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 .
Claim Status
Applicant’s submission filed 02/11/2026 has been received and entered. Claims 7, 13 and 15
have been cancelled. Claims 1, 4-6, 8-9 and 14 have been amended. Accordingly, claims 1-6, 8-12, 14, 16-25 are pending and under current examination.
Status of Prior Rejection/Response to Arguments
The objection to drawings is withdrawn:
Applicant’s submission of replacement drawing sheets is effective to obviate the prior basis of
the objection. The objection is withdrawn.
The objections to claims 1, 4 and 5 is withdrawn:
Applicant’s amendment to claims 1, 4 and 5 is effective to obviate the prior basis of the
objection. The objection is withdrawn.
The rejection to claims 10 and 23 under 35 U.S.C. §112(b) is withdrawn:
Regarding claim 10, Applicant’s argument and clarification regarding the “MOI value” and specified volumes in claim 10 is found persuasive. Regarding claim 23, Applicant’s amendment to claim 1 recites “electroporating” is effective to obviate the prior basis of the rejection. Therefore the rejection is
withdrawn.
The rejection to claims 1-25 under 35 U.S.C. §112(a) is withdrawn:
The cancellation of claims 7, 13 and 15 renders the rejection thereto moot.
Applicant’s amendment to claims 1 and 4-5 limits the species of modifying agents, Applicant’s amendment to claim 6 limits the stimulating agent is able to produce activated immune cells, CD4+ and CD8+ cells or lymphocytes. Applicant’s amendment has the support in the specification and the scope of the claims is enabled. The rejection is withdrawn.
The rejections to claims 1-13, 22, 24 and 25 under 35 U.S.C. 102(a)(1) and (a)(2) over Morgan et al. is withdrawn:
The rejections to claims 1-5 and 8-25 under 35 U.S.C. 102(a)(1)and (a)(2) over Beauchesne et al. is withdrawn:
The cancellation of claims 7, 13 and 15 renders the rejection thereto moot.
Applicant’s amendment to claim 1(c), 4(c) and 5(c) replacing “transfecting” with “electroporating” , neither Morgan et al. or Beauchesne et al. teach electroporating viral vectors to the immune cells, CD4+ and CD8+ cells or lymphocytes. Therefore Applicant’s amendment overcomes the rejection on the record. The rejection is withdrawn.
New grounds of rejection are set forth as necessitated by Applicant’s amendment.
New Grounds of Rejections
New Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 16-18 and 21 are newly 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. The rejection is necessitated by Applicant’s amendment.
Claims 16-18 and 21 depend upon the canceled claim 15. In the current claims, the independent claims 1, 4 and 5 do not refer to “activated” cells, only dependent claim 6 recites cells are “activated” prior to the electroporating step. Since the cancelled claim 15 on record depended upon claim 1, which does not limit the activation needs to prior to the electroporating step, it is not clear when the activated cells in claims 16-18 and 21 are activated in the current claims. The scope of the claims is therefore not definite.
Claim Interpretation
Claims 1 and 4 recite step (a) “enriching”, herein is interpreted the same as “obtain” the cells from the blood of a subject since the process of “obtaining” these cells is the process of enriching the cells by getting rid of other blood components.
As noted above, claims 16-18 are not definite in scope. Herein the claims are interpreted not limiting the activation needs to prior to the electroporating according the cancelled claim 15 on record.
New 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.
Claims 1-6, 8-12, 22, 24 and 25 are newly rejected under 35 U.S.C. 103 as being unpatentable over Morgan et al. (WO 2015/164745 A1, published in 2015, cited in IDS) in view of Foster et al. (US 2024/0401083 A1, with a priority date of 09/24/2021). The rejection is necessitated by Applicant’s amendment.
Morgan et al. teach compositions and methods for manufacturing adoptive cell therapies. In particular embodiments, the invention provides methods of harvesting populations of cells, isolating and activating PBMCs, expanding T cells, and administering the T cell therapeutic to a subject in need thereof (Abstract).
Regarding claim 1, Morgan et al. teach a method for manufacturing a T cell therapeutic is provided comprising: obtaining a population of cells that comprises T cells and antigen presenting cells (APCs); culturing the population of cells in a cell culture medium comprising i) one or more cytokines, ii) an anti-CD3 antibody or CD3-binding fragment thereof, and iii) an anti-CD28 antibody or a CD28-binding fragment thereof, B7-1 or a CD28-binding fragment thereof, or B7-2 or a CD28-binding fragment thereof, wherein the culture activates and stimulates the T cells; transducing the population of activated cells with a viral vector; and culturing the population of cells in a cell growth medium to expand the transduced T cells; thereby manufacturing the T cell therapeutic (p2, L11-19). Herein the teaching of “obtaining a population of cells that comprises T cells and antigen presenting cells (APCs)” reads on “(a) enriching a population of lymphocytes, a population immune cells or a population of CD4+ and CD8+ cells from blood obtained from a subject” in instant claim, as well as transducing the population of cells a modifying agent (a viral vector) as in step (c). Morgan et al. teach in particular embodiments, the methods further comprise washing the population of cells in a buffer or cell culture medium (p3, L13-14). This teaching reads on “ (b) admixing the population of lymphocytes, the population of immune cells or the population of CD4+ and CD8+ cells with one or more buffer solutions” in instant claim. Morgan et al. teach in certain embodiments, cells are harvested, isolated, and washed, cell cultures are initiated and T cells are activated all within a period of about 18 hours to about 36 hours, or within a period of about 24 hours, or any intervening length of time thereof (p35, L17-19). Morgan et al. also teach the populations of cells seeded in the cell culture vessel are activated for at least 30 minutes, at least 1 hour … or at least 24 hours, or any intervening length of time (p35, 11-16). This teaching indicates the steps 1(a)-(b) and (c) transducing a viral vector to the population of cells can be taken place within 24 hours (i.e., cells are harvested, isolated, and washed, cell cultures are initiated and T cells are activated all within a period of about 18 hours, and cells are activated for 1 hour then transduce the cells).
Morgan et al. do not specifically teach in step (c) that the transducing the population of cells with a viral vector by electroporation. However, this was disclosed by Foster et al. at the time of instant invention.
Foster et al. disclose method of cell-editing comprising combining a cell or cell line with a virus, viral vector or virus like particle to form a mixture and performing simultaneous electroporation and transduction on the mixture to insert therein the virus, viral vector or virus like particle (Abstract).
Regarding claim 1, Foster et al. teach a method of enhanced viral transduction using electroporation into a cell, comprising: selecting one or more cells-to-be-modified; harvesting the cells-to-be-modified; concentrating the cells to-be-modified; combining the cells-to-be-modified with a
virus, viral vector or virus like particle to form a mixture; simultaneously performing electroporation and transduction on the mixture to insert therein the virus, viral vector or virus like particle; and forming one or more co-electroporated cells (parag 0010).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Morgan et al.’s method for manufacturing a T cell therapeutic, and transduce the viral vectors to the population of cells intended to be modified by electroporation as taught by Foster et al.. The skilled artisan would have been motivated to electroporating viral vectors to the population of cells intended to be modified since Foster et al. teach this operation would enhance viral transduction (parag 0010). There would be a reasonable expectation of success of electroporating viral vectors to cells since Foster et al. teach the method of electroporation (i.e., see Examples, parag 0043).
Regarding claim 2, Morgan et al. teach harvesting cells (p26), cell populations comprising T cells are obtained from an individual and subjected to the manufacturing methods contemplated herein. In one embodiment, cells from the circulating blood of an individual are obtained by a method of apheresis, e.g., leukapheresis (p26, L15-18). The apheresis product may contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets or may be a leukapheresis product comprising lymphocytes, including T cells, monocytes, granulocytes, B cells, and other nucleated white blood cells (p26, L15-18).
Regarding claim 3, as discussed above, Morgan et al. teach harvesting cells (p26), cell populations comprising T cells are obtained from an individual and subjected to the manufacturing methods contemplated herein. In one embodiment, cells from the circulating blood of an individual are obtained by a method of apheresis, e.g., leukapheresis (p26, L15-18).
Regarding claim 4, following the discussion above, Morgan et al. teach a method for manufacturing a T cell therapeutic is provided comprising: obtaining a population of cells that comprises T cells and antigen presenting cells (APCs); culturing the population of cells in a cell culture medium comprising i) one or more cytokines, ii) an anti-CD3 antibody or CD3-binding fragment thereof, and iii) an anti-CD28 antibody or a CD28-binding fragment thereof, B7-1 or a CD28-binding fragment thereof, or B7-2 or a CD28-binding fragment thereof, wherein the culture activates and stimulates the T cells; transducing the population of activated cells with a viral vector; and culturing the population of cells in a cell growth medium to expand the transduced T cells; thereby manufacturing the T cell therapeutic (p2, L11-19). Morgan et al. teach harvesting cells (p26), cell populations comprising T cells are obtained from an individual and subjected to the manufacturing methods contemplated herein. In one embodiment, cells from the circulating blood of an individual are obtained by a method of apheresis, e.g., leukapheresis (p26, L15-18). The teaching reads on “(a) enriching” step as well as transducing step in step (c) in instant claim. Morgan et al. teach in particular embodiments, the methods further comprise washing the population of cells in a buffer or cell culture medium (p3, L13-14). This teaching reads on “ (b) admixing” step in instant claim. Morgan et al. teach in certain embodiments, cells are harvested, isolated, and washed, cell cultures are initiated and T cells are activated all within a period of about 18 hours to about 3 6 hours, or within a period of about 24 hours, or any intervening length of time thereof (p35, L17-19). Morgan et al. also teach the populations of cells seeded in the cell culture vessel are activated for at least 30 minutes, at least 1 hour … or at least 24 hours, or any intervening length of time (p35, 11-16). This teaching indicates the steps 4(a)-(c) can be taken place within 24 hours (i.e., cells are harvested, isolated, and washed, cell cultures are initiated and T cells are activated all within a period of about 18 hours, and cells are activated for 1 hour then transfect the cells). Morgan et al. do not specifically teach in step (c) that the transducing the population of cells with a viral vector by electroporation. However, Foster et al. teach a method of enhanced viral transduction using electroporation into a cell, comprising: selecting one or more cells-to-be-modified; harvesting the cells-to-be-modified; concentrating the cells to-be-modified; combining the cells-to-be-modified with a virus, viral vector or virus like particle to form a mixture; simultaneously performing electroporation and transduction on the mixture to insert therein the virus, viral vector or virus like particle; and forming one or more co-electroporated cells (parag 0010).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Morgan et al.’s method for manufacturing a T cell therapeutic, and transduce the viral vectors to the population of cells intended to be modified by electroporation as taught by Foster et al.. The skilled artisan would have been motivated to electroporating viral vectors to the population of cells intended to be modified since Foster et al. teach this operation would enhance viral transduction (parag 0010). There would be a reasonable expectation of success of electroporating viral vectors to cells since Foster et al. teach the method (i.e., parag 0043).
Regarding claim 5, following the discussion above, Morgan et al. teach a method for manufacturing a T cell therapeutic is provided comprising: obtaining a population of cells that comprises T cells and antigen presenting cells (APCs); culturing the population of cells in a cell culture medium comprising i) one or more cytokines, ii) an anti-CD3 antibody or CD3-binding fragment thereof, and iii) an anti-CD28 antibody or a CD28-binding fragment thereof, B7-1 or a CD28-binding fragment thereof, or B7-2 or a CD28-binding fragment thereof, wherein the culture activates and stimulates the T cells; transducing the population of activated cells with a viral vector; and culturing the population of cells in a cell growth medium to expand the transduced T cells; thereby manufacturing the T cell therapeutic (p2, L11-19). Morgan et al. teach in one embodiment, the cells are obtained from a mammalian subject (p26, L12-13). This teaching reads on “(a) obtaining a population of eukaryotic donor cells from a subject” and transducing step in (c) in instant claim. Morgan et al. teach in particular embodiments, the methods further comprise washing the population of cells in a buffer or cell culture medium (p3, L13-14). This teaching reads on “ (b) admixing the population of eukaryotic donor cells with one or more buffer solutions” in instant claim. Morgan et al. teach in certain embodiments, cells are harvested, isolated, and washed, cell cultures are initiated and T cells are activated all within a period of about 18 hours to about 36 hours, or within a period of about 24 hours, or any intervening length of time thereof (p35, L17-19). Morgan et al. also teach the populations of cells seeded in the cell culture vessel are activated for at least 30 minutes, at least 1 hour … or at least 24 hours, or any intervening length of time (p35, 11-16). This teaching indicates the steps 5(a)-(c) can be taken place the same day (i.e., cells are harvested, isolated, and washed, cell cultures are initiated and T cells are activated all within a period of about 18 hours, and cells are activated for 1 hour then transfect the cells). Morgan et al. do not specifically teach in step (c) that the transducing the population of cells with a viral vector by electroporation. However, Foster et al. teach a method of enhanced viral transduction using electroporation into a cell, comprising: selecting one or more cells-to-be-modified; harvesting the cells-to-be-modified; concentrating the cells to-be-modified; combining the cells-to-be-modified with a virus, viral vector or virus like particle to form a mixture; simultaneously performing electroporation and transduction on the mixture to insert therein the virus, viral vector or virus like particle; and forming one or more co-electroporated cells (parag 0010).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Morgan et al.’s method for manufacturing a T cell therapeutic, and transduce the viral vectors to the population of cells intended to be modified by electroporation as taught by Foster et al.. The skilled artisan would have been motivated to electroporating viral vectors to the population of cells intended to be modified since Foster et al. teach this operation would enhance viral transduction (parag 0010). There would be a reasonable expectation of success of electroporating viral vectors to cells since Foster et al. teach the method (i.e., parag 0043).
Regarding claim 6, Morgan et al. teach a method for manufacturing a T cell therapeutic is provided comprising: obtaining a population of cells that comprises T cells and antigen presenting cells (APCs); culturing the population of cells in a cell culture medium comprising i) one or more cytokines, ii) an anti-CD3 antibody or CD3-binding fragment thereof, and iii) an anti-CD28 antibody or a CD28-binding fragment thereof, B7-1 or a CD28-binding fragment thereof, or B7-2 or a CD28-binding fragment thereof, wherein the culture activates and stimulates the T cells; transducing the population of activated cells with a viral vector; and culturing the population of cells in a cell growth medium to expand the transduced T cells; thereby manufacturing the T cell therapeutic (p2, L11-19). This teaching reads on the cells are stimulated and activated prior to the transfecting step, as recited in instant claim.
Regarding claim 8, following the discussion above, Morgan et al. teach in particular embodiments, population of cells comprising T cells, e.g., PBMCs, or a purified population of T cells is transduced with a retroviral vector, e.g., a lentiviral vector (p64, L26-28). Morgan et al. do not teach transducing by electroporation. However, Foster et al. teach a method of enhanced viral transduction using electroporation into a cell (parag 0010).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Morgan et al.’s method for manufacturing a T cell therapeutic, and transduce a retroviral vector, e.g., a lentiviral vector to the population of cells intended to be modified by electroporation as taught by Foster et al.. The skilled artisan would have been motivated to electroporating viral vectors to the population of cells intended to be modified since Foster et al. teach this operation would enhance viral transduction (parag 0010). There would be a reasonable expectation of success of electroporating viral vectors to cells since Foster et al. teach the method (i.e., parag 0043).
Regarding claims 9 and 10, Morgan et al. teach in one embodiment, the manufacturing methods contemplated herein comprise transducing PBMCs comprising activated T cells in a cell culture vessel with a vector at an MOI of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100, or any intervening integer (which means the MOI can be 0.08, 0.2 or 0.4 as recited in instant claim 10). This teaching reads on the MOI as recited in instant claim 9 (i.e, with an MOI of 1) and lentiviral vector with a MOI as recited in instant claim 10.
Regarding claim 11, following the discussion above, Morgan et al. teach the lymphocyte population consists of CD4+ and CD8+ T cells, B cells and Natural Killer cells, CD 14+ monocytes, and basophils/ neutrophils/eosinophils/dendritic cells (p14, L27-29), reads on the population of immune cells can be i.e., B lymphocytes, T lymphocytes, CD4+ T lymphocytes, CD8+ T lymphocytes, as recited in instant claim.
Regarding claim 12, following the discussion above, Morgan et al. teach in particular embodiments, culture initiation comprises seeding a population of cells comprising T cells, e.g., PBMCs, in a cell culture vessel, at a desired density, e.g., 1-5 x 106 cells/mL in a suitable cell culture medium (p31, L15-17). 1-5 x 106 cells/mL is in the range of (c) from about 0.5 x 106 cells/mL to about 1 x 108 cells/mL, as recited in instant claim.
Regarding claim 22, Morgan et al. teach in certain embodiments, cells are harvested, isolated, and washed, cell cultures are initiated and T cells are activated all within a period of about 18 hours to about 36 hours, or within a period of about 24 hours, or any intervening length of time thereof (p35, L17-19). Morgan et al. teach the populations of cells seeded in the cell culture vessel are activated for at least 30 minutes, at least 1 hour … or at least 24 hours, or any intervening length of time (p35, 11-16). Morgan et al. also teach in Example 1, cells were transduced with virus for about 48 hours (p90, L17-18). Therefore the total time can be i.e., about 4 days (in the case that cells are harvested, isolated, and washed, cell cultures are initiated and T cells are activated in 24 hours, activated for 24 hours, and transduced with virus for about 48 hours), as recited in instant claim.
Regarding claim 24, Morgan et al. teach in Example 1, T cells were activated by adding 5 µL of anti-CD3 antibody at 100 ng/µL and 5 µL of anti-CD28 antibody at 100 ng/µL to the culture (p90, L9-11). This teaching reads on (a) in instant claim.
Regarding claim 25, Morgan et al. teach in particular embodiments, population of cells comprising T cells, e.g., PBMCs, or a purified population of T cells is transduced with a retroviral vector, e.g., a lentiviral vector, encoding an engineered TCR or CAR as contemplated herein (p64, L26-28).
Claims 1-5, 8-12, 14, 16-25 are newly rejected under 35 U.S.C. 103 as being unpatentable over Beauchesne et al. (WO 2018/106732 A1, published in 2018, cited in IDS) in view of Foster et al. (US 2024/0401083 A1, with a priority date of 09/24/2021). The rejection is necessitated by Applicant’s amendment.
Beauchesne et al. teach methods for genetically engineering cells, including cells for use in connection with genetic engineering. In some embodiments, the provided methods including transduction of cells by incubation with a retroviral vector particle, e.g. lentiviral vector, in which, prior to the incubation, the cells have not been incubated with an activating or stimulating agent, such as have not been incubated with anti-CD3/anti-CD28 antibodies and/or one or more recombinant cytokines (Abstract).
Regarding claim 1, Beauchesne et al. teach a method for transducing T cells including incubating a viral vector particle containing a recombinant nucleic acid and an input composition containing a plurality of T cells, said plurality of T cells having been obtained from a sample containing cells derived from a subject, wherein the incubating is initiated no more than 24 hours after obtaining the sample from the subject (parag 0005). In some of any such embodiments, the T cells are unfractionated T cells, are enriched or isolated CD3+ T cells, are enriched or isolated CD4+ T cells or are enriched or isolated CD8+ T cells. In some of any such embodiments, the T cells have been selected or enriched from the sample from the subject (parag 0015). This teaching reads on “(a) enriching” step as well as (c) incubating / transducing step and the limitation “steps 1(a)-(c) take place within 24 hours” in instant claim. In some embodiments, the blood cells collected from the subject are washed, e.g., to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing steps (parag 0116). This teaching reads on the “(b) admixing” step in instant claim.
Beauchesne et al. teach the incubating / transducing step, do not specifically teach that the transducing the population of activated cells with a viral vector by electroporation. However, this was disclosed by Foster et al. at the time of instant invention.
Foster et al. disclose method of cell-editing comprising combining a cell or cell line with a virus, viral vector or virus like particle to form a mixture and performing simultaneous electroporation and transduction on the mixture to insert therein the virus, viral vector or virus like particle (Abstract).
Regarding claim 1, Foster et al. teach a method of enhanced viral transduction using electroporation into a cell, comprising: selecting one or more cells-to-be-modified; harvesting the cells-to-be-modified; concentrating the cells to-be-modified; combining the cells-to-be-modified with a
virus, viral vector or virus like particle to form a mixture; simultaneously performing electroporation and transduction on the mixture to insert therein the virus, viral vector or virus like particle; and forming one or more co-electroporated cells (parag 0010).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Beauchesne et al.’s method for transducing T cells, and transduce the viral vectors to the population of cells intended to be modified by electroporation as taught by Foster et al.. The skilled artisan would have been motivated to electroporating viral vectors to the population of cells intended to be modified since Foster et al. teach this operation would enhance viral transduction (parag 0010). There would be a reasonable expectation of success of electroporating viral vectors to cells since Foster et al. teach the method (i.e., see parag 0043).
Regarding claims 2 and 3, following the discussion above, Beauchesne et al. a teach in some examples, cells from the circulating blood of a subject are obtained, e.g., by apheresis or leukapheresis. The samples, in some aspects, contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and/or platelets (parag 0115).
Regarding claim 4, following the discussion above, Beauchesne et al. a teach method for transducing T cells including incubating a viral vector particle containing a recombinant nucleic acid and an input composition containing a plurality of T cells, said plurality of T cells having been obtained from a sample containing cells derived from a subject, wherein the incubating is initiated no more than 24 hours after obtaining the sample from the subject (parag 0005). In some of any such embodiments, the T cells are unfractionated T cells, are enriched or isolated CD3+ T cells, are enriched or isolated CD4+ T cells or are enriched or isolated CD8+ T cells. In some of any such embodiments, the T cells have been selected or enriched from the sample from the subject (parag 0015). Beauchesne et al. also teach in some examples, cells from the circulating blood of a subject are obtained, e.g., by apheresis or leukapheresis. The samples, in some aspects, contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and/or platelets (parag 0115). This teaching reads on “(a) enriching” step as well as the transducing step in (c), and the limitation “steps (a)-(c) take place within 24 hours” in instant claim. In some embodiments, the blood cells collected from the subject are washed, e.g., to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing steps (parag 0116). This teaching reads on the “(b) admixing” step. Beauchesne et al. do not specifically teach that the transducing the population of activated cells with a viral vector by electroporation. However, Foster et al. teach a method of enhanced viral transduction using electroporation into a cell, comprising: selecting one or more cells-to-be-modified; harvesting the cells-to-be-modified; concentrating the cells to-be-modified; combining the cells-to-be-modified with a virus, viral vector or virus like particle to form a mixture; simultaneously performing electroporation and transduction on the mixture to insert therein the virus, viral vector or virus like particle; and forming one or more co-electroporated cells (parag 0010).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Beauchesne et al.’s method for transducing T cells, and transduce the viral vectors to the population of cells intended to be modified by electroporation as taught by Foster et al.. The skilled artisan would have been motivated to electroporating viral vectors to the population of cells intended to be modified since Foster et al. teach this operation would enhance viral transduction (parag 0010). There would be a reasonable expectation of success of electroporating viral vectors to cells since Foster et al. teach the method (i.e., see parag 0043).
Regarding claim 5, as discussed above, Beauchesne et al. teach method for transducing T cells including incubating a viral vector particle containing a recombinant nucleic acid and an input composition containing a plurality of T cells, said plurality of T cells having been obtained from a sample containing cells derived from a subject, wherein the incubating is initiated no more than 24 hours after obtaining the sample from the subject (parag 0005). In some of any such embodiments, the subject is a human (parag 0012). In some of any such embodiments, the T cells are unfractionated T cells, are enriched or isolated CD3+ T cells, are enriched or isolated CD4+ T cells or are enriched or isolated CD8+ T cells. In some of any such embodiments, the T cells have been selected or enriched from the sample from the subject (parag 0015). This teaching reads on “(a) obtaining” step as well as the step of transducing in c), and the limitation “steps (a)-(c) take place the dame day” in instant claim. In some embodiments, the blood cells collected from the subject are washed, e.g., to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing steps (parag 0116). This teaching reads on the “(b) admixing” step. Beauchesne et al. do not specifically teach that the transducing the population of activated cells with a viral vector by electroporating. However, Foster et al. teach a method of enhanced viral transduction using electroporation into a cell, comprising: selecting one or more cells-to-be-modified; harvesting the cells-to-be-modified; concentrating the cells to-be-modified; combining the cells-to-be-modified with a virus, viral vector or virus like particle to form a mixture; simultaneously performing electroporation and transduction on the mixture to insert therein the virus, viral vector or virus like particle; and forming one or more co-electroporated cells (parag 0010).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Beauchesne et al.’s method for transducing T cells, and transduce the viral vectors to the population of cells intended to be modified by electroporation as taught by Foster et al.. The skilled artisan would have been motivated to electroporating viral vectors to the population of cells intended to be modified since Foster et al. teach this operation would enhance viral transduction (parag 0010). There would be a reasonable expectation of success of electroporating viral vectors to cells since Foster et al. teach the method (i.e., see parag 0043).
Regarding claim 8, following the discussion above, Beauchesne et al. teach method for transducing T cells including incubating a viral vector particle containing a recombinant nucleic acid and an input composition containing a plurality of T cells (parag 0005). In some embodiments, the provided methods involve incubating and/or contacting a retroviral vector particle, such as a lentiviral vector, with a population of cells, such as immune cells, e.g. T cells (parag 0058). Beauchesne et al. do not teach transducing by electroporation. However, Foster et al. teach a method of enhanced viral transduction using electroporation into a cell (parag 0010).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Beauchesne et al.’s method for transducing T cells, and transduce a retroviral vector, such as a lentiviral vector to the population of cells intended to be modified by electroporation as taught by Foster et al.. The skilled artisan would have been motivated to electroporating viral vectors to the population of cells intended to be modified since Foster et al. teach this operation would enhance viral transduction (parag 0010). There would be a reasonable expectation of success of electroporating viral vectors to cells since Foster et al. teach the method (i.e., see parag 0043).
Regarding claims 9 and 10, Beauchesne et al. teach in some embodiments, transduction can be achieved at a multiplicity of infection (MOI) of less than 100, such as generally less than 60, 50, 40, 30, 20, 10, 5 or less (i.e., at an MOI of 0.08, 0.2 or 0.4 as recited in instant claim 10). Herein the range of 5 or less anticipate the range of instant claims.
Regarding claim 11, Beauchesne et al. teach method for transducing T cells including incubating a viral vector particle containing a recombinant nucleic acid and an input composition containing a plurality of T cells, said plurality of T cells having been obtained from a sample containing cells derived from a subject, wherein the incubating is initiated no more than 24 hours after obtaining the sample from the subject (parag 0005). In some of any such embodiments, the T cells are unfractionated T cells, are enriched or isolated CD3+ T cells, are enriched or isolated CD4+ T cells or are enriched or isolated CD8+ T cells (parag 0015). This teaching reads on “CD4+ T lymphocytes and CD8+ T lymphocytes” in instant claim.
Regarding claim 12, following the discussion above, Beauchesne et al. teach in some embodiments, the concentration of cells of the input composition is from or from about 1.0 x 105 cells/mL to 1.0 x 108 cells/mL, such as at least or about at least or about 1.0 x 105 cells/mL, 5 x 105 cells/mL, 1 x 106 cells/mL, 5 x 106 cells/mL, 1 x 107 cells/mL, 5 x 107 cells/mL or 1 x 108 cells/mL (parag 0356).
Regarding claim 14, following the discussion above, Beauchesne et al. teach method for transducing T cells including incubating a viral vector particle containing a recombinant nucleic acid and an input composition containing a plurality of T cells, said plurality of T cells having been obtained from a sample containing cells derived from a subject, wherein the incubating is initiated no more than 24 hours after obtaining the sample from the subject (parag 0005). In some of any such embodiments, prior to said incubation, the method does not include stimulating the T cells under conditions that promote cell activation (parag 0006). This teaching reads on “(a) the population of modified immune cells, the population of modified CD4+ and CD8+ cells, or the population of lymphocytes is not activated with one or more stimulating agents before incubating / transduction (i.e., electroporation)” in instant claim. Furthermore, Beauchesne et al. teach in some embodiments of the methods provided herein, engineered cells, e.g. output composition or formulated composition, are administered to the subject immediately or shortly after transduction, without significant ex vivo expansion (parag 0380). This teaching reads on “(b) the population of modified immune cells, the population of modified CD4+ and CD8+ cells, or the population of modified lymphocytes is not expanded ex vivo following incubating / transduction (i.e., electroporation)” in instant claim.
Regarding claims 16 and 21, following the discussion above, Beauchesne et al. teach in some embodiments, the further culturing or incubation, e.g. to facilitate ex vivo expansion, is carried out of for greater than or greater than about 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days. In some embodiments, the further culturing or incubation is carried out for no more than 6 days, no more than 5 days, no more than 4 days, no more than 3 days, no more than 2 days or no more than 24 hours (parag 0376). This teaching reads on “expanding the cells for a predetermined time” in instant claim 16 and the “predetermined time” of (b) in instant claim.
Regarding claim 17, Beauchesne et al. teach in some embodiments of such a process, the cells are isolated, separated or selected, transduced, washed, optionally activated or stimulated and formulated, all within a closed system, reads on “the expanding step is performed: (b) in a closed system” in instant claim.
Regarding claim 18, Beauchesne et al. teach in some embodiments, the provided methods include administering to a subject a sub-optimal dose of cells. In some embodiments, the dose of cells is less than or less than about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold or 10-fold less than a therapeutically effective dose of cells for treating the disease or condition. In such an example, expansion of cells to yield a therapeutically effective amount of cells can occur in vivo upon administration of cells to a
subject (parag 0086). This teaching indicates that the expansion can be 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold or 10-fold to achieve the therapeutically effective amount, where in the 2-fold, 3-fold, 4-fold, 5-fold or 10-fold of expansion reads on instant claim.
Regarding claims 19 and 20, following the discussion above, Beauchesne et al. teach in some embodiments, subsequent to the further incubation, the process for preparing the cells can further include washing or formulating the cells (parag 0384). In some embodiments, the cells and compositions are administered to a subject in the form of a pharmaceutical composition or formulation (parag 0386). This teaching reads on harvesting and formulating (as recited in instant claim 20 (b)) the (engineered T-cells) for administration (as recited in instant claim 19).
Regarding claim 22, Beauchesne et al. teach method for transducing T cells including incubating a viral vector particle containing a recombinant nucleic acid and an input composition containing a plurality of T cells, said plurality of T cells having been obtained from a sample containing cells derived from a subject, wherein the incubating is initiated no more than 24 hours after obtaining the sample from the subject (parag 0005). Beauchesne et al. also teach in Table 1, transduced post-selection (no activation) and cultured for 3 days (parag 0560). This teaching reads on from obtaining to harvesting takes (c) about 4 days (in the case that obtaining and start transduction in 24 hours and culture the transduced cells for 3 days), as recited in instant claim.
Regarding claim 23, Beauchesne et al. teach in some embodiments of such a process, the cells are isolated, separated or selected, transduced, washed, optionally activated or stimulated and formulated, all within a closed system (parag 0083). Beauchesne et al. teach in some embodiments, the viral vectors and the packaging and/or helper plasmids are introduced via transfection or infection into the packaging cell line. The packaging cell line produces viral vector particles that contain the viral vector genome. Methods for transfection or infection are well known. Non-limiting examples include calcium phosphate, DEAE-dextran and lipofection methods, electroporation and microinjection (parag 0341). This teaching reads on “the electroporating step is performed in a closed system”, as recited in instant claim.
Regarding claim 24, following the discussion above, Beauchesne et al. teach in some embodiments, the further incubation is performed under conditions for stimulation and/or activation of cells, which conditions can include one or more of particular media, temperature, oxygen content, carbon dioxide content, time, agents, e.g., nutrients, amino acids, antibiotics, ions, and/or stimulatory factors, such as cytokines, chemokines, antigens, binding partners, fusion proteins, recombinant soluble receptors, and any other agents designed to activate the cells (parag 0367). In some embodiments, the stimulating conditions or agents include one or more agent (e.g. stimulatory and/or accessory agents), e.g., ligand, which is capable of activating an intracellular signaling domain of a TCR complex. In some aspects, the agent turns on or initiates TCR/CD3 intracellular signaling cascade in a T cell, such as agents suitable to deliver a primary signal, e.g., to initiate activation of an !TAM-induced signal, such as those specific for a TCR component, and/or an agent that promotes a costimulatory signal, such as one specific for a T cell costimulatory receptor, e.g., anti-CD3, anti-CD28, or anti-41-BB (parag 0368). The teaching or using anti-CD3 or anti-CD28 reads on the one or more stimulating agents in (a) in instant claim.
Regarding claim 25, following the discussion above, Beauchesne et al. teach in some embodiments, the provided methods are used to genetically engineer such cells with a heterologous molecule, such as with a recombinant receptor, for example an antigen receptor, such as a chimeric antigen receptor (CAR) or transgenic T cell receptor (TCR) (parag 0059).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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