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 .
Claim Status
Claims 28, 30-34, 44-46 ,48, 50, 52-55 and 57 are pending.
Claims 44-46 are withdrawn.
Claims 28, 30-34, 48, 50, 52-55 and 57 are under examination.
Moot Claim Rejections - 35 USC § 112a
Written Description
The rejection of claims 29 and 59 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement as set forth in the previous office action is moot in view of the cancellation of these claims.
Withdrawn Claim Rejections - 35 USC § 112a
Written Description
The rejection of claims 28, 30-34, 48, 50, 52-55 and 57 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Moot Claim Rejections - 35 USC § 112a
Scope of Enablement
The rejection of claims 29 and 56 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable the full scope of the claims as set forth in the previous office action is moot in view of the cancellation of these claims.
Withdrawn Claim Rejections - 35 USC § 112a
Scope of Enablement
The rejection of claims 28, 30-34, 48, 50, 52-55 and 57 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable the full scope of the claims as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Moot Claim Rejections 35 USC § 112b
The rejection of claim 56 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is moot in view of the cancellation of this claim.
Withdrawn Claim Rejections 35 USC § 112b
The rejection of claims 28, 32-34, 37, 48, 50, 52-55 and 57 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Moot Claim Rejections - 35 USC § 112(d)
The rejection of claim 56 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends as set forth in the previous office action is moot in view of the cancellation of this claim.
Claim Interpretation
Instant claim 28 recites “a nucleotide sequence lacking introns and encoding a FOXP3
polypeptide, wherein the FOXP3 polypeptide comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 68 having 0 to 43 amino acid substitutions, wherein a substitution
in the amino acid sequence is a conservative amino acid substitution.”
Similarly, claim 55 recites “a nucleotide sequence lacking introns and encoding FOXP3 wherein the encoded FOXP3 comprises at least 90% sequence identity to the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 68.”
Although, the claims recites SEQ ID NO: 68, the claims specifically recite “wherein the FOXP3 polypeptide comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 68” which is product-by process language with respect to the amino acid sequence. The amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 68, is the sequence “MPNPRPGKPSAPSLALGPSPGASPSWRAAPKASDLLGARGPGGTFQGRDLRGGAHASSSSLNPMPPSQLQLPTLPLVMVAPSGARLGPLPHLQALLQDRPHFMHQLSTVDAHARTPVLQVHPLESPAMISLTPPTTATGVFSLKARPGLPPGINVASLEWVSREPALLCTFPNPSAPRKDSTLSAVPQSSYPLLANGVCKWPGCEKVFEEPEDFLKHCQADHLLDEKGRAQCLLQREMVQSLEQQLVLEKEKLSAMQAHLAGKMALTKASSVASSDKGSCCIVAAGSQGPVVPAWSGPREAPDSLFAVRRHLWGSHGNSTFPEFLHNMDYFKFHNMRPPFTYATLIRWAILEAPEKQRTLNEIYHWFTRMFAFFRNHPATWKNAIRHNLSLHKCFVRVESEKGAVWTVDELEFRKKRSQRPSRCSNPTPGP” and is a 100% match to the wildtype FOXP3 sequence (see BLAST Result 1).
Therefore, instant claims are met by any nucleotide sequence that also encodes this same FOXP3 sequence, and otherwise meet the recited claim limitations. In other word, SEQ ID NO: 68 is not a required element of instant claims.
For instant claim 28, the nucleotide sequence is met by any nucleotide sequence that also encodes this same wildtype FOXP3 sequence, with from 0 to 43 amino acid substitutions, wherein a substitution in the amino acid sequence is a conservative amino acid substitution.
For instant claim 28, the nucleotide sequence is met by any nucleotide sequence that also encodes this same wildtype FOXP3 sequence, with from 0 to 21 amino acid substitutions, wherein a substitution in the amino acid sequence is a conservative amino acid substitution.
Moot Claim Rejections - 35 USC § 103
The rejection of claim 29 under 35 U.S.C. 103 as being unpatentable over Marson et al. (WO 2016/123578-A1; see IDS filed 15th, September, 2020; henceforth “Marson”) in view of Kohn et al. (US-20200347404-A1; PCT filed 22nd, August 2018 with domestic benefit of US Provisional Application 62/548,891 filed on 22nd, August, 2017; henceforth “Kohn”) as set forth in the previous office action is moot in view of the cancelation of this claim.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claim 33 under 35 U.S.C. 103 as being unpatentable over Marson et al. (WO 2016/123578-A1; see IDS filed 15th, September, 2020; henceforth “Marson”) in view of Kohn et al. (US-20200347404-A1; PCT filed 22nd, August 2018 with domestic benefit of US Provisional Application 62/548,891 filed on 22nd, August, 2017; henceforth “Kohn”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claim 33 under 35 U.S.C. 103 under 35 U.S.C. 103 as being unpatentable over Marson et al. (WO 2016/123578-A1; see IDS filed 15th, September, 2020; henceforth “Marson”) in view of Kohn et al. (US-20200347404-A1; PCT filed 22nd, August 2018 with domestic benefit of US Provisional Application 62/548,891 filed on 22nd, August, 2017; henceforth “Kohn”) as applied to claims 28-29 above, and in further view of Singh et al. (Mol Ther Methods Clin Dev. 2016 Dec 18:4:1-16.; henceforth “Singh”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Maintained and 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.
Claim 28, 30-32, 34, 53 and 55 remain rejected and amended claim 57 is newly rejected under 35 U.S.C. 103 as being unpatentable over Marson et al. (WO 2016/123578-A1; see IDS filed 15th, September, 2020; henceforth “Marson”) in view of Kohn et al. (US-20200347404-A1; PCT filed 22nd, August 2018 with domestic benefit of US Provisional Application 62/548,891 filed on 22nd, August, 2017; henceforth “Kohn”).
Regarding claims 28 and 55, Marson discloses a method of modifying a lymphocytic cell in vitro (primary hematopoietic stem cells or primary T cells; para. [0149]), the method comprising delivering to a lymphocytic cell a
donor template (oligonucleotide DNA template; para [0011]) comprising:
a) a first homology arm having homology to a nucleotide sequence in the FOXP3 gene of the lymphocytic cell;
b) a second homology arm having homology to a nucleotide sequence in the same FOXP3 gene as the first homology arm; (Figure 5A);
c) a heterologous constitutive promoter (para. [0131])
d) a nucleotide (template nucleic acid) sequence encoding a protein of interest or a functional derivative thereof flanked by said homology arms (see Fig. 5 and para. [0105]);
and a DNA endonuclease (para. [0017, 0048, 0053-54, 0067, 0092, 0140, 0166, 0167, 0176, 0180, 0196, 0204, 0207-208]; Figure 1, 6; Example 3; Claim 50).
Marson discloses the template nucleic acid can encode wild-type sequence for rescuing the expression level of the FOXP3 protein (para. [0105]).
However, regarding claims 28 and 55, Marson does not teach a specific FOXP3 sequence to be used to rescue the expression level of the FOXP3 gene.
Nevertheless, regarding claims 28 and 55, Kohn teaches a method of modifying a cell, the method comprising delivering to a cell a vector comprising:
a nucleotide sequence lacking introns and encoding FOXP3 (FOXP3 cDNA based on human genomic NCBI reference sequence file NM_014009 Table 1 pg. 18), to rescue the expression level of the FOXP3 protein (abstract; Figures 2-3, 5-6, 9A, 10, 11, 18; para. [0003-0004, 0008, 0010-0015, 0025, 0037, 0039-0042, 0044, 0052-0066, 0069-0079, 0092, 0098, 0106-0107, 0111, 0116-0117, 0120, 0132]; Examples 1-2; Claims 1-3 and 31-34; see in particular Figure 2; para. [0008, 0010, 0025, 0039-0041] Examples 1-2). The FOXP3 cDNA of Kohn encodes the same (100% match) FOXP3 amino acid sequence as instant SEQ ID NO:68 and therefore meets instant claims (see claim interpretation above).
Therefore, regarding claims 28 and 55, it would have been obvious to a person of ordinary skill in the art to combine the known prior art element of the FOXP3 cDNA sequence of Kohn with the method of editing a lymphocytic cell of Marson to obtain the predictable result of restoring FOXP3 function in the lymphocytic cell. One of ordinary skill would have been motivated to do so because Kohn teaches the FOXP3 cDNA sequence was effective at restoring FOXP3 function in deficient cells (Example 2). Regarding the reasonable expectation of success, Marson evidences editing of the FOXP3 gene with CRISPR/Cas components and homology arms (Figures 3 and 5; para. [0011; 0050, 0114]), and Kohn evidences restoring FOXP3 expression in a cell by delivering a FOXP3 cDNA sequence.
Regarding the limitation of “lacking introns” of claim 28, as stated above, Kohn suggests cDNA. cDNA does not comprise introns and therefore the cDNA sequence as suggested by Kohn meets the limitation of “lacking introns.”
Regarding claim 30, further to the discussion of claim 28 above, Marson discloses the endonuclease is an RNA-guided DNA endonuclease (Cas9 nuclease; abstract; Detailed Description; para. [0003-4, 0006-7 , 0009, 0011-12, 0017-19, 0031, 0035-39, 0048-50, 0053-57, 0059-61, 0063-0115, 0117- 0120, 0124-125, 0134, 0135, 0137-139, 0140-142, 0144-146, 0147-0151, 0153-154, 0156, 0159-0163, 0166, 0167, 0170, 0172, 0175-0189, 0190, 0192, 0194, 0196, 0202, 0204, 0207-208, 0210] ; Figures 1-2, 4, 6-8, 10, 12, 20, 48-50, ; Examples 1-4; Claims, 1, 3, 10, 11-13, 19, 50-55, 57, 59-62 ), and Marson teaches the method further comprises delivering to the lymphocytic cell a gRNA comprising a spacer sequence that is complementary to the FOXP3 gene (Figure 3A of Marson contains a gRNA spacer sequence which includes a 100% match to instant SEQ ID NO: 5).
Regarding claim 31, further to the discussion of claims 28-30 above, Marson teaches the gRNA comprises a spacer sequence of SEQ ID NO: 5 (Figure 3A of Marson contains a gRNA spacer sequence which includes a 100% match to instant SEQ ID NO: 5).
Regarding claim 32, further to the discussion of claim 28 above, as stated above, Marson teaches the first homology arm has homology to a first nucleotide sequence in the FOXP3 gene, and the second homology arm has homology to a second nucleotide sequence in the FOXP3 gene (see claim 28 rejection above).
Regarding claim 34, further to the discussion of claim 28 above, the cDNA sequence as suggested by Kohn (see claim 28 rejection above), is a codon-optimized cDNA sequence (para. [0011, 0070]; claim 3).
Regarding claim 53, further to the discussion of claims 28-30 above, Marson teaches the RNA guided DNA endonuclease is Cas9 (Cas9 nuclease; abstract; Detailed Description; para. [0003-4, 0006-7 , 0009, 0011-12, 0017-19, 0031, 0035-39, 0048-50, 0053-57, 0059-61, 0063-0115, 0117-0120, 0124-125, 0134, 0135, 0137-139, 0140-142, 0144-146, 0147-0151, 0153-154, 0156, 0159-0163, 0166, 0167, 0170, 0172, 0175-0189, 0190, 0192, 0194, 0196, 0202, 0204, 0207-208, 0210]; Figures 1-2, 4, 6-8, 10, 12, 20, 48-50, ; Examples 1-4; Claims, 1, 3, 10, 11-13, 19, 50-55, 57, 59-62 ).
Regarding claim 57, further to the discussion of claim 28 above, as stated above (see claim 28 rejection above), the FOXP3 polypeptide comprises the amino acid sequence which is 100% identical to the sequence encoded by SEQ ID NO: 68 and therefore meets instant claim limitations that the FOXP3 polypeptide comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 68 having 0 amino acid substitutions.
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 23th, February, 2026, have been fully considered but are not found persuasive.
Applicant argues the combination is not predictable (pg. 9). Specifically, Applicant argues “As Applicant previously indicated, the instant application discloses at least data showing successful targeted insertion of a polynucleotide encoding a heterologous promoter operably linked to a FOXP3-encoding sequence lacking introns into a genome of T cells” (pg. 9). Applicant further argues “Applicant respectfully submits that the successful targeted insertion of a polynucleotide encoding a heterologous promoter operably linked to a FOXP3-encoding sequence lacking introns into a genome of a T cell would not have been readily predicted from the cited references” (pg. 9). Applicant argues “For example, Marson relates to editing of a gene by either targeted disruption of the gene, or targeted insertion of a short 10-12 nucleotide oligonucleotide into the gene” (pg. 9).
In response, in the combination above, as stated above, one of ordinary skill would have had a reasonable expectation of success performing the method of the claimed combination because Marson evidences editing of the FOXP3 gene with CRISPR/Cas components and homology arms (Figures 3 and 5; para. [0011; 0050, 0114]), and Kohn evidences restoring FOXP3 expression in a cell by delivering a FOXP3 cDNA sequence.
Furthermore, Applicant is reminded that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). In the instant case, the combination of references set forth above provide some predictability because Marson evidences editing of the FOXP3 gene with CRISPR/Cas components and homology arms and specifically evidences insertion of nucleotide sequences (“short 10-12 nucleotide oligonucleotide into the gene” cited by Applicant in arguments pg. 10), and therefore one of ordinary skill would have had some predictability in performing the claimed method with a larger cDNA sequence, like that taught by Kohn.
Importantly, to complete the art of record and rebut Applicant’s arguments, Applicant is additionally directed to the art of He et al. (Nucleic Acids Res. 2016 May 19;44(9):e85. Epub 2016 Feb 4.; henceforth “He”). He evidences targeted insertions of 4 kb nucleotides into human cells with CRISPR/Cas methods (abstract; Figure 1) and further evidences reasonable predictability of targeted insertion of a larger size nucleic acid.
Applicant argues there is no reason to modify (pg. 10). Specifically, Applicant argues “that there would have been no reason to modify the method of Marson with the FOXP3 cDNA of Kohn because Marson teaches targeted insertion of a short 10-12 nucleotide oligonucleotide into the gene. Thus, the successful targeted insertion of a polynucleotide encoding a heterologous promoter operably linked to a FOXP3-encoding sequence lacking introns into a genome of a T cell would not have been readily predicted from at least Marson and Kohn” (pg. 10).
In response, as set forth above, Marson specifically teaches “the template nucleic acid can encode wild-type sequence for rescuing the expression level of the FOXP3 protein (para. [0105]).
Further in response, concerning the cited teachings of Marson (see pg. 9 last para. and pg. 10 1st para.), MPEP 2123 (I) states that patents are relevant as prior art for all they contain, and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. In instant case, as set forth above, Marson specifically teaches the template nucleic acid can encode wild-type sequence for rescuing the expression level of the FOXP3 protein (para. [0105]) as an alternative embodiment than those discussed by Applicant.
Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989).
As discussed above, because Marson does not specifically teach a specific wild-type sequence for rescuing the expression level of the FOXP3 protein, it would be obvious to combine the known prior art element of the FOXP3 cDNA sequence of Kohn for this purpose, and Kohn evidences that the sequence is effective for restoring FOXP3 function in deficient cells (Example 2).
New Claim Rejections - 35 USC § 103
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Marson et al. (WO 2016/123578-A1; see IDS filed 15th, September, 2020; henceforth “Marson”) in view of Kohn et al. (US-20200347404-A1; PCT filed 22nd, August 2018 with domestic benefit of US Provisional Application 62/548,891 filed on 22nd, August, 2017; henceforth “Kohn”) as applied to claim 28 above, and in further view of Henley et al. (WO-2018081470-A1; published 5th, May, 2018 with priority to 30th January 2017 and 27th, October, 2016; see IDS filed 15th, September, 2020; henceforth “Henley”) Feelixge (2017, accessed at: https://blog.addgene.org/adeno-associated-virus-aav-for-cell-and-gene-therapy) and
Regarding claim 33, further to the discussion of claim 28 above, the FOXP3 sequence as suggested by Kohn (see claim 28 rejection above),
encodes a wild-type human FOXP3 (Kohn; para. [0106-0107, 0110]; Example 1) and
c) the heterologous constitutive promoter of Marson is a PGK promoter (para. [0131]).
or E2F promoter.
However, regarding claim 33, although Marson teaches viral vectors for use in the methods (para. [0003, 0019, 0062] and Marson teaches the donor template can be provided in the form of a viral vector (para. [0100]), Marson and Kohn are silent to and AAV viral vector specifically (as claimed in b)).
Nevertheless, regarding claim 33, Henley teaches methods of editing cells in vitro including providing an AAV viral vector comprising a donor template (abstract; para. [0010, 0013-0014, 0104-106, 00108, 00117-00118, 00126-00133, 00135-00137]; Figures; see in particular Examples 12-13) for integration of the donor template into the genome (“integrate the exogenous transgene into a genomic locus of the primary cell”; abstract)
Additionally, Feelixge teaches AAV vectors are also capable of infecting a wide range of cell types including but not limited to muscle, liver, and brain cells, they are able to facilitate and enhance DNA repair via homology directed repair, which makes them especially amenable to correcting disease-associated mutations, and they maintain persistent transgene expression over many years in postmitotic, long-lived cell types (pg. 3)
Therefore, regarding claim 33, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Marson in view of Kohn, and combine the known prior art element of the AAV vector of Henley and Feelixge to obtain the predictable result of a viral vector comprising a donor template. One of ordinary skill would have been motivated to do so as taught by Feelixge because AAV vectors facilitate and enhance DNA repair via homology directed repair, which makes them especially amenable to correcting disease-associated mutations, and they maintain persistent transgene expression over many years in postmitotic, long-lived cell types (pg. 3). Regarding the reasonable expectation of success, Henley evidences AAV vectors comprising donor templates (Examples 14-15).
Hence, the claimed invention as a whole was prima facie obvious.
Maintained Claim Rejections - 35 USC § 103
Claim 37 remains rejected under 35 U.S.C. 103 as being unpatentable over Marson et al. (WO 2016/123578-A1; see IDS filed 15th, September, 2020; henceforth “Marson”) in view of Kohn et al. (US-20200347404-A1; PCT filed 22nd, August 2018 with domestic benefit of US Provisional Application 62/548,891 filed on 22nd, August, 2017; henceforth “Kohn”) as applied to claim 28 above, and in further view of Jonnalagadda et al. (Gene Ther. 2013 Aug; 20(8): 853–860. Published online 2013 Jan 10; henceforth “Jonnalagadda”).
Regarding claim 37, further to the discussion of claim 28 above, although Marson teaches Cas9 RNP-mediated HDR also allows introduction of genetic markers (para. [0153]), Marson is silent to the donor template comprising a selectable marker.
Additionally, regarding claim 37, Kohn teaches including a selectable marker, and Kohn teaches a method step of separating cells expressing the selectable marker from cells that do not express the selectable marker (para. [0108]).
Therefore, regarding claim 37, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Marson in view of Kohn, and combine the known prior art element of the sequence encoding a selectable marker of Kohn into the donor template of Marson, and combine the subsequent method step of separating cells expressing the selectable marker from cells that do not express the selectable marker to achieve the predictable result of cells expressing a marker when they have received the donor template. One of ordinary skill would have been motivated to do so as taught by Marson to purify homogenously edited cells for applications (para. [0153]). Regarding the reasonable expectation of success, Jonnalagadda evidences expressing a selectable marker in T cell lymphocytes and subsequently performing a method step of selecting step of separating cells expressing the selectable marker from cells that do not express the selectable marker (“In vitro selection of gene-modified T cells” pg. 7).
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 23th, February, 2026, have been fully considered but are not found persuasive.
Applicant argues “Jonnalagadda relates to a self-inactivating (SIN) lentiviral vector containing a
polynucleotide encoding a CD19 chimeric antigen receptor, a truncated human epidermal growth
factor polypeptide, and a human dihydrofolate reductase. See e.g., Jonnalagadda at Abstract and figure 2A. Thus, like Marson, Jonnalagadda teaches use of a lentiviral vector system for nontargeted
integration of a polynucleotide into a cell genome. Therefore, Jonnalagadda does not cure
the deficiencies of Marson and Kohn.” (pg. 10-11).
In response, Marson and Kohn provide enough predictability for a reasonable expectation of success and provide a reason to combine for the reasons set forth above. Jonnalagadda is relied upon for a reasonable expectation of success in evidences expressing a selectable marker in T cell lymphocytes and subsequently performing a method step of selecting step of separating cells expressing the selectable marker from cells that do not express the selectable marker, and is not relied upon to support targeted integration.
Maintained Claim Rejections - 35 USC § 103
Claims 48, 50 and 52 remain rejected under 35 U.S.C. 103 as being unpatentable over Marson et al. (WO 2016/123578-A1; see IDS filed 15th, September, 2020; henceforth “Marson”) in view of Kohn et al. (US-20200347404-A1; PCT filed 22nd, August 2018 with domestic benefit of US Provisional Application 62/548,891 filed on 22nd, August, 2017; henceforth “Kohn”) as applied to claim 28 above, and in further view of Singh et al. (Mol Ther Methods Clin Dev. 2016 Dec 18:4:1-16.; henceforth “Singh”).
Regarding claim 48, further to the discussion of claim 28 above, although Marson teaches heterologous constitutive promoters (para. [0131]), Marson and Kohn are silent to the MND promoter.
Nevertheless, reading claim 48, Singh teaches the MND promoter for use in gene replacement in T cells (abstract; Figures 1-2; pg. 3).
Therefore, regarding claim 48, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Marson in view of Kohn and combine the known prior art element of the MND promoter of Singh to achieve the predictable result of expression of the donor template in T cell lymphocytes. One of ordinary skill would have been motivated to do so as taught by Singh because the MND promoter was a known suitable promoter for expressing genes at a clinically effective level safely and efficiently in T cells (abstract; Figures 1-2; pg. 3). Regarding the reasonable expectation of success, Sing evidences the MND promoter can be used for gene replacement in T cells (abstract; Figures 1-2; pg. 3).
Regarding claim 50, further to the discussion of claims 28-29 and 48 above, as stated above (see claim 34 rejection above), the cDNA sequence as suggested by Kohn (see claim 28 rejection above), is a codon-optimized cDNA sequence (para. [0011, 0070]; claim 3).
Regarding claim 52, further to the discussion of claims 28-29 and 48 above, as stated above, Marson teaches the first homology arm has homology to a first nucleotide sequence in the FOXP3 gene, and the second homology arm has homology to a second nucleotide sequence in the FOXP3 gene (see claim 28 rejection above).
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 23th, February, 2026, have been fully considered but are not found persuasive.
Applicant argues “Marson relates to editing of a gene by either targeted disruption of the
gene, or targeted insertion of a short 10-12 nucleotide oligonucleotide into the gene, and Kohn
relates to use of a lentiviral vector system for non-targeted integration of a FOXP3 cDNA into a
cell genome. Singh relates to a SIN lentiviral vector containing a chromatin insulator upstream of
a viral MND promoter linked to a Wiskott-Aldrich syndrome protein. See e.g., Singh at Abstract
and figure lA. Thus, like Marson, Singh teaches use of a lentiviral vector system for non-targeted
integration of a polynucleotide into a cell genome. Therefore, Singh does not cure the deficiencies
of Marson and Kohn.” (pg. 11).
In response, Marson and Kohn provide enough predictability for a reasonable expectation of success and provide a reason to combine for the reasons set forth above. Singh is relied upon reasonable teaching the MND promoter and evidencing a reasonable expectation of success in using the MND promoter, and is not relied upon to support targeted integration.
Maintained Claim Rejections - 35 USC § 103
SEQ ID NO:3 Spacer
Claims 31 and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Marson et al. (WO 2016/123578-A1; see IDS filed 15th, September, 2020; henceforth “Marson”) in view of Kohn et al. (US-20200347404-A1; PCT filed 22nd, August 2018 with domestic benefit of US Provisional Application 62/548,891 filed on 22nd, August, 2017; henceforth “Kohn”), as applied to claims 28, 30 and 53 above, and in further view of Meissner et al. (WO-2016183041-A2).
Regarding claims 31 and 54, further to the discussion of claims 28, 30, and 53 above, although Marson teaches a gRNA sequence that targets the second Exon of the FOXP3 gene (Figure 3; sequence comprises an identical sequence to instant SEQ ID NO:5; see BLAT alignment), Marson and Kohn are silent to a gRNA comprising a spacer sequence of elected SEQ ID NO: 3.
Nevertheless, regarding claims 31 and 54, Meissner teaches a gRNA for altering a target FOXP3 gene in a cell which is 100% identical to SEQ ID NO: 3 (SEQ ID NO 572635; pg. 75; see SCV rnpbm file 8th, February 2024). The gRNA of Meissner also targets the second Exon of the FOXP3 gene (see BLAT alignment below wherein Meissner’s spacer comprising SEQ ID NO:3 is highlighted in light gray, and SEQ ID NO:5 is highlighted in dark gray. Note the PAM motifs are in bold and underlined).
PNG
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110
939
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Therefore, regarding claims 31 and 54, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Marson in view of Kohn, and simply substitute the known prior art element of a gRNA targeting Exon 2 of Meissner (SEQ ID NO 572635; pg. 75; see SCV rnpbm file 8th, February 2024) for the alternative known prior art element of a gRNA targeting Exon 2 (Figure 3 sequence of Marson) to achieve the predictable result of editing Exon2 of the FOXP3 gene. Furthermore, because the Cas9 requires an NGG sequence, and there is a finite number of NGG sequences for Exon2 which is only about 300 nucleotides, and the NGG PAM motif typically only occurs once about every 40 nucleotides, it also would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to choose a gRNA targeting Exon2 of the FOXP3 gene from the finite number of predictable gRNA sequences targeting Exon2 of the FOXP3 gene to achieve the predictable result of editing Exon2 in the FOXP3 gene. Regarding the reasonable expectation of success, Marson evidences effectively targeting Exon2 of the FOXP3 gene (Figure 3; sequence comprises an identical sequence to instant SEQ ID NO:5; see BLAT alignment).
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 23th, February, 2026, have been fully considered but are not found persuasive.
Applicant argues “As indicated above, Marson relates to editing of a gene by either targeted disruption of the gene, or targeted insertion of a short 10-12 nucleotide oligonucleotide into the gene, and Kohn relates to use of a lentiviral vector system for non-targeted integration of a FOXP3 cDNA into a
cell genome. Meissner relates to targeted disruption of certain genes using certain gRNAs. See e.g., Meissner at page 27, line 26 - page 28, line 23. Therefore, Meissner does not cure the deficiencies of Marson and Kohn” (pg. 11).
In response, Marson and Kohn provide enough predictability for a reasonable expectation of success and provide a reason to combine for the reasons set forth above. Meissner is relied upon for teaching a gRNA for altering a target FOXP3 gene in a cell which is 100% identical to SEQ ID NO: 3 and is not relied upon to support targeted integration.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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