitable to study in vivo responses of human leukocytes to human tumors (page 12, right column, paragraph 1). The ability of the humanized mice to accept and support allogeneic tumor growth, non-HLA matched with the CB donor used to humanize the mouse, strongly suggests that the human immune system (HIS) in these mice is immunosuppressed, and thus may recapitulate some aspects of the TME. T cells in the humanized mice express high levels of PD-1, and treatment with anti-human PD-1 therapy resulted in tumor-specific responses. Therefore, the HIS is not capable of rejecting the tumor, but requires modulation to mount an effective immune response. Capasso discloses that this immunosuppressed nature of the HIS in these mice is a quality necessary for acceptance of the tumors and an important basis for the utility of this novel preclinical platform. In essence, these experiments measure the degree to which we alleviate this immunosuppression, which we quantify both by tumor growth measurements and changes in molecular readouts from the immune system and tumor.
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 evaluate the ability of the CAR to activate dendritic cells by using CAR engineered dendritic cells in place of the CAR engineered macrophages in the mouse models of US’748 and to detect markers for activation of the dendritic cells including infiltration into the tumor microenvironment compared to controls as well as T cell activation, including T cell and NKT cell activation, resulting from increased antigen presentation. It would have further been obvious to modify the NSGS mice used by US’748 to comprise humanized hematopoietic cells through the injection of human CD34+ stem cells as taught by Capasso.
It would have been obvious to one of ordinary skill in the art to evaluate dendritic cell activation using the in vivo mouse models of US’748 as US’748 teaches dendritic cells as alternative cells for engineering with the disclosed CARs. Additionally, US’748 teaches that the CAR cells disclosed can improve infiltration into tumor cites as well as antigen presentation, which leads to T cell and NKT cell activation, targeted cellular cytotoxicity, and cytokine secretion, demonstrating that these markers are valid for detecting the effectiveness of the CAR dendritic cell activation. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
One of ordinary skill in the art would have been motivated to modify the mice to include human hematopoietic cells through the injection of human CD34+ stem cells in order to evaluate the dynamic interactions between the tumor, tumor microenvironment (TME), and the immune system and to investigate in vivo conditions that may influence the tumor-immune system interaction. Additionally, Capasso teaches that the human immune system (HIS) in these mice is immunosuppressed, and thus may recapitulate some aspects of the tumor microenvironment. An ordinarily skilled artisan would have had a reasonable expectation of success as Capasso is teaching methods of improving in vivo evaluation of immunotherapeutics through the use of humanized hematopoietic systems in mice models and US’748 is testing immunotherapies in mouse models.
Claim 103 is rejected under 35 U.S.C. 103 as being unpatentable over US 20180244748 A1 (Gill, S., et al) 30 Aug 2018 in view of Capasso, A., et al (2019) Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts Journal for ImmunoTherapy of cancer 7(37); 1-16 as applied to claim 102 above, and in further view of Allen, T.M., et al (2019) Humanized immune system mouse models: progress, challenges and opportunities Nat Immunol 20(7); 770-774.
The combination of US’748 and Capasso teach the method of claim 102 as discussed in detail above.
As discussed in detail above, the combination teaches the injection of human hematopoietic stem cells in mouse models to develop a humanized immune system in the mice.
The combination of applied references, however, do not disclose the further inclusion of human fetal thymus in the non-human models.
Allen teaches that immunocompetent mice are widely used in biomedical research, and the use of such mice has supported many advances across multiple scientific disciplines. However, critical differences in the genetics and immune systems of mice and those of humans have precluded studies in mice of uniquely human immune responses. One way to address these species-specific differences is to conduct in vivo preclinical studies using immunodeficient mice engrafted with human cells or tissues – i.e., ‘humanized’ mice or ‘human immune system’ (HIS) mice. Engraftment of immunodeficient mice with PBMCs, HSCs or human fetal tissues from the thymus or liver, began in 1988 (page 2, paragraph 1).
Allen teaches that T cell education in the thymus is restricted largely by mouse MHC. The development of human MHC (HLA)-restricted T cells can be accomplished through the implantation of fetal human thymus and liver tissue along with autologous fetal liver HSCs (paragraph bridging pages 2-3). In Figure 1, Allen provides methods of humanizing mouse models, which include neonatal/fetal thymus fragments and HSCs (page 8).
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 mouse models in the method taught by the combination of US’748 and Capasso to further include human fetal thymus tissue as taught by Allen with the human CD34+ hematopoietic stem cells. An ordinarily skilled artisan would have been motivated to further include human fetal thymus tissue in order to further humanize the immune system of the mouse models and promote development of human MHC restricted T cells. An ordinarily skilled artisan would have particularly been motivated to make this modification as US’748 teaches that antigen presentation can be increased through the use of the disclosed CAR cells and that TCRs on T cells activate T cells in response to antigen presentation by MHC molecules. An ordinarily skilled artisan would have had a reasonable expectation of success as Allen and Capasso are teaching methods of improving in vivo evaluation of immunotherapeutics through the use of humanized hematopoietic systems in mice models and US’748 is testing immunotherapies in mouse models
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 79-94 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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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.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693