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 03/07/2023, is a continuation of PCT/CN2021/116950, filed 09/07/2021, and claims foreign priority to PCT/CN2020/114012, filed 09/08/2020.
Status of Claims/Application
The preliminary amendment of 08/18/2023 is acknowledged. Claims 1-132 are cancelled and claims 133-157 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/06/2024 and 01/17/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
It is noted that in the IDS of 03/06/2024 NPL reference 075 had author’s name listed as “Woodbridge”. The correct spelling of the author’s name is “Wooldbridge”. The IDS was annotated to correct the author’s name and the reference was considered.
Drawings
The drawings filed 08/18/2023 are objected to for the following informalities:
Fig 1D has domains of the CAR that are marked with lines making it difficult to read the text overlay (Dual scFv in Loop domains).
Figure 9 appears to have text that is obstructed by the arrows on the bottom of each row of plots.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The specification recites the following hyperlinks on page 94, [0354]:
http://crispr.mit.edu and http://www.synthego.com
Correction to remove the prefix is required.
Claim Objection
Claims 140, 142, and 153 are objected to for the following informalities: each of the claims recite duplicate antigens as follows:
Claim 140: line 6 recites “ErbB2/HER2” and “HER-2”; as well as “ErbB3” and “HER3”; line 8 recites “TGFBR1” twice;
Claim 142: line 6 recites “ErbB2/HER2” and “HER-2”; as well as “ErbB3” and “HER3”; line 8 recites “TGFBR1” twice; and
Claim 153: line 6 recites “ErbB2/HER2” and “ErbB3” and line 7 recites “HER-2” and “HER3”; lines 8-9 recites “TGFBR1” twice.
ErbB2 and ErbB3 are art recognized alternative names for HER2 and HER3, respectively. Therefore recitation of “ErbB2/HER2” and “HER-2” is a duplicate recitation and “ErbB3” and HER3” are also duplicate recitations.
Correction to remove duplicate recitations is suggested.
Claim 156 is objected to for the following informality: The claim depends on claim 155 and recites that the binding domains are arranged from amino to carboxyl terminus in the order of “VH1-VH2-VL2-VL1”. Claim 155, on which claim 156 depends, recites “VH1” and “VL1” as “VHCD7” and “VLCD7”, respectively. It is suggested that claim 156 be amended to have the nomenclature “VH CD7-VH2-VL2-VL CD7” for consistency with that used in claim 155.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 146 and 157 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Instant claims 146 and 157 depend on claims 133 and 153, respectively, and recite the functional limitation that the engineered immune cells claimed exhibit enhanced cytotoxicity against target cells compared to control immune cells that have the same antigen binding domains, the same CD8 hinge domain, the same costimulatory domain, and the same CD3ζ intracellular signaling domain, but comprise a CD8 transmembrane domain that does not comprise the amino acid of SEQ ID NO: 19.
Claim 146 depends on claim 133 which encompasses a CAR that binds to any first and any second antigen, comprises a CD8 hinge that comprises SEQ ID NO: 18, but has one or more amino acid modifications compared to SEQ ID NO: 17, a CD8 transmembrane domain of SEQ ID NO: 19, any costimulatory domain, and any CD3ζ intracellular signaling domain.
Claim 157 depends on claim 153 which encompasses a CAR that binds to CD7 and an additional antigen from those recited in instant claim 153, a CD8 hinge domain comprising SEQ ID NO: 18, a CD8 transmembrane domain comprising SEQ ID NO: 19, any costimulatory domain, and any CD3ζ intracellular signaling domain.
As such, the claims are drawn to a genus of CAR constructs that are expressed in immune cells that are limited by the functional limitations recited in instant claims 146 and 157. The disclosure, however, does not identify a representative number of CAR species within the claimed genus performing the claimed function, nor does the disclosure provide a structure-function relationship which would allow one of ordinary skill in the art to identify which CARs would have the claimed function.
MPEP 2173.05(g) states that “A claim term is functional when it recites a feature ‘by what it does rather than by what it is’” and that “Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph.
The instant disclosure describes the design of CD7 targeting CARs and CD7-CD19 dual CARs (page 92, Example 1). The CARs comprised native or extended CD8 hinge regions; native or extended CD7 transmembrane domains, native or truncated CD28 transmembrane domains, a 4-1BB costimulatory domain, and native or truncated CD3ζ intracellular signaling domains with an optional loss of function insertion in tandem (pages 91-92, Example 1). The structure of the CARs are disclosed in Figures 1A-D and in Table 1.
With regards to dual targeting CARs, the examples disclose CARs #15-21, all of which comprise CD7 and CD19 dual scFv (pages 92-93, Table 1). The CAR constructs are shown below for convenience:
PNG
media_image1.png
503
567
media_image1.png
Greyscale
CAR construct # 16, 17, 19, and 21 appear to be the only species of the claimed dual CARs tested in the instant disclosure.
Of these dual targeting CARs, # 15 and 16; 18 and 19; and 20 and 21 present comparisons between dual constructs where the only difference between the CARs is the length of the CD8 transmembrane domain. Specifically, CAR #s 16, 19, and 21 comprise the additional amino acids NHRN at the end of the transmembrane domain (SEQ ID NO: 19).
The examples discuss the killing activity of the CARs in [0375]-[0381]. Example 8, results shown in Fig. 6, studied killing activity against HeLa CD7+ or HeLa CD19+ cells demonstrate that CAR #s 16 and 17 displayed overall stronger killing activities compared to CAR #15 (page 96, [0376]). Example 9 tested killing activity of the CARs against CCRF and Nalm6 cells (page 96), the results of which are presented in Figures 7 and 10. Under some conditions, the CARs with the extended CD8 transmembrane domains (#s 16, 19, and 21) appear to have higher cytotoxicity against target cells than CARs that are the same but with a native CD8 transmembrane domain. The increase in cytotoxicity with an extended transmembrane domain, however, only occurs at specific E:T ratios and, in the examples provided, the extended transmembrane domain is only compared to a native transmembrane domain that is 4 amino acids shorter. The examples do not demonstrate the claimed function over the entire scope of the claim, which includes an increase in cytotoxicity compared to any other CD8 transmembrane domain. Particularly as the comparison encompasses a wide genus of transmembrane domains that could include, for example, a sequence that is one amino acid short of SEQ ID NO:19 or CD8 transmembrane domains that are the same length, or longer, but with amino acid modifications within the domain.
As such, dual CAR #s 16, 19, and 21 compared to dual CAR #s 15, 18, and 20, respectively, represent the species of the instantly claimed genus that applicant demonstrates as having the claimed structure and function and represent the species of the claimed genus that applicant was in possession of at the time of filing.
The disclosure does not demonstrate that these results would be achieved with any other dual targeting CARs of the claimed genus or compared to a CAR comprising any other CD8 transmembrane domain other than the native TM tested. The disclosure also does not provide a structure function correlation that would allow for an ordinarily skilled artisan to reasonably and predictably identify which species of the claimed genus would have the claimed function.
The prior art also does not provide a representative number of species of the claimed genus as to support the full scope of the claims or a structure-function relationship that would allow for the predictable identification of which dual CAR species would result in the claimed function.
For instance, Ramos, C.A., et al (2016) CAR-T cell therapy for lymphoma Annu. Rev. Med. 67; 165-183 teaches that, to date, all CARs in use for lymphoma have been based on scFvs, whose effectiveness depends in part on the affinity of the CAR itself and on the properties of the antigenic epitope recognized. For instance CARs containing high-affinity scFvs for ROR1 confer greater effector function to T cells than those containing low-affinity scFvs. However, the location of the recognized epitope on the antigen also affects CAR functions. For example, T cells expressing a CAR with an scFv that recognizes a membrane proximal epitope on CD22 have greater antileukemic activity than a CAR-T recognizing a distant epitope. Other components of the ectodomain may also influence the CAR effectiveness, such as the presence of a flexible linker sequences in the scFv and the type of elements connecting the ecto-to the endodomains, specifically the hinge and transmembrane regions. The hinge and transmembrane regions can affect the CAR-T cell profoundly by modifying the length and flexibility of the resulting CAR, its cell surface density, its tendency to self-aggregate and produce T cell exhaustion by tonic signaling, and its potential binding to molecules other than the intended target antigen (pages 167-168, Design of CAR ectodomains). Upon antigen recognition, CAR endodomains transmit activation and costimulatory signals to T cells. T cell activation relies on the phosphorylation of ITAMs present in the cytoplasmic CD3ζ domain of the TCR complex. T cells further require costimulation for sustained growth and function, as TCR stimulation without costimulation induces T cell anergy (page 169, Design of CAR endodomains). Although costimulatory signals from CD28 seemed to improve expansion and persistence, a trial using second-generation CAR incorporating 41BB as an alternative costimulatory domain reported the most dramatic expansion and clinical activity in indolent B cell malignancies CD28 costimulation is usually provided physiologically by professional antigen-presenting cells and represents an “early” costimulatory signal, but “late” costimulatory molecules, including members of the TNF family such as OX40 and 41BB also play crucial roles (page 172, Late-acting costimulatory domains may be more efficacious than CD28).
The teachings of Ramos demonstrate that all of the parts of the CAR contribute to the cytotoxicity of the CAR through their interaction with each other and also in their resulting length and flexibility. The teachings suggest that the cytotoxicity of each CAR depends on all domains including the specific binding domains, any linkers in the binding domains, the hinge and transmembrane regions, the costimulatory region and the intracellular signaling domains. From the teachings of Ramos it is not clear that the use of a CD8 transmembrane domain of SEQ ID NO: 19 in any dual targeting CAR within the genus of the instantly claimed invention would predictably have higher cytotoxicity compared to a CAR with all of the same domains but not comprising a CD8 transmembrane domain of SEQ ID NO: 19.
The instant disclosure and the prior art do not provide a representative number of species of the claimed genus performing the claimed function nor do they provide a structure-function correlation that would allow an ordinarily skilled artisan to predictably identify which dual CARs within the claimed genus would perform the function claimed in instant claims 146 and 157. Therefore, the instant claims do not meet the written description requirements of 35 USC 112(a).
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 133-136, 140, and 142-143 are rejected under 35 U.S.C. 103 as being unpatentable over US 9,447,194 B2 (Jensen, M.) 20 Sept 2016 in view of CN 105949325 A (Cheng, Q., et al) 21 Sept 2016.
US’194 teaches bispecific chimeric antigen receptors comprising: (a) at least two antigen-specific targeting regions; (b) an extracellular spacer domain; (c) a transmembrane domain; (d) at least one co-stimulatory domain; and (e) an intracellular signaling domain, wherein each antigen-specific targeting region comprises an antigen specific single chain Fv (scFv) fragment and binds a different antigen (abstract). US’194 teaches that chimeric antigen receptors are engineered receptors which graft an immune specificity onto a genetically engineered cell. By housing specificities to multiple antigens in a single CAR, various benefits may be achieved, including, among others, a significant reduction in effort as compared to making multiple T cell products per patient (col. 3, lines 60-67). US’194 further teaches that the bispecific CARs may overcome conventional therapeutic failures due to, for example, outgrowth of antigen loss escape variants that can arise in the course of various therapies when a single antigen is targeted (col. 9, lines 44-58).
US’194 further teaches genetically engineered cells which comprise and stably express the CARs disclosed (col. 20, lines 56-58). US’194 teaches that cell types that maybe used to generate genetically modified cells expressing the bispecific CAR include, but are not limited to, T lymphocytes (T-cells), natural killer cells, hematopoietic stem cells, and/or pluripotent embryonic/induced stem cells capable of giving rise to therapeutically relevant progeny (col. 22, lines 34-39), teachings which meet the instant limitation of immune cells.
US’194 further teaches an embodiment in which the bispecific antigen receptor comprises: a. at least two antigen-specific targeting regions; b. a CD8α hinge extracellular domain; c. a CD8α transmembrane domain; d. a 4-1BB co-stimulatory domain; and e. a CD3 zeta intracellular signaling domain, wherein each antigen specific targeting region comprises an antigen-specific scFv and binds a different antigen (col. 94, claim 26).
US’194 exemplifies a bispecific CAR specific for CD19 and CD20, which comprises single chain Fv fragments specific for CD19 and CD20 linked by a Gly4Ser linker, a CD8α hinge extracellular domain, a CD8α transmembrane domain, a 41BB costimulatory domain, and the cytoplasmic domain from CD3 zeta chain (col 18, line 62 – col 19, line 2; Figs 11-12). US’194 teaches the nucleic acid and amino acid sequence for the CD19-CD20 CAR in SEQ ID NOs: 11 and 12, respectively.
The CAR of SEQ ID NO: 12 comprises a hinge matching instant SEQ ID NO: 18 as shown in the ABSS alignment below:
PNG
media_image2.png
110
583
media_image2.png
Greyscale
The hinge also comprises a plurality of amino acid deletions compared to SEQ ID NO: 17 as shown in the alignment below, which shows that US’194, SEQ ID NO: 12 does not comprise the first 8 amino acids of SEQ ID NO: 17:
PNG
media_image3.png
107
579
media_image3.png
Greyscale
US’194 further teaches that the antigen-specific targeting regions of the CAR can target antigens specific for cancer and further teaches the following as alternative antigen targets: 4-1BB, 5T4, adenocarcinoma antigen, alpha-fetoprotein, BAFF, B-lymphoma cell, C242 antigen, CA-125, carbonic anhydrase 9 (CA-IX), C-MET, CCR4, CD152, CD19, CD20, CD200, CD22, CD221, CD23 (IgE receptor), CD28, CD30 (TNFRSF8), CD33, CD4, CD40, CD44 v6, CD51, CD52, CD56, CD74, CDS0, CEA, CNTO888, CTLA-4, DR5, EGFR, EpCAM, CD3, FAP, fibronectin extra domain-B, folate receptor 1, GD2, GD3 ganglioside, glycoprotein 75, GPNMB, HER2/neu, HGF, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgGl, LI-CAM, IL-13, IL-6, insulin-like growth factor I receptor, integrin a5β1, integrin avβ3, MORAb-009, MS4A1, MUC1, mucin CanAg, N-glycolylneuraminic acid, NPC-1C, PDGF-Ra, PDL1 92, phos-phatidylserine, prostatic carcinoma cells, RANKL, RON, ROR1, SCH900105, SDC1, SLAMF7, TAG-72, tenascin C, TGF beta 2, TGF-β, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGFR-1, VEGFR2 or vimentin (col. 13, lines 9-49).
US’194 also teaches alternative costimulatory domains, teaching that the costimulatory domain refers to the portion of the CAR which enhances the proliferation, survival, and/or development of memory cells. The CARs may comprise one or more co-stimulatory domains. Each co-stimulatory domain comprises the costimulatory domain of one or more of, for example, members of the TNFR superfamily, CD28, CD137 (4-1BB), CD134 (OX40), Dap10, CD27, CD2, CD5, ICAM-1, LFA-1 (CD11a/CD18), Lck, TNFR-I, TNFR-II, Fas, CD30, CD40, or combinations thereof (col. 4, lines 44-56).
While US’194 teaches that the transmembrane domain is from CD8α, US’194 does not teach that the transmembrane domain comprises SEQ ID NO: 19.
CN’325 teaches chimeric antigen receptors composed of an antigen recognition domain, a hinge region, a transmembrane region and an intracellular signaling domain connected in sequence. The intracellular signaling domain is usually the CD3ζ chain or FcRγ, or is connected to one or more co-stimulatory molecules, such as 4-1BB, CD28, and ICOS. When the antigen receptor on the surface of a tumor cell binds to the antibody (ligand) of the CAR, the signal is transmitted to the cell through the hinge and transmembrane regions. The intracellular signaling domain converts the signal into an activation signal, activating the effector cells. The effector cells proliferate and produce cytokines thereby killing the tumor cells (page 3, [0005]).
CN’325 teaches a CD8a transmembrane domain of SEQ ID NO: 10 (page 8, [0017]; sequence on pdf pg 65). SEQ ID NO: 10 of CN’325 is identical to instantly claimed SEQ ID NO: 19 as shown in the ABSS alignment below:
PNG
media_image4.png
113
585
media_image4.png
Greyscale
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 bispecific CAR in the immune cell taught by US’194 by substituting the CD8α transmembrane domain in the CAR with the CD8α transmembrane domain of CN’325, SEQ ID NO: 10. An ordinarily skilled artisan would have been able to make this substitution and the results would have been predictable as CN’325 is teaching an alternative sequence for the CD8α transmembrane domain for use in CAR production suggesting analogous properties. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 137-139 are rejected under 35 U.S.C. 103 as being unpatentable over US 9,447,194 B2 (Jensen, M.) 20 Sept 2016 in view of CN 105949325 A (Cheng, Q., et al) 21 Sept 2016 as applied to claim 133 above, and in further view of WO 2012/079000 A1 (June, C.H., et al) 14 June 2012.
The combination of US’194 and CN’325 teach the engineered immune cell of claim 133 as discussed in detail above.
While the combination of US’194 and CN’325 teaches that the intracellular signaling domain is CD3ζ, the combination of US’194 and CN’325 does not teach that the CD3ζ intracellular signaling domain comprises SEQ ID NOs: 15 or 45 as recited in claim 137. The combination of US’194 and CN’325 also does not teach that the CD3ζ intracellular signaling domain is truncated or comprises at least one insertion to reduce signaling activity as recited in claims 138-139.
WO’000 teaches compositions and methods for treating cancer in a human comprising administering a genetically modified T cell to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain (abstract). WO’000 teaches that the CAR binds a tumor antigen, including CD19, CD20, CD22, ROR1, mesothelin, CD33/IR13Ra, c-met PSMA, Glycolipid F77, EGFRvIII, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, and any combination thereof; and that the costimulatory molecule may be selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, LFA-1, CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof (page 2, lines 14-25).
WO’000 teaches that the CD3 zeta signaling domain comprises the sequence of SEQ ID NO: 24 (page 2, lines 1-6). WO’000, SEQ ID NO: 24 is identical to instant SEQ ID NO: 15 as shown in the ABSS alignment below:
PNG
media_image5.png
174
585
media_image5.png
Greyscale
WO’000 further teaches that, while usually the entire intracellular signaling domain can be employed, in many cases it is not necessary to include the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces effector function. The term “intracellular signaling domain” is thus meant to include any truncated portion of the intracellular signaling domain sufficient to transduce the effector function signal (page 31, lines 19-33).
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 CD3ζ intracellular signaling domain in the CAR disclosed by the combination of US’194 and CN’325 with the CD3ζ intracellular signaling domain sequence disclosed by WO’000. It would have also been obvious to use a truncated intracellular signaling domain based on the teachings of WO’000. One of ordinary skill in the art would have been able to make this substitution and the substitution would have led to predictable results as US’194 teaches the inclusion of a CD3ζ intracellular signaling domain in the bispecific CAR and WO’000 is teaching an alternative amino acid sequence for a CD3ζ intracellular signaling and teaches the use of the sequence in CAR constructs. It would have been obvious to use a truncated CD3ζ intracellular signaling domain as WO’000 teaches that truncated intracellular signaling domains can be used so long as it is sufficient to transduce effector function signal.
Regarding claim 139, neither claims 139 nor 138 require that the CD3ζ intracellular signaling domain have at least one insertion to reduce signaling activity of the CD3ζ intracellular signaling domain. The combination of US’194, CN’325, and WO’000 teach the alternative limitation in claim 138 of a truncated CD3ζ intracellular signaling domain, meeting the limitations of both claims 138 and 139.
Claims 140 and 141 are rejected under 35 U.S.C. 103 as being unpatentable over US 9,447,194 B2 (Jensen, M.) 20 Sept 2016 in view of CN 105949325 A (Cheng, Q., et al) 21 Sept 2016 as applied to claim 133 above, and in further view of US 2019/0144522 A1 16 May 2019.
The combination of US’194 and CN’325 teach the engineered immune cell of claim 133 as discussed in detail above.
US’194 further teaches methods for treating a disease associated with antigens targeted by the CAR in a subject in need thereof (col. 23, lines 10-21). US’194 teaches that the CARs can be used to treat cancers including chronic lymphocytic leukemia, Hodgkin’s lymphomas, and non-Hodgkin’s lymphomas (col. 6, lines 9-29). US’194 further teaches that the antigen targets can include antigens expressed on immune cells (col. 7, lines 14-26).
The combination of US’194 and CN’325, however, does not disclose that one of the antigen binding domains of the bispecific CAR binds to CD7.
US’522 teaches nucleic acid constructs and mammalian cells harboring nucleic acids that encode anti-CD7 chimeric antigen receptors and methods of treating cancers, particularly hematological cancers, using the CARs described (abstract). US’522 teaches that patients having B-cell malignancies, including chronic lymphocytic leukemia (CLL) have few treatment options. One approach is treatment with genetically modified T cells that target antigens expressed on tumor cells through the expression of chimeric antigen receptors (CARs) (page 1, [0002]). In most cancers, tumor specific antigens are not yet well defined. However, expression of CD7 has been linked to epigenetic modifications in chronic myeloid leukemia and has been shown to be overexpressed in classical Hodgkin lymphoma-infiltrating T lymphocytes. In addition, CD7 expression has been associated with low remission rates and biological aggressiveness in a significant proportion of acute leukemias (page 1, [0003]). US’522 teaches that the anti-CD7 CARs of the invention can be used to treat hematological cancers including chronic lymphocytic leukemia, Hodgkin’s disease and non-Hodgkin’s lymphoma (page 7, [0054]-[0056]).
US’522 teaches T cells genetically modified to express a CAR and teaches that the anti-tumor immunity response elicited by the CAR modified T cells may be an active or passive response (page 7, [0055]).
US’522 teaches that the CARs comprise an anti-CD7 binding domain, which is an antibody or an antigen binding fragment thereof including an scFv, a transmembrane domain, and a cytoplastic domain. US’522 further teaches that the mammalian cell is a T cell, NK cell, cytotoxic T lymphocyte, or a regulatory T cells, all of which are immune cells (page 1, [0004]).
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 bispecific CAR taught by the combination of US’194 and CN’325 to have at least one of the binding domains bind to CD7 as taught by US’522. It would have been obvious to use a CD7 binding domain as US’522 teaches that it is a cancer associated antigen and also demonstrates the use of anti-CD7 binding domains in CAR constructs. An ordinarily skilled artisan would have had a reasonable expectation of success as US’522 teaches that the anti-CD7 CAR can be used to treat cancers including CLL, non-Hodgkin’s lymphoma, and Hodgkin’s lymphoma, all of which overlap with the cancers disclosed by US’194 as being treatable with the disclosed bispecific CARs.
Claims 144-145 are rejected under 35 U.S.C. 103 as being unpatentable over US 9,447,194 B2 (Jensen, M.) 20 Sept 2016 in view of CN 105949325 A (Cheng, Q., et al) 21 Sept 2016 as applied to claim 133 above, and in further view of CN 108285486 A (Huashun, L) 17 July 2018.
The combination of US’194 and CN’325 teach the engineered immune cell of claim 133 as discussed in detail above.
US’194 teaches a bispecific CAR where, from N to C terminus, the construct comprises an anti-CD19 VL- anti-CD19 VH- anti-CD20 VL- anti-CD20 VH (Figure 2, sheet 2/22).
The combination of applied references, however, does not disclose that the first and second antigen binding domains are arranged from amino to carboxyl terminus in one of the patterns recited in claims 144 or 145.
CN’486 teaches that chimeric antigen receptor modified immune cells use genetic engineering to modify immune cells to express exogenous antitumor genes. The CAR gene mainly includes an extracellular recognition domain and an intracellular signaling domain. The former is used to recognize tumor surface-specific molecules and the latter is used to initiate immune cell responses after recognizing tumor surface molecules and exert cytotoxic effects, and CARs mainly use T cells as carriers (page 2, [0006]). CN’486 also teaches that NK cells can express CAR molecules (page 3, [0008]-[0010]).
CN’486 teaches the structure of a chimeric antigen receptor comprising scFv1-scFv2-CD8-41BB-CD3ζ which can specifically recognize CD20 (page 5, [0029]; Figure 1, page 65 of pdf).
CN’486 teaches an anti-CD20 binding fragment comprising a VH1, VL1, VH2, and VL2 chain (page 3, [0011]) and teaches that the structure can comprise VH1-VL1-VH2-VL2; VH1-VH2-VL2-VL1; VH1-VL2-VL1-VH2; VL1-VH1-VH2-VL2; VL1-VL2-VH1-VH2; VH2-VH1-VL1-VL2; VH2-VL1-VH1-VL2; VH2-VL2-VH1-VL1; VL2-VH1-VL1-VH2; VL2-VL1-VH1-VH2; or VL2-VH2-VH1-VL1 (page 4, [0019]-[0020]). CN’486, Figure 1 on pdf page 65 demonstrates that the scFv of the CAR are in order from the amino terminus to the carboxyl terminus. Additionally, as CN’486 teaches two scFv in the CAR structures, an ordinarily skilled artisan would reasonably recognize that VH1 and VL1 are the heavy and light variable regions of the first scFv, respectively, and VH2 and VL2 are the heavy and light variable regions of the second scFv, respectively.
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 pattern of the scFvs in the bispecific CAR taught by the combination of US’194 and CN’325 to include one of the patterns taught by CN’486, including a pattern of VH1-VH2-VL2-VL1. It would have been obvious to use one of the binding domain patterns taught by CN’486 as CN’486 establishes the patterns as alternatives to the VH1-VL1-VH2-VL2 pattern disclosed in the CAR taught by the combination of US’194 and CN’325 thereby providing a reasonable expectation of success.
Claims 147-149 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0144522 A1 16 May 2019 in view of CN 105949325 A (Cheng, Q., et al) 21 Sept 2016.
The teachings of US’522 are as discussed above.
As discussed above, US’522 teaches an engineered mammalian cell modified to express a CAR having an antigen binding domain that specifically binds to CD7. US’522 also teaches that the mammalian cell is a T cell, NK cell, cytotoxic T lymphocyte, or a regulatory T cells, all of which are immune cells. US’522 also teaches that the CAR comprises an anti-CD7 binding domain, a transmembrane domain, a costimulatory signaling domain and a CD3 signaling domain (abstract; page 1, [0004]).
US’522 teaches that the transmembrane domain may be derived from, i.e. comprise at least the transmembrane region of a group including CD8 (page 2, [0014]).
US’522 further teaches that the cytoplasmic domain includes a costimulatory domain and a CD3 signaling domain. The costimulatory signaling domain is the intracellular signaling domain of a costimulatory molecule selected from the group consisting of CD2, CD4, CD5, CD8α, CD8β, CD27, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, LFA-1, LIGHT, NKG2C, B7-H2, and a ligand that specifically binds with CD83, and any combination thereof.
US’522 teaches an anti-CD7 CAR with an amino acid sequence of SEQ ID NO: 2 (page 2, [0012]). The amino acid sequence of US’522 SEQ ID NO: 2 comprises a sequence that is identical to the instantly claimed CD8 hinge of SEQ ID NO: 18 as shown in the ABSS alignment below, further indicating a CD8 hinge in the anti-CD7 CAR of US’522.
PNG
media_image6.png
114
584
media_image6.png
Greyscale
US’522 further teaches that that in a preferred embodiment the CAR is designed to include the CD3ζ signaling domain by itself or in combination with any other desired cytoplasmic domain(s) useful in the context of the CAR. For example, the cytoplasmic domain of the CAR can include a CD3ζ chain portion and a co-stimulatory region. In one embodiment, the cytoplasmic domain is designed to include the signaling domain of CD3ζ and the signaling domain of 4-1BB. US’522 further teaches that the CAR of SEQ ID NO: 2 comprises CD3ζ and 4-1BB signaling domains (page 3, [0019]).
US’522, however, does not disclose that the CD8 transmembrane domain comprises an amino acid sequence of instant SEQ ID NO: 19.
The teachings of CN’325 are as discussed in detail above.
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 anti-CD7 CAR in the immune cell taught by US’522 by using the CD8α transmembrane domain of CN’325, SEQ ID NO: 10 as the transmembrane domain. An ordinarily skilled artisan would have been able to make this substitution and the results would have been predictable as CN’325 is teaching an alternative sequence for a CD8 transmembrane domain for use in CAR production and US’522 teaches that the transmembrane domain can be from CD8. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 150-152 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0144522 A1 16 May 2019 in view of CN 105949325 A (Cheng, Q., et al) 21 Sept 2016 as applied to claim 147 above, and in further view of WO 2012/079000 A1 (June, C.H., et al) 14 June 2012.
The combination of US’522 and CN’325 teach the engineered immune cell of claim 147 as discussed in detail above.
In the CAR of US’522, however, in the CAR disclosed by US’522, SEQ ID NO: 2, the CD3ζ intracellular signaling domain has a single conservative amino acid difference compared to instant SEQ ID NO: 15 as shown in the ABSS alignment below:
PNG
media_image7.png
174
579
media_image7.png
Greyscale
US’522 does not disclose that the CAR comprises a CD3ζ intracellular signaling domain of instant SEQ ID NOs: 15 or 45.
The teachings of WO’000 are as discussed above.
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 CD3ζ intracellular signaling domain in the CAR disclosed by the combination of US’522 and CN’325 with the CD3ζ intracellular signaling domain sequence disclosed by WO’000. It would have also been obvious to use a truncated intracellular signaling domain based on the teachings of WO’000. One of ordinary skill in the art would have been able to make this substitution and the substitution would have led to predictable results as US’522 teaches the inclusion of a CD3ζ intracellular signaling domain in the anti-CD7 CAR and WO’000 is teaching an alternative amino acid sequence for a CD3ζ intracellular signaling domain and teaches the use of the sequence in CAR constructs. It would have been obvious to use a truncated CD3ζ intracellular signaling domain as WO’000 teaches that truncated intracellular signaling domains can be used so long as it is sufficient to transduce effector function signal.
Regarding claim 152, neither claims 151 nor 152 require that the CD3ζ intracellular signaling domain have at least one insertion to reduce signaling activity of the CD3ζ intracellular signaling domain. The combination of US’194, CN’325, and WO’000 teach the alternative limitation in claim 151 of a truncated CD3ζ intracellular signaling domain, meeting the limitations of both claims 151 and 152.
Claim 153 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0144522 A1 16 May 2019 in view of CN 105949325 A (Cheng, Q., et al) 21 Sept 2016 as applied to claim 147 above, and in further view of US 9,447,194 B2 (Jensen, M.) 20 Sept 2016.
The combination of US’522 and CN’325 teach the engineered immune cell of claim 147 as discussed in detail above.
The combination of US’522 and CN’325, however, does not disclose that the CAR comprises an additional antigen binding domain that binds an antigen selected from those recited in instant claim 153.
The teachings of US’194 are as discussed in detail above.
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 anti-CD7 CAR of US’522 to further include an additional antigen binding domain as taught by US’194, including an antigen binding domain that binds to an antigen disclosed by US’194. An ordinarily skilled artisan would have been motivated to include an additional binding domain as US’194 teaches that bispecific CARs overcome failures in conventional therapies, for example, outgrowth of antigen loss escape variants that can arise in the course of therapies when a single antigen is targeted. An ordinarily skilled artisan would have had a reasonable expectation of success because US’522 teaches that the anti-CD7 CAR can be used to treat cancers including CLL, non-Hodgkin’s lymphoma, and Hodgkin’s lymphoma, all of which overlap with the cancers disclosed by US’194 as being treatable with the bispecific CARs targeting the disclosed antigens.
Claims 153 and 154 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0144522 A1 16 May 2019 in view of CN 105949325 A (Cheng, Q., et al) 21 Sept 2016 as applied to claim 147 above, and in further view of US 9,447,194 B2 (Jensen, M.) 20 Sept 2016 and US 10,221,245 B2 (Brogdon, J., et al) 5 Mar 2019.
The combination of US’522 and CN’325 teach the immune cell of claim 147 as discussed in detail above.
As discussed above, US’522 teaches that the anti-CD7 CAR can be used in the treatment of CLL and non-Hodgkin lymphomas.
US’522 further teaches that the cancers that can be treated include acute lymphoid leukemia, chronic myelogenous leukemia, multiple myeloma, myelodysplastic syndrome, hairy cell leukemia, and myelodysplasia (page 7, [0056]).
The combination of US’522 and CN’325, however, does not disclose that the CAR further comprises an additional antigen binding domain or that the additional antigen binding domain binds to CD19.
The teachings of US’194 are as discussed above.
US’245 teaches methods for treating diseases associated with expression of CD19 using chimeric antigen receptors specific to CD19, vectors encoding the same, and recombinant T cells comprising the CD19 targeting CARs. US’245 also teaches methods of administering modified T cell expressing CARs that comprise a CD19 binding domain (abstract)
US’245 teaches methods of treating a mammal having a disease associated with expression of CD19 comprising administering to the mammal an effective amount of cells comprising a CAR molecule. The disease associated with CD19 expression is selected from a proliferative disease, such as a cancer, including acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, multiple myeloma, myelodysplasia, myelodysplastic syndrome, and non-Hodgkin’s lymphoma (col. 12, lines 39-67).
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 anti-CD7 CAR taught by the combination of US’522 and CN’325 to further include an additional antigen binding domain as taught by US’194, and to specifically include a second antigen binding domain that binds to CD19 based on the teachings of US’245. An ordinarily skilled artisan would have been motivated to include an additional binding domain as US’194 teaches that bispecific CARs overcome failures in conventional therapies, for example, outgrowth of antigen loss escape variants that can arise in the course of therapies when a single antigen is targeted. An ordinarily skilled artisan would have been motivated to specifically use a second antigen binding domain that binds CD19 as US’245 teaches that anti-CD19 CARs can be used to target diseases that overlap with those of the anti-CD7 CAR of US’522. An ordinarily skilled artisan would have had a reasonable expectation of success as all of US’522, CN’325, US’194, and US’245 are teaching CAR constructs and their use in treating cancer.
Claims 155-156 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0144522 A1 16 May 2019 in view of CN 105949325 A (Cheng, Q., et al) 21 Sept 2016 and US 9,447,194 B2 (Jensen, M.) 20 Sept 2016 as applied to claim 153 above, and in further view of CN 108285486 A (Huashun, L) 17 July 2018.
The combination of US’522, CN’325, and US’194 teach the immune cell of claim 153 as discussed in detail above.
As discussed above, US’194 teaches a bispecific CAR where, from N to C terminus, the construct comprises an anti-CD19 VL- anti-CD19 VH- anti-CD20 VL- anti-CD20 VH (Figure 2, sheet 2/22).
The combination of applied references, however, does not disclose that the first and second antigen binding domains are arranged from amino to carboxyl terminus in one of the patterns recited in claims 155 or 156.
The teachings of CN’486 are as discussed in detail above.
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 pattern of the scFvs in the bispecific CAR taught by the combination of US’522, CN’325, and US’194 to include one of the patterns taught by CN’486, including a pattern of VH1-VH2-VL2-VL1. It would have been obvious to use one of the binding domain patterns taught by CN’486 as CN’486 establishes the patterns as alternatives to the VH1-VL1-VH2-VL2 pattern disclosed in the CAR taught by the combination of US’522, CN’325, and US’194 thereby providing a reasonable expectation of success.
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 12,454,564
Claims 133-157 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. US 12,454,564 in view of US 9,447,194 B2 (Jensen, M.) 20 Sept 2016, CN 105949325 A (Cheng, Q., et al) 21 Sept 2016, and WO 2012/079000 A1 (June, C.H., et al) 14 June 2012.
US’564 claims a method for treating cancer in a human subject while reducing host versus graft rejection by an innate T cell or NK cell in the human subject, the method comprising administering an engineered cytotoxic T cell to the human subject, wherein the engineered cytotoxic T cell comprises one or more CAR receptors comprising a first binding domain specific to CD7 comprising a scFv and a second antigen binding moiety exhibiting specific binding to CD18 compri