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 .
Claims Status
Claims 1, 5-7, 10, 15, 24, 43-44, 46-47, 49, 55-56, 67, 117-119, 122, 125-126, 133, and 142 are pending and are examined on the merits.
Drawings
The drawings are objected to because Fig. 48, 52, and 60 are low quality and illegible.
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.
Claim Objections
Claims 1, 47, 56, 133, and 142 objected to because of the following informalities:
Claims 1, 47, 56, 133, and 142 contain periods within the body of the claim (e.g. “a.”). Each claim must begin with a capital letter and end with a period. Periods may not be used elsewhere in the claims except for abbreviations. See MPEP 608.01(m).
Appropriate correction is required.
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 46, 55, and 67 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.
Claims 46 and 55 recite “The allogeneic of” which contains an adjective without a noun/subject. For the purposes of examination, the claims are interpreted to read “The allogeneic immune cell of...”
Claim 67 recites “wherein the shRNA comprises SEQ ID NOs: 21899-21901”. It is unclear if the claim is drawn to an shRNA comprising any one of the recited sequences, or all three together. Moreover, SEQ ID NO: 21899 is 502 nucleotides in length and lacks the general structure of an shRNA, which are short sequences comprising a sense/stem-loop/antisense architecture (e.g. see ¶0290 of the instant specification).
Claim Rejections - 35 USC § 112
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.
Claim 49 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 49 is drawn to an HLA-A*02:01:01:01 shRNA having a sequence complementary to any one of the over 8000 sequences represented by SEQ ID NOs: 8476-16870. Example 25 of the instant specification details the identification of potential target sequences for HLA-A specific shRNA molecules from “all possible 18bp, 19bp, 20bp, 21bp, and 22bp transcribed sequences corresponding to HLA-A*02:01:01:01 mRNA” (¶0857). However, after eliminating sequences with unfavorable GC content and repetitive sequences followed by filtering the remaining sequences through computational tools that identify favorable characteristics, only 278 of the possible 8,397 sequences were considered potential targets. Among these remaining candidates, the specification details only “several” that were able to reduce HLA-A*02 by over 50%, with a single species “shRNA-12” showing over 90% target knockdown (Example 26; Fig. 49).
In addition, the disclosure does not appear to identify which of the sequences among SEQ ID NOs: 8476-16870 correspond to targets of any of the active shRNAs identified, such as “shRNA-12”. Accordingly, given that the disclosure suggests that the majority of sequences represented by SEQ ID NOs: 8476-16870 are unsuitable for use as shRNA, and in view of the lack of disclosure of the identity of sequences complementary to functionally active shRNAs (e.g. “shRNA-12”), one of ordinary skill in the art would be faced with an undue amount of experimentation to uncover which sequences within the claimed genus are suitable shRNA targets.
Note that while ¶0857 of the specification states that Fig. 48 contains “illustrative alignments” for shRNA target complementary sequences, Fig. 48 is illegible and the identity of the sequences or which functional shRNA molecules they may correspond to could not be determined.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 117-119, 122, 125-126, 133, and 142 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gross et al. 2020 (US 2020/0316120 A1; PTO-892), herein “Gross”.
Gross teaches immune cells comprising both an activating-CAR (aCAR) and inhibitory-CAR (iCAR) wherein the iCAR recognizes an allelic variant of a cell surface antigen expressed by normal cells but not by tumors as a result of loss of heterozygosity (LOH) (¶0004) wherein each the iCAR and aCAR contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular inhibitory or activating domain, respectively (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches the iCAR recognizes, for example, HLA-A (¶0974), which is universally expressed on all mammalian cells including immune cells (¶0783; Example 7).
Gross teaches the cells can be universal/allogeneic (¶0080).
Regarding instant Claims 117-119, Gross teaches that the immune cells are T cells isolated from healthy donors and electroporated with nucleic acids encoding the aCAR and iCAR (making the cells “non-natural”) (¶0989-0990).
Regarding instant Claim 122, Gross teaches the cells can be prepared as a pharmaceutical composition (¶0628-0634).
Regarding instant Claims 125-126, Gross teaches a method of treating cancer comprising administering the immune cells containing the aCAR and iCAR, and that the treatment results in reduced off-tumor reactivity (Gross claims 28 and 30).
Regarding instant Claims 133 and 142, Gross teaches vectors containing nucleic acid sequences encoding for both the aCAR and iCAR joined by a P2A peptide in a single vector (¶0358; ¶0551; Gross SEQ ID NO: 33), as well as a method of making immune cells containing the pair of engineered receptors comprising contacting the cells with said vector (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Claim Rejections - 35 USC § 102/103
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.
Claims 5 is rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Gross et al. 2020 (US 2020/0316120 A1; PTO-892), herein “Gross”, as evidenced by the instant specification.
The teachings of Gross are summarized above.
Gross further teaches that the iCAR confers protection of normal cells from the aCAR (¶0215) and “[d]ominance of the iCAR guarantees that activation of the killer cell upon encounter with normal cells expressing both alleles would be prevented” (¶0220).
Regarding Claim 5, Gross is silent on whether the inhibitory CAR reduces graft versus host disease.
However, the instant specification evidences that inhibitory CAR directed to HLA-A reversibly suppresses graft-versus-host response (¶0846). Because the immune cells comprising an inhibitory CAR and activating CAR of Gross satisfy all the limitations of the instant claim 1, and the inhibitory CAR of Gross targets the same antigen as the instantly disclosed example (HLA-A), the property of reducing graft versus host disease (GvHD) would be considered inherent to the iCAR/aCAR cells of Gross.
Alternatively, it would have been obvious to one of ordinary skill in the art that the iCAR/aCAR cells of Gross reduce GvHD. GvHD is characterized by the instant specification as when “donor immune cells attack healthy cells of the recipient” (¶0151). Accordingly, the skilled artisan would recognize that immune cells containing the iCAR of Gross would prevent GvHD that would otherwise be mediated by the aCAR through the capacity of the iCAR to prevent targeting of normal cells by the aCAR.
Claim Rejections - 35 USC § 103
Claims 6-7, 10, 24, 43-44, 46-47, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Gross et al. 2020 (US 2020/0316120 A1; PTO-892), herein “Gross”, as applied to claim 1 above, and further in view of Shang et al. 2022 (US 2022/0193135 A1; Priority to 01/02/2020; PTO-892), herein “Shang”, and as evidenced by the instant specification.
The teachings of Gross are summarized above.
Gross does not teach that the cells comprising the iCAR/aCAR pair further comprise shRNA or endonuclease knockdown of HLA-A. This deficiency is cured by Shang.
Shang teaches allogeneic CAR-T cells wherein expression of an HLA-A allele is downregulated (¶0157) by means of shRNA (¶0189; ¶0202-0204) or CRISPR/Cas9 (i.e. “a nucleic acid guided endonuclease in a complex with at least one gNA”; ¶0189; ¶0207-239).
Regarding instant Claim 47, Shang teaches that the HLA-A allele can be HLA-A*02:01:01:01 (¶0173; Shang SEQ ID NO: 56).
Regarding instant Claim 47, Shang teaches an shRNA comprises two invert repeat sequences of at least 18bp in length with complementarity to a target mRNA joined by a loop sequence forming a hairpin structure (¶0202-0204).
Shang teaches that HLA expression on allogeneic T cells leads to rejection by the host immune system (¶0003) and that down-regulating HLA-A*02 expression protected grafted T cells from NK cytotoxicity and immune rejection (Pg. 22-23, Examples 11-12; Fig. 15-16).
Shang teaches that CAR-T cells modified by HLA-A knockout maintained strong anti-tumor efficacy (Examples 14-15).
It would have been obvious to one of ordinary skill in the art to modify the iCAR/aCAR cells taught by Gross to further include a shRNA or CRISPR knock-down of an HLA-A*02 allele (such as HLA-A*02:01:01:01). The skilled artisan would have been motivated by the suggestion of Gross that the iCAR/aCAR cells can be universal/allogeneic and the teachings of Shang that allogeneic cells can be protected from host immune rejection by down-regulating HLA-A*02. There would have been a reasonable expectation of success because Shang teaches that CAR-T cells comprising HLA-A*02 knockdown maintained their ability to inhibit tumor growth.
Further regarding instant Claim 49, as evidenced by the instant specification, SEQ ID NOs: 8476-16870 represent “all possible 18bp, 19bp, 20bp, 21bp, and 22bp transcribed sequences corresponding to HLA-A*02:01:01:01” (¶0857). Accordingly, were one of ordinary skill in the art construct an shRNA targeting HLA-A*20:01:01:01 according to the guidance of Shang it would necessarily contain a sequence complementary to one of instant SEQ ID NOs: 8476-16870.
Claims 6-7, 10, 15 and 55-56 are rejected under 35 U.S.C. 103 as being unpatentable over Gross et al. 2020 (US 2020/0316120 A1; PTO-892), herein “Gross”, as applied to claim 1 above, and further in view of Metelitsa et al. 2018 (US 2020/0216810 A1; PTO-892), herein “Metelitsa”.
The teachings of Gross are summarized above.
Gross does not teach immune cells further comprising nucleic acid guided endonuclease or shRNA knockdown of beta-2-microglobulin (B2M). This deficiency is cured by Metelitsa.
Metelitsa teaches that all cells express HLA class I molecules and adoptively transferred allogeneic immune cells from HLA mismatched donors will be eliminated by the host immune system (¶0011-0012). Metelitsa further teaches that surface expression of HLA Class I molecules is dependent on B2M and therefore targeting B2M in the allogeneic immune cells prevents their recognition and rejection by host CD8 T cells (¶0014).
Metelitsa teaches that B2M expression on immune cells can be reduced by either shRNA knockdown or CRISPR/Cas9 knockout (Fig. 2) and that CRISPR and shRNA are “equally effective” in reducing CD4+ and CD8+ T cell stimulation in an allogeneic mixed lymphocyte assay (Fig. 4; ¶0028).
Metelitsa teaches that B2M knockout immune cells can further comprise a CAR (Example 4), and that said cells avoided alloreactivity by unmatched CD8+ and CD4+ T cells (¶0138; Fig. 13).
It would have been obvious to one of ordinary skill in the art to modify the iCAR/aCAR cells taught by Gross to further include a shRNA or CRISPR knock-down of B2M as taught by Metelistsa. The skilled artisan would have been motivated by the suggestion of Gross that the iCAR/aCAR cells can be universal/allogeneic and the teachings of Metelitsa that allogeneic cells can be protected from host immune rejection by down-regulating B2M. There would have been a reasonable expectation of success because Metelitsa teaches that B2M is required for surface expression of HLA class I molecules and that immune cells comprising both a CAR and B2M knockdown avoided alloreactivity by HLA unmatched T cells.
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.
Claims 1, 5-7, 10, 24, 43-44, 46-47, 49, 117-119, 122, 125-126, 133, and 142 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-27 of U.S. Patent No. 11,602,543
claims 1-27 of U.S. Patent No. 11,602,544
claims 1-30 of U.S. Patent No. 11,433,100
claims 1-22 of U.S. Patent No. 11,730,764
in view of Gross et al. 2020 (US 2020/0316120 A1; PTO-892), herein “Gross”, Shang et al. 2022 (US 2022/0193135 A1; Priority to 01/02/2020; PTO-892), herein “Shang”, and as evidenced by the instant specification.
Regarding instant Claim 1, the claims of ‘543, ‘544, ‘100, and ‘764 are each drawn to immune cells comprising and/or polynucleotides encoding a pair of receptor polypeptides wherein one polypeptide is an activating receptor with an extracellular binding domain specific for a tumor antigen and the other polypeptide is an inhibitory receptor with an extracellular binding domain that targets an HLA-A*02 antigen.
However, the claims of ‘543, ‘544, ‘100, and ‘764 are not drawn in particular to “allogeneic” immune cells, nor the particular HLA-A modifications of instant Claims 6-7, 10, 24, 43-44, 46-47, and 49. These limitations are rendered obvious by Gross and Shang.
Gross teaches immune cells comprising both an activating-CAR (aCAR) and inhibitory-CAR (iCAR) wherein the iCAR recognizes an allelic variant of a cell surface antigen expressed by normal cells but not by tumors as a result of loss of heterozygosity (LOH) (¶0004) wherein each the iCAR and aCAR contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular inhibitory or activating domain, respectively (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches the iCAR recognizes, for example, HLA-A (¶0974), which is universally expressed on all mammalian cells including immune cells (¶0783; Example 7).
Gross teaches the cells can be universal/allogeneic (¶0080).
Regarding instant Claims 117-119, Gross teaches that the immune cells are T cells isolated from healthy donors and electroporated with nucleic acids encoding the aCAR and iCAR (making the cells “non-natural”) (¶0989-0990).
Regarding instant Claim 122, Gross teaches the cells can be prepared as a pharmaceutical composition (¶0628-0634).
Regarding instant Claims 125-126, Gross teaches a method of treating cancer comprising administering the immune cells containing the aCAR and iCAR, and that the treatment results in reduced off-tumor reactivity (Gross claims 28 and 30).
Regarding instant Claims 133 and 142, Gross teaches vectors containing nucleic acid sequences encoding for both the aCAR and iCAR joined by a P2A peptide in a single vector (¶0358; ¶0551; Gross SEQ ID NO: 33), as well as a method of making immune cells containing the pair of engineered receptors comprising contacting the cells with said vector (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches that the iCAR confers protection of normal cells from the aCAR (¶0215) and “[d]ominance of the iCAR guarantees that activation of the killer cell upon encounter with normal cells expressing both alleles would be prevented” (¶0220).
Regarding instant Claim 5, the instant specification evidences that inhibitory CAR directed to HLA-A reversibly suppresses graft-versus-host response (¶0846). Because the immune cells comprising an inhibitory CAR and activating CAR of Gross satisfy all the limitations of the instant claim 1, and the inhibitory CAR of Gross targets the same antigen as the instantly disclosed example (HLA-A), the property of reducing graft versus host disease (GvHD) would be considered inherent to the iCAR/aCAR cells of Gross.
Shang teaches allogeneic CAR-T cells wherein expression of an HLA-A allele is downregulated (¶0157) by means of shRNA (¶0189; ¶0202-0204) or CRISPR/Cas9 (i.e. “a nucleic acid guided endonuclease in a complex with at least one gNA”; ¶0189; ¶0207-239).
Regarding instant Claim 47, Shang teaches that the HLA-A allele can be HLA-A*02:01:01:01 (¶0173; Shang SEQ ID NO: 56).
Regarding instant Claim 47, Shang teaches an shRNA comprises two invert repeat sequences of at least 18bp in length with complementarity to a target mRNA joined by a loop sequence forming a hairpin structure (¶0202-0204).
Shang teaches that HLA expression on allogeneic T cells leads to rejection by the host immune system (¶0003) and that down-regulating HLA-A*02 expression protected grafted T cells from NK cytotoxicity and immune rejection (Pg. 22-23, Examples 11-12; Fig. 15-16).
Shang teaches that CAR-T cells modified by HLA-A knockout maintained strong anti-tumor efficacy (Examples 14-15).
It would have been obvious to one of ordinary skill in the art to modify the claims of ‘543, ‘544, ‘100, and ‘764 to further encompass allogeneic iCAR/aCAR cells comprising a shRNA or CRISPR knock-down of an HLA-A*02 allele (such as HLA-A*02:01:01:01). The skilled artisan would have been motivated by the suggestion of Gross that the iCAR/aCAR cells can be universal/allogeneic and the teachings of Shang that allogeneic cells can be protected from host immune rejection by down-regulating HLA-A*02. There would have been a reasonable expectation of success because Shang teaches that CAR-T cells comprising HLA-A*02 knockdown maintained their ability to inhibit tumor growth.
Further regarding instant Claim 49, as evidenced by the instant specification, SEQ ID NOs: 8476-16870 represent “all possible 18bp, 19bp, 20bp, 21bp, and 22bp transcribed sequences corresponding to HLA-A*02:01:01:01” (¶0857). Accordingly, were one of ordinary skill in the art construct an shRNA targeting HLA-A*20:01:01:01 according to the guidance of Shang it would necessarily contain a sequence complementary to one of instant SEQ ID NOs: 8476-16870.
Claims 6-7, 10, 15, 55-56, 117-119, 122, 125-126, 133, and 142 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-27 of U.S. Patent No. 11,602,543
claims 1-27 of U.S. Patent No. 11,602,544
claims 1-30 of U.S. Patent No. 11,433,100
claims 1-22 of U.S. Patent No. 11,730,764
in view of Gross et al. 2020 (US 2020/0316120 A1; PTO-892), herein “Gross”, Metelitsa et al. 2018 (US 2020/0216810 A1; PTO-892), herein “Metelitsa”, and as evidenced by the instant specification.
Regarding instant Claim 1, the claims of ‘543, ‘544, ‘100, and ‘764 are each drawn to immune cells comprising and/or polynucleotides encoding a pair of receptor polypeptides wherein one polypeptide is an activating receptor with an extracellular binding domain specific for a tumor antigen and the other polypeptide is an inhibitory receptor with an extracellular binding domain that targets an HLA-A*02 antigen.
However, the claims of ‘543, ‘544, ‘100, and ‘764 are not drawn in particular to “allogeneic” immune cells, nor the particular B2M modifications of instant Claims 6-7, 10, 15 and 55-56. These limitations are rendered obvious by Gross and Metelitsa.
Gross teaches immune cells comprising both an activating-CAR (aCAR) and inhibitory-CAR (iCAR) wherein the iCAR recognizes an allelic variant of a cell surface antigen expressed by normal cells but not by tumors as a result of loss of heterozygosity (LOH) (¶0004) wherein each the iCAR and aCAR contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular inhibitory or activating domain, respectively (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches the iCAR recognizes, for example, HLA-A (¶0974), which is universally expressed on all mammalian cells including immune cells (¶0783; Example 7).
Gross teaches the cells can be universal/allogeneic (¶0080).
Regarding instant Claims 117-119, Gross teaches that the immune cells are T cells isolated from healthy donors and electroporated with nucleic acids encoding the aCAR and iCAR (making the cells “non-natural”) (¶0989-0990).
Regarding instant Claim 122, Gross teaches the cells can be prepared as a pharmaceutical composition (¶0628-0634).
Regarding instant Claims 125-126, Gross teaches a method of treating cancer comprising administering the immune cells containing the aCAR and iCAR, and that the treatment results in reduced off-tumor reactivity (Gross claims 28 and 30).
Regarding instant Claims 133 and 142, Gross teaches vectors containing nucleic acid sequences encoding for both the aCAR and iCAR joined by a P2A peptide in a single vector (¶0358; ¶0551; Gross SEQ ID NO: 33), as well as a method of making immune cells containing the pair of engineered receptors comprising contacting the cells with said vector (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches that the iCAR confers protection of normal cells from the aCAR (¶0215) and “[d]ominance of the iCAR guarantees that activation of the killer cell upon encounter with normal cells expressing both alleles would be prevented” (¶0220).
Regarding instant Claim 5, the instant specification evidences that inhibitory CAR directed to HLA-A reversibly suppresses graft-versus-host response (¶0846). Because the immune cells comprising an inhibitory CAR and activating CAR of Gross satisfy all the limitations of the instant claim 1, and the inhibitory CAR of Gross targets the same antigen as the instantly disclosed example (HLA-A), the property of reducing graft versus host disease (GvHD) would be considered inherent to the iCAR/aCAR cells of Gross.
Metelitsa teaches that all cells express HLA class I molecules and adoptively transferred allogeneic immune cells from HLA mismatched donors will be eliminated by the host immune system (¶0011-0012). Metelitsa further teaches that surface expression of HLA Class I molecules is dependent on B2M and therefore targeting B2M in the allogeneic immune cells prevents their recognition and rejection by host CD8 T cells (¶0014).
Metelitsa teaches that B2M expression on immune cells can be reduced by either shRNA knockdown or CRISPR/Cas9 knockout (Fig. 2) and that CRISPR and shRNA are “equally effective” in reducing CD4+ and CD8+ T cell stimulation in an allogeneic mixed lymphocyte assay (Fig. 4; ¶0028).
Metelitsa teaches that B2M knockout immune cells can further comprise a CAR (Example 4), and that said cells avoided alloreactivity by unmatched CD8+ and CD4+ T cells (¶0138; Fig. 13).
It would have been obvious to one of ordinary skill in the art to modify the claims of ‘543, ‘544, ‘100, and ‘764 to further encompass allogeneic iCAR cells further encompassing an aCAR as taught by Gross. The skilled artisan would have been motivated by the suggestion of Gross that the iCAR/aCAR cells can be universal/allogeneic and the teachings of Metelitsa that allogeneic cells can be protected from host immune rejection by down-regulating B2M. There would have been a reasonable expectation of success because Metelitsa teaches that B2M is required for surface expression of HLA class I molecules and that immune cells comprising both a CAR and B2M knockdown avoided alloreactivity by HLA unmatched T cells.
Claims 1, 5-7, 10, 15 and 55-56, 117-119, 122, 125-126, 133, and 142 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22, 24-25, 29, 33, 36, and 70-74 of copending Application No. 17/706,134 in view of in view of Gross et al. 2020 (US 2020/0316120 A1; PTO-892), herein “Gross”, Metelitsa et al. 2018 (US 2020/0216810 A1; PTO-892), herein “Metelitsa”, and as evidenced by the instant specification.
The claims of ‘134 are drawn to immune cells (claim 1), pharmaceutical compositions comprising said cells (claim 33), and methods of treatment comprising administering said cells (claims 36) wherein the immune cell comprises an inhibitory receptor comprising a ligand binding domain specific to an MHC-I molecule and wherein B2M expression in the immune cell is reduced or eliminated.
Regarding instant Claims 43-44 and 55-56 ‘134 claims 4-21 further specify B2M is reduced by shRNAs specific to B2M.
The claims of ‘134 are not drawn to allogeneic cells nor several of the particular limitations of the instant claims. These deficiencies are cured by Gross and Metelitsa.
Gross teaches immune cells comprising both an activating-CAR (aCAR) and inhibitory-CAR (iCAR) wherein the iCAR recognizes an allelic variant of a cell surface antigen expressed by normal cells but not by tumors as a result of loss of heterozygosity (LOH) (¶0004) wherein each the iCAR and aCAR contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular inhibitory or activating domain, respectively (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches the iCAR recognizes, for example, HLA-A (¶0974), which is universally expressed on all mammalian cells including immune cells (¶0783; Example 7).
Gross teaches the cells can be universal/allogeneic (¶0080).
Regarding instant Claims 117-119, Gross teaches that the immune cells are T cells isolated from healthy donors and electroporated with nucleic acids encoding the aCAR and iCAR (making the cells “non-natural”) (¶0989-0990).
Regarding instant Claim 122, Gross teaches the cells can be prepared as a pharmaceutical composition (¶0628-0634).
Regarding instant Claims 125-126, Gross teaches a method of treating cancer comprising administering the immune cells containing the aCAR and iCAR, and that the treatment results in reduced off-tumor reactivity (Gross claims 28 and 30).
Regarding instant Claims 133 and 142, Gross teaches vectors containing nucleic acid sequences encoding for both the aCAR and iCAR joined by a P2A peptide in a single vector (¶0358; ¶0551; Gross SEQ ID NO: 33), as well as a method of making immune cells containing the pair of engineered receptors comprising contacting the cells with said vector (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches that the iCAR confers protection of normal cells from the aCAR (¶0215) and “[d]ominance of the iCAR guarantees that activation of the killer cell upon encounter with normal cells expressing both alleles would be prevented” (¶0220).
Regarding instant Claim 5, the instant specification evidences that inhibitory CAR directed to HLA-A reversibly suppresses graft-versus-host response (¶0846). Because the immune cells comprising an inhibitory CAR and activating CAR of Gross satisfy all the limitations of the instant claim 1, and the inhibitory CAR of Gross targets the same antigen as the instantly disclosed example (HLA-A), the property of reducing graft versus host disease (GvHD) would be considered inherent to the iCAR/aCAR cells of Gross.
Metelitsa teaches that all cells express HLA class I molecules and adoptively transferred allogeneic immune cells from HLA mismatched donors will be eliminated by the host immune system (¶0011-0012). Metelitsa further teaches that surface expression of HLA Class I molecules is dependent on B2M and therefore targeting B2M in the allogeneic immune cells prevents their recognition and rejection by host CD8 T cells (¶0014).
Metelitsa teaches that B2M expression on immune cells can be reduced by either shRNA knockdown or CRISPR/Cas9 knockout (Fig. 2) and that CRISPR and shRNA are “equally effective” in reducing CD4+ and CD8+ T cell stimulation in an allogeneic mixed lymphocyte assay (Fig. 4; ¶0028).
Metelitsa teaches that B2M knockout immune cells can further comprise a CAR (Example 4), and that said cells avoided alloreactivity by unmatched CD8+ and CD4+ T cells (¶0138; Fig. 13).
It would have been obvious to one of ordinary skill in the art to modify the claims of ‘134 to further encompass allogeneic cells comprising both an iCAR and aCAR, according to the teachings of Gross. The skilled artisan would have been motivated by the teachings of Gross that pairing an aCAR with the iCAR protects against off-tumor targeting by the aCAR, the suggestion of Gross that the iCAR/aCAR cells can be universal/allogeneic, and the teachings of Metelitsa that allogeneic cells can be protected from host immune rejection by down-regulating B2M. There would have been a reasonable expectation of success because Metelitsa teaches that B2M is required for surface expression of HLA class I molecules and that immune cells comprising both a CAR and B2M knockdown avoided alloreactivity by HLA unmatched T cells.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 6-7, 10, 15, 24, 43-44, 117, 119, 122, 125-126, and 133 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-60 of copending Application No. 18/844,372 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The claims of ‘372 are drawn to immune cells comprising an activator receptor and inhibitory receptor (claim 1) wherein the inhibitory receptor binds HLA-A (claims 4-7), and wherein the immune cell is allogeneic (claim 48).
Regarding instant Claims 6-7, 10, 15, 24, and 43-44, the claims of ‘372 are further drawn to modifications of said immune cells comprising nucleic acid guided endonucleases to B2M (claim 42) or HLA-A*02 (claim 46), or small interfering RNA complementary to a B2M sequence (claim 40) or an HLA-A*02 sequence (claim 44).
Regarding instant Claims 117, ‘372 claim 14 specifies that the immune cell is a T cell or an NK cell.
Regarding instant Claim 119, an immune cell comprising a pair of chimeric receptors and genetic modifications to B2M or HLA as encompassed by the claims of ‘372 is inherently “non-natural”.
Regarding instant Claim 122, ‘372 claims 49-51 are drawn to pharmaceutical compositions.
Regarding instant Claims 125-126, ‘372 claims 54-55 are drawn to methods of treating cancer or selectively killing cells comprising administering engineered immune cells.
Regarding instant Claim 133, ‘372 claim 60 is drawn to a method of making the immune cells.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5-7, 10, 24, 43-44, 46-47, 49, 117-119, 122, 125-126, 133, and 142 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-60 of copending Application No. 18/844,372
claims 1-22, 24-25, 29, 33, 36, and 70-74 of copending Application No. 17/706,134
claims 100, and 105-123 of copending Application No. 17/814,434
claims 100-125 of copending Application No. 18/062,873
claims 1-2, 7-8, 12, 14-15, 18-19, 21-22, 31-32, 58, 61-62, and 66 of copending Application No. 17/633,358
claims 1-87 of copending Application No. 18/165,623
claims 61-81 of copending Application No. 18/340,435
claims 97-118 of copending Application No. 18/833.321
in view of Gross et al. 2020 (US 2020/0316120 A1; PTO-892), herein “Gross”, Shang et al. 2022 (US 2022/0193135 A1; Priority to 01/02/2020; PTO-892), herein “Shang”, and as evidenced by the instant specification.
Regarding instant Claim 1, the claims of ‘372, ‘134, ‘434, ‘873, ‘358, ‘623, ‘435, and ‘321 are each drawn to immune cells comprising and/or polynucleotides encoding a pair of receptor polypeptides wherein one polypeptide is an activating receptor with an extracellular binding domain specific for a tumor antigen and the other polypeptide is an inhibitory receptor with an extracellular binding domain that targets an HLA antigen.
However, the claims of ‘372, ‘134, ‘434, ‘873, ‘358, ‘623, ‘435, and ‘321 do not encompass all of the limitations of the instant claims nor the particular HLA-A modifications of instant Claims 6-7, 10, 24, 43-44, 46-47, and 49. These limitations are rendered obvious by Gross and Shang.
Gross teaches immune cells comprising both an activating-CAR (aCAR) and inhibitory-CAR (iCAR) wherein the iCAR recognizes an allelic variant of a cell surface antigen expressed by normal cells but not by tumors as a result of loss of heterozygosity (LOH) (¶0004) wherein each the iCAR and aCAR contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular inhibitory or activating domain, respectively (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches the iCAR recognizes, for example, HLA-A (¶0974), which is universally expressed on all mammalian cells including immune cells (¶0783; Example 7).
Gross teaches the cells can be universal/allogeneic (¶0080).
Regarding instant Claims 117-119, Gross teaches that the immune cells are T cells isolated from healthy donors and electroporated with nucleic acids encoding the aCAR and iCAR (making the cells “non-natural”) (¶0989-0990).
Regarding instant Claim 122, Gross teaches the cells can be prepared as a pharmaceutical composition (¶0628-0634).
Regarding instant Claims 125-126, Gross teaches a method of treating cancer comprising administering the immune cells containing the aCAR and iCAR, and that the treatment results in reduced off-tumor reactivity (Gross claims 28 and 30).
Regarding instant Claims 133 and 142, Gross teaches vectors containing nucleic acid sequences encoding for both the aCAR and iCAR joined by a P2A peptide in a single vector (¶0358; ¶0551; Gross SEQ ID NO: 33), as well as a method of making immune cells containing the pair of engineered receptors comprising contacting the cells with said vector (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches that the iCAR confers protection of normal cells from the aCAR (¶0215) and “[d]ominance of the iCAR guarantees that activation of the killer cell upon encounter with normal cells expressing both alleles would be prevented” (¶0220).
Regarding instant Claim 5, the instant specification evidences that inhibitory CAR directed to HLA-A reversibly suppresses graft-versus-host response (¶0846). Because the immune cells comprising an inhibitory CAR and activating CAR of Gross satisfy all the limitations of the instant claim 1, and the inhibitory CAR of Gross targets the same antigen as the instantly disclosed example (HLA-A), the property of reducing graft versus host disease (GvHD) would be considered inherent to the iCAR/aCAR cells of Gross.
Shang teaches allogeneic CAR-T cells wherein expression of an HLA-A allele is downregulated (¶0157) by means of shRNA (¶0189; ¶0202-0204) or CRISPR/Cas9 (i.e. “a nucleic acid guided endonuclease in a complex with at least one gNA”; ¶0189; ¶0207-239).
Regarding instant Claim 47, Shang teaches that the HLA-A allele can be HLA-A*02:01:01:01 (¶0173; Shang SEQ ID NO: 56).
Regarding instant Claim 47, Shang teaches an shRNA comprises two invert repeat sequences of at least 18bp in length with complementarity to a target mRNA joined by a loop sequence forming a hairpin structure (¶0202-0204).
Shang teaches that HLA expression on allogeneic T cells leads to rejection by the host immune system (¶0003) and that down-regulating HLA-A*02 expression protected grafted T cells from NK cytotoxicity and immune rejection (Pg. 22-23, Examples 11-12; Fig. 15-16).
Shang teaches that CAR-T cells modified by HLA-A knockout maintained strong anti-tumor efficacy (Examples 14-15).
It would have been obvious to one of ordinary skill in the art to modify the claims of ‘372, ‘134, ‘434, ‘873, ‘358, ‘623, ‘435, and ‘321 to further encompass allogeneic iCAR/aCAR cells comprising a shRNA or CRISPR knock-down of an HLA-A*02 allele (such as HLA-A*02:01:01:01). The skilled artisan would have been motivated by the suggestion of Gross that the iCAR/aCAR cells can be universal/allogeneic and the teachings of Shang that allogeneic cells can be protected from host immune rejection by down-regulating HLA-A*02. There would have been a reasonable expectation of success because Shang teaches that CAR-T cells comprising HLA-A*02 knockdown maintained their ability to inhibit tumor growth.
Further regarding instant Claim 49, as evidenced by the instant specification, SEQ ID NOs: 8476-16870 represent “all possible 18bp, 19bp, 20bp, 21bp, and 22bp transcribed sequences corresponding to HLA-A*02:01:01:01” (¶0857). Accordingly, were one of ordinary skill in the art construct an shRNA targeting HLA-A*20:01:01:01 according to the guidance of Shang it would necessarily contain a sequence complementary to one of instant SEQ ID NOs: 8476-16870.
This is a provisional nonstatutory double patenting rejection.
Claims 6-7, 10, 15, 55-56, 117-119, 122, 125-126, 133, and 142 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-60 of copending Application No. 18/844,372
claims 100, and 105-123 of copending Application No. 17/814,434
claims 100-125 of copending Application No. 18/062,873
claims 1-2, 7-8, 12, 14-15, 18-19, 21-22, 31-32, 58, 61-62, and 66 of copending Application No. 17/633,358
claims 1-87 of copending Application No. 18/165,623
claims 61-81 of copending Application No. 18/340,435
claims 97-118 of copending Application No. 18/833.321
in view of Gross et al. 2020 (US 2020/0316120 A1; PTO-892), herein “Gross”, Metelitsa et al. 2018 (US 2020/0216810 A1; PTO-892), herein “Metelitsa”, and as evidenced by the instant specification.
Regarding instant Claim 1, the claims of ‘372, ‘434, ‘873, ‘358, ‘623, ‘435, and ‘321 are each drawn to immune cells comprising and/or polynucleotides encoding a pair of receptor polypeptides wherein one polypeptide is an activating receptor with an extracellular binding domain specific for a tumor antigen and the other polypeptide is an inhibitory receptor with an extracellular binding domain that targets an HLA antigen.
However, the claims of ‘372, ‘434, ‘873, ‘358, ‘623, ‘435, and ‘321 do not encompass all of the limitations of the instant claims, nor the particular B2M modifications of instant Claims 6-7, 10, 15 and 55-56. These limitations are rendered obvious by Gross and Metelitsa.
Gross teaches immune cells comprising both an activating-CAR (aCAR) and inhibitory-CAR (iCAR) wherein the iCAR recognizes an allelic variant of a cell surface antigen expressed by normal cells but not by tumors as a result of loss of heterozygosity (LOH) (¶0004) wherein each the iCAR and aCAR contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular inhibitory or activating domain, respectively (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches the iCAR recognizes, for example, HLA-A (¶0974), which is universally expressed on all mammalian cells including immune cells (¶0783; Example 7).
Gross teaches the cells can be universal/allogeneic (¶0080).
Regarding instant Claims 117-119, Gross teaches that the immune cells are T cells isolated from healthy donors and electroporated with nucleic acids encoding the aCAR and iCAR (making the cells “non-natural”) (¶0989-0990).
Regarding instant Claim 122, Gross teaches the cells can be prepared as a pharmaceutical composition (¶0628-0634).
Regarding instant Claims 125-126, Gross teaches a method of treating cancer comprising administering the immune cells containing the aCAR and iCAR, and that the treatment results in reduced off-tumor reactivity (Gross claims 28 and 30).
Regarding instant Claims 133 and 142, Gross teaches vectors containing nucleic acid sequences encoding for both the aCAR and iCAR joined by a P2A peptide in a single vector (¶0358; ¶0551; Gross SEQ ID NO: 33), as well as a method of making immune cells containing the pair of engineered receptors comprising contacting the cells with said vector (Example 5 “CAR-T Design and Construction”, ¶0973-0987).
Gross further teaches that the iCAR confers protection of normal cells from the aCAR (¶0215) and “[d]ominance of the iCAR guarantees that activation of the killer cell upon encounter with normal cells expressing both alleles would be prevented” (¶0220).
Regarding instant Claim 5, the instant specification evidences that inhibitory CAR directed to HLA-A reversibly suppresses graft-versus-host response (¶0846). Because the immune cells comprising an inhibitory CAR and activating CAR of Gross satisfy all the limitations of the instant claim 1, and the inhibitory CAR of Gross targets the same antigen as the instantly disclosed example (HLA-A), the property of reducing graft versus host disease (GvHD) would be considered inherent to the iCAR/aCAR cells of Gross.
Metelitsa teaches that all cells express HLA class I molecules and adoptively transferred allogeneic immune cells from HLA mismatched donors will be eliminated by the host immune system (¶0011-0012). Metelitsa further teaches that surface expression of HLA Class I molecules is dependent on B2M and therefore targeting B2M in the allogeneic immune cells prevents their recognition and rejection by host CD8 T cells (¶0014).
Metelitsa teaches that B2M expression on immune cells can be reduced by either shRNA knockdown or CRISPR/Cas9 knockout (Fig. 2) and that CRISPR and shRNA are “equally effective” in reducing CD4+ and CD8+ T cell stimulation in an allogeneic mixed lymphocyte assay (Fig. 4; ¶0028).
Metelitsa teaches that B2M knockout immune cells can further comprise a CAR (Example 4), and that said cells avoided alloreactivity by unmatched CD8+ and CD4+ T cells (¶0138; Fig. 13).
It would have been obvious to one of ordinary skill in the art to modify the claims of ‘372, ‘434, ‘873, ‘358, ‘623, ‘435, and ‘321 to further encompass allogeneic iCAR cells further encompassing an aCAR as taught by Gross. The skilled artisan would have been motivated by the suggestion of Gross that the iCAR/aCAR cells can be universal/allogeneic and the teachings of Metelitsa that allogeneic cells can be protected from host immune rejection by down-regulating B2M. There would have been a reasonable expectation of success because Metelitsa teaches that B2M is required for surface expression of HLA class I molecules and that immune cells comprising both a CAR and B2M knockdown avoided alloreactivity by HLA unmatched T cells.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/BRYAN WILLIAM HECK/ Examiner, Art Unit 1643
/GARY B NICKOL/ Primary Examiner, Art Unit 1643