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 .
Status of the Claims
This action is in response to the papers filed on 08/31/2026. Claims 10-26 are currently pending. Claims 10 and 26 are independent claims. Therefore, claims 10-26 are subject to examination to which the following grounds of rejection are applicable.
Priority
This application is a CON of 17/233,643 filed 04/19/2021 now abandoned. 17/233,643 is a DIV of 15/932,317 filed 02/16/2018 now patent 10982192. 15/932,317 claims priority to PRO 62/460,348 filed 02/17/2017.
Information Disclosure Statement
No IDS has been filed.
Claim Objections
Claim 14 objected to because of the following informalities: Claim 14 recites “cultured in the presence of FGF2, VEGF, IL6, CSF, TPO, and IL3”. However, the specification does not describe the use of CSF. The specification describes only the use of SCF (stem cell factor), in combination with FGF2, VEGF, IL6, TPO, and IL3. Appropriate correction is required.
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 10-25 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.
Claim 10 recites at lines 1-2 “A method for producing a cellular composition comprising more than 95% arterial-type hemogenic endothelium (AHE) cells…”. However, steps (c) and (d) require detecting and isolating a 95% pure cell fraction. It is unclear whether the resulting cellular composition is required to contain exactly 95% AHE cells, at least 95% AHE cells or more than 95% AHE cells. Therefore, the metes and bounds of the claimed purity requirements cannot be determined, and the claim is rendered indefinite.
Claim 10 recites at step (a) differentiating human pluripotent stem cells (hPSCs) in to induce formation of immature CD144+CD43-CD73-DLL4+ hemogenic endothelial (HE) cells which express HAND 1. The specification characterizes the immature HE cells as CD144+CD43-CD73- (Pg. 2, Paragraph [0007]) and states that DLL4 is first expressed on D5 following the immature HE stage (Pg. 8, Paragraph [0019], final 6 lines of the page; Pg. 4, Paragraph [0014]). It is unclear whether the cells of step (a) are intended to be the immature DLL4- HE precursor population described in the specification or a DLL4+ population. Therefore, the metes and bounds cannot be determined, and the claim is rendered indefinite.
Claims 11-25 are rejected as they ultimately depend on and inherit the deficiencies of claim 10.
Claim 15 recites the limitation "The method of claim 10, wherein step (a) defined conditions… ". There is insufficient antecedent basis for “defined conditions” in the claim.
Claim 16 is rejected as it ultimately depends on and inherits the deficiencies of claim 15.
Claim 26 recites “creating the AHE cells of claim 10 and further differentiating the cells
into a cell type selected from the group of platelet-producing megakaryocytes, adult-globin expressing erythrocytes, and T-lymphocytes prior to isolation (substep d).” Claim 10 requires in step (d) isolating the 95% pure AHE cell fraction. As written, claim 26 appears to require differentiation of the AHE cells before the cells are isolated as the 95% pure AHE fraction required by (d). It would be unclear to one having ordinary skill in the art exactly how cells that have already been differentiated into the recited cell type are thereafter to be isolated as the AHE cell fraction required by claim 10. Therefore, the claim is indefinite.
Further, Claim 26 recites “(substep d)” with respect to claim 10. There is insufficient antecedent basis for “(substep d)” in the instant claim 10.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 10-11, 15-16, 18-21, and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over Slukvin et al. (WO 2013/028684 Al; hereafter “Slukvin”) in view of Ayllón et al. (Ayllón V et al., Leukemia., 2015; hereafter “Ayllón”) and Yamamizu et al. (Yamamizu K et al., J Cell Biol. 2010; hereafter “Yamamizu”)
Regarding Claim 10, Slukvin teaches a method of obtaining hPSC-derived hemogenic endothelial progenitors by differentiating pluripotent stem cells, identifying and subsequently isolating a VE-cadherin+ CD73- CD235A/CD43- population, wherein the VE-cadherin is CD144 (Pgs. 2-3, Paragraphs [0009], [0014] Pg. 16, Paragraph [0064]; Pg. 40-41, claims 4 and 11). Slukvin teaches sorting the identified cells to obtain purified populations including population of up to 99% (Pg. 9, Paragraph [0037]). Slukvin further teaches that the VE-cadherin+ CD73- CD235A/CD43- population constitutes hemogenic endothelial progenitors (HEPs) capable of generating blood and endothelial cells upon culture with stromal cells (Pg. 19, Paragraphs [0076-0077]). Slukvin further teaches that HEPs generated from hPSCs have the capacity to generate the entire spectrum of myeloid progenitors, including β -hemoglobin producing erythroid cells and pan-myeloid CFC GEMM (Pg. 16, Paragraph [0064]). Slukvin provides molecular profiling of the VE-cadherin+ CD73- CD235A/CD43- population, which demonstrates the presence HAND1 expression in the HEP population (Figure 3A).
Slukvin does not teach that the immature VE-cadherin+ CD73- CD235A/CD43- are selected as DLL4+. Slukvin does not teach exposing the HEPs to NOTCH activation agent.
Ayllón et al. teaches that DLL4 expression is induced during hematopoietic differentiation of human embryonic stem cells and is specifically expressed in a subpopulation of bipotent hematoendothelial progenitors (Abstract). Ayllón further teaches HEPs express NOTCH1, NOTCH4, AND DLL4, and that DLL4 stimulation activates NOTCH signalling in HEPs (Pg. 1743, 1st Paragraph of Results section), which enhances hematopoietic differentiation, and increases clonogenic hematopoietic progenitors (Abstract).
Yamamizu et al. teaches that activation of NOTCH signalling promotes arterial specification of vascular progenitors (Abstract) and that arterial endothelial cells are characterized by the expression of ephrinB2 (EFNB2), NOTCH1, and DLL4 (Pg. 330, Section: Activation of β -catenin and Notch signaling induces arterial ECs, 2nd Paragraph). Yamamizu teaches distinguishing arterial from venous endothelial cells by expression of EFNB2, NOTCH1, and DLL4 (Figure 5B) and demonstrates a role for activated notch signaling in induction of arterial differentiation.
It would have been prima facie obvious to a person having ordinary skill in the art at the time of the instant application filing to select the HEP population of Slukvin on the basis of DLL4 expression and to expose the HEP population to a DLL4-mediated notch activation signal as taught by Ayllón, because Ayllón expressly teaches that DLL4 distinguishes subpopulations of human HEPs and that the DLL4-mediated NOTCH activation regulates HEP fate, enhances hematopoietic differentiation, and increases clonogenic hematopoietic progenitors. Further, Yamamizu teaches that NOTCH signaling plays a role in arterial endothelial specification and that arterial endothelial cells are characterized by expression of EFNB2 and NOTCH1. Thus, one of ordinary skill in the art would have been motivated to use the known DLL4/NOTCH signalling pathway to promote arterial specification of the Slukvin HEP population and to identify the resulting cells by the known arterial markers EFNB2 and NOTCH1.
There would be a reasonable expectation of success in combining these teachings as the Slukvin HEP population would be expected by one of ordinary skill in the art to respond to such activation as both Slukvin and Ayllón teach hPSC-derived hemogenic endothelial progenitors, Ayllón experimentally demonstrates that human HEPs respond to DLL4-mediated NOTCH activation, and the teachings of Yamamizu establish the association between NOTCH signaling and the arterial endothelial cell specification.
Regarding Claim 11, Slukvin teaches the use of defined medium conditions for the culture of hESCs and demonstrates that such medium was well known in the art (Pg. 9, Paragraph [0039]).
Regarding Claims 15-16, Slukvin teaches co-culture with stromal cells to induce hematopoietic differentiation and specifically teaches OP9 as a stromal cell that can be used for co-culture and hematopoietic differentiation (Pg. 9, Paragraphs [0040]-[0041]).
Regarding Claim 18, Slukvin teaches both hESC and iPSCS as a starter population to be differentiated (Pg. 9, Paragraphs [0038]-[0040]).
Regarding Claim 19-21, Ayllón teaches HEPs were cultured for 12 days in plates coated with immobilized DLL4 protein (Pg. 1750, Figure 5e and Figure legend).
Regarding Claim 24, Slukvin teaches that the human pluripotent stem cells used in their methods include both human embryonic stem cells and human induced pluripotent stem cells (Pg. 8, Paragraph [0036]).
Regarding Claim 25, the combined teachings of Slukvin, Ayllón, and Yamamizu render obvious the method of claim 10. The ratios recited in claim 25 are inherent in erythrocytes produced by the same or substantially the same NOTCH dependent AHE to hematopoietic progenitor to erythroid differentiation process.
Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of the invention, but only that the subject matter is in fact inherent in the prior art reference. See Schering Corp. v. Geneva Pharm. Inc, 339 F.3d 1373, 1377, 67, USPQ2d 1664, 1668 (Fed. Cir. 2003). See also Toro Co. v. Deere & Co. 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004). See MPEP 2112.02.
Regarding Claim 26, Please note - For the purpose of examination, claim 26 is being interpreted as requiring differentiation of the AHE-derived cells into at least one of the recited hematopoietic cell types, without construing the phase “prior to isolation (substep d)” as requiring that the differentiated hematopoietic cells thereafter be isolated as the AHE fraction of claim 10. (See 112b rejection above).
Slukvin teaches that the VE-cadherin+ CD73-CD235a/CD43- hemogenic endothelial progenitors are capable of generating hematopoietic progeny under stromal coculture, including B-hemoglobin producing erythroid cells and pan-myeloid progenitors (Pg. 16, Paragraph [0064];Pg. 25, Paragraph [0099]).
Claim(s) 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Slukvin et al. (WO 2013/028684 Al; hereafter “Slukvin”) in view of Ayllón et al. (Ayllón V et al., Leukemia., 2015; hereafter “Ayllón”) and Yamamizu et al. (Yamamizu K et al., J Cell Biol. 2010; hereafter “Yamamizu”) as applied to claim 10 above and further in view of Slukvin 2014 et al. (US 2014/0273211 A1; hereafter “Slukvin-2014”). The combined teachings of Slukvin, Ayllón, and Yamamizu render obvious the method of claim 10, the contents of which is incorporated herein in its entirety.
Regarding Claim 12, Slukvin, Ayllón, and Yamamizu together do not teach the “…defined conditions include xenogen-free and serum albumin-free media containing about 25 ng/ml to about 50 ng/ml FGF2, at least 50 ng/ml ofBMP4, less than or equal to 15 ng/ml of Activin A, and about I mM to about 2mM Li Cl under hypoxic conditions.”
Slukvin-2014 teaches differentiation of human pluripotent stem cells under chemically defined, xenogeny-free conditions using an albumin free base medium supplement with BMP4, Activin A, FGF2, and LiCl under hypoxic conditions (Pg. 1, Paragraph [0005]). These defined conditions are used to overcome the limitations of co-culture and serum based conditions (Pg. 1, Paragraphs [0003] – [0004]). Slukvin-2014 teaches the FGF2 at about 10-50 ng/ml, BMP4 at about 50-250ng/ml, Activin A at about 10-15ng/ml, and LiCl at about 1-2mM under approximately 3-10% oxygen, including about 5% oxygen (Pg. 6, Paragraphs [0062], [0065], and table 3 (provided below).
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It would have been prima facie obvious to a person of ordinary skill at the time of the instant application filing to employ Slukvin-2014’s defined differentiation conditions in the combined method of Slukvin, Ayllón, and Yamamizu because Slukvin-2014 specifically teach these conditions for reproducible hematoendothelial differentiation of hPSCs, thereby providing a known defined alternative to less controlled serum or stromal dependent culture conditions. There would be a reasonable expectation of success in using these conditions as Slukvin-2014 demonstrates their successful use to produce hemogenic endothelial progenitors.
Regarding Claim 13, The combined teachings of Slukvin, Ayllón, Yamamizu, and Slukvin-2014 render obvious the method of claim 12. Moreover, Slukvin-2014 teaches their defined conditions can be used for hPSCs for about two days to produce EMHlin-KDR+APLNR+PDGFRa+ primitive mesoderm cells having mesenchymmoangioblast potential (Pg. 5, Paragraph [0058]; Pgs. 11-12, example 3).
Regarding Claim 14, The combined teachings of Slukvin, Ayllón, Yamamizu, and Slukvin-2014 render obvious the method of claims 12-13. Moreover, Slukvin-2014 teaches progressive differentiation of primitive mesoderm toward hemogenic endothelium. After the day-2 EMHlin-KDR+APLNR+PDGFRa+ primitive mesoderm stage, Slukvin-2014 teaches continued culture with FGF2 and VEGF to generate hematovascular mesoderm, followed by culture under hypoxic conditions in medium containing FGF2, VEGF, IL-6, SCF, TPO AND IL-3 for about one day, resulting in the formation of CD144+CD73-CD235A/CD43- hemogenic endothelial progenitors (Pg. 5-6, Paragraph [0059]; Pgs. 11-12, example 3).
Slukvin-2014 teaches that because formation of hematovascular mesoderm is closely followed by development of hemogenic endothelium and blood progenitors, the cultures were supplemented with SCF, TPO, IL-6 AND IL-3 in addition to VEGF and FGF2, and the addition of these hematopoietic cytokines increased the output of endothelial and hematopoietic progenitors (Pg. 12, Paragraph [0116]). Slukvin teaches culturing in these conditions to result in the emergence of populations of cells having the characteristics of CD144+CD43-CD73-, CD144+CD43/CD235A+CD41A- Pg. 12, Paragraph [0116]).
It would have been prima facie obvious to a person having ordinary skill in the art before the filing of the instant application to modify the teachings of Slukvin, Ayllón, and Yamamizu to further include culture the differentiating primitive-mesoderm lineage in the FGF2, VEGF, IL-6, SCF, TPO and IL-3 cytokine environment taught by Slukvin-2014 to promote progression toward and increase the yield of hemogenic endothelial progenitors.
There would have been a reasonable expectation of success because Slukvin-2014 demonstrates successful formation of the CD144+CD43-CD73- HEPs through use of this staged differentiation system.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Slukvin et al. (WO 2013/028684 Al; hereafter “Slukvin”) in view of Ayllón et al. (Ayllón V et al., Leukemia., 2015; hereafter “Ayllón”) and Yamamizu et al. (Yamamizu K et al., J Cell Biol. 2010; hereafter “Yamamizu”) as applied to claim 10 above and further in view of Ditadi et al. (Ditadi A et al. Nat Cell Biol. 2015; hereafter “Ditadi”).
The combined teachings of Slukvin, Ayllón, and Yamamizu render obvious the method of claim 10, the contents of which is incorporated herein in its entirety.
Regarding Claim 17, Slukvin, Ayllón, and Yamamizu together do not specifically teach that following exposure to a NOTCH activation agent that the AHE will undergo endothelial to hematopoietic transition and produce definite type hematopoietic progeny having adult like characteristics of T-cells.
However, as discussed in the 103 rejection to claim 10 above, Ayllón teaches that DLL4-mediated NOTCH activation of human hematoendothelial progenitors enhances hematopoietic differentiation and increases clonogenic hematopoietic progenitors. Ayllón further teaches that hemogenic endothelial cells receiving DLL4-mediated NOTCH activating signals undergo endothelial to hematopoietic transition and differentiation in CD45+ hematopoietic cells (Abstract).
Ditadi teaches that hPSC-derived definitive hemogenic endothelium undergoes endothelial to hematopoietic transition in a NOTCH dependent manner to generate definitive hematopoietic progeny (Abstract). Specifically, inhibition of NOTCH signalling during endothelial to hematopoietic transition inhibits formation of CD45+ hematopoietic cells and reduces development of myeloid, erythroid, and T-cell progenitors (Figure 3), thereby demonstrating that NOTCH signaling is required during endothelial to hematopoietic transition for development of the definitive hematopoietic progeny, including myeloid, erythroid, and T-cell progenitors.
It would have been prima facie obvious to a person of ordinary skill in the art at the time of the instant application filing to continue NOTCH activation of the arterial/hemogenic endothelial population produced by the combined teachings of Slukvin, Ayllón, and Yamamizu to promote endothelial to hematopoietic transition and definitive hematopoietic differentiation because Ayllón teaches that DLL4-mediated NOTCH activation promotes endothelial to hematopoietic transition and hematopoietic differentiation of human HEPs, and Ditadi teaches that NOTCH signalling during endothelial to hematopoietic transition is required for production of definitive hematopoietic progeny having myeloid, erythroid, and T-cell potential.
There would be a reasonable expectation in combining these teachings as both Ayllón and Ditadi have experimentally demonstrated the role of NOTCH signaling in the endothelial to hematopoietic transition.
Claim 22-23 is rejected under 35 U.S.C. 103 as being unpatentable over Slukvin et al. (WO 2013/028684 Al; hereafter “Slukvin”) in view of Ayllón et al. (Ayllón V et al., Leukemia., 2015; hereafter “Ayllón”) and Yamamizu et al. (Yamamizu K et al., J Cell Biol. 2010; hereafter “Yamamizu”) as applied to claims 10 and 21 above and further in view of Hadland et al. (Hadland BK et al., J Clin Invest. 2015; hereafter “Hadland”)
The combined teachings of Slukvin, Ayllón, and Yamamizu render obvious the method of claims 10 and 21, the contents of which is incorporated herein in its entirety.
Regarding Claim 22-23, Slukvin, Ayllón, and Yamamizu combined do not teach using a plate coated with DLL1-fc as the NOTCH activation agent.
Hadland teaches activation of NOTCH signaling using immobilized NOTCH ligands (Abstract). Specifically, Hadland teaches Delta1 (Delta1ext-IgG), consisting of the extracellular domain of human Delta1 fused to the Fc domain of human IgG1 (hIgG1) (Pg. 2039, 1st column, 2nd Full paragraph; Fig. 6). This reads on a DLL1-Fc. Hadland further teaches that the immobilized NOTCH ligand activates NOTCH signaling and supports hematopoietic stem and progenitor population having multilineage hematopoietic activity (Pg. 2039, 2nd Column, 1st Paragraph).
It would have been prima facie obvious to one having ordinary skill in the art at the time of the instant application filing to utilize the DLL1-Fc taught by Hadland as the NOTCH activation agent in the method of Slukvin, Ayllón, and Yamamizu because DLL1-Fc was a known, immobilized NOTCH ligand capable of activating NOTCH signaling in developing hematopoietic cells. There would have been a reasonable expectation of success as Hadland demonstrates NOTCH activation using the immobilized ligand.
Nonstatutory 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 10-26 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-9 of US Patent 10,982,192. Although the conflicting claims are not identical, they are not patentably distinct from each other because they are obvious variants.
Claim 1 of US Patent is directed to a method of inducing differentiation of human pluripotent stem cells into an arterial type hemogenic endothelium (AHE) cell population, comprising the steps of
(a) differentiating pluripotent stem cells (PSCs) in a xenogen-free and serum albumin-free medium containing FGF2, BMP4, Activin A, and LiCl under hypoxic conditions for about two days to obtain a population of EMHlin-KDR+APLNR+PDGFRalpha+mesoderm cells without the formation of embryoid bodies or coculture with stromal cell lines;
(b) culturing the population of EMHlin-KDR+APLNR+PDGFRalpha+mesoderm cells of step (a) in a medium containing FGF2 and VEGF, for about two days to obtain a population of CD144+CD43−CD73− immature hemogenic endothelial (HE) cells, and
(c) culturing the CD144+CD43−CD73− immature HE cells of step (b) in a medium containing a sufficient amount of a NOTCH activation agent to obtain arterial hemogenic endothelial (AHE) cells, wherein the AHE cells are detected as CD144+CD43−CD73−DLL4+ HE that express EFNB2 and NOTCH1 arterial markers and MYB gene, and wherein the AHE cells have the potential to produce lympho-myeloid cells and erythrocytes with increased ratios of adult β-globin expression to embryonic ε-globin and adult β-globin expression to fetal γ-globin expression when compared to erythrocytes generated from HE cells without NOTCH activation agent.
Claim 10 of the invention is directed to A method for producing a cellular composition comprising more than 95% arterial-type hemogenic endothelium (AHE) cells, comprising the steps of:
(a) differentiating human pluripotent stem cells (hPSCs) in to induce formation of immature CD144+CD43-CD73-DLL4+ hemogenic endothelial (HE) cells which express HAND 1;
(b) exposing the HE cells to a sufficient amount of a NOTCH activation agent, resulting in differentiation of HE cells into AHE cells that express EFNB2 and NOTCH1 arterial markers, and a MYB gene;
(c) detecting a 95% pure cell fraction characterized by a CD144+CD43-CD73-DLL4+ phenotype that expresses EFNB2 and NOTCH1 arterial markers, with the potential to produce lympho-myeloid cells and definitive erythroid progenitors;
( d) isolating the 95% pure cell fraction.
The instant claims differ from claim 1 of U.S. Patent 10,982,192 by not requiring the specific sequential culture conditions, media components, intermediated mesoderm population, culture durations, or hypoxic conditions required by the patent claims.
The instant claims are therefore generic to the US Patent 10,982,192 claims in these respects because both claims are directed to methods of producing arterial type hemogenic endothelial cells (AHE) from human pluripotent stem cells by first differentiating the pluripotent stem cells to hemogenic endothelial cells and thereafter subjecting the hemogenic endothelial cells to NOTCH activation to obtain AHE cells having the CD144+CD43-CD73-DLL4+ phenotype that expresses EFNB2 and NOTCH1 arterial markers. Instant claim 10 broadly recites this differentiation scheme without requiring the particular culture conditions, media components, intermediate mesoderm population, culture durations required by the claim 1 of US patent 192’. Accordingly claim 1 of the ‘192 patent represents a species of the more generic AHE-production method recited in instant claim 10.
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).
Furthermore, there is no apparent reason why applicant was prevented from presenting claims corresponding to those of the instant application during prosecution of the application, which matured into a patent. See In re Schneller, 397 F.2d 350, 158 USPQ 210 (CCPA 1968). See also MPEP § 804.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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/KODYE LEE ABBOTT/ Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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