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 .
New claims 23-29 are pending and under consideration in this office action.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: METHODS FOR DIFFERENTIATING HUMAN PLURIPOTENT STEM CELLS INTO HEPATOCYTES.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/465,188, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. While this provisional application does contemplate differentiating pluripotent cell into hepatocytes using a Sendai virus encoding transcription factor HNF1A. It does not describe also using FOXA1 as the claims require. As such, this provisional lacks adequate written description of the claimed invention. Thus, the claims are denied that benefit of its earlier filing date and the effective filing date for the claims is 6/22/2017.
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.
(1) Claim(s) 23-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Simeonov (WO 2014/039768 A1 pub date:3/13/2014) in further view of Ban (Ban et al. PNAS 108(34):14234-14239, 2011; of record in IDS).
Regarding claim 23, Simeonov teaches a method of producing an induced hepatocyte from non-hepatocyte cells, the method comprising providing a non-hepatocyte cell, contacting the non-hepatocyte cell with an agent that increases or induces the expression or activity of one or more reprogramming factors, and culture the non-hepatocyte cell under conditions suitable for reprogramming the non-hepatocyte cell, thereby producing an induced hepatocyte cell from a non-hepatocyte cell. In some embodiments, the agent that is a nucleic acid encoding one or more of the following factors: FOXA1, FOXA2, FOXA3, HNF1A, HNF4A and GATA4 (p. 4, lines 13-23). In various aspects of the methods provided herein, the non-hepatocyte cell is a human non-hepatocyte cells (p. 12, lines 25-26). Non-limiting examples of non-hepatocyte cells include fibroblasts, bone marrow cells, blood cells, endothelial cells, keratinocytes, mesangial cells, embryonic stem cells, etc. (p. 20, lines 8-10).
Simeonov does not teach the nucleic acids encoding the above reprogramming agents is comprised in a Sendai virus vector. However, However, Ban teaches the successful transduction of cells with reprogramming transcription factors using a temperature-sensitive Sendai viral vector encoding said transcription factors. Ban further teaches that using a temperature sensitive form of the Sendai virus allows for easy removal of the vector at non-permissive temperatures and thus providing an end-product cell that is free of the exogenous transcription factors introduced (abstract; p. 14238 col 2, paragraph under material and methods section).
Thus it would have been obvious to an artisan of ordinary skill at the time of effectively filing to incorporate the nucleic acids encoding the reprogramming factors in Simeonov into the Sendai viral vector taught by Ban to transduce the non-hepatocyte embryonic stem cells in the method of Simeonov to predictably arrive at the limitations of claim 23. The artisan would have a reasonable expectation of success in using the temperature-sensitive form of the Sendai virus because Ban teaches that it successfully transduces cells and results in exogenous transcription factor expression. Further, the artisan would have been motivated to use the temperature-sensitive form of the Sendai viral vector because Ban teaches that it would allow for easy removal of the exogenous transcription products from the end product differentiated cell. Thus, Simeonov in view of Ban renders claim 23 obvious.
Regarding claims 24 and 25, Ban teaches the Sendai virus vector is a temperature sensitive form (claim 24) as discussed above. Ban teaches their Sendai virus vector transduces and expresses the transgene at lower temperatures of 32 to 35C but does not transduce and express the transgene at higher temperatures such as 37 to 38C (paragraph bridging pp. 14234-14235), thus teaching the limitations of claim 25. As such, Simeonov in view of Ban renders claims 24 and 25 obvious for reasons discussed above.
Regarding claim 26, the claims generically specifies two types of basal cell culture media are used. The claim does not specify how they are used and what constitutes basal media. As teaching or suggestion of any two medias will be the limitations of the claim. Simeonov teaches a reprogramming cell culture media and non-reprogramming media (p. 14, lines 11-19). As such, Simeonov in view of Ban renders claim 26 obvious.
Regarding claim 27, Simeonov teaches that the introduction of the nucleic acids into non-hepatocyte cells can occur at any of these frequences and for durations sufficient enough to produce induced hepatocytes, such as, for example, for 1 day, for 2 days, for 3 days, for 4 days, for 5 days, for 6 days, for 7 days, for 8 days, for 9 days, etc. (p. 39, lines 14-17). Thus Simeonov in view of Ban teach the limitations of claim 27.
(2) Claim(s) 28-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Simeonov (WO 2014/039768 A1 pub date:3/13/2014) in further view of Ban (Ban et al. PNAS 108(34):14234-14239, 2011; of record in IDS) and Akiyama (Akiyama et al. Development 143:3674-3685, 2016; of record in IDS).
Simeonov in view of Ban teach the claims as discussed above. Simeonov in view of Ban does not teach that the method further comprises adding a gene for a compound having an action of substantially removing or reducing an expression amount of a POUF1 protein to the pluripotent stem cell.
However, Akiyama teaches introducing an expression vector into human pluripotent stem cells, wherein the expression vector encoding HA-JMJD3c (p. 3676, figure 1 and p. 3683, col 2, second paragraph under the materials and methods section). Akiyama further teaches that as expected, pluripotency-related genes (e.g. POU5F1, NANOG, SOX2, DNMT3B, TDGF1, LIN28, ZFP42, DPPA2, KDM4C, TET1, MYC and UTF1) were downregulated in the JMJD3c-overexpressing hESCs. Akiyama further teaches that they reasoned that the H3K27me3-deficient hESCs could be efficiently differentiated by the forced expression of lineage-defining transcription factors. They transiently overexpressed JMJD3c in hESCs and subsequently expressed one of the transcription factors MYOD1, HNF1A, RUNX2 or SPI1, which are known to regulate the differentiation of myogenic (Tapscott, 2005), hepatogenic (Si-Tayeb et al., 2010), osteogenic (Lian and Stein, 2003) or hematopoietic (Kastner and Chan, 2008) lineages, respectively, to test this hypothesis. In this procedure, we transfected the Dox-treated or untreated JMJD3c-hESCs with synthetic mRNAs encoding each transcription factor (Fig. 4A). Real-time PCR analysis revealed that when the transcription factors were overexpressed in the JMJD3cexpressing hESCs, the relevant differentiation markers [MYOG for myogenesis, AFP for hepatogenesis, COL1A1 for osteogenesis, and CD45 (PTPRC) for hematogenesis] were more significantly upregulated compared with the hESCs that did not express JMJD3c (Fig. 4B). Notably, JMJD3c alone did not change the expression patterns of these tissue-related genes. These results suggest that the combination of JMJD3c and a lineage-defining transcription factor can promote hPSC differentiation towards specific tissues or cell types
Thus it would have been obvious to an artisan of ordinary skill at the time of effectively filing to further introduction a transgene encoding JMJD3, as taught by Aikiyama, into the non-hepatocyte embryonic stem cells, as taught by Simeonov in view of Ban, to predictably arrive at the limitations of claims 28 and 29. An artisan would have a reasonable expectation of introducing such a transgene into the non-hepatocyte embryonic stem cell of Simeonov in view of Ban because introducing transgenes into pluripotent stem cells was well established in the prior art, as demonstrated by both Ban and Aikiyama. Further, the artisan would have been motivated to include said transgene taught by Aikiyama into the non-hepatocyte pluripotent stem cell of Simeonov in view of Ban because Aikiyama teaches that the expression of said transgene enhances the differentiation of the pluripotent stem cells by upregulation differentiated cell specific genes to a greater degree than if said transgene was not present. Thus, Simeonov in view of Ban and Aikiyama render claims 28 and 29 obvious.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. The claimed method was known in the art at the time of filing as indicated by Simeonov in view of Ban and Aikiyama. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/ Primary Examiner, Art Unit 1632
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