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 .
DETAILED ACTION
Amendments
In the reply filed 07/02/2025, Applicant has amended claims 12, 29, 34 and 41, canceled claims 30 and 35.
Reminder of Election/Restriction
In the reply filed on 12/30/2024, Applicant has elected KLF4 in claim 25, SEQ ID NO: 62 in claim 26, and SEQ ID NO: 62 in claim 27, with traverse. The requirement has been made FINAL.
Claim Status
Claims 12, 23-29, 31-34 and 36-41 are pending and are considered on the merits.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 12, 23-29, 31-34 and 36-41 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for reciting an ambiguous term “a TF barcode” has been withdrawn in light of Applicant’s amendment.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 12, 24-25, 28-29, 31-32, 34 and 36-40 under 35 U.S.C. 103 as being unpatentable over Sack et al., (Cell. 2018; 173: 499-514 and Methods e1-e13 and Tables S1 and S4. Cited in IDS) has been withdrawn in light of Applicant’s amendment to recite the limitation “the barcode nucleic acid is located about 200 base pairs upstream of the 3'-LTR region”.
The prior rejection of claims 26-27 under 35 U.S.C. 103 as being unpatentable over Sack et al., (Cell. 2018; 173: 499-514 and Methods e1-e13 and Tables S1 and S4. Cited in IDS) in view of NCBI (Alignment of human KLF4 NM_004235 with instant SEQ ID NO: 62, p. 1-6, prior art of record) has been withdrawn in light of Applicant’s amendment to recite the limitation “the barcode nucleic acid is located about 200 base pairs upstream of the 3'-LTR region”.
The prior rejection of claim 41 under 35 U.S.C. 103 as being unpatentable over Sack et al., (Cell. 2018; 173: 499-514 and Methods e1-e13 and Tables S1 and S4. Cited in IDS) in view of NCBI (Alignment of human KLF4 NM_004235 with instant SEQ ID NO: 62, p. 1-6, prior art of record) has been withdrawn in light of Applicant’s amendment to recite the limitation “the barcode nucleic acid is located about 200 base pairs upstream of the 3'-LTR region”.
New 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 12, 23-25, 28-29, 31-34 and 36-40 are rejected under 35 U.S.C. 103 as being unpatentable over Sack et al., (Cell. 2018; 173: 499-514 and Methods e1-e13 and Tables S1 and S4. Cited in IDS) in view of Adamson et al., (Cell. 2016; 167: 1867-1882. Cited in IDS) and Invitrogen (pcDNA3.1 information sheet, published 2010, p. 1-23. Prior art of record).
It is noted that the prior rejection of claims 23 and 33-34 has been maintained and incorporated into the following rejection.
With respect to claim 12, Sack teaches construction of barcoded genome-scale ORF expression libraries for performing gain-of-function screens (see cover page “Highlights”). Sack teaches two human ORF expression libraries are transduced into human mammary epithelial cell (HMEC) clones and human pancreatic nestin-expressing epithelial cells (HPNEs) and performs screens with both ORF libraries in the rtTA-HMEC and rtTA-HPNE clonal cell lines (p. 500 – p. 502, left col), related to the preamble of claim 12.
In regard to (a) a library of polynucleotides, Sack teaches two libraries (Library 1 and 2) contain nearly 30,000 ORFs, corresponding to more than 16,000 unique full-length genes (Table S1) (p. 500). In regard to (a) (i) a transcription factor (TF) ORF, Sack teaches the polynucleotides comprise TF ORFs (see e.g. Fig 3F showing transcription factor ORFs such as MYC, and see Table S1 in the last two pages for TF ORFs such as KLF4). In regard to (a) (ii) a selectable marker, Sack teaches the polynucleotide comprises a puromycin resistance gene (see Fig 1B for Puro).
In regard to (b) a library of barcode nucleic acids, Sack teaches two barcoded ORF expression libraries comprising libraries of barcode nucleic acids (see Fig 1E for 59115 barcodes in Library 1 and 88668 barcodes in Library 2).
In regard to limitation (c) directed to optional instructions for use, Applicant is reminded that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04 I. Thus, this limitation does not provide any patentable weight in determining patentability of the claimed product.
In regard to the last wherein clause that the TF gene being a wild-type TF gene, Sack teaches the ORF sequences are full-length, wild-type ORFs (p. e10, para 2).
In regard to the limitation wherein when incorporated into a lentiviral vector comprising a 3’-LTR, each barcode nucleic acid is introduced 3’ to the nucleic acid encoding the TF ORF, Sack teaches the polynucleotide is incorporated into a lentiviral vector (see p. 500, left col and p. e4, last para), which comprises a 3’ LTR (see Fig 1B), and teaches the barcode is at the 3’ to the ORF (see Fig 1B diagram).
In regard to the location of the barcode relative to the 3’ LTR and the selectable marker, Sack teaches the lentiviral vector comprises two expression cassettes (a TRE promoter-driving ORF/barcode expression cassette and a PGK promoter-driving Puro selectable marker expression cassette, see Fig 1B), both expression cassettes being inserted in forward orientation between the 5’-LTR and the 3’-LTR, resulting in the TRE-ORF/barcode being upstream of the PGK-Puro (i.e., the barcode being 5’ to the selectable marker) and the PGK-Puro being immediately upstream of the 3’-LTR (see Fig 1B).
However, Sack is silent on the barcode being 3’ to the selectable marker in claim 34.
Nevertheless, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have simply reversed the order of the two expression cassettes so as to obtain the TRE-ORF/barcode being downstream of the PGK-Puro (i.e., the barcode being 3’ to the selectable marker in claim 34) and the TRE-ORF/barcode being immediately upstream of the 3’-LTR with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to make this simple reversal since it has been held that rearranging parts of an invention involves only routine skill in the art. See MPEP 2144.04 VI.
However, Sack is silent on the barcode being located about 200 base pairs upstream of the 3’ LTR in claim 12, nor teach the TF ORF being linked to the selectable marker by a 2A peptide in claim 23 or an EF1A promoter in claim 33.
Adamson teaches a lentiviral vector for genome-scale screening of phenotypic output from single cells (abstract). In regard to the vector, Adamson uses a third-generation lentiviral vector that comprises a polynucleotide sequence of a bicistronic barcode and selectable marker expression cassette comprising, from 5’ to 3’, an EF1A promoter, a selectable marker puromycin resistance gene, T2A, a gene-of-interest, a barcode, and a BGH polyA sequence (see Fig 1B). Thus, Adamson teaches a vector comprising a barcode and selectable marker expression cassette comprising an EF1A promoter in claim 33, a gene-of-interest/barcode being linked to the selectable marker by a 2A peptide in claim 23, and the barcode being 3’ to the selectable marker in claim 34. Adamson teaches the BGH polyA signal is located at the 3’ end of the expression cassette (see Fig 1B) which is amplified from pcDNA3.1(+) from Invitrogen (Cat No: V790-20) (p. e1, last para – p. e2, line 1). Invitrogen pcDNA3.1(+) (V790-20) information sheet teaches the BGH polyA sequence is 224-base-pair in length (bases 1028-1252, see p. 10).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the lentiviral vector comprising two separate expression cassettes for selectable marker and ORF/barcode suggested by Sack, by substituting the two expression cassettes with a single-promoter bicistronic expression cassette as taught by Adamson and choosing the TF ORF as the gene-of-interest in the cassette with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to make this substitution to ensure co-expression of the TF ORF and the selectable marker in the same cell. Furthermore, since Sack’s two-promoter cassettes and Adamson’s single-promoter bicistronic cassette are for the same purpose (i.e., to co-express the selectable marker and the gene-of-interest, such as the TF ORF), the expression cassettes of Sack and Adamson are art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have substituted Sack’s two-promoter cassettes with Adamson’s single-promoter bicistronic cassette. See MPEP 2144.06. Since Adamson has reduced to practice a bicistronic expression cassette comprising, from 5’ to 3’, an EF1A promoter, a selectable marker, T2A, a gene-of-interest, a barcode, and a BGH polyA sequence, one of ordinary skill in the art would have had a reason to substitute with Adamson’s cassette and to choose TF ORF as the gene-of-interest. One of ordinary skill in the art would have appreciated that by making this substitution, the polynucleotide of Sack would have had the TF ORF being operably linked to the selectable marker by a nucleic acid encoding a 2A peptide in claim 23, an EF1A promoter in claim 33, the barcode being 3’ to the selectable marker in claim 34, and the barcode/BGH polyA being immediately upstream of the 3’-LTR of Sack. Since Invitrogen teaches the BGH polyA sequence is 224-base-pair in length (bases 1028-1252, see p. 10), one of ordinary skill in the art would have appreciated that the barcode nucleic acid is located about 200 base pairs (i.e., the length of the BGH polyA) upstream of the 3’-LTR region in claim 12.
In regard to a kit, although Sack in view of Adamson and Invitrogen does not specifically recite a kit, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have combined said components suggested by Sack in view of Adamson and Invitrogen into a kit with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so for the purposes of convenience and economy. Furthermore, since the claimed product merely serves as a support for printed matter (i.e., instructions), no functional relationship exists between the product and the printed matter because MPEP 2111.05 (I)(B) states “For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals.” Thus, the limitation of instructions does not provide any patentable weight in determining patentability of the claimed product.
With respect to claim 24 directed to the TF driving differential expression of more than 100 genes, as stated supra, Sack teaches a TF MYC (see e.g. Fig 3F) and performs RNA-seq analysis on overexpression of MYC (p. e10, “RNA Seq Analysis” and see Fig 4F). Sack teaches in Supplemental Table S4E a list of 919 genes that are differentially expressed driven by MYC overexpression (see Table S4E: GSEA analysis for MYC OE), thus teaches the TF such as MYC drives differential expression of more than 100 genes.
With respect to claim 25 directed to a developmentally critical TF being KLF4, as stated supra, Sack teaches TF KLF4 in Table S1 (see KLF4 in the last two pages).
With respect to claim 28 directed to the library of polynucleotides comprising at least 10 or at least 100 polynucleotides, as stated supra, Sack teaches two libraries (Library 1 and 2) contain nearly 30,000 ORFs, corresponding to more than 16,000 unique full-length genes (Table S1) (p. 500), thus teaches the library of polynucleotides comprises at least 100 polynucleotides.
With respect to claim 29 directed to the vector comprising an expression control element, Sack teaches the lentiviral vector comprises an expression control element (a tetracycline responsive element (TRE, see Fig 1B) or a CMV promoter (see p. e4)) and Adamson teaches the vector comprising an EF1A promoter (see Fig 1B).
With respect to claim 31 directed to the vector being a viral particle, Sack teaches the vector is a lentiviral particle (see p. e4, last para for virus production).
With respect to claim 32 directed to the expression control element comprising a promoter or a 5’ LTR, Sack teaches the lentiviral vector comprises a tetracycline responsive element (TRE, one type of promoter, see Fig 1B) or a CMV promoter (see p. e4) and a 5’ LTR (see Fig 1B), and Adamson teaches the vector comprising an EF1A promoter (see Fig 1B).
With respect to claim 36 directed to a target cell and being in the same kit, and claim 37 directed to the target cell being a human cell, as stated supra, Sack teaches two cell lines, human mammary epithelial cell (HMEC) clones and human pancreatic nestin-expressing epithelial cells (HPNEs) into which the libraries are transduced (p. 500 – p. 502, left col), thus teaches a target cell that is a human cell. Furthermore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the target cell disclosed by Sack into the same kit with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so for the purposes of convenience and economy.
With respect to claims 38, 39 and 40 directed to the contents of the optional instructions, as stated supra, claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04 (I). Furthermore, since the claimed product merely serves as a support for printed matter (i.e., instructions), no functional relationship exists between the product and the printed matter because MPEP 2111.05 (I)(B) states “For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals.” Thus, the limitations in claims 38-40 do not provide any patentable weight in determining patentability of the claimed product and are rejected the same as claim 12 as stated supra.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 07/02/2025 are acknowledged.
Applicant argues that the combination of art would not have been predictable to one of ordinary skill in the art and the cited references do not provide the necessary motivation to modify Adamson to arrive at the claimed vector. The "Perturb-seq vector" of Adamson does not have the claimed structure since the barcode nucleic acid (orange) is NOT located about 200 base pairs upstream of the 3'-LTR region. The region between the 3'-LTR and the GBC includes: mU6 sequence, the sgRNA, the EF1a promoter sequence, the puro sequence, the t2a, and the BFP sequence. And modifying the viral vector structure of Adamson would change its principle of operation or would render it inoperable for its intended purpose because the entire expression region was engineered in reverse orientation that puts a distance between the 3’-LTR and the GBC having the elements cited above. As such, changing the orientation of elements within the "Perturb-seq vector" of Adamson to arrive at the claimed vector would render the "Perturb-seq vector" of Adamson unsatisfactory for its intended purpose, namely to prevent the internal BGH pA from disrupting transcription of the lentiviral genome; and would change the principle of operation of the "Perturb-seq vector," namely the faithful transmission of GBC sequences into single-cell RNAseq libraries and the enhancement of the transduction competency. Therefore, Adamson and Sack do not provide the necessary motivation to modify the "Perturb-seq vector" of Adamson to arrive at the claimed invention (Remarks, p. 8, last para-p. 10).
Applicant’s arguments have been fully considered but they are not persuasive. Therefore, the prior rejection of claims 23 and 33-34 has been maintained. The prior rejections of claims 12, 24-29, 31-32, 34 and 36-41 have been withdrawn in light of Applicant’s amendment, however, as necessitated by amendment, a new ground of rejection has been made over Sack in view of Adamson and Invitrogen.
In response to Applicant’s arguments that the combination of art would not have been predictable and the cited references do not provide the necessary motivation to modify Adamson to arrive at the claimed vector (Remarks, p. 8, last para-p. 10 as recited above), Applicant is reminded that the prior rejection of claims 23 and 33-35 (claim 35 having been incorporated into amended claim 12) is based on Sack, in view of Adamson and Invitrogen. In other words, the prior rejection (and the instant rejection) is to modify Sack’s vector, by substituting Sack’s two-promoter expression cassettes expressing selectable marker and barcode with Adamson’s single bicistronic expression cassette, to arrive at the claimed vector.
Specifically, Sack teaches a lentiviral vector comprising two expression cassettes (a TRE promoter-driving ORF/barcode expression cassette and a PGK promoter-driving Puro selectable marker expression cassette), both expression cassettes being inserted in forward orientation between the 5’-LTR and the 3’-LTR, resulting in the TRE-ORF/barcode being upstream of the PGK-Puro and the PGK-Puro being immediately upstream of the 3’-LTR (see Fig 1B and attached below). It would have been obvious for one of ordinary skill in the art to have simply reversed the order of the two expression cassettes so as to obtain the TRE-ORF/barcode being downstream of the PGK-Puro and the TRE-ORF/barcode being immediately upstream of the 3’-LTR (see attached below). Adamson teaches a lentiviral vector comprising a bicistronic barcode and selectable marker expression cassette comprising, from 5’ to 3’, an EF1A promoter, a selectable marker puromycin resistance gene, T2A, a gene-of-interest, a barcode, and a BGH polyA sequence (Fig 1B and attached below, see the black rectangle). It would have been obvious for one of ordinary skill in the art to have substituted Sack’s two expression cassettes with Adamson’s single bicistronic cassette so as to obtain a lentiviral vector comprising, from 5’ to 3’, a 5’-LTR, an EF1a promoter, a selectable marker, T2A, a TF ORF, a barcode, a BGH pA and a 3’-LTR (see attached below). Since Invitrogen teaches the BGH pA is 224 base pairs in length, one of ordinary skill in the art would have appreciated the barcode is located about 200 base pairs upstream of the 3’-LTR. Thus, modifying Sack’s vector by substituting with Adamson’s bicistronic expression cassette would have arrived at the claimed vector.
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Claims 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Sack et al., (Cell. 2018; 173: 499-514 and Methods e1-e13 and Tables S1 and S4. Cited in IDS) in view of Adamson et al., (Cell. 2016; 167: 1867-1882. Cited in IDS) and Invitrogen (pcDNA3.1 information sheet, published 2010, p. 1-23. Prior art of record), as applied to claim 12 above, and further in view of NCBI (Alignment of human KLF4 NM_004235 with instant SEQ ID NO: 62, p. 1-6, prior art of record).
Claims 26-27 are directed to the sequences of the library of polynucleotides. Applicant has elected SEQ ID NO: 62 for examination in the reply filed on 12/30/2024.
As stated supra, Sack teaches human TF KLF4 in Table S1 (see KLF4 in the last two pages) and teaches the ORF sequences are full-length, wild-type ORFs (p. e10, para 2).
However, Sack, Adamson and Invitrogen do not specifically teach the sequence of human KLF4 ORF.
NCBI has taught the mRNA sequence of human KLF4, transcript variant 2 (NM_004235, see p. 4-6) that has a sequence that is 100% identical to the sequence of instant SEQ ID NO: 62 (see alignment in p. 1-3).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the kit comprising a library of polynucleotides comprising a human KLF4 ORF suggested by Sack in view of Adamson and Invitrogen, by choosing the mRNA sequence of human KLF4 (100% identical to SEQ ID NO: 62) as taught by NCBI with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to choose the sequence taught by NCBI because this is a well-known sequence in the art. Furthermore, the successful cloning and sequencing of the cDNA encoding a known protein (KLF4) is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 07/02/2025 are acknowledged and have been discussed above.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Sack et al., (Cell. 2018; 173: 499-514 and Methods e1-e13 and Tables S1 and S4. Cited in IDS) in view of NCBI (Alignment of human KLF4 NM_004235 with instant SEQ ID NO: 62, p. 1-6. Prior art of record), Adamson et al., (Cell. 2016; 167: 1867-1882. Cited in IDS) and Invitrogen (pcDNA3.1 information sheet, published 2010, p. 1-23. Prior art of record).
With respect to claim 41, Sack teaches construction of barcoded genome-scale ORF expression libraries for performing gain-of-function screens (see cover page “Highlights”). Sack teaches two human ORF expression libraries are transduced into human mammary epithelial cell (HMEC) clones and human pancreatic nestin-expressing epithelial cells (HPNEs) and performs screens with both ORF libraries in the rtTA-HMEC and rtTA-HPNE clonal cell lines (p. 500 – p. 502, left col), related to the preamble of claim 41.
In regard to (a) a barcoded ORF library of TF expressed by a lentiviral vector, Sack teaches a lentiviral vector expression system is used to construct two libraries (Library 1 and 2) contain nearly 30,000 ORFs, corresponding to more than 16,000 unique full-length genes (Table S1) (p. 500).
In regard to (a) (i) a transcription factor (TF) ORF, Sack teaches the polynucleotides comprise TF ORFs (see e.g. Fig 3F showing transcription factor ORFs such as MYC, and see Table S1 in the last two pages for TF ORFs such as KLF4).
In regard to (a) (ii) a selectable marker, Sack teaches the polynucleotide comprises a puromycin resistance gene (see Fig 1B for Puro).
In regard to (a) (iii) a nucleic acid barcode, Sack teaches two barcoded ORF expression libraries comprising libraries of barcode nucleic acids (see Fig 1E for 59115 barcodes in Library 1 and 88668 barcodes in Library 2).
In regard to (a) (iv) a 3’-LTR, Sack teaches the viral vector comprises a 3’-LTR (see e.g., Fig 1B).
However, Sack teaches the barcode nucleic acid is located upstream of the selectable marker (see Fig 1B), but is silent on the barcode being downstream of the selectable marker in claim 41 (a) (iii).
Nevertheless, Sack teaches the lentiviral vector comprises two expression cassettes (a TRE promoter-driving ORF/barcode expression cassette and a PGK promoter-driving Puro selectable marker expression cassette, see Fig 1B), both expression cassettes being inserted in forward orientation between the 5’-LTR and the 3’-LTR, resulting in the TRE-ORF/barcode being upstream of the PGK-Puro and the PGK-Puro being immediately upstream of the 3’-LTR (see Fig 1B).
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have simply reversed the order of the two expression cassettes so as to obtain the TRE-ORF/barcode being downstream of the PGK-Puro and the TRE-ORF/barcode being immediately upstream of the 3’-LTR with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to make this simple reversal since it has been held that rearranging parts of an invention involves only routine skill in the art. See MPEP 2144.04 VI.
In regard to limitation (b) directed to optional instructions for use, Applicant is reminded that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04 I. Thus, this limitation does not provide any patentable weight in determining patentability of the claimed product.
In regard to the wherein clause that the library of polynucleotides comprises the nucleic acid sequence of SEQ ID NO: 62, Sack teaches the library of polynucleotides comprises human TF KLF4 in Table S1 (see KLF4 in the last two pages) and teaches the ORF sequences are full-length, wild-type ORFs (p. e10, para 2).
However, Sack does not specifically teach the sequence of human KLF4 ORF being the sequence of SEQ ID NO: 62.
NCBI has taught the mRNA sequence of human KLF4, transcript variant 2 (NM_004235, see p. 4-6) that has a sequence that is 100% identical to the sequence of instant SEQ ID NO: 62 (see alignment in p. 1-3).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the library of polynucleotides comprising a human KLF4 ORF disclosed by Sack, by choosing the mRNA sequence of human KLF4 (100% identical to SEQ ID NO: 62) as taught by NCBI with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to choose the sequence taught by NCBI because this is a well-known sequence in the art. Furthermore, the successful cloning and sequencing of the cDNA encoding a known protein (KLF4) is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
However, as stated supra, although Sack makes obvious a simple reversal of the barcode expression cassette and the selectable marker expression cassette that would result in the barcode being downstream of the selectable marker and the barcode being immediately upstream of the 3’-LTR, Sack is silent on the barcode being about 200 base pairs upstream of the 3’-LTR.
Adamson teaches a lentiviral vector for genome-scale screening of phenotypic output from single cells (abstract). In regard to the vector, Adamson uses a third-generation lentiviral vector that comprises a bicistronic barcode and selectable marker expression cassette comprising, from 5’ to 3’, an EF1A promoter, a selectable marker puromycin resistance gene, T2A, a gene-of-interest, a barcode, and a BGH polyA sequence (see Fig 1B). Adamson teaches the BGH polyA sequence is located at the 3’ end of the expression cassette (see Fig 1B) which is amplified from pcDNA3.1(+) from Invitrogen (Cat No: V790-20) (p. e1, last para – p. e2, line 1). Invitrogen pcDNA3.1(+) (V790-20) information sheet teaches the BGH polyA sequence is 224-base-pair in length (bases 1028-1252, see p. 10).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the lentiviral vector comprising two expression cassettes for selectable marker and ORF/barcode suggested by Sack, by substituting the two cassettes with a single bicistronic expression cassette as taught by Adamson and choosing the TF ORF as the gene-of-interest in the cassette with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to make this substitution to ensure co-expression of the TF ORF and the selectable marker in the same cell. Furthermore, since Sack’s two-promoter cassettes and Adamson’s single-promoter bicistronic cassette are for the same purpose (i.e., to co-express the selectable marker and the gene-of-interest, such as the TF ORF), the expression cassettes of Sack and Adamson are art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have substituted Sack’s two-promoter cassettes with Adamson’s single bicistronic cassette. See MPEP 2144.06. Since Adamson has reduced to practice a bicistronic expression cassette comprising, from 5’ to 3’, an EF1A promoter, a selectable marker, T2A, a gene-of-interest, a barcode, and a BGH polyA sequence, one of ordinary skill in the art would have substituted with Adamson’s cassette and chosen TF ORF as the gene-of-interest in Sack’s vector to obtain the barcode being downstream of the selectable marker and the barcode/BGH polyA being immediately upstream of the 3’-LTR of Sack’s vector. Since Invitrogen teaches the BGH polyA sequence is 224-base-pair in length (bases 1028-1252, see p. 10), one of ordinary skill in the art would have appreciated that the barcode nucleic acid is located about 200 base pairs (i.e., the length of the BGH polyA) upstream of the 3’-LTR region.
In regard to a kit, although Sack, in view of NCBI, Adamson and Invitrogen, does not specifically recite a kit, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have combined said components suggested by Sack in view of NCBI, Adamson and Invitrogen into a kit with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so for the purposes of convenience and economy. Furthermore, since the claimed product merely serves as a support for printed matter (i.e., instructions), no functional relationship exists between the product and the printed matter because MPEP 2111.05 (I)(B) states “For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals.” Thus, the limitation of instructions does not provide any patentable weight in determining patentability of the claimed product.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 07/02/2025 are acknowledged and have been discussed above.
Maintained Double Patenting Rejections
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).
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Claims 12, 23-29, 31-34 and 36-41 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of US Patent No: 11,912,986 in view of NCBI (Alignment of human KLF4 NM_004235 with instant SEQ ID NO: 62, p. 1-6. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patented claims recite method of performing a high throughput gene overexpression screen, the method comprising using of the instantly claimed products including (a) transducing target cells with a barcoded open reading frame (ORF) library of transcription factor (TF) genes comprising viral particles (related to preamble and limitation (a) of instant claims 12 and 41, and claims 31 and 36), wherein each of the viral particles comprises an isolated polynucleotide or vector comprising: (i) a polynucleotide encoding an open reading frame (ORF) of a TF gene (related to instant claims 12 and 41 (a)(i)), wherein the polynucleotide is operably linked to a nucleic acid encoding a 2A peptide (related to instant claim 23); (ii) a nucleic acid encoding a selectable marker (related to instant claims 12 and 41 (a)(ii)); and (iii) a nucleic acid barcode located downstream of the selectable marker (related to instant claims 12 (b), claim 34, and claim 41 (a)(iii)); wherein the nucleic acid barcode is located 3′ to the polynucleotide encoding the ORF of the TF gene (related to instant claim 12) and wherein the TF gene is a wild type TF gene, an engineered TF gene, or a mutated TF gene (all the above related to instant claims 12 and 38-40); wherein the target cells are mammalian cells selected from equine cells, bovine cells, canine cells, murine cells, porcine cells, feline cells, or human cells (related to instant claim 37), the target cells are stem cells (related to instant claim 37). The TF gene drives differential expression of more than 100 genes (related to instant claim 24). The isolated polynucleotide or vector further comprises a 3′-long terminal repeat (LTR) region and wherein the nucleic acid barcode is located about 200 base pairs upstream of the 3′-LTR region (related to instant claims 12 and 41). The selectable marker is operably linked to the TF via the 2A peptide (related to instant claim 23). The isolated polynucleotide or vector further comprises a nucleic acid encoding an expression control element (related to instant claim 29). The expression control element is a promoter (related to instant claim 32) or wherein the expression control element is a translation elongation factor 1A (EF1A) promoter (related to instant claim 33). The wild type TF gene encodes a developmentally critical TF selected from ASCL1, ASCL3, ASCL4, ASCL5, ATF7, CDX2, CRX, ERG, ESRRG, ETV2, FLI1, FOXA1, FOXA2, FOXA3, FOXP1, GATA1, GATA2, GATA4, GATA6, GLI1, HAND2, HNF1A, HNF1B, HNF4A, HOXA1, HOXA10, HOXA11, HOXB6, KLF4, LHX3, LMX1A, MEF2C, MESP1, MITF, MYC, MYCL, MYCN, MYOD1, MYOG, NEUROD1, NEUROG1, NEUROG3, NRL, ONECUT1, OTX2, PAX7, POU1F1, POU5F1, RUNX1, SIX1, SIX2, SNAI2, SOX10, SOX2, SOX3, SPI1, SPIB, SPIC, SRY, TBX5, or TFAP2C (related to instant claim 25). The library comprises at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 nucleic acids or vectors (related to instant claim 28). The target cells are embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) (related to instant claim 37).
However, patented claims do not specifically recite the sequence of KLF4 ORF being the sequence of instant SEQ ID NO: 62 in instant claims 26-27 and 41.
NCBI has taught the mRNA sequence of human KLF4, transcript variant 2 (NM_004235, see p. 4-6) that has a sequence that is 100% identical to the sequence of instant SEQ ID NO: 62 (see alignment in p. 1-3, related to claims 26-27 and 41).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the polynucleotides comprising a KLF4 ORF recited in the patented claims, by choosing the mRNA sequence of human KLF4 (100% identical to SEQ ID NO: 62) as taught by NCBI with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to choose the sequence taught by NCBI because this is a well-known sequence in the art. Furthermore, the successful cloning and sequencing of the cDNA encoding a known protein (KLF4) is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
Although patented claims do not specifically recite the viral vector/particle being a lentiviral vector in claims 12 and 41, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen a lentiviral vector because it is a well-known and commonly-used viral vector in the art.
Although patented claims do not recite a kit, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have combined said components recited in the patent into a kit with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so for the purposes of convenience and economy. Furthermore, since the claimed product merely serves as a support for printed matter (i.e., instructions), no functional relationship exists between the product and the printed matter because MPEP 2111.05 (I)(B) states “For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals.” Thus, the limitation of instructions does not provide any patentable weight in determining patentability of the claimed product.
Since the instant application claims are obvious over cited patent claims, in view of NCBI, said claims are not patentably distinct.
Response to Traversal:
Applicant’s arguments filed on 07/02/2025 are acknowledged.
Applicant argues that claims 1-13 of US Patent No: 11,912,986 do not disclose a lentiviral vector having the claimed structure (Remarks, p. 11).
Applicant’s argument has been fully considered but it is not persuasive.
As stated in the prior rejection, although patented claims do not specifically recite the viral vector/particle being a lentiviral vector in previous claim 30 (now incorporated into claim 12) and claim 41, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen a lentiviral vector because it is a well-known and commonly-used viral vector in the art (see above). Therefore, the prior rejection has been maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631