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 1, and 7-30 were previously pending.
Receipt is acknowledged of the Amendments filed 15 October, 2025. Claims 1, 7-14, and 16-30 are amended. Claim 15 is cancelled.
Therefore, claims 1, 7-14, and 16-30 are pending and under examination in the instant Official Action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/JP2021/002336, filed 22 January, 2021, which claims priority to United State Provisional Application Nos. 62965669, filed 24 January, 2020, 62988131, filed 11 March, 2020, 63025814, filed 15 May, 2020, and 63131451, filed 29 December, 2020. Acknowledgment is made of applicant’s claim for priority and filing of a certified untranslated copy of the WO 2021/149823 Al publication on 7/22/2022.
The earliest possible priority for the instant application is 24 January, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 30 October, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because Fig. 14, 18, 20, 22, 25, 27 (first panel), 28, 30, 33, 35, 36, 37, 39, 41(a), and 42(a) have no descriptive information present within the figures. There is no title, there are no axis labels, even the scale bar is not clearly labelled. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Withdrawn Rejections/Objections in view of Applicant’s Amendments/Arguments
Claim objection
The objection to claims 1, 7-14, 16, and 24-25 is withdrawn in view of Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 7-17, 19-22, and 24-25 under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al., US 2014/0242695 A1, Published: 28 August, 2014 is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended claim 1 to require the use of vectors. Wang does not teach vectors.
Double Patenting
The provisional rejection of claims 1, and 7-30 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 17759315 (reference application) in view of Wang et al., US 2014/0242695 A1, Published: 28 August, 2014, Devito et al., Cell Death & Disease 10.4 (2019): 277. (hereinafter “Devito”), Wong et al., Stem cell reports 9.1 (2017): 355-365. (hereinafter “Wong”), Jehuda et al., Stem Cell Reviews and Reports 14 (2018): 323-336. (hereinafter “Jehuda”), and Appelt-Menzel et al., Journal of Translational Science 2.5 (2016): 277-285. (hereinafter “Appelt-Menzel”) is withdrawn.
The copending application has been abandoned.
Maintained Rejections/Objections in view of Applicants Amendments/Arguments
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7-14, and 16-30 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. This rejection is necessitated by Applicant’s amendments to the claims.
Amended claim 1 now recites “extinguishing the vectors in the cells”. It is unclear how one extinguishes vectors in cells. A person having ordinary skill in the art would understand that vectors can be extinguished from cells but not in cells. Claims 7-14 and 16-30 are further rejected for their dependency on a rejected base claim.
Amended claim 1 also recites “using vectors” without stating how the vectors are to be used to fall within the scope of the claimed invention. Consequently, the scope of claim 1 cannot be determined and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
Claim 7 recites the limitation "further comprising mixing the cells in which the factors were introduced”. There is insufficient antecedent basis for this limitation in the claim. Claim 1 from which claim 7 depends recites introducing factors into cells using vectors and extinguishing the vectors in the cells in which the factors were introduced. Thus, there are multiple antecedents for “the cells in which the factors were introduced”, one before the step of extinguishing and one after the step of extinguishing and it is unclear which antecedent claim 7 intends to reference. Thus, the metes and bounds of the claim cannot be determined and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought. Claims 8-14, 16, 18-21, 23-30 also each recite the same limitation and, thus, are all individually rejected on the same basis as presented here for claim 7.
Claim 8 recites the limitation "the mixed cells in which the factors were introduced". There is insufficient antecedent basis for this limitation in the claim. Claim 8 does not recite mixed cells in which the factors were introduced. Rather, claim 8 recites a step of mixing clones of the cells in which the factors were introduced. Thus, the metes and bounds of the claim cannot be determined and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
Claim 9 recites the limitation "the mixed cells in which the factors were introduced". There is insufficient antecedent basis for this limitation in the claim. Claim 9 does not recite mixed cells in which the factors were introduced. Rather, claim 9 recites a step of mixing different clones of the cells in which the factors were introduced. Thus, the metes and bounds of the claim cannot be determined and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
Claim 11 recites the limitation "the mixed cells in which the factors were introduced". There is insufficient antecedent basis for this limitation in the claim. Claim 11 does not recite mixed cells in which the factors were introduced. Rather, claim 11 recites a step of mixing a plurality of colonies formed by the cells in which the factors were introduced. Thus, the metes and bounds of the claim cannot be determined and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
Claims 8-11 each require clones, different clones, or a plurality of colonies. The instant specification does not include a definition for the term “cloning” and a person having ordinary skill in the art understands that “cloning” is the process of making genetically identical copies of cells which, under culture conditions, means generating colonies (Britannica Cloning Definition, https://www.britannica.com/science/cloning, Accessed: 10 June, 2025). Further, a person having ordinary skill in the art understands that colonies generated through cloning need to be “picked” in some capacity to be further used (even if the picking comprises merely spraying a solution over an entire agar plate). Thus, forming colonies as required by instant claims 8-11 involves forming copies of genetically identical cells which would be understood by a person having ordinary skill in the art as cloning which requires colony picking. Claim 1 from which claims 8-11 depends requires the method to be performed “without colony picking”. Therefore, claims 8-11 are indefinite because the metes and bounds of the claims cannot be determined as written and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought. For the purpose of compact prosecution, claims 8-11 are interpreted as adding a mixing step to the method of claim 1 and nothing more.
Claim 13 recites “attaching the cells in which the factors were introduced to an incubator”. It is unclear how a cell might be “attached to an incubator”. Thus, claim 13 is confusing as written and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought. For the purpose of compact prosecution, claim 13 is interpreted as requiring a step of incubation, a step of recovery, and a step of seeding at least a part of the recovered cells into a medium.
Claim 22 recites “cloning the somatic cells”. Claim 1 from which claim 22 ultimately depends requires the method to be “without cloning”. Thus, it is unclear whether applicant intends the claims to encompass a method without cloning or with cloning and the metes and bounds of claim 22 cannot be determined as written. Further, the somatic cells of claim 21 encompass terminally differentiated somatic cells and it is unclear how one clones a terminally differentiated cell. Neither claim 22 nor the specification teach how to clone a terminally differentiated cell. Therefore, a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought by instant claim 22. A majority of the pending claims read on a method of culturing cells without cloning. Since claim 22 only adds a cloning limitation which is directly in conflict with the thrust of the pending claims, claim 22 is being interpreted for the purpose of compact prosecution as having the same claim scope as instant claim 1 (that is: claim 22 is interpreted as not adding a step of cloning).
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 7-14, and 16-30 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 claims contain 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.
Applicant has amended claim 1 to recite “introducing factors into cells using vectors” and “extinguishing the vectors in the cells in which the factors were introduced by culturing the cells without colony picking”. These amendments fail to overcome the previously issued written description rejection. Therefore, the rejection is restated in pertinent part below.
Amended claim 1 broadly encompasses and is interpreted as a method for culturing any cells introduced with any factors comprising introducing any factors by any means to any cells using any vectors and extinguishing the vectors in the cells by culturing without colony picking. Claim 13 adds a step of recovering the cells wherein at least part of the recovered cells are seeded in any medium. Claims 14 and 16 add a step of seeding any amount of the cells into anything. Claim 16 adds inducing the cells to pluripotent stem cells without stating how the induction is performed. Claim 17 adds inducing the pluripotent stem cells to somatic cells without stating how this induction is performed. It is noted that claims 16-17 taken together encompass methods wherein the step of inducing pluripotent stem cells and the step of inducing those cells into somatic cells can comprise the same exact elements. Further, the contemplated function of the genus of methods claimed is clearly the production of induced pluripotent stem cells and the differentiation of those cells into other cells as provided for in instant claims 16-17 and as supported by the specification (See discussion below). Claim 18 adds the step of freezing the factor-introduced cells. Claim 19 adds a step of differentiating the factor-introduced cells into at least one selected from among the endoderm, the mesoderm, and the ectoderm but does not provide any limitation for how the differentiating is to be performed, nor what factors are necessary to accomplish the differentiating. Further, it is noted that claim 19 depends directly from claim 1 which does not require inducing the cells into pluripotent stem cells so claim 19 reads on a method of somehow differentiating cells directly from merely being transfected with any “factors” to at least one of the endoderm, mesoderm, or ectoderm without stating how such a feat is accomplished. Claim 20 limits the scope of claim 1 by requiring forming at least one selected from among embryoid bodies, organoids, and spheres from the factor-introduced cells. Again, it is noted that claim 20 reads on a method of forming said structures directly from cells transfected with any “factors” without stating how to do so. Claim 21 is even more specific, limiting the scope of claim 1 to inducing the factor-introduced cells to somatic cells different from pluripotent stem cells. Thus, claim 21 even more precisely embraces somehow bypassing a pluripotent state and going directly from cells introduced with any “factors” to somatic cells without any limitations providing how this is done. Claim 22 as interpreted has the same claim scope as instant claim 1. Claim 24 limits the factor-introduced cells to blood cells, fibroblasts or any cells contained in urine. Claim 25 limits the factor introduced cells to cells derived from a plurality of humans or a plurality of non-human animals. However, claim 24 still reads on a very broad genus of cells due to any blood cell and any cell that could possibly be found in urine being included in the scope, claim 25 still reads on any cell so long as it is of an animal origin, and claim 1 still reads on any cell. Claim 26 requires culturing any cells introduced with any “factors” in a closed incubator. Claims 27-30 add the limitation that the induction be performed without passaging.
Applicant is reminded that “the purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.’ Rochester, 358 F.3d at 920 (quoting Reiffin v. Microsoft Corp., 214 F.3d 1342, 1345 (Fed. Cir. 2000)). It is part of the quid pro quo of the patent grant and ensures that the public receives a meaningful disclosure in exchange for being excluded from practicing an invention for a period of time. Enzo, 323 F.3d at 970.” Id. 598 F.3d at 1353-1354. In this instance, the claims broadly encompass a very large genus of methods wherein any cells introduced with any factors are cultured involving any steps except cloning to accomplish the contemplated functions of producing induced pluripotent stem cells and differentiating those cells into other cells. Where steps are recited in the claims, they continue to encompass large genera of methods which contain inoperative and contradictory embodiments without setting forth any structures or further steps required to accomplish the contemplated functions (induction, differentiation, etc.). The specification bears the burden of supporting such a vast genus of methods by disclosing a sufficient number of methods encompassing a sufficient number of species contained within the claimed genera to show that the inventors had possession of the entire genus claimed.
The instant specification teaches culturing human peripheral blood mononuclear cells at 37 degrees C for 1-7 days in “a blood medium”, adding Sendai virus (SeV) (PM) hKOS/TS12ΔF and SeV (HNL) hC-Myc-TS12ΔF to the culture, adjusting the temperature to 34 degrees C, and culturing the virus/cell mixture for 2 days before replacing the medium with “an iPS cell medium” and replacing the iPS cell medium every 2 days while gradually increasing the temperature to 37-38 degrees C until “stem-cell-like” cell masses were generated (Specification, [0154]-[0156]). The specification teaches the same method performed with Chimpanzee fibroblasts (Specification [0210]). The specification teaches that the cells were TRA1-60 positive 14 days after infection, at which point TrypLE was added to release the cells and the cells were sucked up, incubated at 37 degrees C for 10 minutes before adding them to a 15mL tube for recovery, then the cells were seeded into a plate and passaged with or without cloning of the first-formed colonies and that after one passage the cells were free of SeV (Specification, [0156]-[0159]). The specification also teaches cryopreserving the “iPS-cell-like cells” using STEM-CELLBANKER (Specification, [0161]). The specification also teaches forming “clamps” in the cells, but it is unclear what is meant by this as it is not further defined in the specification and it is not a practice regularly referred to in the field of iPSC generation (Specification, [0165]). The specification also teaches differentiating the iPS-cell-like cells into cardiomyocytes using a “PSC Cardiomyocyte Differentiation Kit” from Gibco (Specification, [0168]). The specification also teaches the differentiation of the “iPS-cell-like cells” into neural progenitor cells by culturing them in 8GMK medium to which “ALK-4, -5, -7 selective inhibitor for TGF-β1 activin receptor-like kinase (ALK)”, membrane permeable inhibitor for BMP type I receptor (ALK2, ALK3), 1% non-essential amino acid, and 1% sodium pyruvate with 100nmol/L 2-mercaptoethanol were added, and replacing said medium 5, 8, and 11 days after seeding the cells (Specification, [0173]-[0174]). The specification also teaches the production of embryoid bodies from the “iPS-cell-like cells” by culturing them in a non-adhesive dish with human ES cell medium without bFGF and replacing the medium every two days for 9 days (Specification, [0177-[0178]). The specification also teaches culturing fibroblasts with SeV (PM) hKOS/TS12ΔF, SeV (HNL) hC-Myc-TS12ΔF, and SeV18+hKLF4/TSΔF under the same conditions as above to generate “stem-cell-like cell masses” (Specification, [0179]-[0185]). The specification teaches that SeV (PM) hKOS/TS12ΔF, SeV (HNL) hC-Myc-TS12ΔF, and SeV18+hKLF4/TSΔF are all temperature sensitive sendai virus vectors and that SeV (PM) hKOS/TS12ΔF encodes KLF4, OCT3/4, and SOX2 genes, SeV (HNL) hC-Myc-TS12ΔF encodes c-Myc, and SeV18+hKLF4/TSΔF encodes KLF4, and that the three vectors together are all part of the commercially available Cytotune-iPS2.0 kit (Specification [0185]). The specification also teaches a method of generating “iPS-cell-like cells” by culturing fibroblasts with silkworm-derived laminin then culturing the cells in stem cell induction medium containing OCT4, SOX2, KLF4, and c-Myc RNAs at 100ng/μL with 0.1 to 100 μL of lipofection reagent (Specification, [0199]-[0202]). The specification also teaches the differentiation of the “iPS-cell-like cells” into nervous system cells without passaging them by infecting the cells with Sendai virus expressing Ngn2-Puro, then 2 days later replacing the medium with 500mL DMEMF12 supplemented with 2 μg/mL puromycin 10mL B27, 5mL N2, and 1.6mL of insulin at a concentration of 6.25 mg/mL (Specification, [0207]-[0208]). The specification also teaches the isolation of cells from urine, then the transfection of those cells with M3O, SOX2, KLF4, C-MYC, and LIN28 RNA modified with pseudouridine and lipofection reagent, and the culturing and passaging of those cells to produce “ES-cell-like cells” (Specification, [0213]-[0291]). Thus, the specification teaches (1) one method of producing “iPS-cell-like cells” from PBMCs or fibroblasts using a specific protocol requiring SeV (PM) hKOS/TS12ΔF encoding KLF4, OCT3/4, and SOX2 genes, and SeV (HNL) hC-Myc-TS12ΔF encoding c-Myc, (2) one method of producing “iPS-cell-like cells” from PBMCs or fibroblasts using a specific protocol requiring SeV (PM) hKOS/TS12ΔF encoding KLF4, OCT3/4, and SOX2 genes, SeV (HNL) hC-Myc-TS12ΔF encoding c-Myc, and SeV18+hKLF4/TSΔF encoding KLF4, (3) one method of differentiating “iPS-cell-like cells” into cardiomyocytes, (4) one method of differentiating “iPS-cell-like cells” into neural progenitor cells, (5) one method of generating “iPS-cell-like cells” from fibroblasts with OCT4, SOX2, KLF4, and c-Myc RNAs at 100ng/μL with 0.1 to 100 μL of lipofection reagent with one method of generating nervous system cells without passaging them by infecting the cells with Sendai virus expressing Ngn2-Puro, then 2 days later replacing the medium with 500mL DMEMF12 supplemented with 2 μg/mL puromycin 10mL B27, 5mL N2, and 1.6mL of insulin at a concentration of 6.25 mg/mL, and (6) one method of generating “ES-cell-like cells” from cells isolated from human urine by using M3O, SOX2, KLF4, C-MYC, and LIN28 RNA modified with pseudouridine and lipofection reagent. When the specification teaches cells sourced from urine, passaging is taught, when the specification teaches other cells, only PBMCs and fibroblasts are taught, when the specification teaches factors, SOX2, KLF4, and C-MYC are consistently required and the inclusion of M3O, OCT4, and LIN28 depends on the specific cell type. Not all factors are taught as sufficient for generating pluripotent cells from every cell type taught and each method taught requires specific culture conditions with specific durations of steps in specific media. Thus, the specification’s teachings are limited to very specific methods which differ from each other depending on the cell type (of which only 3 specific cell types with one defined by its source rather than what it is are taught), the method of introducing the factors (SeV or lipofection of RNA) and which factors are required to induce pluripotency and differentiate the pluripotent cells into other cell types.
At the time of filing, it was known that methods for the generation of iPSCs vary from one another depending on the starting cell type, the reprogramming cocktail, the culture conditions, and the method of reprogramming factor delivery (González et al., Nature Reviews Genetics 12.4 (2011): 231-242., hereinafter “González”). González teaches that reprogramming requires the delivery of certain factors into a specific cell type for a period of time which varies depending on cell type, species, and delivery method (González, page 232, “The donor cell type” subheading, first paragraph). González goes on to teach that 8-12 days are required to reprogram mouse embryonic fibroblasts, whereas the same process takes 20-25 days for human foreskin fibroblasts (González, page 232, “The donor cell type” subheading, first paragraph). González also teaches that endogenous levels of reprogramming factors differ between cell types which further complicates reprogramming factor requirements between cell types as evidenced by the lack of a need for SOX2 when reprogramming neural progenitor cells (González, page 232, “The donor cell type” subheading, second paragraph). González also teaches that the differentiation status of the starting cell type further complicates reprogramming method efficiency as evidenced by the increased efficiency of reprogramming hematopoietic stem cells as opposed to terminally differentiated T and B cells (González, page 232, “The donor cell type” subheading, third paragraph). González also teaches the importance of reprogramming factor selection in an iPSC generation method as evidenced by the findings that (1) mouse B cells transduced with OCT4, SOX2, KLF4, and c-MYC (OSKM) and NANOG produce iPSCs twice as fast as when transduced with OSKM alone, (2) when SALL4 is co-expressed with OSK in human fibroblasts they result in ten times more iPSC colonies than when OSK are expressed alone, and (3) co-expression of telomerase reverse transcriptase (TERT) and SV40 large T antigen (SV40LT) alongside OSKM increases the appearance of iPSCs (González, page 233, “The Reprogramming Cocktail” subheading, first and second paragraphs). González also teaches that the culture conditions that effectively result in iPSCs vary by cell type as evidenced by the increased efficiency of iPSC generation in hypoxic conditions, the use of conditioned media to replace the need for c-MYC, and the use of serum-free medium to obtain iPSCs at an earlier timepoint (González, page 234, “The Culture Conditions” subheading, first paragraph). González also teaches both integrative and non-integrative reprogramming factor delivery methods and that, depending on the starting population, non-integrative methods result in poorer cell survival, and longer reprogramming kinetics (González, page 236, Figure 2; page 237, “Non-integrative approaches” subheading, first paragraph). González also teaches the comparative differences between DNA-based, RNA, and protein reprogramming factor delivery methods and describes varying method concerns along with a need for multiple rounds of introduction for RNA and protein methods as opposed to a single transfection for some DNA-based approaches (González, page 238, Figure 3). González goes on to teach that the RNA-based delivery method only required 17 days to complete reprogramming of neonatal fibroblasts into iPSCs whereas a protein-based delivery method took 6 weeks to accomplish the same reprogramming of the same cell type (González, pages 239-240, “RNA delivery” subheading and “Protein delivery” subheading). Thus, a skilled artisan knew from the art at the time of filing that methods of generating iPSCs vary widely and are particular to the starting cell type, the species source of the starting cells, the reprogramming factors used, the method of delivery of the factors (integrative, non-integrative, RNA, DNA, protein), and the culture conditions required to generate the iPSCs.
Therefore, in view of the vast genus of methods claimed for achieving the contemplated functions of producing induced pluripotent stem cells and differentiating those cells into other cells, the lack of claimed corresponding structures required for achieving those functions, the limitation of the specification to very specific methods for only 3 different starting cell types (PBMCs, fibroblasts, and cells from urine) two types of factor delivery (SeV and RNA), and a very specific set of reprogramming factors that was particular to the cell type used, and the art at the time of filing evidencing a wide degree of variance in methods for iPSC generation which are particular to the starting cell type, the species source of the starting cells, the reprogramming factors used, the method of delivery of the factors (integrative, non-integrative, RNA, DNA, protein), and the culture conditions required to generate the iPSCs, the specification has not disclosed a sufficient number of methods encompassing a sufficient number of species contained within the claimed genera to show that the inventors had possession of the entire genus claimed at the time of filing.
Response to Arguments
Applicant states that “Applicant respectfully traverses” the above 35 U.S.C. 112 rejections without specifically arguing for any particular position on the rejections at issue. Thus, the mere traversal on its own has been considered but is not found to be persuasive.
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 1, 18, 23, and 26 remain rejected and claims 7-14, 16-17, 19-22, and 24-25 are newly rejected under 35 U.S.C. 103 as being unpatentable over Wang et al., US 2014/0242695 A1, Published: 28 August, 2014 in view of Papapetrou et al., Nature protocols 6.9 (2011): 1251-1273. (hereinafter “Papapetrou”), Wong et al., Stem cell reports 9.1 (2017): 355-365. (hereinafter “Wong”), Jehuda et al., Stem Cell Reviews and Reports 14 (2018): 323-336. (hereinafter “Jehuda”), and Appelt-Menzel et al., Journal of Translational Science 2.5 (2016): 277-285. (hereinafter “Appelt-Menzel”). This rejection has been modified as necessitated by Applicant’s amendments to the claims.
Wang discloses a method of generating induced pluripotent stem cells by delivering bacterially expressed reprogramming proteins (interpreted as factors) to somatic cells (Wang, Abstract). Wang also discloses that the method comprises whole dish passaging and nowhere in Wang is a step of cloning required as in instant claims 1 (Wang, [0103]).
Wang does not disclose introducing the factors to the cells using vectors then extinguishing the vectors as required by amended claim 1.
Papapetrou teaches a polycistronic vector for the introduction of the same four reprogramming factors as Wang (OCT4, SOX2, KLF4, and c-MYC) to human cells to reprogram them into iPSCs (Papapetrou, Figure 1, page 1251, third paragraph, Abstract). Papapetrou specifically teaches a method of reprogramming MSCs or fibroblasts using the polycistronic vector and teaches the excision of the vector following reprogramming (Papapetrou, pages 1253-1254, last partial and first partial paragraphs; page 1258, first full paragraph). Papapetrou teaches that this method using the polycistronic vector is an efficient and robust method for iPSC generation from any starting cell type (Papapetrou, page 1253, second paragraph).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have used the excisable polycistronic vector of Papapetrou to introduce the factors of Wang in the method of Wang and to have excised said vector of Papapetrou to arrive at the invention claimed in instant claim 1 with a reasonable expectation of success because they would have been motivated to do so to generate iPSCs robustly from any starting cell type and they would have reasonably expected success in doing so because the factors utilized in both Wang and Papapetrou are the same with the only difference being their delivery in a vector as opposed to translated protein.
Regarding claim 7-11 as interpreted, Wang discloses that the method comprises whole dish passaging following factor introduction and that the cells were seeded into wells (Wang, [0103], [0107]). Thus, Wang discloses mixing the factor introduced cells and seeding the cells.
Regarding claim 10, the method of Wang does not include isolating a plurality of colonies.
Regarding claim 11 as interpreted, the method of Wang comprises a step of mixing (Wang, [0107]) (See 112(b) rejection above for interpretation).
Regarding claim 12, the method of Wang does not include cloning a single colony.
Regarding claim 13, the instant specification contains no specific definition of the term “recovered” and Wang discloses that the method comprises a post-reprogramming culture without reprogramming factors for 48 hours which is encompassed by the broadest reasonable interpretation of the term “recovered” (Wang, [0101]). Further in regard to claim 13, Wang discloses seeding after the post-reprogramming culture (Wang [0107]) and that the method requires incubation (Wang, [0101]) (See 112(b) rejection above for interpretation).
Regarding claim 14, the method of Wang does not require distinguishing the cells according to a gene expression before seeding.
Regarding claim 16, Wang discloses seeding iPSCs (Wang, [0117]).
Regarding claim 17, Wang discloses differentiating the iPSCs into neurons which are somatic cells (Wang, [0140]).
Regarding claim 19, Wang discloses differentiating the iPSCs into endoderm, mesoderm, and ectoderm (Wang, [0140]).
Regarding claim 20, Wang discloses forming embryoid bodies (Wang, [0140]).
Regarding claim 21, Wang discloses differentiating the iPSCs into neurons which are somatic cells different from pluripotent cells (Wang, [0140]).
Regarding claim 24, the starting cells of Wang are fibroblasts (Wang, [0043]).
Regarding claim 25, the method of Wang uses cells from a plurality of human and animal patients (Wang, claim 12).
Wang and Papapetrou do not disclose freezing the factor-introduced cells as required by instant claim 18.
Wong teaches a method of cryopreserving iPSCs (Wong, page 363, fourth and fifth full paragraphs). Wong teaches that their method of cryopreserving the iPSCs is simple and produces better-controlled, more robust PSC experiments (Wong, page 363, third full paragraph).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have implemented cryopreservation as taught by Wong in the method of producing iPSCs of Wang and to have arrived at the invention claimed in instant claim 18 with a reasonable expectation of success because they would have been motivated to do so as a simple way to produce better-controlled, more robust PSC experiments.
Regarding claim 23, Wang, Papapetrou, and Wong do not teach a step of performing a gene editing process on the iPSCs.
Jehuda teaches the application of CRISPR-Cas9 (a gene editing technology) to knockout genes in iPSCs and to correct mutated genes in iPSCs (Jehuda, Abstract; pages 325-326). Jehuda teaches that applying CRISPR in these ways is useful for modelling and investigating different human diseases (Jehuda, page 332, last partial paragraph).
Therefore, it would have been prima facie obvious to have performed a gene editing process as taught by Jehuda on the iPSCs of Wang and to have arrived at the invention claimed in instant claim 23 with a reasonable expectation of success because they would have been motivated to do so for modelling and investigating different human diseases.
Regarding claim 26, Wang, Papapetrou, Wong, and Jehuda do not disclose culturing the factor-introduced cells in a closed incubator.
Appelt-Menzel teaches a method of culturing iPSCs in a stirred bioreactor (Appelt-Menzel, Abstract; Graphical Abstract; page 279, “Stirred Bioreactor” subheading). The stirred bioreactor of Appelt-Menzel is a closed system and a standard incubator was used (Appelt-Menzel, Graphical abstract; page 278, fourth full paragraph). The instant specification contains no specific definition of “closed incubator” and the broadest reasonable interpretation of this claim term encompasses a closed bioreactor placed in an incubator). Thus, the closed bioreactor in an incubator taught by Appelt-Menzel is a closed incubator. Appelt-Menzel also teaches that the closed bioreactor enabled a high level of standardization, and high cell yields with low variability (Appelt-Menzel, page 283, “Standardization” and “Yield and product quality” subheadings).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have used the closed bioreactor of Appelt-Menzel to culture the iPSCs of Wang and to have arrived at the invention claimed in instant claim 26 with a reasonable expectation of success because they would have been motivated to do so to enabled a high level of standardization, and high cell yields with low variability.
Claims 1, and 27-30 remain rejected under 35 U.S.C. 103 as being unpatentable over Wang et al., US 2014/0242695 A1, Published: 28 August, 2014 in view of Papapetrou et al., Nature protocols 6.9 (2011): 1251-1273. (hereinafter “Papapetrou”) as applied to claims 1, 7-14, and 16-26 above and further in view of Devito et al., Cell Death & Disease 10.4 (2019): 277. (hereinafter “Devito”), Wong et al., Stem cell reports 9.1 (2017): 355-365. (hereinafter “Wong”), and Appelt-Menzel et al., Journal of Translational Science 2.5 (2016): 277-285. (hereinafter “Appelt-Menzel”). This rejection has been modified to address Applicant’s amendments to the claims.
As discussed above, Wang and Papapetrou render obvious amended claim 1.
Wang and Papapetrou do not disclose the induction of iPSCs to somatic cells without passaging as in instant claim 27.
Wang does teach that ectoderm, endoderm, and mesoderm include more than 220 cell types and suggests that the ability of a stem cell to differentiate into ectoderm, endoderm, and mesoderm is an indicator of pluripotency (Wang, [0004]). Wang also teaches allowing the iPSCs to spontaneously differentiate into ectoderm, endoderm, and mesoderm as a method of confirming pluripotency (Wang, [0050], [0052], [0140]).
Devito teaches the characterization of iPSC cell lines and specifically teaches leaving iPSCs to differentiate without passaging into ectoderm, endoderm, and mesoderm as a well-understood method of doing so (Devito, page 2, “Characterization of iPSC lines” subheading). Thus, a person having ordinary skill in the art before the effective filing date of the claimed invention understood that allowing iPSCs to differentiate into ectoderm, endoderm, and mesoderm was an effective way of confirming pluripotency and doing so without passaging was a well understood method.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have spontaneously induced differentiation of the iPSCs of Wang into ectoderm, endoderm, and mesoderm cells by culturing the iPSCs without passaging as taught by Devito and to have arrived at the invention claimed in instant claim 27 with a reasonable expectation of success because they would have understood that doing so was a well understood method of confirming pluripotency of the iPSCs.
Regarding claim 28, the combined teachings of Wang, Papapetrou and Devito do not disclose freezing the factor-introduced cells.
Wong teaches a method of cryopreserving iPSCs (Wong, page 363, fourth and fifth full paragraphs). Wong teaches that their method of cryopreserving the iPSCs is simple and produces better-controlled, more robust PSC experiments (Wong, page 363, third full paragraph).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have implemented cryopreservation as taught by Wong in the method of producing iPSCs of Wang and Devito and to have arrived at the invention claimed in instant claim 28 with a reasonable expectation of success because they would have been motivated to do so as a simple way to produce better-controlled, more robust PSC experiments.
Regarding claim 29, the iPSCs of Wang and Devito are both induced to differentiate into endoderm, mesoderm, and ectoderm cells.
Regarding claim 30, the combined teachings of Wang and Devito also do not disclose culturing the factor-introduced cells in a closed incubator.
Appelt-Menzel teaches a method of culturing iPSCs in a stirred bioreactor (Appelt-Menzel, Abstract; Graphical Abstract; page 279, “Stirred Bioreactor” subheading). The stirred bioreactor of Appelt-Menzel is a closed system and a standard incubator was used (Appelt-Menzel, Graphical abstract; page 278, fourth full paragraph). The instant specification contains no specific definition of “closed incubator” and the broadest reasonable interpretation of this claim term encompasses a closed bioreactor placed in an incubator). Thus, the closed bioreactor in an incubator taught by Appelt-Menzel is a closed incubator. Appelt-Menzel also teaches that the closed bioreactor enabled a high level of standardization, and high cell yields with low variability (Appelt-Menzel, page 283, “Standardization” and “Yield and product quality” subheadings).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have used the closed bioreactor of Appelt-Menzel to culture the iPSCs of Wang and Devito and to have arrived at the invention claimed in instant claim 30 with a reasonable expectation of success because they would have been motivated to do so to enabled a high level of standardization, and high cell yields with low variability.
Response to Arguments
Applicant argues against the application of Wang because Wang does not teach “extinguishing the vectors in the cells in which the factors were introduced by culturing the cells without colony picking”. This argument has been fully considered but has not been found persuasive because Papapetrou (provided above) teaches these limitations and provides motivation to combine the teachings found therein with the teachings of Wang.
Double Patenting
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).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1, 7-14, and 16-30 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of copending Application No. 17759308 (reference application) in view of Wang et al., US 2014/0242695 A1, Published: 28 August, 2014, Papapetrou et al., Nature protocols 6.9 (2011): 1251-1273. (hereinafter “Papapetrou”), Devito et al., Cell Death & Disease 10.4 (2019): 277. (hereinafter “Devito”), Wong et al., Stem cell reports 9.1 (2017): 355-365. (hereinafter “Wong”), Jehuda et al., Stem Cell Reviews and Reports 14 (2018): 323-336. (hereinafter “Jehuda”), and Appelt-Menzel et al., Journal of Translational Science 2.5 (2016): 277-285. (hereinafter “Appelt-Menzel”). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims render obvious the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Copending claim 1 is broader that instant claim 1 in that it encompasses methods in which cloning is a step and does not require extinguishing a vector and it is narrower than instant claim 1 in that it requires seeding the cells. Instant claim 1 is directed to a method of culturing factor-introduced cells without cloning. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann , 572 F.2d 312, 197 USPQ 5 (CCPA 1978). Further, Wang teaches a method of culturing iPSCs without cloning comprising a step of seeding and introducing reprogramming factors to the cells (iPSCs are cells into which factors have been introduced (see above prior art rejections)). Thus, copending claim 1 renders instant claim 1 obvious in view of the teachings of Wang. Papapetrou teaches a polycistronic vector for reprogramming cells into iPSCs (See above rejections).
Dependent limitations contained within instant claims 7-30 can be found either in claims 2-23 of the copending application or else supplied by the combined teachings of Devito, Wong, Jehuda, and Appelt-Menzel (See above prior art rejections).
Therefore, instant claims 1, 7-14, and 16-30 are rendered obvious in view of claims 1-23 of the copending application, and the combined teachings of Wang, Devito, Wong, Jehuda, and Appelt-Menzel.
New Rejections in view of Applicant’s Amendments to the claims
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 7-14, and 16-30 are 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. This is a new matter rejection.
Amended claim 1 recites “extinguishing the vectors”. However, this is not supported by the specification. The MPEP teaches, “New or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (a subgenus is not necessarily described by a genus encompassing it and a species upon which it reads). (see e.g. MPEP 2105).
In the instant case, nowhere in the specification or claims as originally filed is there a recitation of “extinguishing” in relation to vectors generally. Applicant has not pointed to any particular location within the specification where a step of “extinguishing” is supported and the Examiner has not been able to locate such support. The instant specification teaches culturing human peripheral blood mononuclear cells at 37 degrees C for 1-7 days in “a blood medium”, adding Sendai virus (SeV) (PM) hKOS/TS12ΔF and SeV (HNL) hC-Myc-TS12ΔF to the culture, adjusting the temperature to 34 degrees C, and culturing the virus/cell mixture for 2 days before replacing the medium with “an iPS cell medium” and replacing the iPS cell medium every 2 days while gradually increasing the temperature to 37-38 degrees C until “stem-cell-like” cell masses were generated (Specification, [0154]-[0156]). The specification teaches that the cells were TRA1-60 positive 14 days after infection, at which point TrypLE was added to release the cells and the cells were sucked up, incubated at 37 degrees C for 10 minutes before adding them to a 15mL tube for recovery, then the cells were seeded into a plate and passaged with or without cloning of the first-formed colonies and that after one passage the cells were free of SeV (Specification, [0156]-[0159]). Thus, while the disclosure may support the passive loss of SeV after passaging, this falls short of a supporting disclosure for “extinguishing” vectors more generally as claimed. Accordingly, the skilled artisan would not conclude that Applicant was in possession of the method claimed in instant claim 1.
Conclusion
No claims are 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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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634