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 .
Status of the Claims
Applicant’s preliminary amendments to the claims submitted 16 May 2025 are acknowledged and entered into the application file. Claims 1, 4, 17, 25-28, 30-31, 33-34, and 40-43 are pending. Claims 1, 4, 25, 27, and 31 have been amended, while claims 2-3, 5-16, 18-24, 29, 32, and 35-39 have been cancelled without prejudice or disclaimer and claims 40-43 have been newly added. Therefore, prosecution on the merits commences for claims 1, 4, 17, 25-28, 30-31, 33-34, and 40-43.
Priority
The instant application is a national stage entry under 35 USC 371 of PCT/GB2021/050862, filed
08 April 2021. Acknowledgement is made of Applicant’s claim for foreign priority under 35 USC 119(a)-(d) to United Kingdom of Great Britain and Northern Ireland application GB2005216.3, filed 08 April 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). More specifically, the amino acid sequence of “GGGGS” in Page 58 of the instant disclosure is missing it’s corresponding sequence identifier of SEQ ID NO: 52.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: EFFECTOR IMMUNE CELLS ENGINEERED TO BE CALCINEURIN INHIBITOR-RESISTANT.
In addition, amendments to the Specification filed 29 September 2022 are acknowledged and entered into the application file. However, the disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in Pages 17 and 34 of the Specification filed 29 September 2022. 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.
Claim Objections
Claims 1, 4, 17, 31, 33, and 40-43 are objected to because of the following informalities:
Regarding claims 1 and 40: The instant claims each recite the limitation, “which effector immune cell is engineered to…” in Line 3 of the respective claims. Applicant must amend the claim to recite, “wherein the effector immune cell is engineered to…” in order to improve the claim language.
Appropriate correction is required.
Regarding claims 4 and 42: The instant claims each are respectively directed to “[a]n effector immune cell according to claim…”. In order to better represent the dependency upon the parent claim, Applicant must amend each claim to recite, “[t]he effector immune cell according to claim…”.
Appropriate correction is required.
Regarding claim 17: The instant claim is directed to “[a]n effector immune cell according to claim…”. In order to better represent the dependency upon the parent claim, Applicant must amend each claim to recite, “[t]he effector immune cell according to claim…”.
Applicant must also correct the spelling of “signaling” in Line 3.
Appropriate correction is required.
Regarding claim 31: The instant claim is directed to “[a] method according to claim…”. In order to better represent the dependency upon the parent claim, Applicant must amend the claim to recite, “[t]he method according to claim…”.
In addition, the instant claim recites the limitation, “which pharmaceutical composition…” in Lines 3-4. Applicant must amend the claim to recite, “wherein the pharmaceutical composition…” in order to improve the claim language.
Appropriate correction is required.
Regarding claim 33: The instant claim is directed to “[a] method according to claim…”. In order to better represent the dependency upon the parent claim, Applicant must amend the claim to recite, “[t]he method according to claim…”.
Appropriate correction is required.
Regarding claim 41: The instant claim is directed to “[a]n effector immune cell according to claim…”. In order to better represent the dependency upon the parent claim, Applicant must amend each claim to recite, “[t]he effector immune cell according to claim…”.
Applicant must also correct the spelling of “localization” in Line 3.
Appropriate correction is required.
Regarding claim 43: The instant claim is directed to “[a]n effector immune cell according to claim…”. In order to better represent the dependency upon the parent claim, Applicant must amend the claim to recite, “[t]he effector immune cell according to claim…”.
Applicant must also correct the spelling of “signaling” in Line 3.
Appropriate correction is required.
In addition, Applicant is advised that should claim 17 be found allowable, claim 43 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Interpretation
Instant claim 1 is directed to an “effector immune cell which expresses a cell surface receptor or receptor complex which specifically binds an antigen recognition receptor of a target immune cell”, wherein the “effector immune cell is engineered to be resistant to one or more calcineurin inhibitors”. It is of note that the only “engineered” requirement of the claim is that the effector immune cell is “engineered to be resistant to one or more calcineurin inhibitors.” Therefore, the scope of instant claim 1 encompasses genetically engineering isolated antigen-specific T-cells that are targeted to immune cells, as well as genetically engineering effector immune cells that comprise a chimeric antigen receptor (CAR) or engineered TCR that is specific for an antigen recognition receptor of a target immune cell.
In addition, the instant Specification has failed to define a “membrane localization domain”, as detailed in instant claim 41. Given that the claim as written requires a fusion protein comprising an extracellular domain, which reads on a chimeric antigen receptor (CAR), the broadest reasonable interpretation of a “membrane localization domain” includes the transmembrane domain of the CAR. More specifically, the transmembrane domain is known in the art for anchoring – or localizing – the CAR to the membrane of the cell. See Page 147 of Guedan et al (Mol Ther Methods Clin Dev, 2018). Therefore, any transmembrane domain comprised with a CAR will read on the “membrane localization domain” as recited in the instant claim.
Claim Rejections - 35 USC § 112
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 4 and 27 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.
Regarding claim 4: The instant claim is dependent upon cancelled claim 3. This therefore renders the claim indefinite.
Appropriate correction is required.
For the sake of compact prosecution, the instant claim will be interpreted as depending from independent claim 1.
Regarding claim 27: The instant claim is directed to a kit of “vectors” comprising a first vector, a second vector “and/or” a third vector. The scope of the claim is indefinite, as it is unclear if the pluralization of “vectors” indicates that the kit must comprise at least two of the three vectors, or rather if the claim is directed to a kit comprising one or more vectors. Therefore, the metes and bounds of the claim cannot be determined, thus rendering the claim indefinite.
Appropriate correction is required.
For the sake of compact prosecution, the instant claim will be interpreted as if only one of the three recited vectors is required within the kit.
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.
(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 1, 4, 17, 25-28, 30, 33-34, and 43 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Cost (WO 2019/210280 A1, of record on IDS filed 01 February 2023) as evidenced by ATCC (RPMI 8226 Technical Document, 2024).
Cost discloses compositions and methods for controlled plasma cell depletion, such as for the
treatment of various diseases and conditions associated with plasma cells (Abstract).
As such, Cost discloses engineered immune cells comprising a nucleic acid encoding a chimeric antigen receptor (CAR) that recognizes B-cell maturation antigen (BCMA) and confers cytotoxicity towards BCMA-expressing cells – including BCMA-expressing RPMI-8226 B lymphocytes (See ATCC, Page 1) – and/or a nucleic acid encoding a CAR that comprises a β2-microglobulin (B2M) extracellular domain that is linked to a cytoplasmic signaling domain (Paragraphs [0007]-[0009], [0028], [0068], [0105], [0157]-[0159], [0216], [0255], [0324], [0374], [0376], [0409]-[0410]). Cost further discloses the engineered immune cells include T cells and NK cells (Paragraphs [0006]-[0007], [0089], [0126]-[0128], [0134]-[0140], [0298]-[0301], [0304]).
Cost further discloses that the engineered immune cells further comprise a polypeptide that confers resistance to one or more calcineurin inhibitors, including the mutant calcineurin polypeptide of CNb30 having a sequence as set forth in SEQ ID NO: 67 (Paragraphs [0036]-[0041], [0073]-[0074], [0110]-[0111], [0157], [0218], [0228], [0259], [0269], [0280], [0324], [0408]).
Cost further discloses that the nucleic acids encoding at least the chimeric antigen receptors are comprised within vectors, which are further comprised within a kit (Paragraphs [0120], [0147], [0167], [0233]-[0239], [0269]-[0270], [0282], [0302]-[0304], [0326]-[0332], [0393]).
Cost further discloses compositions comprising the engineered immune cells that are administered to subjects for the treatment of diseases, including cancer and autoimmune diseases (Paragraphs [0006], [0133]-[0134], [0149]-[0150], [0204], [0279]-[0301], [0405], [0411]-[0412]).
Accordingly, Cost anticipates the claims as follows:
Regarding claims 1 and 25: Cost discloses engineered immune cells comprising a nucleic acid encoding CAR that recognizes BCMA (claim 25) and further comprising a polypeptide that confers resistance to one or more calcineurin inhibitors. As BCMA is an antigen that is expressed on target B lymphocytes, this therefore reads on the effector immune cell of instant claim 1.
Regarding claim 4: Following the discussion of claim 1, Cost further discloses that the polypeptide that confers resistance to one or more calcineurin inhibitors is the mutant calcineurin polypeptide of CNb30 having a sequence as set forth in SEQ ID NO: 67. As SEQ ID NO: 67 has 100% identity to instant SEQ ID NO: 131 – which is the calcineurin B polypeptide sequence as set forth in instant SEQ ID NO: 66 having L124T and K-124-LA-Ins mutations (see Page 72 of instant Specification) – this therefore reads on the effector immune cell of the instant claim. See sequence alignment below.
Query Match 100.0%; Length 172; Matches 172; Gaps 0;
Qy 1 MGNEASYPLEMCSHFDADEIKRLGKRFKKLDLDNSGSLSVEEFMSLPELQQNPLVQRVID 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MGNEASYPLEMCSHFDADEIKRLGKRFKKLDLDNSGSLSVEEFMSLPELQQNPLVQRVID 60
Qy 61 IFDTDGNGEVDFKEFIEGVSQFSVKGDKEQKLRFAFRIYDMDKDGYISNGELFQVLKMMV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 IFDTDGNGEVDFKEFIEGVSQFSVKGDKEQKLRFAFRIYDMDKDGYISNGELFQVLKMMV 120
Qy 121 GNNTKLADTQLQQIVDKTIINADKDGDGRISFEEFCAVVGGLDIHKKMVVDV 172 (SEQ ID NO: 131)
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GNNTKLADTQLQQIVDKTIINADKDGDGRISFEEFCAVVGGLDIHKKMVVDV 172 (SEQ ID NO: 67)
Regarding claims 17 and 43: Following the discussion of claim 1, Cost further discloses that the engineered immune cell comprises a nucleic acid encoding a CAR that comprises a β2-microglobulin (B2M) extracellular domain that is linked to a cytoplasmic signaling domain. This therefore reads on the effector immune cell of the instant claims.
Regarding claims 26-27: Following the discussion of claim 25, Cost further discloses that the nucleic acid encoding the CAR is comprised within a vector, which is further comprised within a kit. This therefore reads on the vector of instant claim 26 and kit of vectors of instant claim 27.
Regarding claims 28, 30, and 33: Following the discussion of claim 1, Cost further discloses compositions comprising the engineered immune cells that are administered to subjects for the treatment of diseases, including cancer (claim 33). This therefore reads on the pharmaceutical composition of instant claim 28 and treatment method of instant claim 30.
Regarding claim 34: Following the discussion of claim 1, Cost further discloses that the engineered immune cells are generated via the introduction of a first nucleic acid sequence encoding the anti-BCMA CAR, and a second nucleic acid sequence encoding the CNb30 sequence – which is the mutant calcineurin polypeptide sequence (Paragraph [0405]). This therefore reads on the method of the instant claim.
Claim 40 is rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Brogdon et al (US 2016/0051651 A1) as evidenced by ATCC (THP-1 Technical Document, 2024).
Brogdon et al disclose compositions and methods for treating diseases associated with
expression of CLL-1. Brogdon et al further disclose chimeric antigen receptors (CARs) specific to CLL-1, vectors encoding the same, and recombinant cells comprising the CLL-1 CAR (Abstract). It is of note that Brogdon et al disclose that CLL-1 is expressed on THP-1 target cells, which is a monocytic cell line (Paragraphs [1032]-[1036]; see ATCC, Page 1).
As such, Brogdon et al disclose that the CLL-1 CAR-expressing cell further comprises PD-L1 or PD-L2, such that the CAR-expressing cell expresses PD-L1 or PD-L2 (Paragraphs [0059], [0468], [0479], [0604], [0941], [0967]-[0969]).
Brogdon et al further disclose that the CAR-expressing cell is an immune effector cell (Paragraphs [0615]-[0616]).
Accordingly, Brogdon et al anticipate the claim as follows:
Regarding claim 40: Brogdon et al disclose a CLL-1 CAR-expressing immune effector cell that further comprises PD-L1 or PD-L2. As CLL-1 is an antigen that is expressed on target immune cells, and the CAR-expressing immune effector cell expresses PD-L1 or PD-L2, this therefore reads on the effector immune cell of the instant claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 17, 25-28, 30-31, 33-34, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Cost (WO 2019/210280 A1, of record on IDS filed 01 February 2023) as evidenced by ATCC (RPMI 8226 Technical Document, 2024) in view of Rezvani et al (US 2022/0325245 A1).
The discussion of Cost as evidenced by ATCC regarding claim 30 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Cost as evidenced by ATCC anticipates claims 1, 4, 17, 25-28, 30, 33-34, and 43. Rezvani et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 29 March 2019.
Regarding claim 31: Following the discussion of claim 30, Cost further discloses that the disease to be treated via the administration of the composition comprising the engineered immune cells is an autoimmune disease (Paragraphs [0133], [0151]-[0156], [0291]-[0296]). Cost further discloses the engineered immune cells are NK cells (Paragraphs [0300]-[0301], [0304]).
Cost further discloses that the immune cells comprising resistance to calcineurin inhibitors are resistant to tacrolimus and/or cyclosporin A, and are thereby unaffected by administered tacrolimus and/or cyclosporin A (Paragraphs [0037], [0039], [0218], [0259]-[0260]).
Cost does not disclose that a calcineurin inhibitor is further administered to the subject in need thereof, as required by instant claim 31.
Rezvani et al, however, disclose methods of treating autoimmune diseases by administering CAR NK cells that are specific for BCMA to a subject in need thereof in conjunction with a calcineurin inhibitor (Abstract; Paragraphs [0008], [0013], [0017], [0063], [0068]-[0070], [0234], [0239], [0241]-[0242]). It is of note that Rezvani et al further disclose that the anti-BCMA CAR-NK cells confer cytotoxicity to the target BCMA-expressing cells, while the calcineurin inhibitor – specifically tacrolimus or cyclosporin – function as an immunosuppressive or tolerogenic agent that aid in the treatment of the autoimmune disease (Paragraphs [0005], [0013], [0194], [0241], [0255]).
Therefore, it would have been prima facie obvious to have modified the autoimmune disease treatment method of Cost such that the engineered immune effector cells, including NK cells that are resistant to calcineurin inhibitors, are administered in conjunction with a calcineurin inhibitor, as detailed in Rezvani et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to combine the administration of a calcineurin inhibitor into the method of treating an autoimmune disease via the administration of engineered NK cells as detailed in Cost, as Rezvani et al disclose that calcineurin inhibitors serve as an immunosuppressive or tolerogenic agent that aid in the treatment of the autoimmune disease, and the engineered NK cells that are resistant to calcineurin inhibitors of Cost will have an improved survival in the presence of calcineurin inhibitors and/or proliferate in the presence of calcineurin inhibitors, thereby providing a more effective, longer-lasting therapy. The ordinary artisan would have had a reasonable expectation of success given that the disclosure of Rezvani et al teaches the administration of immune cells comprising a CAR and the calcineurin inhibitor. See MPEP § 2143(I)(G).
Consequently, Cost as evidenced by ATCC and as modified by Rezvani et al render obvious a method of treating an autoimmune disease in a subject wherein CAR-T cells engineered to be resistant to calcineurin inhibitors are administered to the subject in conjunction with a calcineurin inhibitor. This therefore renders obvious the method of the instant claim.
Claims 40-42 are rejected under 35 U.S.C. 103 as being unpatentable over Brogdon et al (US 2016/0051651 A1) as evidenced by ATCC (THP-1 Technical Document, 2024).
The discussion of Brogdon et al as evidenced by ATCC regarding claim 40 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Brogdon et al as evidenced by ATCC anticipate claim 40.
Regarding claims 41-42: Following the discussion of claim 40, Brogdon et al further disclose a PD-1 CAR-expressing cell, wherein the CAR comprises a PD-1 extracellular binding domain that is fused to a transmembrane domain and co-stimulatory intracellular signaling domains (Paragraphs [0469], [0480]-[0483]).
Brogdon et al further disclose that the transmembrane domain can be derived from HVEM or CEACAM1, which are inherently immunoinhibitory molecules (Paragraph [0059], [0447]-[0448], [0479]).
However, Brogdon et al do not exemplify or reduce to practice a CAR-expressing cell wherein the CAR comprises a PD-L1 extracellular domain that is fused to a HVEM transmembrane domain and co-stimulatory intracellular signaling domains, as required by instant claims 41-42.
Therefore, it would have been prima facie obvious to have modified the CAR-expressing immune effector cell of Brogdon et al such that the CAR comprises a PD-L1 extracellular domain that is fused to a HVEM transmembrane domain and co-stimulatory intracellular signaling domains. One of ordinary skill in the art before the effective filing date of the invention would have recognized that the PD-1 and PD-L1 extracellular domains are functionally comparable, as they are both immunoinhibitory molecules wherein PD-L1 is the ligand for PD-1 (Paragraphs [0479], [0897]), and thereby could have been substituted within the CAR with predictable results. See MPEP § 2143(I)(B). Furthermore, the ordinary artisan would have recognized that CARs are modular fusion proteins that can be comprised of a variety of different domains (Paragraph [0206]). Therefore, the ordinary artisan would have had a reasonable expectation of success in combining the aforementioned domains, as Brogdon et al reasonably suggest all of the PD-L1 extracellular domain, HVEM transmembrane domain, and co-stimulatory intracellular domains (Paragraphs [0059], [0207], [0319]-[0320], [0446]-[0448], [0454]-[0467], [0479]). See MPEP § 2143(I)(G).
Consequently, given the claim interpretation above, Brogdon et al as evidenced by ATCC render obvious a CAR-expressing immune effector cell, wherein the CAR comprises a PD-L1 extracellular domain that is fused to a HVEM (immunoinhibitory molecule) transmembrane domain (membrane localization domain) (claim 41) and co-stimulatory intracellular signaling domains (co-stimulatory endodomains) (claim 42). This therefore renders obvious the effector immune cell of the instant claims.
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.
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Claims 1, 4, 17, 25-28, 30-31, 33-34, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 7, 14, and 19 of copending Application No. 17/915,737 in view of Cost (WO 2019/210280 A1, of record on IDS filed 01 February 2023).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims render obvious the instant claims. More specifically, the copending claims are not identical because no single copending claim discloses all of the limitations of any of the instant claims; however, each of the limitations of the instant claims are disclosed by separate copending claims, or rendered obvious by the accompanying prior art. The fact that each of the elements were claimed in the copending application, just not in a single claim, still renders obvious the instant invention because each of the features, though separately claimed, can be physically combined into a single embodiment.
Copending claim 1 is directed to a method for treating a disease in a subject who is receiving or has received treatment with a calcineurin inhibitor, which method comprises the step of administering to the subject a plurality of cells which express: (a) a chimeric antigen receptor (CAR); and (b) a mutant version of calcineurin A and/or calcineurin B which is resistant to the calcineurin inhibitor.
Copending claim 1 does not disclose that the plurality of cells are effector immune cells.
Cost, however, discloses engineered T cells comprising a nucleic acid encoding a CAR that recognizes BCMA and further comprise a polypeptide that confers resistance to one or more calcineurin inhibitors (Paragraphs [0007]-[0009], [0028], [0036]-[0041], [0068], [0073]-[0074], [0105], [0110]-[0111], [0157], [0216], [0218], [0255], [0259], [0269], [0280], [0324], [0408]-[0410]).
Therefore, it would have been prima facie obvious to have substituted the cells within the method of the copending application with the immune effector cells of Cost, as doing so would have been a simple substitution of one calcineurin inhibitor-resistant CAR-expressing cell for another. See MPEP § 2143(I)(B). One of ordinary skill in the art would have recognized that the cells are functionally comparable, as both express a CAR and have been engineered to be resistant to calcineurin inhibitors, and thereby would have been able to substitute the two with predictable results.
Consequently, instant claim 1 is an obvious variant of copending claim 1 in view of Cost, as the plurality of effector immune cells comprising the CAR and a mutant version of calcineurin A and/or calcineurin B which is resistant to the calcineurin inhibitor render obvious the effector immune cell of instant claim 1.
With that, instant claims 4, 17, 25-28, 30-31, 33-34, and 43 are known from the copending claims or prior art and can be further incorporated into the effector immune cell rendered obvious by copending claims 1 as modified by Cost:
Copending claims 4-5, 7, 14, and 19 teach the limitations recited in instant claims 4, 31, and 33.
Cost further teaches the limitations recited in instant claims 17, 25-28, 30, 34, and 43.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633