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 .
Application Status
Claims 1-2, 5-6, 9, 11-13, 15, 18-19, 22, 26, 31, 33-35, 37-39, and 44-46 are pending and examined on the merits herein.
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 5-6, 11-13, and 22 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 5-6 and 11-13 recite the limitation "the IPSCs". There is insufficient antecedent basis for this limitation in the claims. Claims 5-6, 11 and 13 depend from claim 1; claim 1 does not include a recitation of IPSC that is not included until dependent claim 2, therefore there is no antecedent basis for this limitation in the dependent claims. Claim 12 depends from 11 and therefore there is no antecedent basis for this limitation in this claim as well.
Claim 22 recites “the method of claim 1, wherein inducing hematopoietic differentiation comprises or further comprises,” as there is already a method of differentiation described in claim 1, it is unclear how claim 22 can “comprise or further comprise” additional elements. This rejection can be obviated by deleting the option “comprises or”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 6, 9, 13, 18, 22, 26, 31, 33-35, 39, and 44-46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yu (US 2017/0107492 A1; IDS entered 08/05/2025), as evidenced by Vodyanyk (US 2014/0349398 A1; IDS entered 06/09/2023).
Regarding claim 1, Yu teaches an in vitro method for producing hematopoietic precursor cells from pluripotent stem cells comprising: (a) providing pluripotent stem cells (PSCs) comprising at least one expression construct encoding hematopoietic precursor programming genes, wherein the hematopoietic precursor programming genes comprise an ETS/ERG gene, GATA2, and HOXA9; and (b) culturing the pluripotent stem cells under conditions such that the hematopoietic precursor programming genes are expressed, thereby producing hematopoietic precursor cells (HPCs) (claim 1), wherein the ETS/ERG gene is ERG or ETV2 (claim 24). Yu further teaches that expression of ETV2 resulted in endothelial cells (para 0204; Fig 1).
As evidenced by Vodyanyk, hemogenic endothelial cells are produced by increasing expression of the endothelial programming factor, ETV2, and such hemogenic endothelial cells may be used to generate hematopoietic cells (para 0033). Therefore, expression of ETV2 in the endothelial cells would naturally produce hemogenic endothelial cells.
Regarding claim 2, Yu teaches wherein the pluripotent stem cells are induced pluripotent stem cells (iPSCs) (claim 9), and that “(iPSCs)” are cells generated by reprogramming a somatic cell by expressing or inducing expression of a combination of factors (para 0058).
Regarding claim 6, Yu teaches PSCs, such as ESCs or iPSCs, are genetically modified to express the hematopoietic precursor programming genes described herein which forward program the PSCs into multi-lineage hematopoietic precursor cells (para 0167) and that the cells may comprise a reporter gene expression cassette comprising tissue-or cell-specific transcriptional regulatory elements, like hematopoietic cell-specific promoters for hematopoietic cell identification (para 0181).
Regarding claim 9, Yu teaches wherein the expression construct is a transposon-or episomal-based expression construct (claim 4).
Regarding claim13, Yu teaches that the differentiation of human PSCs to cells of hematopoietic lineage in vitro recapitulates normal in vivo development including stages of mesoderm induction and specification of multipotent hematopoietic precursors (para 0007).
Regarding claim 18, Yu teaches that one feature of the present invention includes using selection and screenable markers to select for endothelial cells after the programming factors have affected a desired programming change in those cells (para 0190) and that phenotypic markers characteristic of cells of the endothelial cell lineage include CD34 (para 0232).
Regarding claim 22, Yu teaches the medium may also contain one or more hematopoietic cell differentiation and maturation agents…non-limiting examples of such agents include but are not limited to hematopoietic or endothelial growth factors such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), stem cell factor (SCF), thrombopoietin (TPO), FLT-3 ligand (FLT3L), interleukin-3 (IL-3), interleukin-6 (IL-6), interleukin-9 (IL-9), or granulocyte colony-stimulating factor (G-CSF), or isoforms or variants thereof (para 0180).
Regarding claim26, Yu teaches the total CD43+ hematopoietic cells expanded by more than 30-fold in the EGH-induced cells (Fig 1E).
Regarding claim 31, Yu teaches on-adherent cells were collected (para 0207).
Regarding claim 33, Yu teaches further provided are therapeutic compositions including the provided hematopoietic stem cells (abstract).
Regarding claims 34-35, Yu teaches the cells provided herein can be used for therapy of any subject in need thereof including humans with various anemias and hemoglobinopathies such as myelodysplastic syndrome, myelofibrosis, neutropenia, agranulocytosis, Glanzmann's thrombasthenia, thrombocytopenia, and acquired immune deficiency syndrome (para 0199) and that the cells can be administered at any site that has adequate access to the circulation (para 0198).
Regarding claims 39 and 44-46, Yu teaches wherein the HPCs can be differentiated into two or more cell types selected from the group consisting of plasma cell, natural killer cell, macrophage, mast cell, megakaryocyte, erythrocyte, granulocyte, lymphocyte, monocyte, leukocyte, and thrombocyte (claim 21).
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.
Claims 5 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Yu (US 2017/0107492 A1; IDS entered 08/05/2025), as evidenced by Vodyanyk (US 2014/0349398 A1; IDS entered 06/09/2023) as applied to claims 1-2, 6, 9, 13, 18, 22, 26, 31, 33-35, 39, and 44-46 above, and further in view of Torikai (Sci Rep 6, 21757 (2016); PTO-892).
The teachings of Yu regarding claims 1-2, 6, 9, 13, 18, 22, 26, 31, 33-35, 39, and 44-46 are detailed above.
Yu does not teach wherein the iPSCs are HLA-modified or HLA-null; or allogeneic.
Regarding claims 5 or 37, Torikai teaches that to broaden the existing pool of registered unrelated donors of hematopoietic stem cells for transplantation based on analysis that eliminating the expression of the HLA-A increases the chance for finding a donor (abstract). Torikai further teaches that elimination of HLA-A expression in HSC was achieved using artificial zinc finger nucleases designed to target HLA-A alleles and that the engineered HSCs maintain their ability to engraft and reconstitute hematopoiesis (abstract). Torikai further teaches that loss of HLA-A expression decreases the need to recruit large number of donors to match with potential recipients and has particular importance for patients whose HLA repertoire is under-represented in the current donor pool (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use allogeneic HSC or HLA-A null HSC as taught by Torikai in the method of treatment using HSCs generated using ETV2 expression in iPSCs as taught by Yu. The ordinary artisan would have been motivated to do so because Torikai teaches that transplantation of allogeneic hematopoietic stem cells (HSC) into recipients with hematologic disorders reconstitutes normal hematopoiesis. Torikai further teaches loss of HLA-A expression decreases the need to recruit large number of donors to match with potential recipients and has particular importance for patients whose HLA repertoire is under-represented in the current donor pool while maintaining HSC ability to engraft and reconstitute hematopoiesis. The ordinary artisan has a reasonable expectation of success to use allogenic HSCs or HLA-A null engineered HSCs for transplantation in the method of treating a disease using HSCs generated by ETV2 expression.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Yu (US 2017/0107492 A1; IDS entered 08/05/2025), as evidenced by Vodyanyk (US 2014/0349398 A1; IDS entered 06/09/2023) as applied to claims 1-2, 6, 9, 13, 18, 22, 26, 31, 33-35, 39, and 44-46 above, and further in view of Vodyanyk (US 2014/0349398 A1; IDS entered 06/09/2023).
The teachings of Yu regarding claims 1-2, 6, 9, 13, 18, 22, 26, 31, 33-35, 39, and 44-46 are detailed above.
Yu does not teach wherein the ETV2 is expressed from an mRNA introduced into the iPSCs.
Vodyanyk teaches that the ETV2 is in an expression cassette in the form of a gene or gene product (claim 27) and that the format of a gene can include eukaryotic mRNA (para 0078) and that one of skill in the art would be well-equipped to deliver to a cell any mRNA useful in the invention (para 0163).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use mRNA to express ETV2 in the iPSCs as taught by Vodyanyk in the method of generating HSCs using ETV2 expression in iPSCs as taught by Yu. The ordinary artisan would have been motivated to do so because Vodyanyk teaches that one of skill in the art would be well-equipped to deliver to a cell any mRNA useful in the invention, therefore there is a reasonable expectation of success that the ordinary artisan would be able to use mRNA to express ETV2 in iPSCs.
Claims 12 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Yu (US 2017/0107492 A1; IDS entered 08/05/2025) and Vodyanyk (US 2014/0349398 A1; IDS entered 06/09/2023) as applied to claims 1-2, 6, 9, 11, 13, 18, 22, 26, 31, 33-35, 39, and 44-46 above and further in view of Wang (Sci Adv. 2020 Jul 24;6(30):eaba7606; IDS entered 08/01/2025).
The teachings of Yu and Vodyanyk regarding claims 1-2, 6, 9, 11, 13, 18, 22, 26, 31, 33-35, 39, and 44-46 are detailed above.
Yu and Vodyanyk do not teach wherein the ETV2 mRNA is introduced into mesodermal progenitor cells prepared from the iPSCs or use for autologous treatment.
Wang teaches that human induced pluripotent stem cell (h-iPSC)–derived endothelial cells (h-iECs) have become a valuable tool in regenerative medicine however current differentiation protocols remain inefficient and lack reliability (abstract). Wang further teaches development of a novel protocol that enables highly efficient differentiation of h-iPSCs into competent h-iECs comprising a differentiation period of 4 days and comprises two steps:(i) differentiation of h-iPSCs into intermediate h-MPCs and (ii) conversion of h-MPCs into h-iECs upon delivery of modRNA encoding ETV2 (page 8, col 2, para 5; Fig 1A). Wang further teaches that they were able to expand the resulting h-iECs with ease, obtaining an average h-iEC–to–h-iPSC ratio of ~70-fold after 3 weeks in culture (page 9, col 2). Wang further teaches that the delivery of modified mRNA encoding the transcription factor ETV2 at the intermediate mesodermal stage of differentiation led to rapid, consistent, and highly efficient generation of h-iECs (abstract) which has broad application in regenerative medicine because it provides a reliable means to obtain autologous h-iECs for vascular therapies (page 10, col 2, para 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use ETV2 mRNA introduced to MPCs as taught by Wang in the method of generating HSCs using ETV2 mRNA expression in iPSCs as taught by Yu and Vodyanyk. The ordinary artisan would have been motivated to do so because delivery of modified mRNA encoding the transcription factor ETV2 at the intermediate mesodermal stage of differentiation led to rapid, consistent, and highly efficient generation of h-iECs that are easily expanded in culture. The ordinary artisan has a reasonable expectation of success to express ETV2 mRNA in MPCs generated from iPSCs to more efficiently generate h-iECs.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claims 15 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Yu (US 2017/0107492 A1; IDS entered 08/05/2025), as evidenced by Vodyanyk (US 2014/0349398 A1; IDS entered 06/09/2023) as applied to claims 1-2, 6, 9, 13, 18, 22, 26, 31, 33-35, 39, and 44-46 above, and further in view of Scapin (Blood 2019; 134 (Supplement_1): 445; IDS entered 08/01/205).
The teachings of Yu regarding claims 1-2, 6, 9, 13, 18, 22, 26, 31, 33-35, 39, and 44-46 are detailed above.
Yu does not teach wherein the cells are differentiated by addition of a Piezo1 agonist.
Regarding claims 15 and 19, Scapin teaches that the first set of definitive HSCs is born from hemogenic endothelial cells and then goes through an endothelial to HSC transition (para 1). Scapin further teaches that piezo1 activation (via Yoda1) yields 3-times higher amounts of long Term, self-renewing hematopoietic stem cells (LT)-HSC formation which reconstitute to normal multi-lineage adult blood (para 2). Scapin further teaches that Yoda1-mediated Piezo1 activation stimulated human endothelial-to-hematopoietic transition (para 3). Scapin further teaches that use of Piezo1 activated generation of LT-HSCs yields the therapeutic promise of transgene free cellular therapies for the treatment of blood disorders (para 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add a Piezo1 agonist as taught by Scapin in the method of generating HSCs using ETV2 mRNA expression in iPSCs as taught by Yu. The ordinary artisan would have been motivated to do so because Scapin teaches that piezo1 activation (via Yoda1) yields 3-times higher amounts of LT-HSC formation which reconstitute to normal multi-lineage adult blood which can be used for the treatment of blood disorders. The ordinary artisan has a reasonable expectation of success to add a Piezo1 agonist to facilitate the differentiation of endothelial cells to HSCs method of generating HSCs using ETV2 mRNA expression in iPSCs.
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.
Claims 1-2, 5-6, 11-13, 15, 18-19, 22, 26, 31, 33-35, 37-39, and 44-46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 4-5, 7-10, 14-15, and 18-19 of copending Application No. 18/284,577;
Claims 1-2, 5-6, 11-13, 15, 18-19, 22, 26, 31, 33-35, 37-38, 44, and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-5, 7-8, 11, 13-14, 21, 39, 47, and 57 of copending Application No. 19/117,852;
Claims 1-2, 5-6, 11-13, 15, 18-19, 22, 26, 31, 33-35, 37-38, and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-5, 7-8, 10, 15, 22, 25-26, 28, 32-34, and 36-37 of copending Application No. 19/117,863;
Claims 1-2, 5-6, 11-13, 15, 18-19, 22, 26, 31, 33-35, and 37-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16, and 20-21 of copending Application No. 19/117,872
in view of Wang (Sci Adv. 2020 Jul 24;6(30):eaba7606; IDS entered 08/01/2025).
These rejections have been grouped together as the copending applications are directed to overlapping limitations. The relevant claims from each application are identified above.
Regarding claims 1, 18, 39, and 44-46, All of these copending applications are directed to preparing a cell population of a hematopoietic lineage, the method comprising: preparing pluripotent stem cells; enriching for CD34+ cells; inducing endothelial to hematopoietic stem cells and then differentiating the HSC population to various cell types of hematopoietic lineage; including hematopoietic lineage cells, B cells, red blood cells, or macrophages.
Regarding claim 2, the copending claims teach wherein the PSC population is a human iPSC population.
Regarding claims 5 and 37, the copending claims teach wherein the iPSCs comprise a deletion of HLA-A.
Regarding claims 15 and 19, the copending claims teach wherein the induction of the endothelial to hematopoietic transition comprises Piezo1 activation, wherein the Piezo1 activation is by contacting the CD34+ enriched population with one or more Piezo1 agonists.
Regarding claim 22, the copending claims teach wherein the CD34+ population id cultured in medium containing IL-3, IL-6 VEGF, bFGF BMP4, or FLT3.
Regarding claim 31, the copending claims teach harvesting of floating CD34+ cells.
The copending claims do not teach expression of ETV2 to generate the HSCs
Regarding claims 1, 6, 11-13, 26, 33-35, and 38, Wang teaches that human induced pluripotent stem cell (h-iPSC)–derived endothelial cells (h-iECs) have become a valuable tool in regenerative medicine however current differentiation protocols remain inefficient and lack reliability (abstract). Wang further teaches development of a novel protocol that enables highly efficient differentiation of h-iPSCs into competent h-iECs comprising a differentiation period of 4 days and comprises two steps:(i) differentiation of h-iPSCs into intermediate h-MPCs and (ii) conversion of h-MPCs into h-iECs upon delivery of modRNA encoding ETV2 (page 8, col 2, para 5; Fig 1A). Wang further teaches that they were able to expand the resulting h-iECs with ease, obtaining an average h-iEC–to–h-iPSC ratio of ~70-fold after 3 weeks in culture (page 9, col 2). Wang further teaches that the delivery of modified mRNA encoding the transcription factor ETV2 at the intermediate mesodermal stage of differentiation led to rapid, consistent, and highly efficient generation of h-iECs (abstract) which has broad application in regenerative medicine because it provides a reliable means to obtain autologous h-iECs for vascular therapies (page 10, col 2, para 2).
It would have been obvious to one of ordinary skill in the art to use ETV2 mRNA introduced to MPCs as taught by Wang in the method of generating HSCs differentiated to different hematopoietic lineages from iPSCs as taught by the copending claims. The ordinary artisan would have been motivated to do so because delivery of modified mRNA encoding the transcription factor ETV2 at the intermediate mesodermal stage of differentiation led to rapid, consistent, and highly efficient generation of h-iECs that are easily expanded in culture. The ordinary artisan has a reasonable expectation of success to express ETV2 mRNA in MPCs generated from iPSCs to more efficiently generate h-iECs.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm 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, Julie Wu can be reached at 571-272-5205. 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.
/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643