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 .
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to claims 1-22, in the reply filed on 11/12/2025 is acknowledged. Claims 23-46 are withdrawn from consideration as being drawn to a non-elected invention.
Priority
The instant application claims benefit of provisional application 63/284,360 filed 11/30/2021.
Drawings
The drawings filed 11/29/2022 contain color.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claims 10 and 14 are objected to because of the following informalities:
Claim 10 recites the term “sphingosine-1-phosphage,” which should be corrected to “sphingosine-1-phosphate.”
Claim 14 recites the limitation “wherein the Notch agonist is Jagged 1-2 or DLL1-4.” For the sake of clarity, it is recommended that this be amended to recite “wherein the Notch agonist is Jagged-1, Jagged-2, DLL1, DLL2, DLL3, or DLL4.”
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.
Claim 6 is 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. Alantolactone is a TGFß inhibitor or antagonist, not a TGFß agonist, as evidenced by Harata (CA3152505A1, p 20, para 32). Therefore, the metes and bounds of claim 6 are unclear.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2 and 6 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 2: Stem cell factor (SCF) is an alternative name for c-kit ligand, as evidenced by Vilagoftis (J Allergy Clin Immunol 1997, 100: 435-40, p 435, col 1, para 1).
Regarding claim 6: Alantolactone is a TGFß inhibitor or antagonist, not a TGFß agonist, as evidenced by Harata (CA3152505A1, p 20, para 32).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim(s) 1-3, 5, 7-9, 11, 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over Bernstein (WO2015179633A1), in view of Zhao (Biomedicine & Pharmacotherapy, 2012, 66(8): 603-606), Lo (US20180163177A1), Kostic (Scientific Reports, 2015, 5: 16406), Smith (Hematopoiesis and Stem Cells, 2013, 122(3): 376-385), and Hernandez (WO2018197868A1; cited in IDS 04/12/2023).
Bernstein teaches a medium for culturing and expanding precursor cells, which may be human CD34+ hematopoietic stem cells, ex vivo (p 2, para 8; para 28; para 50). The medium comprises a Notch agonist, stem cell factor (SCF), and thrombopoietin (TPO) (p 2, para 8 – p 3, para 12) (claims 1-3). Bernstein teaches that any Notch agonist known in the art, such as Jagged and Delta, can be used (para 79-81), including Delta-1 (DLL-1) (para 11) (claim 14). Bernstein teaches that precursor cells may be obtained from umbilical cord blood (claim 17) or bone marrow (claim 18). Bernstein teaches that the time in culture is a time sufficient to produce an expanded precursor cell population, and may be between 2 and 35 days, or at least 10, 15, or 16 days (para 104) (claim 19).
Bernstein does not teach the inclusion of 1) a TGFß agonist, 2) an antioxidant, 3) a bioactive phospholipid, 4) an aryl hydrocarbon receptor (AhR) agonist, or 5) a histone deacetylase (HDAC) inhibitor.
Regarding 1) a TGFß agonist: Zhao teaches that Activin A, a member of TGFß, promotes the expansion of primitive human umbilical cord CD34+ hematopoietic cells in a cell type-dependent manner (Abstract; Results, 3.1). Zhao teaches that in colony-forming unit (CFU) assays, the plating efficiencies and numbers of total colony forming units were significantly increased in the presence of Activin A for most cell types (Results, 3.1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the medium of Bernstein by adding Activin A, as taught in Zhao. One of ordinary skill in the art would have been motivated to make this modification because Zhao teaches that culturing CD34+ hematopoietic stem cells in the presence of Activin A significantly increases the plating efficiencies and numbers of total colony forming units for most cell types. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Zhao teaches that Activin A can be added to a medium for culturing CD34+ hematopoietic stem cells.
Regarding 2) an antioxidant: Lo teaches a serum-free culture medium for expanding hematopoietic stem cells, wherein the medium comprises vitamin C (ascorbic acid) or vitamin E (α-tocopherol) (Abstract; para 60-62) (claims 1, 7-8). Lo teaches that vitamin C, vitamin E, or a combination thereof, supports the expansion of CD34+ cells (para 95).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the medium of Bernstein by adding vitamin C or vitamin E, as taught in Lo. One of ordinary skill in the art would have been motivated to make this modification because Lo teaches that culturing hematopoietic stem cells in the presence of vitamin C or vitamin E supports the expansion of CD34+ cells. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Lo teaches that vitamin C or vitamin E can be added to a medium for culturing hematopoietic stem cells.
Regarding 3) a bioactive phospholipid: Kostic teaches that lysophosphatidic acid (LPA) enhances survival of human CD34+ cells derived from umbilical cord blood in ischemic conditions (Abstract; Materials and Methods, para 1) (claims 1, 9).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the medium of Bernstein by adding LPA, as taught in Kostic. One of ordinary skill in the art would have been motivated to make this modification because Kostic teaches that LPA enhances survival of human CD34+ cells in ischemic conditions. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Kostic teaches that LPA can be added to a medium for culturing hematopoietic stem cells.
Regarding 4) an aryl hydrocarbon receptor (AhR) agonist: Smith teaches that the addition of the AhR ligand FICZ to cultures resulted in exponential expansion of hematopoietic progenitor cells (Discussion, para 3) (claims 1, 11).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the medium of Bernstein by adding FICZ, as taught in Smith. One of ordinary skill in the art would have been motivated to make this modification because Smith teaches the addition of the FICZ to cultures resulted in exponential expansion of hematopoietic progenitor cells. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Smith teaches that FICZ can be added to a medium for culturing hematopoietic stem cells.
Regarding 5) a histone deacetylase (HDAC) inhibitor: Hernandez teaches a method of expanding hematopoietic stem and progenitor cells (HSPCs) by culturing the HSPCs in the presence of a HDAC inhibitor and an aminothiol compound (claim 1). Hernandez teaches that this method produces expanded cells, wherein the number of total nucleated cells is increased (p 3, Summary of the Invention, para 1). Hernandez teaches that the HDAC inhibitor may be valproic acid (VPA) (claim 15), Scriptaid, Vorinostat, Tacedinaline, RG2833, RGFP966, Trichostatin A, LMK235, Tubastatin A, Quisinostat, or Sodium Phenylbutyrate (claim 16).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the medium of Bernstein by adding an HDAC inhibitor, as taught in Hernandez. One of ordinary skill in the art would have been motivated to make this modification because Hernandez teaches that culturing HSCPs in the presence of an HDAC inhibitor increased the number of nucleated cells. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Hernandez teaches that an HDAC inhibitor can be added to a medium for culturing hematopoietic stem cells.
Claim(s) 4 is rejected under 35 U.S.C. 103 as being unpatentable over Bernstein (WO2015179633A1), in view of Zhao (Biomedicine & Pharmacotherapy, 2012, 66(8): 603-606), Lo (US20180163177A1), Kostic (Scientific Reports, 2015, 5: 16406), Smith (Hematopoiesis and Stem Cells, 2013, 122(3): 376-385), Hernandez (WO2018197868A1; cited in IDS 04/12/2023), and Sun (Stem Cell Research, 2012, 9(2): 77-86).
Bernstein, in view of Zhao, Lo, Kostic, Smith, and Hernandez, renders obvious claim 1.
Bernstein teaches the use of thrombopoietin (TPO) as a thrombopoietin receptor (TPOR) agonist. Bernstein does not teach the use of eltrombopag as the TPOR agonist.
Sun teaches that eltrombopag is a TPO receptor agonist, which enhances expansion of human umbilical cord hematopoietic stem cells in vitro (Abstract). Sun teaches that eltrombopag favors earlier HSC populations compared to recombinant human TPO.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the medium of Bernstein by using eltrombopag as the TPOR agonist instead of TPO, as taught in Sun. One of ordinary skill in the art would have been motivated to make this modification when expansion of earlier HSC population is desired, because Sun teaches that eltrombopag favors earlier HSC populations compared to recombinant human TPO. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Sun teaches that eltrombopag enhances expansion of human umbilical cord hematopoietic stem cells in vitro.
Claim(s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over Bernstein (WO2015179633A1), in view of Zhao (Biomedicine & Pharmacotherapy, 2012, 66(8): 603-606), Lo (US20180163177A1), Kostic (Scientific Reports, 2015, 5: 16406), Smith (Hematopoiesis and Stem Cells, 2013, 122(3): 376-385), Hernandez (WO2018197868A1; cited in IDS 04/12/2023), and Pebay (US7604990B2).
Bernstein, in view of Zhao, Lo, Kostic, Smith, and Hernandez, renders obvious claim 1.
Bernstein, in view of Kostic, teaches the use of lysophosphatidic acid (LPA) as the bioactive phospholipid in culture medium. Bernstein, in view of Kostic, does not teach the use of sphingosine-1-phosphate (S1P) as the bioactive phospholipid.
Pebay teaches that Sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are two small bioactive lysophospholipids, which act on a wide range of cell types derived from the three developmental germ layers (col 2, para 1). Pebay teaches that most of the effects of these lysophospholipids seem to be mediated by specific lysophospholipid G-protein coupled receptors (LPL receptors) previously named endothelial differentiation gene (Edg) receptors (col 2, para 1).
Given the teachings of Pebay, there was a reasonable expectation that S1P would work equivalently as LPA as a bioactive lysophospholipid in culture media. Therefore, it would have been prima facie obvious for someone of ordinary skill in the art before the effective filing date of the claimed invention to have substituted LPA with S1P with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claim(s) 12 is rejected under 35 U.S.C. 103 as being unpatentable over Bernstein (WO2015179633A1), in view of Zhao (Biomedicine & Pharmacotherapy, 2012, 66(8): 603-606), Lo (US20180163177A1), Kostic (Scientific Reports, 2015, 5: 16406), Smith (Hematopoiesis and Stem Cells, 2013, 122(3): 376-385), Hernandez (WO2018197868A1; cited in IDS 04/12/2023), and Neavin (International Journal of Molecular Sciences, 2018, 19(12): 3851).
Bernstein, in view of Zhao, Lo, Kostic, Smith, and Hernandez, renders obvious claim 1.
Bernstein, in view of Smith, teaches the use of FICZ as the AhR agonist in culture medium. Smith teaches that two other AhR agonists, β-naphthoflavone and the prototypic environmental AhR ligand, 2,3,7,8-tetrachlorodibenzo[p]dioxin (TCDD), gave similar results to FICZ when used as the AhR agonist in culture medium (Results, “AhR mediates the expansion and specification of HPs,” para 1).
Bernstein, in view of Smith, does not teach the use of Norisoboldine as the AhR agonist.
Neavin teaches that FICZ, TCDD, and Norisoboldine are all AhR ligands that act through AhR (Table 1; Section 5, “AHR and Inflammatory Bowel Disease).
Given the teachings of Neavin and Smith, there was a reasonable expectation that FICZ, TCDD, and Norisoboldine would work equivalently as an AhR ligand in culture media. Therefore, it would have been prima facie obvious for someone of ordinary skill in the art before the effective filing date of the claimed invention to have substituted FICZ with Norisoboldine with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claim(s) 13 is rejected under 35 U.S.C. 103 as being unpatentable over Bernstein (WO2015179633A1), in view of Zhao (Biomedicine & Pharmacotherapy, 2012, 66(8): 603-606), Lo (US20180163177A1), Kostic (Scientific Reports, 2015, 5: 16406), Smith (Hematopoiesis and Stem Cells, 2013, 122(3): 376-385), Hernandez (WO2018197868A1; cited in IDS 04/12/2023), and Lu (Stem Cells, 2018, 36(8): 1273-1285; cited in IDS 08/15/2024).
Bernstein, in view of Zhao, Lo, Kostic, Smith, and Hernandez, renders obvious claim 1.
Bernstein teaches that any Notch agonist known in the art, such as Jagged and Delta, can be used in the culture medium (para 79-81). Bernstein does not specifically teach the use of Yhhu 3792 as a Notch agonist.
Lu teaches that Yhhu 3792 is a novel compound, which is an activator of the Notch signaling pathway (Abstract).
Given the teachings of Bernstein and Lu, there was a reasonable expectation that Yhhu 3792 would work equivalently as other Notch agonists, such as Jagged and Delta, as a Notch agonist in culture media. Therefore, it would have been prima facie obvious for someone of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the Notch agonists taught in Bernstein with Yhhu 3792 taught in Lu with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claim(s) 20 is rejected under 35 U.S.C. 103 as being unpatentable over Bernstein (WO2015179633A1), in view of Zhao (Biomedicine & Pharmacotherapy, 2012, 66(8): 603-606), Lo (US20180163177A1), Kostic (Scientific Reports, 2015, 5: 16406), Smith (Hematopoiesis and Stem Cells, 2013, 122(3): 376-385), Hernandez (WO2018197868A1; cited in IDS 04/12/2023), and Majeti (Cell Stem Cell, 2007, 1(6): 635-645).
Bernstein, in view of Zhao, Lo, Kostic, Smith, and Hernandez, renders obvious claim 1.
Bernstein does not teach CD34+ HSCs having a phenotype of Lin-CD34+CD38-CD45RA-CD90+.
Majeti teaches that a subpopulation of Lin-CD34+CD38-CD45RA-CD90+ cells from human cord blood fraction contains hematopoietic stem cells (HSCs) (Abstract).
Given the teachings of Bernstein and Majeti, there was a reasonable expectation that CD34+ HSCs with phenotype of Lin-CD34+CD38-CD45RA-CD90+ would work equivalently as other CD34+ HSCs as HSCs to be expanded or maintained in culture media. Therefore, it would have been prima facie obvious for someone of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the CD34+ HSCs in Bernstein with the Lin-CD34+CD38-CD45RA-CD90+ HSCs taught in Majeti with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claim(s) 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Bernstein (WO2015179633A1), in view of Zhao (Biomedicine & Pharmacotherapy, 2012, 66(8): 603-606), Lo (US20180163177A1), Kostic (Scientific Reports, 2015, 5: 16406), Smith (Hematopoiesis and Stem Cells, 2013, 122(3): 376-385), Hernandez (WO2018197868A1; cited in IDS 04/12/2023), and Lu (Stem Cells, 2018, 36(8): 1273-1285; cited in IDS 08/15/2024), as evidenced by Tocris (Yhhu 3792 SDS).
The teachings of Bernstein, Zhao, Lo, Kostic, Smith, and Hernandez are set forth above in the 35 U.S.C. 103 rejection for claim 1.
Regarding claim 21: Following the discussion of claim 1, Bernstein teaches a method of expanding or maintaining human CD34+ hematopoietic stem cells in a culture media comprising SCF, TPO, Activin A, Vitamin C, LPA, FICZ, a Notch agonist, and VPA.
Bernstein does not specifically teach the use of Yhhu 3792 as a Notch agonist.
Lu teaches that Yhhu 3792 is a novel compound, which is an activator of the Notch signaling pathway (Abstract).
Given the teachings of Bernstein and Lu, there was a reasonable expectation that Yhhu 3792 would work equivalently as other Notch agonists, such as Jagged and Delta, as a Notch agonist in culture media. Therefore, it would have been prima facie obvious for someone of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the Notch agonists taught in Bernstein with Yhhu 3792 taught in Lu with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Regarding claim 22:
Regarding SCF, TPO, Vitamin C, LPA, and Yhhu 3792:
Bernstein teaches using SCF at a concentration of 10-100 ng/mL and TPO at a concentration of 5-100 ng/mL (p 3, para 12).
Lo teaches using Vitamin C at a concentration of 50-375 μM (para 61).
Kostic teaches using LPA at a concentration of 100 μM (Materials and Methods: Cell survival analyses: effect of LPA concentration; Fig 1C; Materials and Methods: CD34+ cell proliferation analyses).
Bernstein teaches using a Notch agonist, which includes Yhhu 3792, at a concentration of between 0.025 to 5 μg/mL (claim 166). Yhhu 3792 has a molecular weight of 436.93 g/mol, as evidenced by Tocris, so 0.025 to 5 μg/mL of Yhhu 3792 is approximately 57.2 nM to 11,440 nM.
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding Activin A, FICZ, and VPA:
Zhao teaches using Activin A at a concentration of 50 ng/mL (Materials and Methods, 2.2).
Smith teaches using FICZ at a concentration of 0.2 μM, which is 200 nM (Materials and Methods, para 2).
Hernandez teaches using VPA at concentration of between 0.01 μΜ to 50 μΜ (p 13, lines 9-10).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the concentrations of Activin A, FICZ, and VPA based on factors such as the conditions and duration of culture, to arrive at the claimed invention. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Routine optimization is not considered inventive and no evidence has been presented that changing the concentration of Activin A from 50 ng/mL as taught by Zhao to 20 ng/mL as claimed; changing the concentration of FICZ from 200 nM as taught by Smith to 500 nM as claimed; and changing the concentration of VPA from 50 μΜ as taught by Hernandez to 150 μM as claimed, was other than routine, that the concentrations resulting from the optimization have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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/RISA TAKENAKA/ Examiner, Art Unit 1632
/PETER PARAS JR/ Supervisory Patent Examiner, Art Unit 1632