DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
This action is in response to papers filed October 13, 2025.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/13/2025 has been entered.
Claim 62 is amended, no claims are canceled, no claims are newly added as set forth in the claim set filed 10/13/2025. Claims 42, 62 and 63 are independent.
Claims 42, 43, 50, 52-55, 59, 60, 62 and 63 are currently pending and examined on the merits.
Priority
The present application is a continuation of US Application 14/407,044 filed December 10, 2014.
US Application 14/407,044 is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2020/017987, filed June 19, 2013.
Applicant’s claim for the foreign benefit of UK Application number GB1201857.7 filed June 19, 2012 is acknowledged.
Thus, the earliest possible priority for the instant application is June 19, 2012.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112(b)
The rejection of claims 42, 43, 50, 52-55, 59, 60, 62 are 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failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention is withdrawn.
Applicant arguments and amendments filed 10/13/2025 have been considered and are persuasive. In particular, the explanation of the steps regarding the CDM and growth factors inducing mesoderm progenitors.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 42, 50-52, 54-55, 59-60 and independent claim 63 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Yu (US 2014/0037600, claiming priority to 2/8/2011; previously cited) in view of Poncz et al (WO2012/061146; previously cited), Tijssen et al, (Developmental Cell 20, 597–609, May 17, 2011, IDS), Vallier (Methods Mol Biol. 2011:690, pages 57-67; previously cited) and Spelke (Methods Mol Biol. 2011:690, pages 151-162).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 10/13/2025.
Regarding independent claims 42 and 63, and dependent claim 52, Yu teaches a method of programing hematopoietic precursor cells via introducing a nucleic acid with a promoter which can be inducible into a pluripotent stem cell (i.e. step i) (Abstract, para. 0014, 0163). Moreover, Yu teaches the pluripotent stem cells are induced pluripotent stem cells or embryonic stem cells (para. 0010). The nucleic acid may comprise transcription factors coexpressed such as TAL1 and FLI-1 (para. 0018, 0020). Yu further teaches that there is a second nucleic acid element comprising a non-inducible promoter so as to induce transcription of the first nucleic acid comprising the TAL1 and FLI-1 proteins within the pluripotent cell (para. 0053, Example 2). Therefore, the method of Yu would produce an induced pluripotent stem cell comprising TAL1 and FLI-1 proteins. Moreover, the cells are cultured in a media that may help induce the cells comprising FGF, SCF, TPO as well as other factors such as doxycycline (i.e. chemical agent) (para. 0024, 0216). As Yu also teaches that bFGF or FGF-2 is required for ES cell growth (para. 0086), it would be obvious to one of ordinary skill in the art that the FGF utilized is FGF-2. Yu additionally teaches that chemically defined media is present (para. 0213). Regarding the limitation of stable expression of CD41a in a population of megakaryocyte progenitor cells, Yu teaches that megakaryocyte progenitor cells are produced which express CD41a (para. 0050-0051). Moreover, Yu teaches, multiple open reading frames can be transcribed together, each separated by an IRES, creating polycistronic messages (para. 00171).
While Yu teaches GATA2 as a transcription factor to be utilizes with TFs like TAL1 and FLI-1. Yu does not teach GATA1 as another transcription factor, in addition to TAL1 and FLI-1.
Tijssen teaches a genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators, the five key hematopoietic transcription factors GATA1, GATA2, RUNX1, FLI1, and TAL1/SCL in primary human megakaryocytes (abstract). Hematopoietic differentiation critically depends on combinations of transcriptional regulators controlling the development of individual lineages (abstract).
It would have been obvious it one of ordinary skill in the art to not only express FLI1 and TAL1 as taught by Yu but also GATA1 as taught by Tijssen with a reasonable expectation of success to induce progenitor cells from iPSCs or PSCs. An artisan would be motivated to do so as it would be combining known transcription factors for the same purpose of inducing the development of megakaryocytes and platelets. Therefore, all three factors would be concurrently expressed.
However, Yu and Tijssen do not teach that the chemically defined media is without feeder cells.
Vallier teaches chemically defined media in a feeder free cell culture for the culture of pluripotent stem cells (p. 57). Vallier further teaches that the problem of adhesion will immediately lead to cell death or differentiation of hESCs and that many feeder free systems are available in the art as fibroblasts from other sources and FBS are not compatible with clinical applications (p. 58, 60, Abstract).
Based on Vallier’s teachings on cell adhesion immediately leading to cell death or differentiation of hESCs, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify Yu via utilizing feeder free cell culture conditions as taught by Vallier with a reasonable expectation of success. An artisan would be motivated to exclude feeder cells as the absence of feeder cells in PSC cell culture is well known in the art and feeder cell types from other sources are not compatible with clinical applications.
However, neither Yu nor Vallier teach that that feeder free, chemically defined media is additionally in ultra-low adherent culture conditions.
Note that the examiner has interpreted that “ultra-low adherent culture conditions” is that the cells were cultured on ultra-low adherent plates supplied by Corning as disclosed in the instant specification on p. 26.
Spelke teaches that ultra-low attachment dishes allow for pluripotent stem cells to form embryoid bodies while self-aggregating (Abstract, Figure 1, p. 156 #5). Spelke further teaches that alternatives exist to reduce cell-adhesion and that the reduction of cell adhesion is correlated with an increased retrieval of embryoid bodies within the cell culture (p. 160).
Based on such teachings it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify Yu via utilizing ultra-low attachment conditions as taught by Spelke with a reasonable expectation of success. An artisan would be motivated to utilize ultra-low attachment plates as Spelke shows that ultra-low attachment plates are known in the art for culturing ESCs to embryoid bodies and that the reduced attachment leads to a higher retrieval of the embryoid bodies for future use within the differentiation method (Abstract, p. 156, p. 160).
The combined teachings of Yu, Vallier and Spelke do not teach that the CDM comprises BMP4.
Poncz teaches a method of differentiating pluripotent stem cells (ESCs) into megakaryocytes via culturing in a media comprising BMP4 and FGF-2 (Example 3).
It would have been obvious to a person of ordinary skill in the art to combine the triad combination of introducing a nucleic acid encoding GAT1, TAL1 and FLI1 into pluripotent stem cells and culturing in media comprising FGF by including BMP4 to produce a population of committed megakaryocyte lineage cells as disclosed by Poncz.
Regarding claim 50 and 59, Yu teaches that the pluripotent stem cells are induced pluripotent stem cells or embryonic stem cells (para. 0010).
Regarding claim 54 and 55, Yu teaches that the stem cells are cultured and platelets obtained at least 3 to 20 days (para. 0025).
Regarding claim 60, Yu teaches the iPS cells are human (para. 0054).
Therefore, the invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Response to Applicants’ Arguments as they apply to rejection of claims 42, 50, 52, 54-55 and 59-60 under 35 U.S.C. 103
Applicant’s amendment and response filed 10/13/2025 regarding claims 42, 50, 52, 54-55 and 59-60 have been considered. However, the arguments are not persuasive.
Applicant argues on page 8 of Applicant’s Remarks, that Yu, Poncz, Tjssen, Vallier and Spelke, alone or in combination fail to indicate a specific combination of the GATA1, FLI1 and TAL1 proteins to be induced in the PSCs and wherein the megakaryocyte (MK) progenitors are programmed to express CD41a. Applicant specifically states that it is not taught that “all three of the transcription factors (TFs) are on the same nucleic acid and linked by the same inducible promoter, promotes the induction of the combination of GATA1, FLIl and TAL1 proteins in PSCs, nor do the references identify why, out of all of the transcription factors disclosed or taught, that inducing the combination of proteins would result in megakaryocyte progenitors expressing CD41a from the iPSCs.” Overall, Applicant states there is not suggested why the induction of the specific combination would be chosen nor that it would be predictable and fail to render the independent claims obvious.
The Examiner disagrees. In response to applicant's argument, Examiner states that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Within the previously set forth 103 rejection which has now been modified to include particular newly recited claim language, the motivation and suggestion for the specific combination of GATA1, FLI-1 and TAL1 protein expression is detailed. To reiterate the rejection above, Yu teaches the coexpression of transcription factors such as GATA2, TAL1, and FLI-1 to forward program PSCs and iPSCs to MK progenitors which express CD41a. Tjssen teaches GATA1, GATA2, TAL1, and FLI-1 are key hematopoietic transcription factors which are expressed in primary human MKs. Therefore, there would be a reasonable expectation of success in the combination of GATA1, TAL1 and FLI-1 in reprogramming the PSC cells of Yu to produce MK progenitor cells expressing CD41a. Moreover, based on the teachings of Yu having the capability of concurrent expression of multiple factors, (“Multiple open reading frames can be transcribed together, each separated by an IRES, creating polycistronic messages”, para. 0171, ) it would additionally provide teaching, suggestion and motivation for GATA1, TAL1 and FLI-1 under the same promoter being concurrently expressed. In relation to Applicants’ remarks that “i.e., that all three of the transcription factors (TFs) are on the same nucleic acid and linked by the same inducible promoter, promotes the induction of the combination of GATAI, FLII and TALI proteins in PSCs”, the instant claims require a first nucleic acid comprising an inducible promoter and nucleotide sequences encoding GATAI, FLII and TALI proteins for their concurrent transcription under a control of the inducible promoter, but the instant claims are not so limited such that this is the only possible expression from the claimed first nucleic acid. The claims are "open" and thus lend themselves to additional transgenes, or additional transcription factor which may be specific for binding to the inducible promoter. There is no requirement that the only expression of first nucleic acid of instant claims 42 and 63 is so limited as argued by Applicant. Thus, the combined disclosure of Yu and the cited references is relevant, since GATA1, GATA2, TAL1, and FLI-1 are key hematopoietic transcription factors which are expressed in primary human MKs, rendering obvious the combination of GATA1, TAL1 and FLI-1 in reprogramming the PSC cells to produce MK progenitor cells expressing CD41a.
***
Claim 43, 53 and independent claim 62 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Yu (supra) in view of Poncz et al (supra), Tijssen et al, (supra), Vallier (supra) and Spelke (supra) as applied to independent claims 42 and 52 above and in further view of Li (BIOTECHNOLOGY AND BIOENGINEERING, VOL. 91, NO. 6, SEPTEMBER 20, 2005)
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 10/13/2025.
As discussed above the references of Yu, Poncz, Tijssen, Vallier and Spelke provide for a method of producing platelets and megakaryocyte progenitor cells via introducing TAL1, GATA1, and FLI-1 and culturing in a media comprising BMP-4, FGF-2, TPO, and SCF to produce the desired cell type which stably expresses CD41a, as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety.
However, these references do not teach that the media components are recombinant human growth factor components.
Li teaches culturing human embryonic stem cells in animal free cell cultures comprising human recombinant components in order to culture in a feeder free system (Abstract, p. 689)
It would have been obvious to one of ordinary skill in the art to utilize growth factors which are human recombinant growth factors in the method of Yu with a reasonable expectation of success. An artisan would have been motivated to utilize human recombinant growth factors in media as they are known in the art to be utilized in order to develop a convenient and consistent procedure to produce cells at a large scale with minimal animal-derived products as it would be beneficial to not require conditioning with feeder cells (p. 689, 2nd paragraph).
Therefore, the invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Response to Applicants’ Arguments as they apply to the rejection of claims 43, 53 and 62 remain rejected and independent claim 63 under 35 USC § 103
Applicant’s arguments are the same for this rejection as the above 103, thus the arguments have been addressed and the rejection maintained.
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634