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 .
1. Claims 1, 6, 23 – 25, 40, 42, 45, 51, 52, 67, 69, 71, 83, 87, 93 – 95, and 116 are pending.
Election/Restrictions
2. Applicant’s election of Group I (claims 1, 6, 23 – 25, 40, 42, 45, 51, 52, 67, 69, 71, and 83) in the reply filed on 06/08/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
3. Claims 18, 87, 93 – 95, and 116 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/08/2026.
Priority
4. This application is a National Phase Entry of PCT/US2023/060116 filed 01/04/2023 which claims domestic benefit of U.S. Provisional Application 63/296,544 filed 01/05/2022 and 63/374,622 filed 09/06/2022.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 09/23/2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
6. The drawings filed 07/02/2024 are acknowledged.
Specification
7. The use of the term OptiMEM, Xvivo10, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
8. Claim 1 is objected to because of the following informalities: in line 4, “wherein passing” should read “wherein the passing of” to clarify this is the same passing recited in line 2. Appropriate correction is required.
9. Claim 1 is objected to because of the following informalities: in line 6, “the HSC” should read “the modified HSC” to clarify that is the modified HSC that exhibits one or more of (i) – (v). Appropriate correction is required.
10. Claim 2 is objected to because of the following informalities: in lines 2, 10, and 12, “a hematopoietic stem cell” should read “the modified hematopoietic stem cell” or “the modified HSC” to clarify that these recitations refer to the modified HSC of claim 1 and not another HSC. 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.
11. Claims 6, 24, 25, 40, 51, and 52 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.
12. Regarding claim 6, it is unclear how the scope of claim 2 relates to the scope of claim 1 of a method or producing a modified HSC. The scope of claim 2 appears to be related to a method of treating a subject and not a method of producing a modified HSC.
13. Regarding claim 24, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 25 is also rejected as it depends from claim 24 and does not clarify the grounds of rejection.
14. Regarding claim 40, the phrase "e.g. renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
15. Regarding claim 51, the phrase "e.g. renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 52 is also rejected as it depends from claim 51 and does not clarify the grounds of rejection.
16. Regarding claim 52, recitation of “at least about” and “less than about” lack clarity because it is unclear what the boundaries of the recited numerical values of the parameters encompass. Applicant’s specification discloses “about” is used to mean approximately, roughly, around, or in the regions of and when used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth at para. 0067.
17. Regarding claim 52, it is unclear each of (i) – (v) are required or one or more of (i) – (v) are required because “and” or “or” is not recited after the limitations of (iv).
Claim Interpretation
18. For the purpose of applying prior art, “constriction” of claim 1 is interpreted to include microfluidic channels and surfaces having pores based on Applicant’s disclosure at para. 0069.
19. For the purpose of applying prior art, “payload” of claim 1 and 23 is interpreted to include any molecule (nucleic acid, protein, peptide, small molecule) capable of entering hematopoietic stem cells based on Applicant’s disclosure at para. 0096.
20. For the purpose of applying prior art, the “wherein” clauses of claim 1 “are not given patentable weight because the claim does not require that a payload enter the HSC but instead requires that passing the cell suspension through the constriction allows a payload to enter the HSC. Applicant’s specification teaches that a cell that passes through a constriction experiences various forces including mechanical deforming forces and/or shear forces that causes perturbations in the cell membrane, where “perturbation” is defined as any opening in the cell membrane that is not present under normal stead state conditions (para. 0069 – 0070), which is interpreted as a “modified HSC”. Therefore, passing a suspension of HSCs through a constriction is interpreted to meet the limitations of claim 1 of producing a modified HSC.
21. For the purpose of applying prior art, claim 6 is interpreted as a contingent limitation that is not required to be performed in a method of producing a modified HSC of claim 1. MPEP 2111.04 (II) states that the broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. See Ex parte Schulhauser, Appeal 2013-007847 (PTAB April 28, 2016) for an analysis of contingent claim limitations in the context of both method claims and system claims.
22. For the purpose of applying prior art, “at least about” and “less than about” of claim 52 are interpreted as “about” based on Applicant’s disclosure at para. 0067.
23. For the purpose of applying prior art, claim 52 is interpreted as requiring one or more of (i) – (v).
Claim Rejections - 35 USC § 102
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 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.
24. Claim(s) 1, 6, 23, 24, 45, 51, and 52 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yen (Yen, Jonathan, et al. Scientific reports 8.1 (2018): 16304.), hereinafter Yen as evidenced by El Hoss (El Hoss S, et. al. Haematologica. 2021 Oct 1;106(10):2707-2719), hereinafter Hoss.
Claim 1 is drawn to a method of producing a modified hematopoietic stem cell (HSC), comprising passing a cell suspension, which comprises a population of HSC, through a constriction under one or more parameters, wherein passing the cell suspension through the constriction under the one or more parameters allows a payload to enter the HSC, and wherein the payload is capable of modifying the HSC, such that the HSC exhibits: (i) increased resistance to a mobilization factor, (ii) increased resistance to an apoptotic factor, (iii) increased resistance to a depleting factor, (iv) increased expression of a homing factor, or (v) a combination thereof.
Regarding claim 1 and 51, Yen teaches a method of producing a modified HSC comprising passing a suspension of HSCs through a membrane (“constriction”) via 5 psi of nitrogen pressure (“one or more parameters” of claim 1 and “pressure” of claim 51) where the passing allows a ribonucleoprotein complex (RNP) (“payload”) to enter the HSC (page 7, para. 9 – 11; page 9, para. 3). Yen teaches the RNP complex is capable of modifying the HSCs such that there is a 40% induction of HbF+ (“wherein the payload is capable of modifying the HSC”) (page 4, para. 3 – 8; Figure 3e). HbF increases resistance to apoptosis during erythroid differentiation in sickle cell disease as evidenced by El Hoss (“(ii) increased resistance to an apoptotic factor”) (Abstract; page 2709, right col. para. 2; page 2710, right col.; page 2712, right col. para. 1 – 2; page 2713, right col. last para.; page 2716, left col. para. 1).
Regarding claim 6, Yen teaches the modified HSCs engrafted in the bone marrow of NSG mice (page 4, para. 7 – 8; Figure 3).
Regarding claim 23 and 24, Yen teaches the RNP comprises guide RNA (“regulator” of claim 23) that increases the expression of HbF (“(vi) the regulator is capable of increasing the expression and/or activity of” “the survival factor” of claim 24) (page 4, para. 3 – 8; Figure 3).
Regarding (i) of claim 45, Yen teaches the HSCs are contacted with the RNP prior to passaging through the membrane (page 7, para. 10).
Regarding claim 52, Yen teaches the cell density is 8 x 107 cell/mL (“at least about 8 x 107 cells/mL”) and the pore diameter is 8 µM (“the width of the constriction is less than about 9 µm”) (page 2, para. 6).
Therefore, Yen anticipates claims 1, 6, 23, 24, 45, 51, and 52.
25. Claim(s) 1, 6, 42, 45, 51, 52, and 71 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tran (Tran, Reginald, et al. Molecular Therapy 25.10 (2017): 2372-2382.), hereinafter Tran.
Claim 1 is drawn to a method of producing a modified hematopoietic stem cell (HSC), comprising passing a cell suspension, which comprises a population of HSC, through a constriction under one or more parameters, wherein passing the cell suspension through the constriction under the one or more parameters allows a payload to enter the HSC, and wherein the payload is capable of modifying the HSC, such that the HSC exhibits: (i) increased resistance to a mobilization factor, (ii) increased resistance to an apoptotic factor, (iii) increased resistance to a depleting factor, (iv) increased expression of a homing factor, or (v) a combination thereof.
Regarding claim 1, 6, 42, and (i) of claim 45, Tran teaches contacting a suspension of HSCs with a lentiviral vector (claim 42) containing plasma coagulation factor VIII (fVIII) (“payload” of claim 1) at a MOI of 25 (“parameter”) and transducing using microfluidics (“constriction” of claim 1; (i) of claim 45) thus allowing the vector to enter the HSCs (page 2373, left col. para. 1; page 2376, right col. last para.; page 2379, right col. para. 4; page 2380, right col. para. 2).
Regarding claim 51 and 52, Tran teaches 107 cells (“cell density” of claim 51) were subjected to microfluidics transduction with a total volume of approximately 670 µL (“at least about 1 x 107 cells/mL” of claim 52) (page 2379, left col. para. 3).
Regarding (ii) of claim 71, Tran teaches the microfluidics comprise a plurality of constrictions as shown in Figure 1B and E, each associated with the same lentiviral vector (page 2379, right col. para. 4; page 2380, right col. para. 2).
Therefore, Tran anticipates claims 1, 6, 42, 45, 51, 52, and 71.
26. Claim(s) 1, 6, 45, 51, 52, and 71 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by DiTommaso (DiTommaso, Tia, et al. Proceedings of the National Academy of Sciences 115.46 (2018): E10907-E10914.), hereinafter DiTommaso which is cited on the IDS filed 09/23/2024 as evidenced by Sharei (Sharei, Armon, et al. " Proceedings of the National Academy of Sciences 110.6 (2013): 2082-2087.), hereinafter Sharei.
Claim 1 is drawn to a method of producing a modified hematopoietic stem cell (HSC), comprising passing a cell suspension, which comprises a population of HSC, through a constriction under one or more parameters, wherein passing the cell suspension through the constriction under the one or more parameters allows a payload to enter the HSC, and wherein the payload is capable of modifying the HSC, such that the HSC exhibits: (i) increased resistance to a mobilization factor, (ii) increased resistance to an apoptotic factor, (iii) increased resistance to a depleting factor, (iv) increased expression of a homing factor, or (v) a combination thereof.
Regarding claim 1, 6, and “pressure” of claim 51 and “at least about 2 x 107 cell/mL”, “at least about 90 psi”, “less than about 40 µm”, and “less than about 4 µm” of claim 52, DiTommaso teaches a method of squeezing 20 x 106 million cells/mL CD34+ HSCs through microfluidic channels containing a single 3.5 µm-wide, 30 µm-long constriction at 90 psi (page 10912, right col. last para.; page 10913, left col. para. 1).
Regarding (i) of claim 45, DiTommaso teaches when appropriate, cargo was added to the cells and delivery buffer and then the cells were squeezed (page 10913, left col. para. 1).
Regarding claim 71, DiTommaso teaches cell squeezing was done using previously established methods of Sharei (page 10913, left col. para. 1), which comprises passing the cell suspension through a plurality of constrictions wherein each constriction of the plurality of constrictions are the same as evidenced by Sharei (Figure 1; page 2083, left col. para. 2 and right col. para. 1).
Therefore, DiTommaso anticipates claims 1, 6, 45, 51, 52, and 71.
27. Claim(s) 1, 6, 45, 51, 52, and 71 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li (Li, Jing, et al. ACS chemical biology 12.12 (2017): 2970-2974.), hereinafter Li as evidenced by Chemometec (Chemometec: (10/15/2025). "Hematopoietic Stem Cells (HSCs)." https://chemometec.com/industry/hematopoietic-stem-cells-hscs/. Accessed 07/21/2026), hereinafter Chemometec.
Claim 1 is drawn to a method of producing a modified hematopoietic stem cell (HSC), comprising passing a cell suspension, which comprises a population of HSC, through a constriction under one or more parameters, wherein passing the cell suspension through the constriction under the one or more parameters allows a payload to enter the HSC, and wherein the payload is capable of modifying the HSC, such that the HSC exhibits: (i) increased resistance to a mobilization factor, (ii) increased resistance to an apoptotic factor, (iii) increased resistance to a depleting factor, (iv) increased expression of a homing factor, or (v) a combination thereof.
Regarding claims 1, 6, and 51, Li teaches passing a suspension of PBMCs through a constriction that is the Cell Squeeze platform at 60 psi (“pressure” of claim 51) that allows small molecule JAK inhibitors to enter the cells resulting in a reduction of p-STAT5 (Abstract; Figure 1; page 2970, right col.; Supporting Information page 38, para. 2; page 2972, left col. para. 2 and right col.; Figure 2; page 2973). The suspension of PBMCs comprise hematopoietic stem cells as evidenced by Chemometec (page 1, para. 1).
Regarding claim 45, Li teaches contacting the cells with the small molecules prior to squeezing (Supporting Information, page 38, para. 2).
Regarding claim 52 and 71, Li teaches squeezing 20 x 106 cells/mL to 25 x 106 cells /mL (“at least about 2 x 107 cells/mL” of claim 52) at 60 psi (“at least about 65 psi” of claim 52) where the length of the constriction is 30 µm or 10 µm long with a diameter of 4 µm (“less than about 40 µm” and “at least about 30 µm” of claim 52 and (i) of claim 71) (Supporting Information, page 38, para. 2).
Therefore, Li anticipates claims 1, 6, 45, 51, 52, and 71.
28. Claim(s) 1, 6, 42, 45, 51, and 52 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Belling (Belling, Jason N., et al. Proceedings of the National Academy of Sciences 117.20 (2020): 10976-10982) hereinafter Belling.
Claim 1 is drawn to a method of producing a modified hematopoietic stem cell (HSC), comprising passing a cell suspension, which comprises a population of HSC, through a constriction under one or more parameters, wherein passing the cell suspension through the constriction under the one or more parameters allows a payload to enter the HSC, and wherein the payload is capable of modifying the HSC, such that the HSC exhibits: (i) increased resistance to a mobilization factor, (ii) increased resistance to an apoptotic factor, (iii) increased resistance to a depleting factor, (iv) increased expression of a homing factor, or (v) a combination thereof.
Regarding claims 1, 6, 42, 51, and 52, Belling teaches passing a suspension of 3 million cells/mL (“cell density” of claim 51; “at least about 3 x 106 cells/mL” of claim 52) CD34+ hematopoietic stem cells through a constriction that is an acousticfluidic device that allows an eGFP expression vector (claim 42) to enter the cells (page 10979, right col. para. 2 – 3; page 10980, right col.; page 10981, left col. para. 1; Figure S1 and S6).
Regarding claim 45, Belling teaches contacting the HSCs with an eGFP-expressing plasmid prior to passing through the constriction (page 10981, left col. para. 1).
Therefore, Belling anticipates claims 1, 6, 42, 45, 51, and 52.
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.
29. Claim(s) 1, 6, 23, 24, 25, 40, 42, 45, 51, 52, 67, 69, and 71 is/are rejected under 35 U.S.C. 103 as being unpatentable over Latroche (US20210317411-A1; Filed 05/16/2019; Published 10/14/2021), hereinafter Latroche which is cited on the IDS filed 09/23/2024 in view of DiTommaso (DiTommaso, Tia, et al. Proceedings of the National Academy of Sciences 115.46 (2018): E10907-E10914.), hereinafter DiTommaso which is cited on the IDS filed 09/23/2024 as evidenced by Sharei (Sharei, Armon, et al. " Proceedings of the National Academy of Sciences 110.6 (2013): 2082-2087.), hereinafter Sharei in view of Tran (Tran, Reginald, et al. Molecular Therapy 25.10 (2017): 2372-2382.), hereinafter Tran.
Regarding (iv) of claim 1, claim 23, (i) of claim 24, and claim 42, Latroche teaches a method of modifying a CD34+ cord blood cells (“a cell suspension which comprises a population of HSC” of claim 1) by transduction with a lentiviral vector expressing CXCR4 or electroporation with the Cas9 protein and RNPs and CXCR4 mRNA (“payload” and “(iv) increased expression of a homing factor” of claim 1; “homing receptor” of claim 23; “CXCR4” of claim 24; “DNA” and “mRNA” of claim 42) (page 12, para. 0170, and 0178; page 19, para. 0286 – 0289; page 4, para. 0097 – 0100; Figure 1 and 2; page 5, para. 0109 – 0110; Figure 7; page 20, para. 0310 and 0316). Latroche teaches CXCR4 is a receptor expressed on the surface of HSCs and the interaction of CXCR4 with CXCL12 is one of the major mechanisms that directs migration to the bone marrow (page 7, para. 0134). Latroche does not teach “constriction” of claim 1.
Regarding (i) of claim 1 and “plerixafor” and “G-CSF” of claim 40, Latroche teaches treating mice with GCSF and Plerixafor, which is a specific antagonist of CXCR4, followed by engrafting the CXCR4 overexpressing HSCs into mice resulted in significant overexpression of CXCR4 (page 5, para. 0103 – 0108; Figure 4; page 20, para. 0303). Latroche teaches CXCR4 overexpressing cells efficiently outcompeted the mobilized HPCs and established stable chimerism at a rate higher than control cells (page 20, para. 0303 – 0304; Figure 5; page 5, para. 0105 – 0106; page 20, para. 0314; page 21, para. 0324).
Regarding (i) and (iii) of claim 6, Latroche teaches in vivo engraftment of the cord blood CD34+ cells overexpressing CXCR4 resulted in increased engraftment ((iii)) (page 2, para. 0098; page 19, para. 0291, 0293 – 0296; page 4, para. 0097 – 0100; Figure 1 middle panel and Figure 2; page 5, para. 0109 – 0110; Figure 7; page 21, para. 0319 – 0320). Latroche teaches CXCR4 is a receptor expressed on the surface of HSCs and the interaction of CXCR4 with CXCL12 is one of the major mechanisms that directs migration to the bone marrow ((i)) (page 7, para. 0134).
Regarding claim 25, Latroche teaches the CXCR4 comprises the amino acid sequence SEQ ID NO: 12 or 15 or 18, each of which differs from SEQ ID NO: 1 of the instant claim (page 8, para. 0142; page 10, para. 0154; page 11, para. 0157; page 5, para. 0115 – 0116; Figure 10; page 20, para. 0316; page 21, para. 0325).
Latroche does not teach “constriction” of claim 1 or contacting the HSC with the payload prior to passing of the cell suspension through the constriction of claim 45 or one or more parameters of claims 51 and 52 or “contacted with multiple payloads” of claim 67 or “concurrently or sequentially” of claim 69 or “comprising passing the cell suspension through a plurality of constrictions” of claim 71. However, Latroche teaches hematopoietic cell transplantation (HCT) is a curative therapy for several inherited and acquired disorders but allogeneic HCT is limited by the poor availability of matched donors, the mortality associated with the allogeneic procedure, and infectious complications (page 1, para. 0003). Latroche teaches gene therapy approaches based on the transplantation of genetically modified autologous HSCs offer potentially improved safety and efficacy over allogeneic HCT (page 1, para. 0004). Latroche teaches there is a significant need in the art to improve engraftment of the transplanted HSCs including a need to develop more efficient strategies to improve the ability of HSCs to home and permanently repopulate the recipient bone marrow (page 1, para. 0008). Latroche teaches there is a further need for protocols that reduce genotoxic conditioning regimens before HSC transplantation (page 1, para. 0009). Latroche teaches overexpressing CXCR4 in HSCs increases the efficiency of HSC engraftment (page 1, para. 0011). Latroche teaches the CXCR4 overexpressing HSCs can be advantageously applied in transplantation protocols that utilize mild or no myeloablative conditioning (page 1, para. 0012). Latroche teaches the strategies increase the efficacy of conditioning regimens that bypass the requirement for toxic and mutagenic drugs (such as endogenous HSC mobilization protocol and conditioning regimens), thus reducing risk and long-term toxicity to the patient (page 1, para. 0014).
Regarding allowing a payload to enter the HSC by “constriction” of claim 1 and “pressure” of claim 51 and “at least about 2 x 107 cell/mL”, “at least about 90 psi”, “less than about 40 µm”, and “less than about 4 µm” of claim 52, DiTommaso teaches a method of squeezing 20 x 106 million cells/mL CD34+ HSCs through microfluidic channels containing a single 3.5 µm-wide, 30 µm-long constriction at 90 psi (page 10912, right col. last para.; page 10913, left col. para. 1). DiTommaso teaches squeezed cells form more colonies that electroporated cells (page 10910, right col. para. 3; Figure 2A). DiTommaso teaches electroporation of CD34+ HSCs can result in significant changes in gene expression demonstrating the profound impact that electroporation can have on gene expression including potential knock-on effects in response to electroporation over time (page 10908, right col. last para.; page 10909, left col. para. 1 and right col. para. 1; page 10910, left col. para. 1 – 2). DiTommaso teaches rest times pre- and postelectroporation extend the time that cells must be in culture, and extended ex vivo culture risks terminal differentiation and the loss of a proliferative phenotype for CD34+ HSCs (page 10907, right col. last para.; page 10908, left col. para. 1). DiTommaso teaches while electroporation protocols enable the efficient delivery of some payloads, challenges associated with posttreatment mortality, loss of proliferative potential, and decreased potency have been reported for primary cell types (page 10908, left col. para. 1).
Regarding claim 71, DiTommaso teaches cell squeezing was done using previously established methods of Sharei (page 10913, left col. para. 1), which comprises passing the cell suspension through a plurality of constrictions wherein each constriction of the plurality of constrictions are the same as evidenced by Sharei (Figure 1; page 2083, left col. para. 2 and right col. para. 1).
DiTommaso does not teach contacting the HSC with the payload prior to passing of the cell suspension through the constriction of claim 45 or “contacted with multiple payloads” of claim 67 or “concurrently or sequentially” of claim 69. One would have been motivated to substitute electroporation of Latroche with squeezing of DiTommaso to avoid the significant changes in gene expression and potential knock-on effects of electroporation as taught by DiTommaso.
Regarding (i) of claim 45, Tran teaches contacting HSCs with a lentiviral vector containing plasma coagulation factor VIII (fVIII) and transducing using microfluidics (page 2373, left col. para. 1; page 2376, right col. last para.; page 2379, right col. para. 4; page 2380, right col. para. 2). Tran teaches the microfluidics comprise a plurality of constrictions as shown in Figure 1B and E, each associated with the same lentiviral vector (page 2379, right col. para. 4; page 2380, right col. para. 2). Tran teaches microfluidic transduction using clinically processed lentiviral vectors occurs up to 5-fold faster and requires as little as one-twentieth of lentiviral vector (Abstract). Tran teaches microfluidic transduction of Sca-1+ cells with the lentiviral vector containing fVIII followed by transplantation of these transduced cells into fVIII-deficient mice (page 2377, left col. last para.; page 2381, left col. para. 2 – 5). Tran teaches 3 of 5 mice transplanted with microfluidic-transduced cells at an MOI of 10 produced plasma fVIII levels within the normal range (page 2377, right col. para. 1; Figure 4E). Tran teaches microfluidics demonstrated pre-clinical safety and efficacy with the potential to reduce both transduction times and vector usage (page 2377, right col. para. 1).
Regarding claims 67 and 69, Tran teaches coating microfluidics with RetroNectin (RN) followed by loading with vector followed by cells ((ii) of claim 67) in either vector-free or vector-containing media ((i) of claim 67; “concurrently” of claim 69) where RN coating is shown to clearly bind virus and with greater efficiency in the microfluidic as seen by the greater transduction in microfluidic where cells were seeded without additional vector (page 2376, left col. para. 1; Figure 2C).
Tran teaches ex vivo gene therapy using lentiviral vectors is a proven approach to treat and potentially cure many hematologic disorders and malignancies but remains stymied by cumbersome, cost-prohibitive, and scale-limited production processes that cannot meet the demands of current clinical protocols for widespread clinical utilization (Abstract). Tran teaches limitations in lentiviral vector manufacture coupled with inefficient transduction protocols requiring significant excess amounts of vector currently limit widespread implementation (Abstract; page 2372, left col.). Tran teaches average vector copy number per cell transduced using microfluidics were not statistically different from those in the well plates despite using half the amount of virus in half the transduction time resulting in a higher vector copy number utilization efficiency (page 2376, right col. last para.; Figure 3A and 3B). Tran teaches cell viability was maintained with microfluidic transduction (page 2377, left col. para. 1; Figure 3C). Tran teaches microfluidics are able to improve transduction efficiency in clinically relevant primary human cell types without compromising cell viability or stem cell characteristics (page 2377, left col. para. 1). Tran teaches that an order-of-magnitude reduction in vector costs per patient may be attainable by using microfluidics in their pre-clinical CD34+ fVIII-lentiviral vector gene therapy product candidate (page 2378, right col. last para.). Tran teaches when combined with other cost savings from reduced cytokine and reagent usage typically required for primary cell culture, the microfluidic platform represents an exceptional tool for cell manufacturing for clinical gene therapy (page 2379, right col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Latroche regarding a method of modifying HSCs by transducing with CXCR4 mRNA or lentiviral vector comprising CXCR4 with the teachings of DiTommaso regarding squeezing HSCs as an alternative to electroporation to prevent significant genetic changes in HSCs associated with electroporation with the teachings of Tran regarding microfluidic transduction of HSCs with lentiviral vectors to arrive at the claimed method of producing a modified hematopoietic stem cell (HSC), comprising passing a cell suspension, which comprises a population of HSC, through a constriction under one or more parameters, wherein passing the cell suspension through the constriction under the one or more parameters allows a payload to enter the HSC, and wherein the payload is capable of modifying the HSC, such that the HSC exhibits: (i) increased resistance to a mobilization factor, (ii) increased resistance to an apoptotic factor, (iii) increased resistance to a depleting factor, (iv) increased expression of a homing factor, or (v) a combination thereof. One would have been motivated to combine the teachings of Latroche, DiTommaso, and Tran in a cost-effective method of producing modified HSCs to treat hematologic disorders as Latroche teaches there is a significant need in the art to improve engraftment of the transplanted HSCs including a need to develop more efficient strategies to improve the ability of HSCs to home and permanently repopulate the recipient bone marrow and Latroche teaches overexpressing CXCR4 in HSCs increases the efficiency of HSC engraftment and DiTommaso teaches while electroporation protocols enable the efficient delivery of some payloads, challenges associated with posttreatment mortality, loss of proliferative potential, and decreased potency have been reported for primary cell types and Tran teaches ex vivo gene therapy using lentiviral vectors is a proven approach to treat and potentially cure many hematologic disorders and malignancies but remains stymied by cumbersome, cost-prohibitive, and scale-limited production processes that cannot meet the demands of current clinical protocols for widespread clinical utilization and Tran teaches limitations in lentiviral vector manufacture coupled with inefficient transduction protocols requiring significant excess amounts of vector currently limit widespread implementation. One would have a reasonable expectation of success in combining the teachings as Tran teaches average vector copy number per cell transduced using microfluidics were not statistically different from those in the well plates despite using half the amount of virus in half the transduction time resulting in a higher vector copy number utilization efficiency and Tran teaches cell viability was maintained with microfluidic transduction and Tran teaches microfluidics are able to improve transduction efficiency in clinically relevant primary human cell types without compromising cell viability or stem cell characteristics and Tran teaches that an order-of-magnitude reduction in vector costs per patient may be attainable by using microfluidics in their pre-clinical CD34+ fVIII-lentiviral vector gene therapy product candidate and Tran teaches when combined with other cost savings from reduced cytokine and reagent usage typically required for primary cell culture, the microfluidic platform represents an exceptional tool for cell manufacturing for clinical gene therapy.
30. Claim(s) 83 is/are rejected under 35 U.S.C. 103 as being unpatentable over Latroche (US20210317411-A1; Filed 05/16/2019; Published 10/14/2021), hereinafter Latroche which is cited on the IDS filed 09/23/2024 in view of DiTommaso (DiTommaso, Tia, et al. Proceedings of the National Academy of Sciences 115.46 (2018): E10907-E10914.), hereinafter DiTommaso which is cited on the IDS filed 09/23/2024 as evidenced by Sharei (Sharei, Armon, et al. " Proceedings of the National Academy of Sciences 110.6 (2013): 2082-2087.), hereinafter Sharei in view of Tran (Tran, Reginald, et al. Molecular Therapy 25.10 (2017): 2372-2382.), hereinafter Tran as applied to claims 1, 6, 23, 24, 25, 40, 42, 45, 51, 52, 67, 69, and 71 above, and further in view of Sharei-2020 (US20200277566-A1; Filed 03/13/2020; Published 09/03/2020), hereinafter Sharei-2020.
Latroche in view of DiTommaso and Tran make obvious the limitations of claims 1 and 71 as set forth above. Latroche, DiTommaso, and Tran do not teach “the cell suspension is passed through the first constriction allowing the first payload to enter the HSC, and then the cell suspension is passed through the second constriction allowing the second payload to enter the HSC” of claim 83. However, Latroche teaches electroporation of CD34+ cells with CXCR4 and CD47 RNA where CXCR4 is involved in homing and CD47 is involved in phagocytosis protection (page 20, para. 0310 – 0318). Latroche teaches these cells when engrafted in NSGW41 mice efficiently outcompeted the mobilized HSCs and established stable chimerism at greater than 40% compared to the control cells that were only detectable at 25% level (page 21, para. 0319 – 0325; Figure 9). Latroche teaches transient overexpression of CD47 and CXCR4 shows a long-term increased engraftment advantage (page 5, para. 0102 and 0110; Figure 3 and 7).
Sharei-2020 teaches a constriction device comprising a plurality of microfluidic channels that may be arranged in a series that allows payloads to be delivered to a cell (page 1, para. 0007; page 3, para. 0023; Figure 1, 5, 6; page 6, para. 0091; page 7, para. 0092; page 10, para. 0127). Sharei-2020 teaches this intracellular delivery method is universal in that it works for many different types of material and cells (page 9, para. 0113). Sharei-2020 teaches in Example 2 the intracellular delivery of nucleic acids into mouse embryonic stem cells (page 13, para. 0150 – 0152).
Sharei-2020 teaches proper intracellular delivery is a critical step in the research, development, and implementation of the next generation therapeutics (page 1, para. 0003). Sharei-2020 teaches there is a need for more robust and precise techniques capable of addressing the needs of modern biological/medical research (page 1, para. 0004).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Latroche regarding a method of modifying HSCs by transducing with CXCR4 and CD47 mRNA to improve engraftment of HSCs with the teachings of DiTommaso regarding squeezing HSCs as an alternative to electroporation to prevent significant genetic changes in HSCs associated with electroporation with the teachings of Tran regarding microfluidic transduction of HSCs with nucleic acids with the teachings of Sharei-2020 regarding a constriction device comprising a plurality of microfluidic channels that may be arranged in a series that allows payloads to be delivered to a cell to arrive at the claimed method wherein the plurality of constrictions comprise a first constriction associated with a first payload and a second constriction associated with a second payload, wherein the cell suspension is passed through the first constriction allowing the first payload to enter the HSC, and then the cell suspension is passed through the second constriction allowing the second payload to enter the HSC. One would have been motivated to combine the teachings of Latroche, DiTommaso, Tran, and Sharei-2020 in a method of producing modified HSCs with enhanced engraftment to treat hematologic disorders as Latroche teaches there is a significant need in the art to improve engraftment of the transplanted HSCs including a need to develop more efficient strategies to improve the ability of HSCs to home and permanently repopulate the recipient bone marrow and DiTommaso teaches while electroporation protocols enable the efficient delivery of some payloads, challenges associated with posttreatment mortality, loss of proliferative potential, and decreased potency have been reported for primary cell types and Tran teaches ex vivo gene therapy using lentiviral vectors is a proven approach to treat and potentially cure many hematologic disorders and malignancies but remains stymied by cumbersome, cost-prohibitive, and scale-limited production processes that cannot meet the demands of current clinical protocols for widespread clinical utilization and Sharei-2020 teaches proper intracellular delivery is a critical step in the research, development, and implementation of the next generation therapeutics and Sharei-2020 teaches there is a need for more robust and precise techniques capable of addressing the needs of modern biological/medical research. One would have a reasonable expectation of success in combining the teachings as Sharei-2020 teaches the device can comprise microfluidic channels arranged in a series and that the device allows for the delivery of nucleic acids to stem cells and the method is universal.
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.
31. Claims 1, 23, 24, 25, 42, 45, 51, 52, 67, 69, 71, and 83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 20, 29 – 31, 33, 38, 54, 58, 59, 67, 82, 84, and 337 – 340 of copending Application No. 1858138 in view of Latroche (US20210317411-A1; Filed 05/16/2019; Published 10/14/2021), hereinafter Latroche which is cited on the IDS filed 09/23/2024.
Claim 1 of the reference application recites a method for delivering a compound into a cell, the method comprising passing a cell suspension which comprises the cell through a hydrophilic surface containing pores at a pressure of 25 psi or below and under serum-free conditions; deforming the cell to cause a perturbation of the cell as it passes through the surface; contacting the cell with the compound; and introducing 10-fold or higher quantity of the compound into the cell compared to an endocytosis control.
Claim 54 of the reference application recites a method for delivering a compound into a cell, the method comprising passing a cell suspension which comprises the cell through a hydrophobic surface containing pores at a pressure below 25 psi, wherein the pores deform the cell thereby causing a perturbation of the cell such that the compound enters the cell through the perturbation when contacted with the cell, wherein the cell is an immune cell, a stem or progenitor cell, a fibroblast, a skin cell, a neuron, or a red blood cell, and wherein a width of the pore in a horizontal plane of the surface is less than 8 µm.
Claims 1 and 54 of the reference application lack “a population of HSC”. Latroche teaches hematopoietic cell transplantation (HCT) is a curative therapy for several inherited and acquired disorders but allogeneic HCT is limited by the poor availability of matched donors, the mortality associated with the allogeneic procedure, and infectious complications (page 1, para. 0003). Latroche teaches gene therapy approaches based on the transplantation of genetically modified autologous HSCs offer potentially improved safety and efficacy over allogeneic HCT (page 1, para. 0004). Latroche teaches there is a significant need in the art to improve engraftment of the transplanted HSCs including a need to develop more efficient strategies to improve the ability of HSCs to home and permanently repopulate the recipient bone marrow (page 1, para. 0008). Latroche teaches there is a further need for protocols that reduce genotoxic conditioning regimens before HSC transplantation (page 1, para. 0009). Latroche teaches overexpressing CXCR4 in HSCs increases the efficiency of HSC engraftment (page 1, para. 0011). Latroche teaches the CXCR4 overexpressing HSCs can be advantageously applied in transplantation protocols that utilize mild or no myeloablative conditioning (page 1, para. 0012). Latroche teaches the strategies increase the efficacy of conditioning regimens that bypass the requirement for toxic and mutagenic drugs (such as endogenous HSC mobilization protocol and conditioning regimens), thus reducing risk and long-term toxicity to the patient (page 1, para. 0014). It would have been obvious prior to the effective filing date of the invention as claimed for a person of ordinary skill in the art to include HSCs in the cell suspension of reference claims 1 and 54 to deliver a nucleic acid encoding CXCR4 into HSCs in order to provide CXCR4 expressing HSCs to improve the homing ability of HSCs.
Instant claims 23, 24, 25, and 42 map to reference claims 1 and 54 as the reference claims broadly recite “compound”. Instant claims 23, 24, 25, and 42 map to reference claims 67 and 339.
Instant claim 1 maps to reference claim 58, 59, 337, and 338 as the instant claim recites “a cell suspension, which comprises a population of HSC”.
Instant claim 1, 51, and 52 map to reference claims 1, 54, 33, and 84 as instant claim 1 broadly recites “parameters” and instant claim 51 recites “pressure” and instant claim 52 recites “at least about 25 psi”.
Instant claim 67 and 69 maps to reference claim 82.
Instant claims 71 and 83 map to reference claims 29 – 31.
This is a provisional nonstatutory double patenting rejection.
32. Claims 1, 23, 24, 25, 42, 45, 51, 52, 67, 69, 71, and 83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 7, 8, 9, 10, 12, 13, 14, 22, 23, and 28 of copending Application No. 18190335 in view of Latroche (US20210317411-A1; Filed 05/16/2019; Published 10/14/2021), hereinafter Latroche which is cited on the IDS filed 09/23/2024.
Reference claim 1 of the reference application recites a method for delivering a compound into a cell comprising a cell wall, the method comprising passing a cell suspension which comprises the cell through a constriction, wherein the constriction deforms the cell, thereby causing a perturbation of the cell such that the compound enters the cell through the perturbation when contacted with the cell.
Reference claim 2 of the reference application recites a method for delivering a compound into a cell, which has been modified to remove all or part of a cell wall, the method comprising passing a cell suspension which comprises the cell through a constriction, wherein -sai-4--the constriction deforms the cell modified to, thereby causing a perturbation of the cell such that the compound enters the cell through the perturbation when contacted with the cell.
Reference claim 3 of the reference application recites a method for delivering a compound into a cell comprising a cell wall, the method comprising a) removing all or part of the cell wall, and b) passing a cell suspension which comprises the cell through a constriction, wherein the constriction deforms the cell, thereby causing a perturbation of the cell such that the compound enters the cell through the perturbation when contacted with the cell.
Reference claims 1 – 3 of the reference application lack “a population of HSC”. Latroche teaches hematopoietic cell transplantation (HCT) is a curative therapy for several inherited and acquired disorders but allogeneic HCT is limited by the poor availability of matched donors, the mortality associated with the allogeneic procedure, and infectious complications (page 1, para. 0003). Latroche teaches gene therapy approaches based on the transplantation of genetically modified autologous HSCs offer potentially improved safety and efficacy over allogeneic HCT (page 1, para. 0004). Latroche teaches there is a significant need in the art to improve engraftment of the transplanted HSCs including a need to develop more efficient strategies to improve the ability of HSCs to home and permanently repopulate the recipient bone marrow (page 1, para. 0008). Latroche teaches there is a further need for protocols that reduce genotoxic conditioning regimens before HSC transplantation (page 1, para. 0009). Latroche teaches overexpressing CXCR4 in HSCs increases the efficiency of HSC engraftment (page 1, para. 0011). Latroche teaches the CXCR4 overexpressing HSCs can be advantageously applied in transplantation protocols that utilize mild or no myeloablative conditioning (page 1, para. 0012). Latroche teaches the strategies increase the efficacy of conditioning regimens that bypass the requirement for toxic and mutagenic drugs (such as endogenous HSC mobilization protocol and conditioning regimens), thus reducing risk and long-term toxicity to the patient (page 1, para. 0014). It would have been obvious prior to the effective filing date of the invention as claimed for a person of ordinary skill in the art to substitute the cell comprising a cell wall of reference claims 1 – 3 to deliver a nucleic acid encoding CXCR4 into HSCs in order to provide CXCR4 expressing HSCs to improve the homing ability of HSCs.
Instant claims 23, 24, 25, and 42 map to reference claims 1 and 31 as the reference claims broadly recite “compound” and “transcription factor”.
Instant claim 1 maps to reference claim 20 as the instant claim broadly recites “payload”.
Instant claim 1 maps to reference claim 14 as both recite “cell suspension”.
Instant claim 1, 51, and 52 map to reference claims 12 and 13 as instant claim 1 broadly recites “parameters” and instant claim 51 recites “diameter of the constriction” and instant claim 52 is drawn to the diameter of the constriction as a function of the diameter of the cell.
This is a provisional nonstatutory double patenting rejection.
33. Claims 1, 23, 24, 25, 42, 45, 51, 52, 67, 69, 71, and 83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10, 20, 31, 33, 42, 49, 56, 77, 92, and 101 of copending Application No. 18867542 in view of Latroche (US20210317411-A1; Filed 05/16/2019; Published 10/14/2021), hereinafter Latroche which is cited on the IDS filed 09/23/2024.
Reference claim 10 of the reference application recites a method of reprogramming a cell, comprising passing a cell suspension, which comprises the cell, through a constriction under a set of parameters, wherein passing the cell suspension through the constriction under the set of parameters causes a perturbation within the membrane of the cell, such that a self-amplifying RNA encoding a reprogramming factor can enter the cell through the perturbation when contacted with the cell, and thereby, reprogramming the cell.
Reference claim 10 of the reference application lack “a population of HSC”. Latroche teaches hematopoietic cell transplantation (HCT) is a curative therapy for several inherited and acquired disorders but allogeneic HCT is limited by the poor availability of matched donors, the mortality associated with the allogeneic procedure, and infectious complications (page 1, para. 0003). Latroche teaches gene therapy approaches based on the transplantation of genetically modified autologous HSCs offer potentially improved safety and efficacy over allogeneic HCT (page 1, para. 0004). Latroche teaches there is a significant need in the art to improve engraftment of the transplanted HSCs including a need to develop more efficient strategies to improve the ability of HSCs to home and permanently repopulate the recipient bone marrow (page 1, para. 0008). Latroche teaches there is a further need for protocols that reduce genotoxic conditioning regimens before HSC transplantation (page 1, para. 0009). Latroche teaches overexpressing CXCR4 in HSCs increases the efficiency of HSC engraftment (page 1, para. 0011). Latroche teaches the CXCR4 overexpressing HSCs can be advantageously applied in transplantation protocols that utilize mild or no myeloablative conditioning (page 1, para. 0012). Latroche teaches the strategies increase the efficacy of conditioning regimens that bypass the requirement for toxic and mutagenic drugs (such as endogenous HSC mobilization protocol and conditioning regimens), thus reducing risk and long-term toxicity to the patient (page 1, para. 0014). It would have been obvious prior to the effective filing date of the invention as claimed for a person of ordinary skill in the art to include HSCs into the cell suspension of reference claim 1 to deliver a nucleic acid encoding CXCR4 into HSCs in order to provide CXCR4 expressing HSCs to improve the homing ability of HSCs.
Instant claims 23, 24, 25, and 42 map to reference claims 10, 31, 42, and 101 as the reference claim 10 broadly recites “compound” and reference claim 31 broadly recites “a transcription factor”, and reference claim 42 broadly recites “nucleic acid, a polypeptide”.
Instant claim 42 maps to reference claim 33 as both recite “self-amplifying RNA”.
Instant claim 1 maps to reference claim 49 as both are drawn to tissue-specific stem cells.
Instant claim 1, 51, and 52 map to reference claim 56 as instant claim 1 broadly recites “parameters” and instant claim 51 recites “diameter of the constriction” and instant claim 52 is drawn to the diameter of the constriction as a function of the diameter of the cell.
Instant claims 67 and 69 map to reference claim 77 as all are drawn to multiple payloads prior, during or after passing the cell suspension through the constriction.
Instant claim 71 and 83 map to reference claim 92 as all are drawn to a plurality of constrictions.
This is a provisional nonstatutory double patenting rejection.
34. Claims 1, 23, 24, 25, 42, 45, 51, 52, 67, 69, 71, and 83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18 and 19 of copending Application No. 18983907 in view of Latroche (US20210317411-A1; Filed 05/16/2019; Published 10/14/2021), hereinafter Latroche which is cited on the IDS filed 09/23/2024.
Reference claim 18 of the reference application recites a method for delivering a payload to a cell, the method comprising: providing a cell in a cell suspension; passing the cell suspension into a preparation vessel at a tabletop system; while the cell suspension is in the preparation vessel, preparing the cell suspension including by causing pressure to be applied to the cell suspension; and passing the prepared cell suspension from the preparation vessel through a constriction cartridge of the system, wherein the constriction cartridge is configured to house a component comprising a cell-deforming constriction that causes a perturbation in a membrane of the cell that allows entry of a payload into the cell.
Reference claim 18 of the reference application lack “a population of HSC”. Latroche teaches hematopoietic cell transplantation (HCT) is a curative therapy for several inherited and acquired disorders but allogeneic HCT is limited by the poor availability of matched donors, the mortality associated with the allogeneic procedure, and infectious complications (page 1, para. 0003). Latroche teaches gene therapy approaches based on the transplantation of genetically modified autologous HSCs offer potentially improved safety and efficacy over allogeneic HCT (page 1, para. 0004). Latroche teaches there is a significant need in the art to improve engraftment of the transplanted HSCs including a need to develop more efficient strategies to improve the ability of HSCs to home and permanently repopulate the recipient bone marrow (page 1, para. 0008). Latroche teaches there is a further need for protocols that reduce genotoxic conditioning regimens before HSC transplantation (page 1, para. 0009). Latroche teaches overexpressing CXCR4 in HSCs increases the efficiency of HSC engraftment (page 1, para. 0011). Latroche teaches the CXCR4 overexpressing HSCs can be advantageously applied in transplantation protocols that utilize mild or no myeloablative conditioning (page 1, para. 0012). Latroche teaches the strategies increase the efficacy of conditioning regimens that bypass the requirement for toxic and mutagenic drugs (such as endogenous HSC mobilization protocol and conditioning regimens), thus reducing risk and long-term toxicity to the patient (page 1, para. 0014). It would have been obvious prior to the effective filing date of the invention as claimed for a person of ordinary skill in the art to include HSCs into the cell suspension of reference claim 18 to deliver a nucleic acid encoding CXCR4 into HSCs in order to provide CXCR4 expressing HSCs to improve the homing ability of HSCs.
Instant claims 1, 23, 24, 25, and 42 map to reference claim 18 as the reference claim 10 and instant claim 1 broadly recite “payload”.
Instant claim 1, 51, and 52 map to reference claim 18 as instant claim 1 broadly recites “parameters” and instant claim 51 broadly recites “pressure” and reference claim 18 broadly recites “causing pressure” and instant claim 52 is drawn to the pressure.
Instant claims 67 and 69 map to reference claim 18 as all are drawn to “payload”.
Instant claim 71 and 83 map to reference claims 18 and 19 as all are drawn to a plurality of constrictions.
This is a provisional nonstatutory double patenting rejection.
35. Claims 1, 23, 24, 25, 42, 45, 51, 52, 67, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 88, 90, 91, and 100 of copending Application No. 18997630 in view of Latroche (US20210317411-A1; Filed 05/16/2019; Published 10/14/2021), hereinafter Latroche which is cited on the IDS filed 09/23/2024.
Claim 88 of the reference application recites a method of inducing the expression of multiple antigens in a cell comprising intracellularly delivering the polynucleotide of claim 1 to the cell, wherein the multiple antigens are concurrently expressed in the cell after the intracellularly delivering.
Claim 90 of the reference application recites the method of claim 88, wherein intracellularly delivering the polynucleotide to the cell comprises passing a cell suspension comprising the cell through a constriction under a set of parameters, thereby causing a perturbation within the cell such that the polynucleotide enters the cell through the perturbation when contacted with the cell. Therefore, the reference claims recite delivering a polynucleotide by passing a cell suspension through a constriction.
Reference claim 88 of the reference application lacks “a population of HSC”. Latroche teaches hematopoietic cell transplantation (HCT) is a curative therapy for several inherited and acquired disorders but allogeneic HCT is limited by the poor availability of matched donors, the mortality associated with the allogeneic procedure, and infectious complications (page 1, para. 0003). Latroche teaches gene therapy approaches based on the transplantation of genetically modified autologous HSCs offer potentially improved safety and efficacy over allogeneic HCT (page 1, para. 0004). Latroche teaches there is a significant need in the art to improve engraftment of the transplanted HSCs including a need to develop more efficient strategies to improve the ability of HSCs to home and permanently repopulate the recipient bone marrow (page 1, para. 0008). Latroche teaches there is a further need for protocols that reduce genotoxic conditioning regimens before HSC transplantation (page 1, para. 0009). Latroche teaches overexpressing CXCR4 in HSCs increases the efficiency of HSC engraftment (page 1, para. 0011). Latroche teaches the CXCR4 overexpressing HSCs can be advantageously applied in transplantation protocols that utilize mild or no myeloablative conditioning (page 1, para. 0012). Latroche teaches the strategies increase the efficacy of conditioning regimens that bypass the requirement for toxic and mutagenic drugs (such as endogenous HSC mobilization protocol and conditioning regimens), thus reducing risk and long-term toxicity to the patient (page 1, para. 0014). It would have been obvious prior to the effective filing date of the invention as claimed for a person of ordinary skill in the art to include HSCs into the cell suspension of reference claim 18 to deliver a nucleic acid encoding CXCR4 into HSCs in order to provide CXCR4 expressing HSCs to improve the homing ability of HSCs.
Instant claims 1, 23, 24, 25, and 42 map to reference claim 88 as reference claim 88 broadly recites “polynucleotide”.
Instant claims 1, 51, 52, and 100 map to reference claim 90 as instant claim 1 and reference claim 90 broadly recite “parameters” and instant claim 51 broadly recites “diameter of the constriction” and instant claim 52 is drawn to the diameter of the constriction.
Instant claims 67 and 69 map to reference claim 91 as all are drawn to contacting prior, during, or after the cell suspension passes through the constriction.
This is a provisional nonstatutory double patenting rejection.
36. Claims 1, 23, 24, 25, 42, 45, 51, 52, 67, and 69 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 6, 9 – 14, 15, 16, 18, 19, and 21 – 25 of U.S. Patent No. 11613759 in view of Latroche (US20210317411-A1; Filed 05/16/2019; Published 10/14/2021), hereinafter Latroche which is cited on the IDS filed 09/23/2024.
Patent claim 1 recites a method for delivering a compound into a modified cell which has been modified to remove all or part of a cell wall, the method comprising passing a cell suspension which comprises the modified cell through a constriction, wherein the constriction deforms the modified cell, thereby causing a perturbation of the modified cell such that the compound enters the modified cell through the perturbation when contacted with the modified cell, and wherein the constriction is a pore or contained within a pore.
Patent claim 15 recites a method for delivering a compound into a cell comprising a cell wall, the method comprising a) removing all or part of the cell wall to produce a modified cell, and b) passing a cell suspension comprising the modified cell through a constriction, wherein the constriction deforms the modified cell, thereby causing a perturbation of the modified cell such that the compound enters the modified cell through the perturbation when contacted with the modified cell and wherein the constriction is a pore or contained within a pore.
Patent claims 1 and 15 lack “a population of HSC”. Latroche teaches hematopoietic cell transplantation (HCT) is a curative therapy for several inherited and acquired disorders but allogeneic HCT is limited by the poor availability of matched donors, the mortality associated with the allogeneic procedure, and infectious complications (page 1, para. 0003). Latroche teaches gene therapy approaches based on the transplantation of genetically modified autologous HSCs offer potentially improved safety and efficacy over allogeneic HCT (page 1, para. 0004). Latroche teaches there is a significant need in the art to improve engraftment of the transplanted HSCs including a need to develop more efficient strategies to improve the ability of HSCs to home and permanently repopulate the recipient bone marrow (page 1, para. 0008). Latroche teaches there is a further need for protocols that reduce genotoxic conditioning regimens before HSC transplantation (page 1, para. 0009). Latroche teaches overexpressing CXCR4 in HSCs increases the efficiency of HSC engraftment (page 1, para. 0011). Latroche teaches the CXCR4 overexpressing HSCs can be advantageously applied in transplantation protocols that utilize mild or no myeloablative conditioning (page 1, para. 0012). Latroche teaches the strategies increase the efficacy of conditioning regimens that bypass the requirement for toxic and mutagenic drugs (such as endogenous HSC mobilization protocol and conditioning regimens), thus reducing risk and long-term toxicity to the patient (page 1, para. 0014). It would have been obvious prior to the effective filing date of the invention as claimed for a person of ordinary skill in the art to substitute the cell comprising a cell wall of patent claims 1 and 15 to deliver a nucleic acid encoding CXCR4 into HSCs in order to provide CXCR4 expressing HSCs to improve the homing ability of HSCs.
Instant claims 1, 23, 24, 25, and 42 map to patent claims 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, and 25 as instant claim broadly recites “payload” and instant claims 23 – 25 and 42 encompass nucleic acids.
Instant claim 45, 67, and 69 map to patent claims 1 and 15 as instant claim 45 recites “during the passing” and patent claims 1 and 45 recite “the compound enters the modified cell through the perturbation when contacted with the modified cell”.
Instant claims 1, 51, and 52 map to patent claims 4 and 5 as instant claim 1 broadly recites “parameter”, instant claim 51 recites “diameter of the constriction”, instant claim 52 is drawn to the diameter of the constriction relative to the diameter of the cell, and patent claims 4 and 5 are drawn to the diameter of the constriction relative to the diameter of the cell.
37. Claims 1, 23, 24, 25, 42, and 45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 4 of U.S. Patent No. 12201652 in view of Latroche (US20210317411-A1; Filed 05/16/2019; Published 10/14/2021), hereinafter Latroche which is cited on the IDS filed 09/23/2024.
Patent claim 4 recites a method for delivering a tolerogenic factor into anucleate cells, the method comprising passing a cell suspension comprising a population of the anucleate cells
through a constriction, wherein the anucleate cells are selected from a red blood cell, platelet, or both, wherein the constriction deforms the anucleate cells, thereby causing a perturbation of the anucleate cells such that the tolerogenic factor enters the anucleate cells when contacted with the anucleate cells to produce a population of modified anucleate cells comprising the tolerogenic factor, wherein a therapeutically effective dose of the population of modified anucleate cells exhibits reduced viability compared to a population of anucleate cells not having passed through the constriction, and wherein the perturbation is transient such that after the tolerogenic factor enters the anucleate cells the
perturbation is corrected.
Patent claim 4 lacks “a population of HSC”. Latroche teaches hematopoietic cell transplantation (HCT) is a curative therapy for several inherited and acquired disorders but allogeneic HCT is limited by the poor availability of matched donors, the mortality associated with the allogeneic procedure, and infectious complications (page 1, para. 0003). Latroche teaches gene therapy approaches based on the transplantation of genetically modified autologous HSCs offer potentially improved safety and efficacy over allogeneic HCT (page 1, para. 0004). Latroche teaches there is a significant need in the art to improve engraftment of the transplanted HSCs including a need to develop more efficient strategies to improve the ability of HSCs to home and permanently repopulate the recipient bone marrow (page 1, para. 0008). Latroche teaches there is a further need for protocols that reduce genotoxic conditioning regimens before HSC transplantation (page 1, para. 0009). Latroche teaches overexpressing CXCR4 in HSCs increases the efficiency of HSC engraftment (page 1, para. 0011). Latroche teaches the CXCR4 overexpressing HSCs can be advantageously applied in transplantation protocols that utilize mild or no myeloablative conditioning (page 1, para. 0012). Latroche teaches the strategies increase the efficacy of conditioning regimens that bypass the requirement for toxic and mutagenic drugs (such as endogenous HSC mobilization protocol and conditioning regimens), thus reducing risk and long-term toxicity to the patient (page 1, para. 0014). It would have been obvious prior to the effective filing date of the invention as claimed for a person of ordinary skill in the art to substitute the cell comprising a cell wall of patent claims 1 and 15 to deliver a nucleic acid encoding CXCR4 into HSCs in order to provide CXCR4 expressing HSCs to improve the homing ability of HSCs.
Instant claims 1, 23, 24, 25, and 42 map to patent claim 4 because instant claim 1 broadly recites “payload”, instant claims 23 – 25 and 42 broadly recite various molecules that read on “tolerogenic factor” of patent claim 4.
Instant claim 45 maps to patent claim 4 because both are drawn to a payload entering the cells when contacted with the constriction.
Conclusion
No claims allowed.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632
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