Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application, 18/255,808 filed on 06/02/2023, is a 371 of PCT/CN2021/135151 filed on 12/02/2021 and claims priority to CN202011482080.0 filed on 12/15/2020 and CN202011399860.9 filed on 12/02/2020. The instant application will be examined with an effective priority date of 12/02/2020.
Status of the Application/Claims
The instant application, 18/256,326 filed on 06/07/2023 is a 371 of PCT/US2021/062251 filed on 12/07/2021, of US Provisional Application 63/122,442 filed on 12/07/2020. The instant application will be examined with an effective filing date of 12/07/2020.
Claims 11-13, 20-32, 35 and 37-53 are canceled, claims 4-10 and 15-18 are currently amended, claim 54 is new, and claims 1-10, 14-19, 33-34, 36 and 54 are pending and under examination on the merit herein.
Information Disclosure Statement
The information disclosure statements (IDS)s submitted on 06/07/2023, 10/27/2023 are acknowledged and is in compliances with the provisions of CFR 1.97. It has been considered by the examiner.
Claim Objections
Claim 8 is objected to because of the following informalities: Claim 8 line 3 recites “… CD3ζ (1Δ), (SEQ ID NO: 7) FcεR1γ (SEQ ID NO: 8) …”, it is unclear if SEQ ID NO: 7 is CD3ζ (1Δ). For purposes to advance examination, Examiner will interpret the recited limitation to mean, CD3ζ (1Δ) is SEQ ID NO: 7 and FcεR1γ is SEQ ID NO: 8. Appropriate correction is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5, 9, 17-18, 33-34, are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Altvater et al. 2B4 (CD244) Signaling by Recombinant Antigen-specific Chimeric Receptors Costimulates Natural Killer Cell Activation to Leukemia and Neuroblastoma Cells. Clin Cancer Res 1 August 2009; 15 (15): 4857–4866, herein further referred to as Altvater.
Regarding claim 1, Altvater teaches of engineered NK cells expressing chimeric antigen receptors (Altvater pg. Abstract) (CARs) comprising a transmembrane domain and a cytoplasmic domain (Altvater pg. 4858 col. 2 para 2).
Regarding claims 2 and 3, and further incorporating the analysis of claim 1 above, Altvater further teaches that the engineered cells are natural killer (NK) cells (Altvater pg. 4859 col. 2 para. 3).
Regarding claim 4, and further incorporating the analysis of claim 1 above, Altvater further teaches that the signaling lymphocyte activation molecule-related receptor 2B4 (CD244) which is used in the construct comprises signaling domain, stimulating and co-stimulating domains (Altvater pg. 4858 col. 1 para. 2).
Regarding claim 5, and further incorporating the analysis of claim 1 above, Altvater further teaches an engineered cell comprising a CAR construct (NK-CAR4) comprising an, a 2B4 signaling domain comprising ITAMS (Altvater pg. 4860 col. 2 para. 2 and Fig. 2).
Regarding claim 9, and further incorporating the analysis of claim 1 above, Altvater further teaches engineered cell comprising CAR constructs comprised internal ribosome entry site (IRES) domain, wherein the CARs where subcloned into Agel and Notl sites of the viral vector SFG-IRES-GFP (Altvater pg. 4858 col. 2 para. 2).
Regarding claim 33, Altvater teaches chimeric antigen receptors (CARs) (Altvater pg. Abstract) comprising a transmembrane domain and a cytoplasmic domain (Altvater pg. 4858 col. 2 para 2).
Regarding claims 34, and further incorporating the analysis of claim 33 above, Altvater further teaches a CAR such as 2B4ζ, t2B4ζ comprising a signaling domain (Altvater pg. 4860 col. 2 para 2 and Fig. 2).
Claims 19, 33-34, and 54 are rejected under 35 U.S.C. 102(a)(1) as being anticipated Klob et al. Optimization of Human NK Cell Manufacturing: Fully Automated Separation, Improved Ex Vivo Expansion Using IL-21 with Autologous Feeder Cells, and Generation of Anti-CD123-CAR-Expressing Effector Cells. Hum Gene Ther. 2017 Oct;28(10):897-913, herein further referred to as Klob.
Regarding claim 19, Klob teaches of isolated NK cells comprising a CAR comprising anti-CD123 (Klob Abstract) linked to a transmembrane domain and one or more intracellular domains (Klob pg. 889 col 1 para. 3).
Regarding claim 33-34 and 54, Klob teaches a CAR construct comprising anti-CD123 (Klob Abstract) linked to a CD28 transmembrane domain, CD28 and 4-1BB co-stimulatory signaling endodomain and the CD3ζ signaling domain (Klob pg. 889 col 1 para. 3).
Claim 10 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by CARs: Beyond T Cells and T Cell-Derived Signaling Domains. Int J Mol Sci. 2020 May 15;21(10):3525, herein further referred to as Sievers.
Regarding claim 10, Sievers teaches various CAR design including a fourth generation safety CAR wherein the CAR comprises a transmembrane domain and/or an intracellular domain and a cytokine (IL-15) with a structure of scFv-CD28/CD3z-IL-15+iC9 as well as the fourth generation trucks (Sievers Fig. 1 and Tab. 1).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 6-8, 15-18 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Altvater as applied to claims 1 and 33 above, and further in view of US Patent 10918665 (US 2018/0360880) and UniProt Retrieved from <www.uniprot.org/uniprotkb/Q9BZW8/entry> on 04/23/2023, herein further referred to as Brentjens and UniProt respectively.
Regarding claim 6-8 and 36, and incorporating the analysis of claims 1 and 33 above, Altvater teaches CAR constructs comprising 2B4, t2B4, 2B4ζ, and t2B4ζ, wherein 2B4 comprises the hinge, transmembrane and intracellular region or domains (Altvater Fig. 2). Altvater does not specifically teach that the hinge domain comprises 2B4 comprising SEQ ID NO: 1, or transmembrane region comprising 2B4 comprising SEQ ID NO: 29 or an intracellular domain comprising 2B4 comprising SEQ ID NO: 4.
Brentjens teaches that 2B4 is SEQ ID NO: 203, where SEQ ID NO: 203 comprises SEQ ID NO: 1, SEQ ID NO: 29 and SEQ ID NO: 4 as shown below where SEQ ID NO: 1 is amino acid number 216-229, SEQ ID NO: 29 is amino acid number 230-250 and SEQ ID NO: 4 is amino acid number 251-370 of SEQ ID NO: 203 of Brentjens (Col. 84).
PNG
media_image1.png
246
708
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Greyscale
UniProt teaches that amino acid numbers 216-229, 230-250 and 251-370 are in the extracellular domain or region, transmembrane domain and cytoplasmic domain respectively as shown below.
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media_image2.png
502
1276
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Greyscale
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Altvater in view of Brentjens and UniProt with a reasonable high degree of predictable success to use the SEQ ID NO: 1, SEQ ID NO: 29 and SEQ ID NO: 4 as the hinge domain, transmembrane domain and intracellular domain of the CAR construct since these are already the naturally occurring domains of 2B4 and as indicated by Altvater so as to obtain CAR with improved efficiency for targeting leukemia cells (Altvater pg. 4865 col.2 para 2).
Regarding claims 15-18, an incorporating the analysis of claim 1 above, Altvater teaches that the antigen-specific 2B4ζ expressing NK cells may be powerful new tool for adoptive immunotherapy of leukemia and other malignancies.
Altvater does not specifically teach a pharmaceutical composition comprising the engineered cells.
Brentjens teaches a that immunoresponsive cells expressing a BCMA-targeted CAR can be made into a pharmaceutical composition comprising the cells expressing the CAR construct (Brentjens Col. 126 ln 14-32). Brentjens also teaches that the engineered cells comprising the CAR can be provided in a kit for the treatment or prevention of cancer where in the kit further comprises instructions for use (Brentjens col. 132 ln 49-67 and col. 133 ln 1-13). Brentjens also teach that the engineered cells expressing the CAR construct can be administered to a subject for the treatment of cancer. Brentjens further teaches a method for treatment using the engineered cells comprising the CAR.
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Altvater in view of Brentjens with a reasonable high degree of predictable success to use the engineered cells comprising the CAR construct as described by Altvater in a pharmaceutical composition such as that of Brentjens and provide a kit with instructions for use where in the composition can be administered for the treatment of Acute Myeloid Leukemia (AML) as indicated by Altvater where in the constructs exhibit cytolytic responses against antigen-expressing tumor targets in leukemia and other malignancies as indicated by Altvater. Therefore, a skilled artisan would have been able to modify the teachings of Altvater in view of Brentjens to make the pharmaceutical composition comprising the NK-CAR cells and provide a kit with instructions for use to treat a patient having AML.
Allowable Subject Matter
Claim 14 is allowable.
The following is a statement of reasons for the indication of allowable subject matter:
Regarding claim 14, the claim is drawn to an engineered chimeric antigen receptor comprising a hinge domain, transmembrane domain and/or an intracellular domain and further comprising 2B4.z(truncated).IRES.secrIL15, 2B4.z(1XX).IRES.secIL15 or 2B4.z.IRES.secIL15, wherein 2B4.z(truncated) is SEQ ID NO: 22, 2B4.z(1XX) is SEQ ID NO: 23, 2B4.z is SEQ ID NO: 25 and secIL15 is SEQ ID NO: 10. As per the results of the STIC sequence search, although there where search results with CARs comprising IL15, there were no “hits” or “matches” to a CAR comprising 2B4.z(truncated), 2B4.z(1XX) and/or 2B4.z as per the sequences. Furthermore, the closest prior arts that teaches a CAR as described by instant claim 10 are Altvater and Liu et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia. 2018 Feb;32(2):520-531 (Liu). Altvater only teaches CARs that comprise 2B4.z(truncated), 2B4.z(1XX) or 2B4.z and IRES (Altvater pg. 4858 col. 2 para. 2), but does not teach of a CAR comprising IL-15 or any other cytokine that is linked to the CAR. On the other hand, Lui teaches a CAR comprising IL-15 (Liu Abstract) for the improvement of the persistence and expansion of the NK cells as well as mediating the tonic signaling of the CAR (Liu pg. 11 para 1), but does not teaches a CAR comprising either 2B4.z(truncated), 2B4.z(1XX) or 2B4.z. Therefore, the CAR as recited in claim 14 was not obvious from the prior arts before the effective filing date.
Conclusion
Claim 14 is allowable.
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/EMMANUEL LED YOUTCHOM PENDIE/ Examiner, Art Unit 1647
/JOANNE HAMA/ Supervisory Patent Examiner, Art Unit 1647
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