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 .
Applicant’s amendments to the claims dated 07/07/2023 are acknowledged. Claims 1-24 are cancelled. Claims 25-43 are newly added. Prosecution on the merits commences for claims 25-43.
PRIORITY
The instant Application, filed 07/07/2023, is a DIVISIONAL US Patent No. 11,738,047, filed 12/11/2018, which claims priority to US Provisional Application No. 62/597,717, filed 12/12/2017. Thus, the earliest possible priority for the instant application is 12/12/2017.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, US Non-Provisional Application No. 62/597,717, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The instant claims are directed to methods of making a modified T cell comprising introducing a sequence encoding a heterologous TCR targeted to NU-ESO-1, and the down regulation of endogenous TCR alpha and TCR beta chains.
Dependent claim 28 requires wherein the modified T-cell further comprises a nucleic acid encoding a switch receptor, wherein the switch receptor is encoded by nucleic acid SEQ ID NOs. 15, 135, 137 or 139.
Dependent claim 42 requires wherein the modified T-cell further comprises a nucleic acid encoding a switch receptor, wherein the switch receptor comprises the amino acids sequence set forth in SEQ ID NOs. 14, 134, 136 or 138.
Dependent claims 36, 40-41 require wherein the switch receptor encodes an alanine-to-leucine substitution at position 132 in the PD-1 negative signal domain.
Application 62/597,717 does not disclose the sequences of SEQ ID NOs 134-139; Application 62/597,717 does not disclose a variant of PD-1 comprising an alanine-to-leucine substitution.
Thus, instant claims 28, 36, and 40-42 are given priority to the filing date of the US Patent 11,738,047, filed 12/11/2018. Claims 25-17, 29-35, 37-39, and 43 have priority to 12/12/2017.
Specification – SEQUENCE COMPLIANCE
This application is objected to because the nucleic acid and/or amino acid sequences within FIGs 1, 2, 3 and 28A are not associated with a sequence identifier (a SEQ ID NO) in either the figure or the figure legend. All sequences longer than ten nucleotides or four amino acids referenced in the specification must include a SEQ ID NO and must be included in the Sequence Listing. MPEP 2422.02 requires, "that when a sequence is presented in a drawing, regardless of the format or the manner of presentation of that sequence in the drawing, the sequence must still be included in the Sequence Listing and the sequence identifier ("SEQ ID NO:X') must be used, either in the drawing or in the Brief Description of the Drawings." See MPEP § 2421-2422.
Applicant must amend the Drawings or the brief description of the Drawings on pages 14-17 of the specification filed 07/07/2023 in response to this office action and must confirm that all sequences within the FIGs are in fact included in the sequence listing.
Any response to this office action that fails to meet all of these requirements will be considered non-responsive. The nature of the noncompliance with the requirements of 37 C.F.R. 1.821 through 1.825 did not preclude the examination of the application on the merits, the results of which are communicated below. Appropriate correction is required.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See paragraph [0226] of the published specification.
The specification is also objected to because it is unclear what the amino acid sequence encoding SEQ ID NOs 5 and 12, which encode a TCR alpha chain and a TCR beta chain targeted to NY-ESO-1. The published specification at paragraphs [0241] and [0247] discuss SEQ ID NO: 5 and SEQ ID NO: 12, respectively. These sections show the amino acid sequence of SEQ ID NO: 5 and 12 is identical to that of the sequence listing, and are identical to each other:
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However, the specification here also discloses SEQ ID NO: 5 is encoded by SEQ ID NO: 6 – a nucleic acid sequence of 924 base pairs, and SEQ ID NO: 12 is encoded by SEQ ID NO: 13 – a nucleic acid sequence of 810 bp. These sequences are not identical in length, which would suggest that the difference(s) between the two is not simply the result of codon optimization:
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Translation of SEQ ID NO: 6 and SEQ ID NO: 13 show that they do not encode the same protein sequence, and only the translation of SEQ ID NO:13 results in the protein of SEQ ID NOs: 5 and 12:
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Thus, it is unclear what amino acid sequence is encompassed by SEQ ID NO: 5 and/or 12, and which one encodes a TCR alpha variable domain, and which one encodes a TCR beta chain variable domain?
Applicant is required to review the specification, drawings, and sequence listing, and ensure the sequences recited for each SEQ ID NO are the correct nucleotide and/or amin acid sequences for the encoded product. Applicant is further required to ensure any changes do not introduce new matter.
Appropriate correction is required.
CLAIMS
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Independent claim 25 is directed to a method of making a recombinant T cell that expresses a heterologous TCR gene targeted to NY-ESO-1, and wherein the cell comprises nucleic acids capable of downregulating gene expression from one or more of the endogenous TCR alpha and/or TCR beta genes.
Dependent claim 32 requires the endogenous TCR alpha and beta genes comprise SEQ ID NOs 128 and 129, respectively. The specification discloses SEQ ID NO:128 is encoded within the human TCR alpha gene (Sequence listing; Examples). Thus, prior art which teaches a modification to human TCR alpha genes will read on this limitation. The specification discloses SEQ ID NO:129 is encoded within the human TCR beta gene DNA (Sequence listing; Examples). Thus, prior art which teaches a modification to human TCR beta genes will read on this limitation.
Dependent claim 33 requires the endogenous PD-1 gene comprises SEQ ID NO: 130. The specification discloses SEQ ID NO:130 is encoded within the human PD-1 gene (Sequence listing; Examples). Thus, prior art which teaches a modification to human PD-1 genes will read on this limitation.
Claim Objections
Claim 33 is objected to because of the following informalities:
Claim 33 recites, “comprising” in line 1 instead of “comprises.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 30-31 and 36-41 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 30 recites the limitation "the one or more nucleic acids capable of downregulating gene expression" in lines 1-2.
Claim 30 is dependent upon claim 29, which is dependent upon claim 25:
Claim 25 requires the method comprises introducing “one or more nucleic acids capable of downregulating gene expression” of the TCR alpha and/or TCR beta genes in lines 4-5.
Claim 29 requires the method further comprises introducing “a nucleic acid capable of down regulating gene expression” the PD-1 gene.
It is unclear if claim 30 is referring back only to the “one or more nucleic acids” recited in claim 25, or if the claim is attempting to encompass both the nucleic acids of claim 25 and claim 29. This is a lack of antecedent basis rejection.
Claim 31 is directed to “wherein the exogenous TCR comprises: (i) a TCR alpha chain comprising the amino acid sequence set forth in SEQ ID NO:5; and/or (ii) a TCR beta chain comprising the amino acid sequence set forth in SEQ ID NO: 12.” It is not clear from the sequence listing or specification what the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 12 actually comprises.
The sequence listing of record 07/07/2023, v. 1.1 lists :
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SEQ ID NO: 5 as: and SEQ ID NO: 12 as:
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SEQ ID NO: 5 is identical to SEQ ID NO: 12:
It would be highly unlikely that the variable region of a TCR alpha chain is identical to the variable region of a TCR beta chain.
In an attempt to figure out what the amino acid sequences for either SEQ ID NO: 5 or 12 is, the examiner looked into the specification. The published specification at paragraphs [0241] and [0247] discuss SEQ ID NO: 5 and SEQ ID NO: 12, respectively. These sections show the amino acid sequence of SEQ ID NO: 5 and 12 is identical to that of the sequence listing, and are identical to each other:
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However, the specification here also discloses SEQ ID NO: 5 is encoded by SEQ ID NO: 6 – a nucleic acid sequence of 924 base pairs, and SEQ ID NO: 12 is encoded by SEQ ID NO: 13 – a nucleic acid sequence of 810 bp. These sequences are not identical in length, which would suggest that the difference(s) between the two is not simply the result of codon optimization:
Translation of SEQ ID NO: 6 and SEQ ID NO: 13 show that they do not encode the same protein sequence, and only the translation of SEQ ID NO:13 results in the protein of SEQ ID NOs: 5 and 12:
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Thus, it is unclear what amino acid sequence is encompassed by SEQ ID NO: 5 and/or 12, and which one encodes a TCR alpha variable domain, and which one encodes a TCR beta chain variable domain?
Claim 37 recites the limitation "the third polypeptide" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 34 requires wherein the switch receptor comprises:
a first domain, wherein the first domain is derived from a first polypeptide that is associated with a negative signal;
a second domain comprising a switch receptor transmembrane domain; and
a third domain, wherein the third domain is derived from a second polypeptide that is associated with a positive signal.
Claim 38, dependent upon claim 34, requires wherein the switch receptor comprises:
a first domain comprising at least a portion of the extracellular domain of PD 1;
a second domain comprising a switch receptor transmembrane domain comprising at least a portion of the transmembrane domain of CD28; and
a third domain comprising at least a portion of the intracellular domain of CD28.
Because claim 34 already requires “a first domain” “a second domain” and “a third domain”, it is unclear of the recitations of “a first domain” “a second domain” and “a third domain” in claim 38 are additional first, second and third domains? Or is claim 38 attempting to limit the domains recited in claim 34, and should be referring to wherein “the first domain” “the second domain” and “the third domain”?
Claim 39, dependent upon claim 34, requires wherein the switch receptor comprises:
a first domain comprising at least a portion of the extracellular domain of PD-1;
a second domain comprising a switch receptor transmembrane domain comprising at least a portion of the transmembrane domain of CD8alpha; and
a third domain comprising at least a portion of the intracellular domain of 4-1BB.
Claim 39 is rejected for the same reasons as stated above for claim 38.
Claim 40, dependent upon claim 34, requires wherein the switch receptor comprises:
a first domain comprising at least a portion of the extracellular domain of PD-1, wherein the PD-1 is a variant having an alanine-to-leucine substitution at amino acid position 132 relative to the wild-type PD-1 amino acid sequence;
a second domain comprising a switch receptor transmembrane domain comprising at least a portion of the transmembrane domain of CD28; and
a third domain comprising at least a portion of the intracellular domain of CD28.
Claim 40 is rejected for the same reasons as stated above for claim 38.
Claim 41, dependent upon claim 34, requires wherein the switch receptor comprises:
a first domain comprising at least a portion of the extracellular domain of PD-1, wherein the PD-1 is a variant having an alanine-to-leucine substitution at amino acid position 132 relative to the wild-type PD-1 amino acid sequence;
a second domain comprising a switch receptor transmembrane domain comprising at least a portion of the transmembrane domain of CD8alpha; and
a third domain comprising at least a portion of the intracellular domain of 4-1BB.
Claim 41 is rejected for the same reasons as stated above for claim 38.
Claims 36, 40, and 41 encompass embodiments wherein the switch receptor comprises PD-1 peptide variants, wherein the PD-1 is a variant “having an alanine-to-leucine substitution at amino acid position 132 relative to the wild-type PD-1 amino acid sequence” which is indefinite. The phrase is indefinite because the variant is relative to any wild-type PD-1 sequences, which may not have a leucine at position 132. Therefore, a skilled artisan would not know the metes and bounds of the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 25-26, 32 and 43 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US Patent Application Publication No. 2014/0301990 to Gregory, of record, cited on Applicant’s IDS dated 11/09/2023.
With regard to claim 25, Gregory discloses methods of making modified human T cells wherein the endogenous TCR alpha and TCR beta genes have been modified such that the cells have reduced or no expression of endogenous TCR genes, and wherein the human T cell further comprises expression of a heterologous TCR for a tumor antigen (paragraphs [0009]-[0013], [0019], [0193]). Gregory discloses, and reduces to practice, the modified human T cells comprise heterologous nucleic acids which encode an exogenous TCR (comprising both TCR alpha and TCR beta chains), wherein the exogenous TCR is targeted to (has affinity for) tumor antigen NY-ESO-1 (paragraphs [0018], [0046]; FIG 19, Example 11). Thus, Gregory anticipates claim 25.
With regard to claim 26, Gregory discloses the modification of the genome at the endogenous TCR genes comprises the use of a CRISPR system comprising a cas9/gRNA complex (paragraphs [0003], [0015], [0019]-[0022], [0024], [0146], [0162]-[0164], [0184], [0187]-[0188], and [0195]).
With regard to claim 32, as noted in the CLAIMS INTERPRETATION section above, SEQ ID NOs: 128 and 129 are comprised within the human TCR alpha and TCR beta genes, respectively. Gregory discloses wherein the human TCR alpha gene is modified, and FIG 12A shows the targeted portion of the TCR alpha gene, and upstream of the cleavage site is a sequence that partially overlaps with claimed SEQ ID NO: 128. And, of the portion that overlaps, that portion is 100% identical:
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Thus, the human TCR alpha gene of Gregory necessarily comprises SEQ ID NO: 128, absent evidence to the contrary.
Similarly, Gregory discloses the TCR beta gene is targeted, and discloses the sequences which the targeted nucleases bind therein at Table 4. ZFN16787 binds a 28 base pair sequence that has 100% identity within SEQ ID NO: 129:
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Thus, the human TCR beta gene of Gregory necessarily comprises SEQ ID NO: 129, absent evidence to the contrary.
With regard to claim 43, Gregory discloses the T cell is autologous and derived from a human (paragraph [0183], [0250]).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 27-28, 34-35, 37-38 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2014/0301990 to Gregory, of record as applied to claims 25-26, 32 and 43 above, and further in view of WO2013/019615 to Zhao, of record, cited on Applicant’s IDS dated 11/09/2023. Claim 27 is directed to an embodiment wherein the T-cell further encodes a switch receptor.
The disclosure of Gregory is applied as in the 102 rejection above, the content of which is incorporated herein in its entirety. Gregory discloses a method of making a recombinant T cell expressing a heterologous TCR directed against NY-ESO-1 as required by claim 25.
However, Gregory does not disclose wherein the modified T cell further comprises nucleic acids which encode a “switch receptor” as required by instant claim 27.
Zhao discloses “switch receptors” comprise fusion proteins, wherein the fusion protein comprises at least two domains: a first domain associated with a negative signal, and a second domain associated with a positive signal, wherein the switch receptor is expressed in modified T cells (Abstract, pages 2-3). Zhao discloses switch receptors comprising the extracellular PD-1 negative signal domain linked to an intracellular CD28 positive signal domain utilize the PD ligands in the surrounding tumor environment to upregulate the CD28 positive signaling function within the modified T cell (page 1, lines 14-18; page 16, lines 1-9; page 17, lines 21-34, page 18, lines 8-14). Thus, Zhao discloses the switch receptors are able to convert an otherwise negative signal into a positive signal in the cells in order to enhance an immune response (page 4, lines 19-31). Zhao discloses the switch receptors can be coexpressed in cells genetically modified to express a heterologous CAR and/or TCR gene (page 37, lines 16-21). Zhao states, “This technology could easily be incorporated into other trials that are currently using genetically modified T cells with TCRs as well. For example, switch receptors of the invention can be used in the context of T cells with TCRs specific for cancer antigens such as…NY-ESO-1, and it is believed that the including of the switch receptors with these T cells would increase the potency of the T cells” (page 44, line 30 – page 45, line 2).
It would have been obvious to combine the disclosure a modified T cell comprising a heterologous TCR with affinity to NY-ESO-1; an inactivated endogenous TCR alpha, TCR beta, and PD-1 genes according to Gregory with the disclosure of Zhao. A skilled artisan would have been motivated to utilize a switch receptor in a modified T cell because Zhao expressly suggest utilizing the technology in modified T cells, including those expressing TCRs targeted to NY-ISO-1 for an added benefit. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as using switch receptors in modified T cells to improve the immune response of the modified T cells was known in the art at the time of the invention.
With regard to claim 34, Zhao discloses switch receptors comprise 3 distinct domains: a first domain derived from a first polypeptide that is associated with a negative signal, a second domain comprising a transmembrane domain, and a third domain derived from a polypeptide derived from a positive signal (page 1, lines 1-13; page 15 line 15 – page 18, line 6). This claim is obvious for the same reasons as stated above for claim 27.
With regard to claims 35 and 37-38, Zhao discloses the first polypeptide of the switch receptor that is associated with a negative signal is PD-1 (page 16, lines 1-9). Zhao discloses the polypeptide that is associated with a positive signal is CD28 or 4-1BB (page 18, lines 1-6). Zhao also discloses the transmembrane domain is at least a portion of the transmembrane domain of the peptide associated with the negative signal or at least a portion of the transmembrane domain of the peptide associated with the positive signal. Thus claims 35, and 37-38 are obvious for the same reasons as stated above for claim 27.
Claims 28 and 42 require wherein the switch receptor is encoded by the nucleic acids set forth as SEQ ID NO: 15 (claim 28) and comprises the amino acid sequence set forth as SEQ ID NO: 14 (claim 42). SEQ ID NO: 15 is the nucleic acid that encodes the protein of SEQ ID NO: 14.
Zhao discloses a specific switch receptor comprising a PD1 ligand binding domain, a CD28 TM domain, and a CD28 intracellular signaling domain that is encoded by nucleic acid SEQ ID NO: 11 therein.
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Zhao’s SEQ ID NO: 11 is 100% identical to claimed nucleic acid SEQ ID NO: 15:
Thus, translation of Zhao’s SEQ ID NO: 11 results in a protein that is 100% identical to claimed SEQ ID NO: 14. Thus, claims 28 and 42 are obvious for the same reasons as stated above for claim 27.
Claims 36 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2014/0301990 to Gregory, of record in view of WO2013/019615 to Zhao, of record, as applied to claims 25-28, 32, 34-35, 37-38 and 42-43 above, and further in view of US Patent Application Publication No. 2015/0368316 to Lazar-Molnar, of record. Claims 36 and 40 encompass embodiments wherein the switch receptors comprise a PD-1 domain associated with a negative signal, wherein the PD-1 peptide comprises an alanine-to-leucine substitution at amino acid position 132 relative to wild type.
The disclosures of Gregory and Zhao are applied as in the 102 and 103 rejections above, the content of which are incorporated herein in their entirety. Gregory in view of Zhao render obvious a method of making a recombinant T cell expressing a heterologous TCR directed against NY-ESO-1, wherein the T cell further encodes and expresses a switch receptor, wherein the switch receptor comprises a PD-1 domain as required by claims 27 and 34.
Zhao discloses the ligands for PD-1 are expressed in the tumor microenvironment, and that the switch receptors comprising the PD-1 extracellular negative signal domain linked to a intracellular positive signal domain utilize the extracellular PD ligands in the surrounding tumor environment to upregulate the positive signaling function within the modified T cell (page 1, lines 14-18; page 16, lines 1-9; page 17, lines 21-34, page 18, lines 8-14). Zhao discloses any wild type or variant of PD-1 can be utilized, as long as it maintains binding to its natural ligands (page 16, lines 1-9).
However, none of Gregory or Zhao disclose a PD-1 peptide comprising an alanine-to-leucine substitution at position 132 relative to wild type, as required by instant claims 36 and 40.
Lazar-Molnar discloses PD-1 mutant peptides (abstract). Lazar-Molnar discloses a PD-1 mutant comprising an alanine to leucine substitution relative to wildtype, wherein the A132L mutant has increased binding affinity for PD ligands (paragraphs [0008], [0020], [0054]).
It would have been obvious to combine the disclosures of Gregory and Zhao on methods of making modified T cells expressing switch receptors comprising a PD-1 extracellular domain that binds PD ligands to activate intracellular CD28 signaling, further with the disclosure of Lazar-Molnar on PD-1 mutants comprising a A132L substitution. A skilled artisan would have been motivated to use the A132L PD-1 peptide because Lazar-Molnar discloses the A132L mutant has higher binding affinity for PD-1 ligands. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as switch receptors comprising PD-1 domains were known in the art at the time of the invention.
Claims 29-30 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2014/0301990 to Gregory of record as applied to claims 25-26, 32 and 43 above, and further in view of and further in view of US Patent Application Publication No. 2014/0120622 “the ‘622 Application” of record. Claim 29 encompasses an embodiment wherein the modified T cells further comprise a modification to the endogenous PD-1 gene, wherein the expression of endogenous PD-1 is downregulated.
The disclosure of Gregory is applied as in the 102 rejection above, the content of which is incorporated herein in its entirety. Gregory discloses a method of making a recombinant T cell expressing a heterologous TCR directed against NY-ESO-1, and wherein the T cell comprises nucleic acids which downregulate expression of the endogenous TCR alpha and beta chains as required by claim 25.
However, Gregory does not disclose wherein the modified T cell further comprises nucleic acids which downregulate expression of the endogenous PD-1 coding sequence, as required by claim 29, or wherein the gene encoding PD1 comprises SEQ ID NO: 130, as required by claim 33.
The ‘622 Application discloses modified human T cells expressing heterologous chimeric antigen receptors or chimeric receptors, wherein the T cells comprise alterations in the endogenous PD-1 gene sequence which results in a reduction in PD-1 expression (Abstract; paragraphs [0010], [0016]-[0018], Example 3). Thus, the ‘622 Application necessarily discloses the PD1 gene comprises a sequence identical to SEQ ID NO: 130. The ‘622 Application teaches that endogenous PD-1 expression from modified T cells can cause de-activation of the T cell and/or desensitization of the modified T cell, and/or allow cancer cells to avoid an immune response, and that reducing endogenous PD-1 expression aids at overcoming these problems (paragraphs [0007]-[0008], [0027]), thereby conferring to the T cell resistance to an immunosuppressive PD-1 signal.
The ‘622 Application further teaches that the modified T cells comprise alterations in their endogenous TCR alpha and beta genes which renders the endogenous genes non-functional (paragraphs [0017], [0180]). The ‘622 Application discloses the modified T cells further comprise a heterologous TCR and chimeric antigen receptor (CAR), wherein the heterologous TCR has affinity to a Tumor Associated Antigen (TAA) (paragraphs [0018]-[0020]).
It would have been obvious to combine the disclosure of Gregory on modified human T cells comprising a heterologous TCR receptor directed towards NY-ESO-1, further with the disclosure of the ‘622 Application, and inactivate the endogenous PD-1 gene such that the endogenous PD-1 expression is reduced, wherein the PD1 gene comprises SEQ ID NO: 130. A skilled artisan would be motivated to do so because the ‘622 Application discloses the reduction of endogenous PD-1 expression aids in overcoming known problems associated with modified T cell immunotherapies. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention because inactivating the endogenous PD-1 gene in human T cells for immunotherapy was known in the art at the time of the invention.
With regard to claim 30, Gregory discloses the modification of the genome at the endogenous TCR genes comprises the use of a CRISPR system comprising a cas9/gRNA complex (paragraphs [0003], [0015], [0019]-[0022], [0024], [0146], [0162]-[0164], [0184], [0187]-[0188], and [0195]). Thus, it would have been obvious to use a CRISPR system to generate the modifications which result in the downregulation of PD-1 expression.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2014/0301990 to Gregory, of record as applied to claims 25-26, 32 and 43 above, and further in view of WO2006/031221 to Morgan, of record.
The disclosure of Gregory is applied as in the 102 rejection above, the content of which is incorporated herein in its entirety. Gregory discloses a method of making a recombinant T cell expressing a heterologous TCR directed against NY-ESO-1, as required by claim 25.
However, Gregory does not disclose wherein the heterologous TCR targeted to NY-ESO-1 comprises a TCR alpha variable region comprising SEQ ID NO: 5 and a TCR beta variable region comprising SEQ ID NO: 12, as required by instant claim 31. In light of the 112b rejection above, SEQ ID NO: 5 is interpreted to be the translation of nucleic acid SEQ ID NO: 6 of the specification.
Morgan discloses T cell receptors targeted to NY-ESO-1, wherein the TCR alpha variable region comprises SEQ ID NO: 6 therein and the TCR beta variable region comprise SEQ ID NO: 8, therein. Morgan’s SEQ ID NOs.: 6 is 100% identical to the translation of SEQ ID NO: 6 of the instant specification. Morgan’s SEQ ID NO: 8 is 100% identical to instantly claimed SEQ ID NO: 12 (paragraph [0019]). Morgan discloses the TCRs targeting NY-ESO-1 can be heterologously expressed from modified T cells (paragraphs [0014], [0019]).
It would have been obvious to combine the disclosure of Gregory on modified human T cells comprising a heterologous TCR directed towards NY-ESO-1, further with the disclosure of Morgan on TCR sequences with affinity to NY-ESO-1. A person of ordinary skill in the art would have had a reasonable expectation of success in substituting Morgan’s TCRs directed to NY-ESO-1 for Gregory’s TCRs directed toward NY-ESO-1 because both are explicitly taught as being useful for being expressed from modified T cells. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Claims 39 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2014/0301990 to Gregory, of record, and WO2013/019615 to Zhao, of record, as applied to claims 25-28, 32, 34-35, 37-38 and 42-43 above, and further in view of in view of US Patent Application Publication No. 2014/0120622 “the ‘622 Application” of record, and US Patent Application Publication No. 2015/0368316 to Lazar-Molnar, of record.
The claims encompass embodiments wherein the modified T cell further comprises nucleic acids which encode a switch receptor comprising a transmembrane domain from CD8alpha (claims 39 and 41), and further wherein the switch receptors comprise a PD-1 domain associated with a negative signal, wherein the PD-1 peptide comprises an alanine-to-leucine substitution at amino acid position 132 relative to wild type (claim 41).
The disclosures of Gregory and Zhao are applied as in the 102 and 103 rejections above, the content of which are incorporated herein in their entirety. Gregory in view of Zhao render obvious a method of making a recombinant T cell expressing a heterologous TCR directed against NY-ESO-1, wherein the T cell further encodes and expresses a switch receptor, and wherein the switch receptor comprises a PD-1 domain as required by claims 27 and 34.
Zhao discloses switch receptors are chimeric receptors that comprise 3 distinct domains: a first domain derived from a first polypeptide that is associated with a negative signal, a second domain comprising a transmembrane domain, and an intracellular third domain derived from a polypeptide derived from a positive signal (page 1, lines 1-13; page 15 line 15 – page 18, line 6). The first domain is an extracellular ligand binding domain derived from a protein or receptor, which transmits its signal through a second domain, which comprises the transmembrane domain, to the third domain, a positive signaling domain, to then transmit a positive signal into the cell (page 4, lines 19-31, page 15, line 15- page 16, line 18).
Specific intracellular signaling domains include those from CD28, ICOS, 4-1BB and TCRzeta (page 18, lines 6). Specific transmembrane domains include those from CD28, ICOS, 4-1BB and TCRzeta (FIG 1A).
Zhao discloses the ligands for PD-1 are expressed in the tumor microenvironment, and that the switch receptors comprising the PD-1 extracellular negative signal domain linked to an intracellular positive signal domain utilize the extracellular PD ligands in the surrounding tumor environment to upregulate the positive signaling function within the modified T cell (page 1, lines 14-18; page 16, lines 1-9; page 17, lines 21-34, page 18, lines 8-14). Zhao discloses any wild type or variant of PD-1 can be utilized, as long as it maintains binding to its natural ligands (page 16, lines 1-9).
However, neither Gregory or Zhao disclose wherein the transmembrane domain of the switch receptor is from CD8alpha as required by claims 39 and 41, or wherein the switch receptor comprises a PD-1 peptide comprising an alanine-to-leucine substitution at position 132 relative to wild type, as required by instant claim 41.
The ‘622 Application discloses chimeric receptors (CARs) comprises fusion proteins comprising at least 3 domains: an extracellular “specificity” or “binding” domain operably linked to a transmembrane domain, linked to an intracellular signaling domain that transmits signal into the cell (paragraphs [0065]). The extracellular binding domain comprises antibody fragments as the “specificity” or “binding” extracellular domain, or alternatively is derived from extracellular peptides or receptors (such as cytokines) (paragraph [0065]). The intracellular signaling domain comprises signaling domains from CD28, ICOS, 4-1BB or TCRzeta (CD3 zeta) (paragraphs [0065]-[0067]). The ‘622 Application discloses the transmembrane domains can be derived from CD8 or CD28 (page [0065]). Thus, the CARs of the ‘622 Applicant appear to encompass “switch receptors” according to Zhao.
Lazar-Molnar discloses PD-1 mutant peptides (abstract). Lazar-Molnar discloses a PD-1 mutant comprising an alanine to leucine substitution relative to wildtype, wherein the A132L mutant has increased binding affinity for PD ligands (paragraphs [0008], [0020], [0054]).
It would have been obvious to combine the disclosures of Gregory and Zhao on methods of making a modified T cell expressing a heterologous TCR targeting NY-ESO-1 and a switch receptor that binds PD1 ligand, further with the disclosures of the ‘622 Application and Lazar-Molnar. It would have been obvious to use either a CD28 or CD8 transmembrane domain in the switch receptors. Zhao does not limit the negative or positive peptides, and the CAR receptors of the ‘622 Application disclose known transmembrane domains for chimeric peptides that are encompassed by the instant claims. Thus, a skilled artisan would have success in substituting the transmembrane domains of the ‘622 application for the transmembrane domains of Zhao, as both CD8 and Cd28 transmembrane domains are explicitly taught as being useful for generating fusion peptides in modified T cells. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
It would have been further obvious to combine the disclosures of Gregory and Zhao on methods of making modified T cells expressing switch receptors comprising a PD-1 extracellular domain that binds PD ligands to activate intracellular CD28 signaling, further with the disclosure of Lazar-Molnar on PD-1 mutants comprising a A132L substitution. A skilled artisan would have been motivated to use the A132L PD-1 peptide because Lazar-Molnar discloses the A132L mutant has higher binding affinity for PD-1 ligands. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as switch receptors comprising PD-1 domains were known in the art at the time of the invention.
Conclusion
No claims are allowed.
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