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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/04/2026 has been entered.
Claim Status
In the submission, claims 1, 4 and 5 have been amended. Accordingly, claims 1-6, 8-12, 14 and 16-25 are pending and under current examination.
Priority
The instant application is a U.S. Non-provisional Application filed 10/06/2023. Acknowledgement is made of the applicant's claim for benefit to prior-filed U.S. Provisional Application 63/414,829, which was filed 10/10/2022.
Status of Prior Rejection/Response to Arguments
The rejection to claims 16-18 and 21 under 35 U.S.C. 112(b) is withdrawn:
Applicant’s amendment to claim 16 in the submission filed 08/03/2026 (after the final rejection) is effective to obviate the rejection on record. The rejection is withdrawn.
The rejection to claims 1-6, 8-12, 22, 24 and 25 under 35 U.S.C. 103 rejection over Morgan et al. in view of Foster et al. is maintained:
The rejection to claims 1-5, 8-12, 14 and 16-25 under 35 U.S.C. 103 rejection over Morgan et al. in view of Foster et al. is maintained:
Applicant has traversed the rejection, asserting that there is not a prima facie case of obviousness because: (1) the Examiner's stated rationale improperly conflates a step's purpose with its principle of operation; (2) no cited reference, alone or in combination, provides or suggests contacting the cells with the modifying agent before, or from about 1 minute to about 4 hours after electroporation, rather than simultaneously, as recited in amended claims 1, 4, and 5; and (3) Foster's disclosed cell viability loss independently forecloses a reasonable expectation of success in combining Foster with Morgan or Beauchesne (Remarks, p10).
Regarding (1), Applicant has asserted that principle of operation, not purpose, is the relevant inquiry in modifying Morgan and Beauchesne with Foster. Specifically, Morgan's and Beauchesne's viral transduction consists of a single operation, while Foster's process requires an added operation within that same step. Grafting Foster's electroporation operation onto Morgan's or Beauchesne's disclosed transduction step would require new apparatus and an additional operation that Morgan's or Beauchesne's disclosed step does not otherwise contain (see Remarks, p10-11). In addition, Foster's teaching indicates that electroporation enhances transduction, rather than supplanting it, from the outset. Modifying Morgan's and Beauchesne's disclosed target-cell step to incorporate Foster's technique therefore introduces an entirely new kind of intervention into a process (Remarks, p11-12).
Moreover, the redesign would stop since Foster discloses that its exemplified co-electroporated cells "have a drop in viability ranging from 25-50% compared to the cells-to-be-modified" (Remarks, p11).
Applicant’s arguments have been fully considered but they are not persuasive. Specifically, Applicant is reminded that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references product would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). See MPEP 2145. Adding an additional step which requires new apparatus is obvious to an ordinary skill in the art as long as the combined teachings of the references would have suggested it. In instant case, Morgan et al. and Beauchesne et al. teach viral transducing the population of cells, and Foster et al. teach electroporation would enhance viral transduction, an ordinary skill in the art would have been taught or suggested by the references to use electroporation during the viral transduction. Moreover, Applicant argues that Foster et al. disclose that its exemplified co-electroporated cells "have a drop in viability ranging from 25-50% compared to the cells-to-be-modified". However, the comparison is made with cells-to-be-modified BUT NOT cells with viral transduction. It is known in the art that virus transduction would also cause high cellular stress and cytotoxicity which reduces cell viability. It is Applicant’s burden to showcase the cell viability reduction is caused merely by electroporation.
Regarding (2) no cited reference, alone or in combination, provides or suggests contacting the cells with the modifying agent before, or from about 1 minute to about 4 hours after, electroporation, rather than simultaneously, as recited in amended claims 1, 4, and 5, the Examiner respectfully submits that Foster et al. teach this limitation. Specifically, 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). Herein the step of “combining the cells-to-be-modified with a virus, viral vector or virus like particle to form a mixture” reads on the limitation “the modifying agent is contacted with the population of cells before the electroporating”.
Regarding (3) Foster's disclosed cell viability loss independently forecloses a reasonable expectation of success in combining Foster with Morgan or Beauchesne, the Examiner respectfully submits that as stated above, the comparison is made with cells-to-be-modified BUT NOT cells with viral transduction. It is known in the art that virus transduction would also cause high cellular stress and cytotoxicity which reduces cell viability. It is Applicant’s burden to showcase the cell viability reduction is caused merely by electroporation. Furthermore, the Examiner also submits that it is not required that the expectation of success be a certainty; only one that is reasonable to a person of ordinary skill. In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985) (“Only a reasonable expectation of success, not absolute predictability, is necessary for a conclusion of obviousness”). In instant case, Morgan et al. or Beauchesne et al. teach viral transducing a population of cells, Foster et al. teach using electroporation during viral transduction would enhance viral transduction, the skilled artisan would have been motivated to modify Morgan et al. or Beauchesne et al.’s method of viral transduction, and using electroporation during viral transduction with a reasonable expectation of success that electroporation would have enhanced the efficiency of viral transduction. The rejection is maintained in a modified form to address amended limitations.
Claim Interpretation
Claims 1 and 4 recite step (a) “enriching”, herein is interpreted the same as “obtaining” 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.
Modified 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 stand 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 modified as 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, wherein the modifying agent is contacted with the population of cells before the electroporating, or form about 1 minute to about 4 hours after the electroporating. 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). Herein the step of “combining the cells-to-be-modified with a virus, viral vector or virus like particle to form a mixture” reads on “the modifying agent is contacted with the population of cells before the electroporating” as recited in instant claim.
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, wherein the modifying agent is contacted with the population of cells before the electroporating, or form about 1 minute to about 4 hours after the 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), wherein the step of “combining the cells-to-be-modified with a virus, viral vector or virus like particle to form a mixture” reads on “the modifying agent is contacted with the population of cells before the electroporating” as recited in instant claim.
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, wherein the modifying agent is contacted with the population of cells before the electroporating, or form about 1 minute to about 4 hours after the 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), wherein the step of “combining the cells-to-be-modified with a virus, viral vector or virus like particle to form a mixture” reads on “the modifying agent is contacted with the population of cells before the electroporating” as recited in instant claim.
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 stand 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 modified as 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.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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