DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 4-7, 10, 12 have been canceled. Claims 1-3, 8, 9, 11, 13-21 remain pending.
Applicant's arguments filed 8-19-25 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
Applicants elected Group I, claims 1-20, without traverse in the reply filed on 2-4-25. Claim 21 has been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2-4-25.
Claims 1-3, 8, 9, 13-20 remain under consideration.
Priority
The concept of using one or more non-integrating integrating vector encoding reprogramming factors in claim 1 was not in 60/919687 or 60/974980. The concept is in 60/989058 filed 11-19-07. The priority date for claim 1 is 11-19-07.
The concept of using Nanog and Lin28 in claim 1 was not in 60/919687 or 60/974980. The concept is in 60/989058 filed 11-19-07. The priority date for claim 2 is 11-19-07.
The concept of using a non-integrating viral based vector in claim 7 was not in 60/919687 or 60/974980. The concept is in 60/989058 filed 11-19-07. The priority date for claim 7 is 11-19-07.
The concept of using a non-integrating EBV-based vector in claim 8 was not in 60/919687 or 60/974980. The concept is in 60/989058 filed 11-19-07. The priority date for claim 8 is 11-19-07.
The concept of using a non-integrating EBV-based vector that is an Epstein Barr virus nuclear antigen-based vector in claims 9-11 was not in 60/919687 or 60/974980. The concept is in 60/989058 filed 11-19-07. The priority date for claims 9-11 is 11-19-07.
Claim Rejections - 35 USC § 112
Written Description
Claims 1-3, 8, 9, 13-20 remain rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Pending
A) The specification lacks written description for introducing any non-integrating viral episomal vector encoding reprogramming factors including Oct4 and Sox2 into fibroblasts to make induced pluripotent stem (iPS) cells as broadly encompassed by claims 1, 19 and 20.
Claim 1 is drawn to an in vitro population of primate somatic cells each comprising one or more non-integrating viral episomal vectors comprising nucleotide sequences encoding Oct-4 and Sox2.
Claim 19 is drawn to an in vitro population of primate somatic cells each comprising one or more non-integrating viral episomal vectors comprising nucleotide sequences encoding Oct-4, Sox2 and one of either Nanog or Lin28.
Claim 20 is drawn to a cell line comprising human somatic cells each comprising one or more non-integrating viral episomal vectors comprising nucleotide sequences encoding Oct-4 and Sox2 produced by the process comprising:
(a) contacting an isolated human somatic cell to a one or more non-integrating viral episomal vectors encoding Oct4 and Sox2 under conditions sufficient to reprogram the human somatic cell to a pluripotent cell comprising the human somatic cell; and
(b) culturing the cell obtained in step a) under pluripotent conditions such that an induced pluripotent cell is obtained.
Claims 1, 19, 20 are limited to viral vectors; therefore, they exclude plasmids because plasmids are not viral.
Claims 1, 19, 20 are limited to episomal viral vectors; therefore, they exclude lentiviral vectors because they integrate into the genome.
Pg 11, the end of para 42, teaches:
“Retroviral vectors, particularly lentiviral vectors, are transduced by packaging the vectors into virions prior to contact with a cell. After introduction, the DNA segment(s) encoding the potency-determining factor(s) can be located extra-chromosomally (e.g., on an episomal plasmid) or stably integrated into cellular chromosome(s).”
Pg 12, the end of para 43, teaches:
“Retroviral (e.g., lentiviral) vectors are integrating vectors; however, non-integrating vectors can also be used. Such vectors can be lost from cells by dilution after reprogramming, as desired. A suitable nonintegrating vector is an Epstein-Barr virus (EBV) vector. Ren C, et al., Acta. Biochim. Biophys. Sin. 37:68-73 (2005); and Ren C, et al., Stem Cells 24:1338-1347 (2006), each of which is incorporated herein by reference as if set forth in its entirety.”
Para 64 describes transducing the ES-cell derived myeloid cells:
“Lentivirus encoding a potency-determining factor (MOI: 3 to 10) was added to the cell culture after addition of polybrene carrier at a final concentration of 6 pg/ml (Sigma). The lentivirus-containing medium was replaced with fresh medium the next day, and cells were cultured further in appropriate medium. Drug selection, if needed, started the third day after transduction. As shown in Figure 5B, the transduction efficiency was very low (~18.4% at MOI of 10). Moreover, the expression of EGFP was barely above background. Similar results have been obtained with routine plasmid or EBNA-based plasmid transfections (data not shown).” (para 64)
Fig. 7B discussed in Example 3 on pg 25, para 86 (“the greatest number of colonies having cells with typical morphology of pluripotent cells was obtained using the full complement ofOct-4, Nanog, Sox2 and Fin28. However, when one ofOct-4, Nanog, Sox2 or Fin28 was absent, the number of ES-like colonies was significantly attenuated (e.g., Nanog or Fin28) or absent (e.g., Oct-4 or Sox2)”) and described in detail on pg 6-7, para 27.
Example 9 (pg 32) describes reprogramming 293FT or mesenchymal cells “using potency-determining factors on a single construct”.
“To increase the reprogramming efficiency, the above-identified methods were repeated using the construct shown in FIG. 4A; however, either Oct-4 or Sox2 were inserted in the transgene section, and Sox2 optionally replaced the puromycin resistance gene. The constructs were then expressed either in 293FT cells or in OCT4 knock-in human HI ES cells (p6).
Transgene-expressing lentiviral transduction was carried out as described above. That is, 293FT cells or mesenchymal cells (~ 2 x 105 cells/well of 6-well plate, seeded overnight) were transduced with various transgene combinations.
FIG. 9A demonstrates that Oct-4 and Sox2 expression occurred in 293FT cells following transfection (see, e.g., lanes 1-3). In FIGS. 9A-B, pSin4-EF2-Oct4-IRESl-Sox2 is abbreviated as OS-IRES 1; pSin4-EF2-Oct4-IRES2-Sox2 is abbreviated as OS-IRES2; pSin4- EF2-Oct4-F2A-Sox2 is abbreviated as OS-F2A; pSin4-EF2-Oct4-IRESl-puro is abbreviated as O; andpSin4-EF2-Sox2-IRESl-puro is abbreviated as S.
FIG. 9B shows that reprogramming efficiency increased in mesenchymal cells derived from OCT4 knock-in human HI ES cells (p6) when Oct-4 and Sox2 were provided on the same construct (IRES1 is a very low-efficiency internal ribosome entry site; whereas IRES2 is a high-efficiency internal ribosome entry site). OS-IRES2+N+F (the high-efficiency IRES) showed an approximate fourfold increase in reprogramming efficiency when compared to O+S, O+S+N+F or OS-IRES 1 (the low-efficiency IRES) +N+L. Therefore, providing the potency determining factors in one construct that provides for approximately equal expression levels of each can improve reprogramming efficiency.”
The specification is limited to transfecting isolated somatic cells with a plurality of EBNA plasmids or retroviral vectors encoding reprogramming factors, and culturing the cells such that iPS cells are obtained.
Since EBNA plasmids are not “viral” as required in claims 1, 19, 20, they are excluded from the claims.
Since lentiviral vectors integrate into the genome, they are not “episomal” as required in claims 1, 19, 20.
The specification is limited to using EBNA plasmids described by Ren (“Establishment of human embryonic stem cell line stably expressing Epstein-Barr virus-encoded nuclear antigen 1”, Acta. Biochim. Biophys. Sin., 2005, Vol. 37, pg 68-73) and Ren (Stem Cells, 2006, Vol. 24, pg 1338-1347) (pg 12, end of paragraph 43) which in fact are plasmids encoding EBNA; they are not “viral episomal vectors” as required in claims 1, 19, 20 because they have a plasmid backbone and just express a viral protein. The concept of “viral” vectors as claimed is limited to vectors with a viral backbone and excludes the plasmid vector encoding EBNA described by Ren.
The specification does not correlate the EBNA plasmids of Ren to any other EBV-derived vectors as required in claim 8 or any other EBNA-based vectors as required in claim 9. In fact, the EBNA plasmid of Ren used by applicants is not “EBNA-based” because it has a plasmid backbone as opposed to an EBV backbone.
Accordingly, the concept of “non-integrating episomal viral vectors” in claims 1, 19, 20 lacks written description.
Response to arguments
Applicants argue the amendment overcomes the rejections. Applicants’ argument is not persuasive.
New
B) The specification lacks written description for claim 20. The claim is drawn to a human somatic cell line comprising one or more non-integrating viral episomal vectors comprising nucleotide sequences encoding Oct-4 and Sox2 produced by a process; however, the somatic cells are the starting material and not the final product. The process in claim 20 ends with obtaining pluripotent cells, which are not a somatic cell line in the preamble. The process requires reprogram the human somatic cell to “a pluripotent cell comprising the human somatic cell”; however, the pluripotent cell does not comprise a somatic cell. This concept simply does not make scientific, logical, or legal sense. The process does not end in a “cell line” as required in the preamble. Accordingly, claim 20 lacks written description.
Indefiniteness
Claims 1-3, 8, 9, 13-20 remain 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.
A) The metes and bounds of “non-integrating episomal viral vectors” in claims 1, 19, 20 cannot be determined. Claims 1, 19, 20 are limited to viral vectors; therefore, they exclude plasmids because plasmids are not viral. Claims 1, 19, 20 are limited to episomal viral vectors; therefore, they exclude lentiviral vectors because they integrate into the genome. But the specification is limited to transfecting isolated somatic cells with a plurality of EBNA plasmids or retroviral vectors encoding reprogramming factors, and culturing the cells such that iPS cells are obtained (see citations above). Since EBNA plasmids are not “viral” as required in claims 1, 19, 20, they are excluded from the claims. Since lentiviral vectors integrate into the genome, they are not “episomal” as required in claims 1, 19, 20. The specification is limited to using EBNA plasmids described by Ren (2005) and Ren (2006) (see citations above) which in fact are plasmids encoding EBNA. They are not “viral episomal vectors” as required in claims 1, 19, 20 because they have a plasmid backbone and just express a viral protein. The concept of “viral” vectors as claimed is limited to vectors with a viral backbone and excludes the plasmid vector encoding EBNA described by Ren. Accordingly, it is unclear what IS encompassed by the phrase “non-integrating episomal viral vectors” in claims 1, 19, 20 which makes the claims indefinite.
B) The metes and bounds of “EBV vectors” that are “viral episomal vectors” in claim 8 cannot be determined. It is unclear whether the phrase is limited to EBV vectors, if it encompasses more, or if it encompasses a subgroup of EBV vectors. The specification discusses plasmids encoding EBNA described by Ren (see citations above) which are not “EBV vectors” because they have a plasmid backbone, because they do not have an EBV backbone, and because they just encode an EBV protein called EBNA. Therefore, claim 8 does not further limit claim 1, and it is unclear what IS encompassed by claim 8.
C) The metes and bounds of “Epstein Barr virus nuclear antigen (EBNA) vectors” that are “viral episomal vectors” in claims 9 and 11 cannot be determined. It is unclear whether the phrase is limited to EBV vectors, if it encompasses more, or if it encompasses a subgroup of EBV vectors. It is unclear whether the concept limited to any episomal viral vector encoding EBNA or if it encompasses any episomal vector encoding EBNA. The specification discusses plasmids encoding EBNA described by Ren (see citations above) which are not “EBNA vectors” because they have a plasmid backbone and encode EBNA – they are not “EBNA vectors” and they are not “viral” because they do not have an EBV or other viral backbone. The EBNA plasmid of Ren just encodes an EBV protein called EBNA. Therefore, claims 9 and 11 do not further limit claim 1, and it is unclear what IS encompassed by claim 9 and 11.
D) The metes and bounds of a “heterologous” promoter in claim 13 cannot be determined. While the nucleic acid sequences Oct4 and Sox2 may be operably linked to a promoter, it is unclear when a promoter is “heterologous”. It is unclear whether the promoter is “heterologous” to the Oct4 and Sox2 coding sequences, the backbone of the viral episomal vector, the cell, or a host receiving the cell. If “heterologous” encompasses all of those things, then it does not further limit the promoter and should be deleted. If “heterologous” DOES further limit the promoter, it is unclear how.
E) The metes and bounds of a promoter that “does not promote transcription in pluripotent primate cell” in claim 14 cannot be determined. The metes and bounds of promoters that do not function in “pluripotent” cells cannot be envisioned and is not disclosed. There is no nexus between the “pluripotent primate cell” in claim 14 and the “somatic primate cells” in claim 1.
F) The metes and bounds of promoter that is “selectively active in a primate cell after being reprogrammed to pluripotency” in claim 18 cannot be determined. The specification and the art do not disclose any such promoters, and none can be envisioned. It is unclear when promoters are “selectively active” in general or when they are “selectively active” in primate cells after reprogramming into pluripotent cells. It is unclear how the term “selectively” further limits the term “active” in the phrase “selectively active”. It is unclear if “selectively active” is the same as “active” or if it is narrower than the term “active”. If “selectively active” is narrower than the term “active”, then it is unclear when a promoter is “selectively active”. Therefore, those of skill would not be able to determine when they were infringing on the claim.
G) Claim 20 remains indefinite. The claim is drawn to a human somatic cell line comprising one or more non-integrating viral episomal vectors comprising nucleotide sequences encoding Oct-4 and Sox2 produced by a process; however, the somatic cells are the starting material and not the final product as claimed. The process in claim 20 ends with obtaining pluripotent cells, which are not a somatic cell line in the preamble. The process requires reprogram the human somatic cell to “a pluripotent cell comprising the human somatic cell”; however, the pluripotent cell does not comprise a somatic cell. This concept simply does not make scientific, logical, or legal sense. The process does not end in a “cell line” as required in the preamble. Accordingly, claim 20 is illogical and non-scientific which makes it indefinite. Those of skill would not be able to determine what is included/included in the claim because it does not make sense.
Response to arguments
Applicants argue the amendment overcomes the rejections. Applicants’ argument is not persuasive.
Claim Rejections - 35 USC § 102
Withdrawn
The rejection of claims 1 and 19 under pre-AIA 35 U.S.C. 102a1 as being anticipated by Nakatsuji (EP 1437404) has been withdrawn. Nakatsuji taught reprogramming a human somatic cell into a pluripotent cell (pg 29, para 172-173; pg 37-42). The cell contain a vector encoding Oct4 (para 162). Nakatsuji did not teach using at least one or more “non-integrating viral episomal” vectors encoding Oct4 and Sox2 as required in claims 1 and 19.
Pending
Claims 1-3, 13, 14, 16, 18-20 remain rejected under pre-AIA 35 U.S.C. 102a1 as being anticipated by West (CA 2659945).
Claims 8 and 9 have been removed from the rejection because West did not teach using EBV vectors or EBNA vectors.
Claim 15 has been removed from the rejection because West did not teach using a vector that contains an IRES.
Claim 17 has been removed from the rejection because West did not teach the marker was GFP, EGFP, or luciferase.
West taught transfecting isolated mammalian pluripotent cells that contain a plasmid (pg 29, line 17; pg 85, line 37; Example 11, pg 86, line 26) encoding Oct4 and Sox2 (pg 28, line 12-13; pg 39, para 100; pg 65, para 133; Example 11, pg 86, line 27). West taught using plasmids which inherently are episomal (pg 29, para 88) as required in claims 1, 19, 20. West taught using viral vectors which inherently may or may not be “episomal” (pg 29, para 88) as required in claims 1, 19, 20.
West also used Nanog (pg 86, line 27; claim 9) and Lin28 (pg 41, line 31; pg 83 (line 4) as required in claim 2 and 5.
West taught cMyc was optional (pg 11, line 14) and did not teach using Klf4 which is equivalent to “wherein the potency-determining factors do not comprise cMyc or Klf4” as required in claim 3.
West taught Oct4 and Sox2 were operably linked to a promoter as required in claim 13 as evidenced by expression of Oct4 and Sox2 and reprogramming.
The promoter may be modified (pg 86, line 2) which is “heterologous” as required in claim 14.
West taught using a marker (pg 19, line 16) as required in claim 16.
Claim 18 has been included because the metes and bounds of a promoter that is “selectively active” in pluripotent cells cannot be determined.
Claim 19 has been included for reasons set forth in claim 1.
Claim 20 has been included because West taught transfecting human somatic cells with the vector encoding Oct2 and Sox4 and culturing them under conditions sufficient to obtain pluripotent cells which is all that is required to meet the structural/functional limitations of the human somatic cell line in the preamble of claim 20 and the active steps of the “process” portion of the “product-by-process” claim.
Response to arguments
Applicants argue does not teach all the elements of the claims. Applicants’ argument is not persuasive for reasons set forth above.
Claim Rejections - 35 USC § 103
Withdrawn
The rejection of claims 1, 3, 4, 6, 12-20 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Takahashi (Cell, 2006, Vol. 126, pg 663-676) in view of 7833742 (para 123), 7803389 (para 154), 7700350 (para 28), 7638331 (para 124), 7566548 (para 1622 transient transfection), and 6713070 (para 58) has been withdrawn because the rejection is limited to the concept of using retroviral vectors or plasmids to reprogram primate somatic cells while the claims are limited to using “non-integrating episomal viral” vectors.
The rejection of claims 7-11 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Takahashi (Cell, 2006, Vol. 126, pg 663-676) in view of 7833742 (para 123), 7803389 (para 154), 7700350 (para 28), 7638331 (para 124), 7566548 (para 1622 transient transfection), 6713070 (para 58) as applied to claims 1, 3, 4, 6, 12-20 and further in view of Satoh (Biochem. & Biophysical Res. Comm., 1997, Vol. 238, pg 795-799), Kaneda (Human Gene Therapy, 2000, Vol. 11, pg 471-479), Black (Gene Therapy, 2002, Vol. 9, pg 1447-1454), Ren (“Establishment of human embryonic stem cell line stably expressing Epstein-Barr virus-encoded nuclear antigen 1”, Acta. Biochim. Biophys. Sin., 2005, Vol. 37, pg 68-73), Ren (Stem Cells, 2006, Vol. 24, pg 1338-1347) has been withdrawn in favor of the following rejections:
New
A) Claims 1-3, 8, 9, 11, 13-16, 18-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over West (CA 2659945) in view of Satoh (Biochem. & Biophysical Res. Comm., 1997, Vol. 238, pg 795-799), Kaneda (Human Gene Therapy, 2000, Vol. 11, pg 471-479), Black (Gene Therapy, 2002, Vol. 9, pg 1447-1454), Ren (“Establishment of human embryonic stem cell line stably expressing Epstein-Barr virus-encoded nuclear antigen 1”, Acta. Biochim. Biophys. Sin., 2005, Vol. 37, pg 68-73), Ren (Stem Cells, 2006, Vol. 24, pg 1338-1347).
Assumption
Applicants described “viral vectors” as including the EBNA plasmids of Ren (pg 12, end of paragraph 43) and used them to deliver potency determining factors in fibroblasts (pg 19, end of paragraph 64). However, applicants’ description is repugnant to the art because the ENBA plasmids of Ren are not “viral” because they have a plasmid backbone. However, this rejection assumes EBNA plasmids used by applicants are “viral vectors” as required in claim 1, 19, 20.
Rejection
West taught transfecting isolated human somatic cells (pg 4, para 5) that contain a plasmid (pg 29, line 17; pg 85, line 37; Example 11, pg 86, line 26) encoding Oct4 and Sox2 (pg 28, line 12-13; pg 39, para 100; pg 65, para 133; Example 11, pg 86, line 27). The plasmid of West is “non-integrating” and “episomal” as required in claims 1, 19, 20.
West did not teach using a “non-integrating episomal viral” vector as required in claims 1, 19, 20.
However, using EBNA plasmids to transfect isolated mammalian cells and obtain protein expression was well-known in the art at the time of filing as described by Satoh, Kaneda, Black, Ren (2005), and Ren (2006). Satoh, Kaneda, and Black (Materials and Methods; Results).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to genetically modify isolated primate fibroblasts using vectors encoding reprogramming factors including Oct4 and Sox2, and culturing the genetically modified fibroblasts under pluripotent cell culture conditions such that iPS cells were obtained as described by the combined teachings of Takahashi using an EBNA plasmid described by Satoh, Kaneda, Black, Ren (2005), and Ren (2006). Those of ordinary skill in the art at the time of filing would have been motivated to use EBNA plasmids to avoid using retroviral vectors and to save time and money.
West used Nanog (pg 86, line 27; claim 9) and Lin28 (pg 41, line 31; pg 83 (line 4) as required in claim 2.
Takahashi taught the “4 factors – Klf4” in Table S2 was Oct4, Sox2, and MycT58A; “4 factors – Klf4” did not include cMyc or Klf4 as required in claim 3.
It is assumed the EBNA plasmid of Satoh, Kaneda, Black, Ren (2005), and Ren (2006) is an EBV vector as required in claim 8 because EBNA is derived from EBV.
It is assumed the EBNA plasmid of Satoh, Kaneda, Black, Ren (2005), and Ren (2006) is an EBNA vector as required in claim 9 because it encodes EBNA.
West used two or more vector, and the combined teachings of Takahashi, Satoh, Kaneda, Black, Ren (2005), and Ren (2006) taught using EBNA plasmids, so it would have been obvious to use two or more EBNA plasmids as required in claim 11.
West expressed Oct4 and Sox2 which is evidence that the reprogramming factors were operably linked to a heterologous promoter as required in claim 13.
Claim 14 has been included because the metes and bounds of a promoter that “does not promote transcription in a pluripotent primate cell” cannot be determined (see 112/2nd).
Claim 15 has been included because the EBNA plasmid of at least Ren (2005) and Ren (2006) contained an IRES (Figures, Materials and Methods, Results).
Claim 16 has been included because West taught using a vector encoding the marker (pg 19, line 16).
Claim 18 has been included because the sequence encoding GFP inherently MUST have been operably linked to a promoter “active in the mammalian cell after being reprogrammed to pluripotency” as evidenced by GFP expression in iPS cells.
The combined teachings of West, Satoh, Kaneda, Black, Ren (2005), and Ren (2006) taught human somatic cells containing EBNA plasmids encoding Oct4 and Sox2 and reprogramming them into iPS cells which covers all the structures, functions, and active steps in claim 20.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
B) Claims 1, 3, 8, 9, 11, 13-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Takahashi (Cell, 2006, Vol. 126, pg 663-676) in view of Satoh (Biochem. & Biophysical Res. Comm., 1997, Vol. 238, pg 795-799), Kaneda (Human Gene Therapy, 2000, Vol. 11, pg 471-479), Black (Gene Therapy, 2002, Vol. 9, pg 1447-1454), Ren (“Establishment of human embryonic stem cell line stably expressing Epstein-Barr virus-encoded nuclear antigen 1”, Acta. Biochim. Biophys. Sin., 2005, Vol. 37, pg 68-73), Ren (Stem Cells, 2006, Vol. 24, pg 1338-1347).
Assumption
Applicants described “viral vectors” as including the EBNA plasmids of Ren (pg 12, end of paragraph 43) and used them to deliver potency determining factors in fibroblasts (pg 19, end of paragraph 64). However, applicants’ description is repugnant to the art because the ENBA plasmids of Ren are not “viral” because they have a plasmid backbone. However, this rejection assumes EBNA plasmids used by applicants are “viral vectors” as required in claim 1, 19, 20.
Rejection
Takahashi transfected isolated mammalian fibroblasts with retroviral vectors encoding 3, 4, 10, or 24 reprogramming factors including Oct4 and Sox2 and cultured the cells under pluripotent conditions such that induced pluripotent stem (iPS) cells capable of differentiating in vitro and teratoma formation were obtained (pg 665, Fig. 2C; pg 674, “Cell culture”, “Retroviral construction” “Teratoma formation” “In vitro differentiation of iPS cells”).
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Takahashi did not teach the vectors were “non-integrating viral episomal” vectors as required in claims 1, 19, 20.
However, using EBNA plasmids to transfect isolated mammalian cells and obtain protein expression was well-known in the art at the time of filing as described by Satoh, Kaneda, Black, Ren (2005), and Ren (2006). Satoh, Kaneda, and Black (Materials and Methods; Results).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to genetically modify isolated primate fibroblasts using vectors encoding reprogramming factors including Oct4 and Sox2, and culturing the genetically modified fibroblasts under pluripotent cell culture conditions such that iPS cells were obtained as described by the combined teachings of Takahashi using an EBNA plasmid described by Satoh, Kaneda, Black, Ren (2005), and Ren (2006). Those of ordinary skill in the art at the time of filing would have been motivated to use EBNA plasmids to avoid using retroviral vectors and to save time and money.
Claim 2 has NOT been included because while Takahashi taught using Nanog (Table S2), Takahashi did not teach using Lin28.
Takahashi taught the “4 factors – Klf4” in Table S2 was Oct4, Sox2, and MycT58A; “4 factors – Klf4” did not include cMyc or Klf4 as required in claim 3.
It is assumed the EBNA plasmid of Satoh, Kaneda, Black, Ren (2005), and Ren (2006) is an EBV vector as required in claim 8 because EBNA is derived from EBV.
It is assumed the EBNA plasmid of Satoh, Kaneda, Black, Ren (2005), and Ren (2006) is an EBNA vector as required in claim 9 because it encodes EBNA.
Takahashi used two or more vector, and the combined teachings of Takahashi, Satoh, Kaneda, Black, Ren (2005), and Ren (2006) taught using EBNA plasmids, so it would have been obvious to use two or more EBNA plasmids as required in claim 11.
Takahashi used plasmids that contain promoters operably linked to the coding sequences of the reprogramming factors to make the retroviruses (pg 674, “Plasmid construction”) which is a polynucleotide encoding a reprogramming factor operably linked to a heterologous promoter as required in claim 13.
Claim 14 has been included because the metes and bounds of a promoter that “does not promote transcription in reprogrammed mammalian cell” cannot be determined (see 112/2nd).
Claim 15 has been included because the EBNA plasmid of at least Ren (2005) and Ren (2006) contained an IRES (Figures, Materials and Methods, Results).
Claims 16 and 17 have been included because Takahashi taught using a vector encoding the selectable marker GFP (pg 12 of Supp. Materials).
Claim 18 has been included because the sequence encoding GFP inherently MUST have been operably linked to a promoter “active in the mammalian cell after being reprogrammed to pluripotency” as evidenced by GFP expression in iPS cells.
The combined teachings of Takahashi, Satoh, Kaneda, Black, Ren (2005), and Ren (2006) taught human somatic cells containing EBNA plasmids encoding Oct4 and Sox2 and reprogramming them into iPS cells which covers all the structures, functions, and active steps in claim 20.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Double Patenting
The objection of claim 4 under 37 CFR 1.75 as being a substantial duplicate of claim 1 has been withdrawn because claim 4 has been canceled.
The objection of claim 5 under 37 CFR 1.75 as being a substantial duplicate of claim 2 has been withdrawn because claim 5 has been canceled.
The objection of claim 6 under 37 CFR 1.75 as being a substantial duplicate of claims 1 and 4 has been withdrawn because claims 4, 5 have been canceled.
Claims 1-3, 8, 9, 13-20 remain rejected on the ground of nonstatutory double patenting as being unpatentable over the claim of U.S. Patent No. 11898162, 10106772, 9499786, 8440461, 8183038. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of 11898162 is drawn to:
1 A method of reprogramming primate somatic cells, the method comprising the steps of:introducing a retroviral or non-integrating vector comprising a polynucleotide encoding potency-determining factors into the primate somatic cells under conditions sufficient to express the potency-determining factors, thereby reprogramming the cells, wherein the potency- determining factors comprise Oct-4 and Sox2, and do not comprise c-Myc and Klf4; and culturing the primate somatic cells under embryonic stem cell culture conditions to obtain pluripotent reprogrammed cells.
The instant claims and the claims of ‘461 are related as product and method of making the product. ‘162 discloses the vector is an EBNA plasmid (Detailed description paragraphs 23 and 42) as encompassed by claims 1, 19, 20. The concept of using a “non-integrating viral episomal vector” as now claimed is an obvious variant of claim 1 in ‘162. The breadth in claim ‘162 is an obvious variant of claim 1, 19, 20 in the instant application.
The claims of 10106772 are drawn to:
A method of reprogramming human somatic cells, the method comprising the steps of:
introducing a non-integrating vector encoding Oct-4 and Sox2 and at least one of Nanog and Lin28 operably linked to one or more heterologous promoters into isolated human somatic cells; and culturing the somatic cells under embryonic stem (ES) cell culture conditions such that pluripotent reprogrammed cells are obtained.
The instant claims and the claims of ‘772 are related as product and method of making the product. ‘772 discloses the vector is an EBNA plasmid (Detailed description paragraphs 23 and 42) as encompassed by claims 1, 19, 20. ‘772 claims the vector is EBNA vector (claims 4, 13, 14-17). The concept of using a “non-integrating viral episomal vector” as now claimed is an obvious variant of claim 4, 13, 14-17 in ‘772. The breadth in claim ‘772 is an obvious variant of claim 1, 19, 20 in the instant application.
The claims of 9499786 are drawn to:
1. An enriched population of human pluripotent cells having a normal karyotype, wherein the human pluripotent cells comprise the genome of a single somatic cell of a postnatal individual human and further comprise an integrated non-native polynucleotide sequence encoding potency-determining factors comprising Oct-4 and Sox2.
2. The population of claim 1, wherein the potency-determining factors additionally comprise at least one of Nanog or Lin28.
The claims of ‘786 and the instant application are both drawn to the same product. ‘786 discloses the vector is an EBNA plasmid (Detailed description paragraphs 23 and 42) as encompassed by claims 1, 19, 20. The concept of using a “non-integrating viral episomal vector” as now claimed is an obvious variant of claim 1 in ‘786. The breadth in claim ‘786 is an obvious variant of claim 1, 19, 20 in the instant application.
The claims of 8440461 drawn to:
A method of reprogramming primate somatic cells, the method comprising the steps of: introducing a retroviral vector encoding a plurality of potency-determining factors into the primate somatic cells under conditions sufficient to reprogram the cells, wherein the potency-determining factors comprise Oct-4 and Sox2, and do not comprise c-Myc and Klf4; and culturing the primate somatic cells under embryonic stem cell culture conditions to obtain pluripotent reprogrammed cells. (Claim 1 of Parent application 12/053440 now US patent 8440461)
The instant claims and the claims of ‘461 are related as product and method of making the product. ‘461 discloses the vector is an EBNA plasmid (Detailed description paragraphs 25, 49) as encompassed by claims 1, 19, 20. The concept of using a “non-integrating viral episomal vector” as now claimed is an obvious variant of claim 1 in ‘461. The breadth in claim ‘461 is an obvious variant of claim 1, 19, 20 in the instant application.
Claim 1 of 8183038 is drawn to:
1. A composition comprising recombinant nucleic acid encoding potency-determining factors SOX2, OCT-4, NANOG, and LIN28, the factor-encoding nucleic acid being operably linked to at least one heterologous promoter, wherein the composition induces reprogramming when introduced into a mammalian cell.
‘038 discloses the vector is an EBNA plasmid (Detailed description paragraphs 25, 49) as encompassed by claims 1, 19, 20. The concept of using a “non-integrating viral episomal vector” as now claimed is an obvious variant of claim 1 in ‘038. The breadth in claim ‘038 is an obvious variant of claim 1, 19, 20 in the instant application.
The claims in the instant application are not patentably distinct from the claims in 11898162, 10106772, 9499786, 8440461, and 8183038. The claims in the instant application could have been claimed in 11898162, 10106772, 9499786, 8440461, and 8183038 and vice versa. Accordingly, a terminal disclaimer is required.
Response to arguments
Applicants argue the amendment overcomes the rejections. Applicants’ argument is not persuasive.
Conclusion
No claim is allowed.
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.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638