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 Claims
Claims 1-20 are currently pending and under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 10/27/2020 based on the provisional application 63/106,122 (filed 10/27/2020).
Information Disclosure Statement
The information disclosure statements (IDS) submitted are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
The term “MDN promoter” has been disclosed with seven occurrences on Pg. 4, 8, 118 and 122 of the instant specification. The term “MND promoter” has also been disclosed in the specification on Pg. 15, 16, 44, 47 48, 135-138 (38 occurrences). Unless these refer to two different promoters, the specification should be amended to recite the correct term throughout for consistency.
On Pg. 13 line 16 and line 27, there appear to be typographical errors for the phrase “Format 1 used in Figure 6” in line 16 and “Format 1 used in Figure 7” in line 27 respectively. These phrases should be amended to “Format 3 used in Figure 6” in line 16 and “Format 3 used in Figure 7 in line 27 respectively.
Appropriate correction is required.
Claim Objections
Claims 4 and 13 are objected to because of the following informalities:
Claims 4 and 13 recite in lines 2 “a cytokine receptors trap”. There appears to be a typographical error in which “receptors” should be amended to “receptor”.
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 2 and 7 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 2 is rejected because the claim recites in line 6 the phrase “MDN promoter”. The metes-and-bounds of the claim is unclear because it is unclear what is meant by the “MDN promoter”. It is noted that “MND promoter” is known in the art and where MND is the abbreviation for “myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted”. The instant specification discloses both “MDN promoter” and “MND promoter” throughout the disclosure. (See specification objection above).
Claim 7 recites “The cell of claim 7” in line 1. The metes and bounds of the claim are unclear because what is being further limited by the claim is not clear when dependency is on itself.
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.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over by Moriarity et al. (WO2017023803 Date Published 2017-02-09) in view of Minshull et al. (WO2015157579A2 Date Published 2015-10-15), Albers et al. (Life science alliance 2.2, 2019), Giering et al. (Molecular Therapy, Volume 16, Issue 9, 1630–1636, 2008) and Powell et al. (Discov Med. 2015 Jan;19(102):49-57)
Moriarity et al. teaches genetically modified compositions, including non-viral vectors and T cells, for treating cancer and the methods of making and using the said genetically modified compositions in treating cancer (Abstract). They teach engineered or genetically modified cells (claim 1 and paragraph [0005]) comprising an exogenous polynucleic acid that is introduced into the cell genome (paragraphs [0020] and [00261]) wherein the insertion of the polynucleic acid sequence, also known as a transgene or an exogenous sequence, may be assisted by an exogenous enhancer (paragraphs [00359] and [00363]), and wherein the exogenous sequence may comprise an insulator (paragraph [00363]), a nucleic acid sequence encoding an exogenous TCR (paragraphs [00361] and Table 10 page 134), and a nucleic acid sequence encoding a protein of interest which can be within the same vector as the TCR (paragraphs [00421]), wherein the transgenes may be inserted into a specific locus of the genome of the cell (paragraphs [00256]) where said locus can be adjacent to an endogenous promoter, so that it is under the control of said endogenous promoter (paragraphs [00250) and [00279]), and the vector may include an exogenous promoter, such that the protein of interest is under the control of the said exogenous promoter (paragraphs [0016]).
Moriarity et al. also teaches a vector may comprise a sequence encoding the woodchuck hepatitis virus post-transcriptional regulatory element, which is a sequence that stimulates the expression of transgenes via increased nuclear export (paragraph [00247] and FIG. 3). They teach that the promoter can be constitutive (paragraph [0016]), the promoter can be an MND, an U6, or an EF1a promoter (paragraph [0016]) and the exogenous promoter can be inducible (paragraph [00281]). They also teach that the polynucleic acid can comprise a pair of recombination or homology arms that are homologous to a portion of the gene into which the TCR sequence is inserted (paragraphs [008], [0033] and FIG. 3) and wherein the insertion can be at a TRAC or TRBC gene locus (paragraphs [0008], [0020], [0050], [00352], [00414], and Table 9 page 133).
Moriarity et al. also teaches that targeted insertion of non-coding nucleic acid sequence such as sequences encoding antisense RNAs, RNAi, shRNAs and micro RNAs (miRNAs) may also be used to achieve targeted insertions into the cell genome (paragraphs [0269] and [00360]). They teach that shRNA, siRNA, RNAi, and/or microRNA can be included in the transgene to be delivered to a T cell to suppress genetic expression of a particular gene or genes (paragraph [0277]). They also teach that the transgene can express a TCR recognizing and binding at least one cancer epitope or a mutated epitope on an antigen such as a cancer neo-antigen (paragraphs [00241], [00264] and [00348]).
Moriarity et al. also teaches in FIG. 84 a rAAV polynucleotide encoding an exogenous TCR flanked by 900bp homology arms to an endogenous immune checkpoint locus such as CYLA4 and PD1 (paragraph [00136]). They teach that transgenes can express a TCRα and/or TCRβ chains that can recognize and bind to a cancer epitope or bind to a mutated epitope on an antigen (paragraph [00264]). They also teach that the exogenous sequences may also include sequences encoding 2A peptides and/or the polyadenylation signal sequence (paragraph [00363]). They further teach that a vector can encode transgenes, and that a polynucleotide can be introduced into a cell as part of a vector molecule (paragraphs [0358] and [0359]).
Moriarity et al. also teaches a method comprising introducing into the cell one or more nucleic acids wherein the nucleic acid can be a vector (paragraph [00243 and [00247]). They also teach generation of engineered T cells that express engineered TCRs by electroporation of T cells followed by using gene editing methods that can perform homologous recombination of the exogenous nucleic acids or targeting vector into the cell genome (paragraphs [0050], [00125], [00211], [00504] and Table 2). They further teach that cytokines IL-2, IL-7, and IL-15 are used to culture the engineered T cells (paragraph [00196]).
Moriarity et al. also teaches a pharmaceutical composition comprising a T cell together with a pharmaceutically acceptable carrier or excipient (paragraphs [0050] and [00450]). They teach a method of treating cancer in a recipient comprising transplanting to the recipient one or more cells comprising engineered cells (paragraphs [0051], [00512], [00190], [00453] and [00454]-[00456]). They also teach that the cancer can be breast cancer, esophageal cancer, gastrointestinal cancer, hematopoietic malignancy, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, prostate cancer, sarcoma or stomach cancer (paragraph [0052]).
Moriarity et al. teaches cells comprising exogenous polynucleotides with various components and potential combinations thereof that are recited in instant claims which include an exogenous enhancer, an insulator, a sequence encoding an exogenous TCR, and a sequence encoding at least one Payload, a Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE) and an exogenous promoter consisting of an MND promoter, an EF 1a promoter, or a U6 promoter, wherein the exogenous polynucleotide can be integrated at an endogenous locus within the genome of the cell, wherein the sequence encoding an exogenous TCR can be under control of an endogenous promoter and the sequence encoding at least one Payload can be under control of an exogenous promoter, wherein the at least one Payload can be an inhibitory RNA molecule including shRNA and miRNA (microRNA), wherein the exogenous TCR recognizes a cancer neoantigen, wherein the endogenous locus within the genome of the cell can be a TCR locus, wherein the exogenous TCR is flanked by homology arms to an endogenous immune checkpoint locus, wherein the sequence encoding an exogenous TCR comprises a TCRα gene sequence and a TCRβ gene sequence, and wherein the sequence encoding an exogenous TCR can further comprise a sequence encoding a signal sequence (polyadenylation), and Moriarity et al. also teaches a vector comprising the said polynucleotide sequences or combinations thereof. However, Moriarity et al. does not teach a cell comprising all of the components of an exogenous enhancer, an insulator, a sequence encoding an exogenous TCR, and a sequence encoding at least one Payload, wherein the exogenous polynucleotide is integrated at an endogenous locus within the genome of the cell, wherein the sequence encoding an exogenous TCR is under control of an endogenous promoter and the sequence encoding at least one Payload is under control of an exogenous promoter as recited in claim 1. Moriarity et al. also does not teach a polynucleotide comprising all of the components of an exogenous enhancer, an insulator, a first homology arm, a second homology arm, a sequence encoding an exogenous TCR, and a sequence encoding at least one Payload, wherein the first and second homology arms are homologous to a TRAC or TRBC locus and wherein the sequence encoding at least one Payload is under control of an exogenous promoter as recited in claim 10.
Moriarity et al. also does not specifically teach the cell of instant claim 1 wherein the WPRE comprises the nucleotide sequence set forth in instant SEQ ID NO: 20; or wherein the 3' of the at least one Payload comprises a) a STOP codon; and/or c) a poly-adenylation sequence; or a kit comprising the cell of claim 1.
However, these deficiencies are made up in the teachings of Minshull et al., Giering et al., and Powell et al. .
Minshull et al. teaches polynucleotide vectors for high expression of heterologous genes, and methods for constructing such vectors that can be used in a gene transfer system for stably introducing nucleic acids into the DNA of a cell (Abstract). Minshull et al. also teach the HS4 insulator sequence of SEQ ID NO: 113 (length of 246 nucleotides; paragraph [00132]) which has 100% identity from residues 1 to 244 when compared to the instant insulator nucleotide sequence as set forth in SEQ ID NO: 18 (length of 244 nucleotides; see alignment below where the top sequence is instant SEQ ID NO: 18 and the bottom sequence is SEQ ID NO: 113 of Minshull et al.).
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One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making and using a cell comprising an exogenous polynucleotide comprising an exogenous enhancer, an insulator, a sequence encoding an exogenous TCR, and a sequence encoding at least one Payload, wherein the exogenous polynucleotide is integrated at an endogenous locus within the genome of the cell, wherein the sequence encoding an exogenous TCR is under control of an endogenous promoter and the sequence encoding at least one Payload is under control of an exogenous promoter as taught by Moriarity et al., because Moriarity et al. teaches that the exogenous TCR that comprises a cancer specific neo-antigen TCR, one that can recognize unique tumor-specific mutations in a patient’s tumor, would have a broader application to treat any type of tumor, including solid tumors within a patient (paragraphs [0002] and [0003]). Moriarity et al. also teaches that integrating the exogenous TCR at an endogenous locus can disrupt or remove the genomic nucleic acid sequence thus replacing said endogenous gene with the polynucleotide encoding the exogenous cancer specific TCR (paragraph [0034]). In addition, Albers et al. teaches that under the control of the endogenous promoter of the TRAC locus, the correctly integrated TCR2.5D6 which recognizes a myeloperoxidase-derived peptide in myeloid neoplasias, omitted the need for exogenous regulatory elements that risk insertional mutagenesis (Pg. 2 column right, paragraph first, lines 1-10). Furthermore, Moriarity et al. teaches that a homologous recombination enhancer can block non-homologous end joining so that homology directed repair is performed to repair a double strand break (paragraph [00355]), while Minshull et al. teaches that insulators are able to reduce or prevent the spread of condensed heterochromatin thereby improving heterologous gene expression (paragraphs [0014] and [00132]), and Moriarity et al. also teaches that shRNA or miRNA comprised in the exogenous polynucleic acid can be used to suppress genetic expression of any gene of choice in the cell, specifically suppressing genes involved in immune checkpoints (paragraph [00277]) thus making these appropriate Payload(s). Moreover, Moriarity et al. further teaches that exogenous promoters can control the efficiency of gene transcription (paragraph [00246]) which is confirmed by the teachings of Giering et al. which describes that the U6 promoter is the standard for use in driving shRNA expression as shown by the U6-driven shRNA producing 82% silencing when compared to other tested promoters that performed at a reduced level (Pg. 1630 column left paragraph second, Pg. 1632 column right paragraph spanning and Pg. 1631 Figure 1b).
Further, one of ordinary skill in the art would also have been motivated, with a reasonable expectation of success, to perform a combined method of making and using a polynucleotide comprising an exogenous enhancer, an insulator, a first homology arm, a second homology arm, a sequence encoding an exogenous TCR, and a sequence encoding at least one Payload, wherein the first and second homology arms are homologous to a TRAC or TRBC locus and wherein the sequence encoding at least one Payload is under control of an exogenous promoter as taught by Moriarity et al., and wherein the sequence encoding an exogenous TCR comprises a TCRα and/or TCRβ chains that can recognize and bind to a cancer epitope as taught by Moriarity, because in addition to the advantages described above by Moriarity et al. for a polynucleotide that comprises an exogenous enhancer, an insulator, a sequence encoding an exogenous TCR that can recognize and bind to a cancer epitope, and a sequence encoding at least one Payload, Moriarity et al. also teaches that homology arms, one on either side of the TCR transgene, facilitated the successful integration of the target TCR at the CCR5 gene (paragraph [0068]). In addition, because Moriarity et al. further teaches in Table 9 that the engineered TCR can be inserted into endogenous TRAC gene locus (SEQ ID NO. 146), it is obvious that homology arms that are homologous to a TRAC locus can be comprised within the polynucleotide to arrive at the claimed polynucleotide of claim 10.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making and using a cell comprising an exogenous polynucleotide comprising an exogenous enhancer, an insulator, a sequence encoding an exogenous TCR, and a sequence encoding at least one Payload, wherein the exogenous polynucleotide is integrated at an endogenous locus within the genome of the cell, wherein the sequence encoding an exogenous TCR is under control of an endogenous promoter and the sequence encoding at least one Payload is under control of an exogenous promoter as taught by Moriarity et al., and combine it with the insulator comprising the nucleotide sequence as set forth in SEQ ID NO: 113 taught by Minshull et al., because Minshull et al. teaches that HS4 insulators are able to reduce or prevent the spread of condensed heterochromatin or the interference between one expression control region and another that might otherwise silence expression and prevent interference from a distal enhancer on a promoter, thereby improving heterologous gene expression (paragraphs [0014] and [00132]). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to claim 5, since Moriarity et al. teaches that exogenous sequences may also include sequences encoding polyadenylation signals (paragraph [00363]) and that a stop codon can be inserted in one or more transgenes (paragraph [00299]), it would have been obvious to a person of ordinary skill in the art to perform the method of making and using a cell that comprises an exogenous polynucleotide comprising at least one Payload as taught by Moriarity et al. wherein the polynucleotide comprises a STOP codon or a sequence encoding a polyadenylation sequence as taught by Moriarity et al. and wherein the STOP codon or the polyadenylation sequence is positioned at the 3’ end of the at least one Payload, because having a STOP codon sequence or a polyadenylation sequence at the 3’ end of a nucleotide sequence is a common and established practice in the design of vectors in the field of molecular biology. In addition, Moriarity et al. teaches that a vector comprising polyadenylation possesses additional expression control for the vector (paragraph [00341]).
With regards to claim 12, it would be obvious to perform the combined method of making a polynucleotide wherein the sequence encoding an exogenous TCR as taught by Moriarity et al. further comprises a sequence encoding a sequence encoding the polyadenylation signal sequence as taught by Moriarity et al. because Powell et al. teaches that polyadenylation of a transcript is critical for nuclear export, translation, and mRNA stability of a transgene (Pg. 5 lines 1-2).
With regards to claim 13, it would be obvious to perform the combined method of making a vector comprising an exogenous enhancer, an insulator, a first homology arm, a second homology arm, a sequence encoding an exogenous TCR, and a sequence encoding at least one Payload, wherein the first and second homology arms are homologous to a TRAC or TRBC locus and wherein the sequence encoding at least one Payload is under control of an exogenous promoter as taught by Moriarity et al., because Moriarity et al. teaches a vector can encode transgenes, and that a polynucleotide can be introduced into a cell as part of a vector molecule (paragraphs [0358] and [0359]).
With regards to claims 15 and 16, it would be obvious to generate the modified cell of the combined method by electroporation of T cells with the polynucleotide comprising an exogenous enhancer, an insulator, a first homology arm, a second homology arm, a sequence encoding an exogenous TCR, and a sequence encoding at least one Payload, wherein the Payload is an inhibitory RNA molecule, wherein the first and second homology arms are homologous to a TRAC or TRBC locus and wherein the sequence encoding at least one Payload is under control of an exogenous promoter as taught by Moriarity et al., followed by using gene editing methods that can perform homologous recombination of the exogenous nucleic acids or targeting vector into the cell genome (paragraphs [0050], [00125], [00211], [00504] and Table 2) and further comprising culturing the cells in the presence of cytokines IL-2, IL-7, and IL-15 (paragraph [00196]) because Moriarity et al. teaches generation of engineered T cells that express engineered TCRs by electroporation of T cells followed by using gene editing methods that can perform homologous recombination of the exogenous nucleic acids or targeting vector into the cell genome (paragraphs [0050], [00125], [00211], [00504] and Table 2). They further teach that cytokines IL-2, IL-7, and IL-15 are used to culture the engineered T cells (paragraph [00196]).
With regards to claim 17, it would have been obvious to perform the combined method of making a composition comprising an effective amount of the cell generated by the combined method of Moriarity et al. as described above, wherein the composition is a pharmaceutical composition that further comprises a pharmaceutically acceptable excipient because Moriarity et al. teaches a pharmaceutical composition comprising a T cell and at least one excipient (paragraphs [0051] and [00450]), and that a subject in need thereof receives treatment comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an engineered cell (paragraphs 0012] and [0038]).
With regards to claims 18 and 19, it would have been obvious to perform a method of treating cancer in a subject comprising administering a therapeutically effective amount of the cell of the combined method comprising an exogenous TCR that can bind to cancer neo-antigens, since Moriarity et al. teaches that genetically modified cells comprising an exogenous TCR that can bind to cancer neo-antigens can treat cancers including breast cancer, esophageal cancer, gastrointestinal cancer, hematopoietic malignancy, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, prostate cancer, sarcoma or stomach cancer (paragraph [0052]).
With regards to claim 20, it would also be obvious to generate a kit comprising a cell of the combined method because a kit would facilitate the administration of the cells to a subject in a manner that reduces preparation time, minimizes errors and improves patient safety.
Taken all together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yie-Chia Lee (Tonya) whose telephone number is (571)272-0123. The examiner can normally be reached Monday - Friday 7.30a - 3.30p Eastern Time Zone.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642