Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on January 13, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1 – 2, 4 -5, 7 – 10, 13, 15 – 16, 19 – 21, 24 – 25, 31, 34 – 35, 41, 44 – 46 are currently pending. Claims 1,2, 4 – 5, 7 – 10, 13, 15 - 16, 19 – 21, 24, 31, 35, 44, and 45 were amended in the Applicant’s amendment filed January 13, 2026. Claims 3, 11 - 12, 26 -30, 32 – 33, 36 – 40, 42 – 43 have been cancelled in the Applicant’s amendment filed January 13, 2026. Claims 46 has been added in the Applicant’s amendment filed January 13, 2026.
The Examiner has previously acknowledged receipt the Declaration under 37 CFR § 1.132 executed by Luigi Warren, PhD. on October 24, 2024, and filed October 25, 2024 (hereinafter the “Warren decl.”).
Therefore, claims 1 – 2, 4 -5, 7 – 10, 13, 15 – 16, 19 – 21, 24 – 25, 31, 34 – 35, 41, 44 – 46 are currently pending are currently pending for examination to which the following grounds of rejection are applicable. Claims 1 and 10 are independent claims.
Maintained Objections/Rejections
Claim Rejection - 35 USC § 112(b)
The rejection of claims 4, 10, 13, 19 – 21, 25, 41, and 44 - 45 is maintained, and claim 46 is newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 is indefinite for the recitation of “the somatic cells is reprogrammed into an induced pluripotent stem cell” in lines 1 – 3. There is a lack of antecedent basis for the term “reprogrammed” as the cells of claim 1 are being converted.
Claim 10 is indefinite for the recitation of “reprogrammed to pluripotency, forming pluripotent cells” in line 13 of claim 10. It is unclear and not defined in the as-Filed Specification what are “reprogrammed to pluripotency, forming pluripotent cells.” For compact prosecution, this term has been interpreted as reprogrammed to human pluripotent stem cells (see paragraph [0103] of the published application).
Claims 13, 19 – 21, 25, 41, 44, and 46 are indefinite insofar as they ultimately depend from claim 10.
Claim Rejection - 35 USC § 112(a) Scope of Enablement
While applicant’s amendment to independent claims 1 and 10 partially overcome some of the issues, some additional issues remain that are discussed below.
The rejection of claims 1 – 2, 4 -5, 7 – 10, 13, 15 – 16, 19 – 21, 24 – 25, 31, 34 – 35, 41, 44 – 46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the Specification, while being enabling for
a method for reprograming fibroblasts into an human pluripotent stem cells , comprising transfecting the fibroblasts with a cocktail of mRNAs encoding a fusion protein comprising an Oct4 linked to a C-terminal transactivation domain (TAD) of Gal4, a fusion protein comprising an mRNA encoding Sox2 linked to TAD of YAP, and mRNAs encoding Klf4, Lin28, Nanog, and Myc, wherein individual mRNAs are combined in an equimolar ratio,
does not reasonably provide enablement for converting any type of lineage of somatic cell into any cell type resulting from conversion of said lineage of the somatic cell. Moreover, the claims are not enabling for any unspecified ratio of the individual mRNAs used in the cocktail to induce pluripotency. This rejection has been modified as necessitated by the response filed January 13, 2025.
The Specification does not enable any person skill in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The claims, when given the broadest possible interpretation, encompass a method for converting the lineage of a somatic cell, comprising transfecting the cell with a mRNA encoding an Oct4 linked to a C-terminal transactivation domain (TAD) of Gal4, and one or more additional synthetic mRNAs, selected from the group consisting of Sox2, Klf4, Lin28, Nanog, and Myc. The Specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
Nature of invention. The invention encompasses a method for converting the lineage of a cell, comprising transfecting the cell with a mRNA encoding an Oct4 linked to a C-terminal transactivation domain (TAD) of Gal4, and one or more additional synthetic mRNAs, selected from the group consisting of Sox2, Klf4, Lin28, Nanog, and Myc.
Scope of the invention. The invention encompasses a method of converting a cell lineage.
Number of working examples and guidance. In the instant application, Applicant only discloses one relevant example that teaches the genus of converted cells.
The as-Filed Specification teaches the ultra-rapid mRNA reprogramming of fibroblasts using an Oct4-Gal4 Tad fusion construct, wherein six templates are required (Paragraph [0095]). The six templates required for this protocol contain coding sequences for Oct4-Gal4 TAD fusion protein, the Sox2-YAP TAD fusion protein (Sy), wild-type Klf4, the T58A mutant form of c-Myc (often used in reprogramming because of its heightened potency relative to wild-type c-Myc), Lin28 and Nanog., wherein the individual mRNAs should be combined in an equimolar ratio (Paragraphs [0096] and [0098]). After culturing, the colonies can be picked to established that “passage 1” of iPSCs cultures for expansion and stabilization (Paragraph [0103]). This example teaches that all 6 mRNAs are necessary for the conversion of fibroblasts into iPSCs, and that the mRNAs are in an equimolar ratio. The as-Filed Specification does not teach any examples wherein the any other cell types are formed, or any other concentrations of the 6 mRNAs.
State of the art. Although the field of converting cell lineage is well known in the art, the
method of converting cells using this combination of mRNAs and specifically the use of TAD of a protein is not highly developed. The art must therefore be considered to be poorly developed.
Unpredictability of the art. Before the effective filing date of claimed invention, it was
known in the art that an mmRNA composition kit encoding a cocktail of reprogramming factors, Sox2, Oct4, Nanog, KLF4, and cMYC, was used to transfect fibroblasts to generate induced pluripotent cells, as evidenced by Cooke et al. (US 2015/0225699 A1, published August 13, 2015) (Paragraph [0010] – [0013]).
It was also known in the art that when C-terminal TAD of YAP was linked to Sox2, the iPSC induction efficiency increased 100 fold and reprogrammed the cells within 24 hours, as evidenced by Yang et al. (Yang X. et al. Reprogramming cells with synthetic proteins. Asian J Androl. 2015 May-Jun;17(3):394-402. doi: 10.4103/1008-682X.145433. PMID: 25652623; PMCID: PMC4430937) (pg. 397, Table 1).
Further, it was known in the art that the technique of inducing iPS cells has problems such as in low induction efficiency, long time, and safety problem, which impede rapid and efficient acquisition of high quality iPS cells for clinical application, as evidenced by Chen et al. (US 20160348077 A1 , published 1 December, 2016) (Paragraph [0012]). Chen et al. also teaches a method for safely, rapidly and efficiently inducing and producing pluripotent stem cells to overcome drawbacks, comprising the use of a fusion protein comprising a cell a transcription control domain, which is a TAD of YAP, linked using a linker to a totipotency related gene, such as OCT4, SOX2, NANOG, SOX1, and SOX3 (Paragraphs [0013] – [0017]). Additionally, the applicant is on record as stating that the ordinary artisan would have had no reason to expect that there would be rapid and efficient reprogramming by simply choosing any one or more of the fusion proteins taught by Yang (“Warren decl.”, paragraph 8). Thus, it is necessary to have all the reprogramming factors for the conversion of the cell lineage for conversion to iPSC.
Amount of Experimentation Required. Given the unpredictability of the art, the poorly
developed state of the art efficiency of inducing iPS cells, the particular use of TAD of YAP linked to Sox2, and the particular combination of mRNAs used in the cocktail for reprogramming and converting cells, the skilled artisan would have to conduct undue, and unpredictable experimentation to practice the claimed invention using the Oct4-Gal4 TAD construct, with any of the other mRNAs listed to convert the lineage of a cell. Further, due to the lack of specific guidance in the specification for the mRNA sequences of the other mRNAs used in the claims, it would require undue experimentation to practice the breadth of the instant methods as claimed.
Response to Arguments as they apply to rejection of claims 1 – 2, 4 – 5, 7 – 10, 13, 15 – 21, 24 – 25, 31, 34 – 35, 41, and 44 - 46 under 35 USC § 112 (a)
Applicant’s arguments filed January 13, 2026 have been fully considered but they are not persuasive. Applicant essentially asserts (a) Applicant has amended the independent claims to specify that the exogenous composition is used to reprogram somatic cells (Applicant Remarks, pg. 8, last paragraph).
Regarding (a), Applicant’s arguments are not found persuasive. The instantly filed claims and as-Filed Specification teach that the somatic cells are reprogrammed into iPSCs. The as-Filed Specification does not show support for converting the cell into any other cell type than iPSCs. The Examiner suggests amending the claims to recite “a method for converting the lineage of a somatic cell into an iPSC.”
Conclusion
Claims 1 – 2, 4 -5, 7 – 10, 13, 15 – 16, 19 – 21, 24 – 25, 31, 34 – 35, 41, 44 – 46 remain rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VYOMA SHAILESH THAKKER whose telephone number is (571)272-2954. The examiner can normally be reached M-F 8:30 - 5:30 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
Prosecution Insights