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 .
DETAILED ACTION
Election/Restriction
Applicant’s election, with traverse, of Group I, claims 1-14, drawn to a method for separating, activating, transducing and expansion of T cells, in the reply filed on 07/13/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
The requirement is still deemed proper and is therefore made FINAL.
Claims 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant further elects the species in claim 8 (directed to silica particles) as the species of the material of the antibody labelled particles.
Claim 9 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Status
Claims 1-20 are pending.
Claims 9 and 15-20 are withdrawn.
Claims 1-8 and 10-14 are considered on the merits.
Priority
This application is effectively filed on 05/02/2024 and is granted the earliest benefit date of 05/02/2024.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/06/2024 and 12/11/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-4 and 14 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by June et al., (WO 2012/079000 A1) as evidenced by Dynabeads Info (ThermoFisher Scientific website archived on 02/25/2024, downloaded from https://web.archive.org/web/20240225012527/https://www.thermofisher.com/order/catalog/product/11161D, downloaded on 09/08/2026, p. 1-8).
With respect to claim 1, June teaches a method of producing CAR-T cells to treat cancer and teaches the method comprises selecting and activating CD3/28 positive T cells by anti-CD3/anti-CD28 mAb coated magnetic beads in a gas permeable bag, transducing the T cells with anti-CD19 CAR lentiviral vector and expanding the T cells in WAVE bioreactor (see e.g., Fig 1B attached below), thus teaches a method for separating, activating, transducing and expansion of T cells.
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Regarding step a (ii), as stated supra, June teaches a gas permeable bag comprising anti-CD3/anti-CD28 mAb coated magnetic beads (seeded together with T cells) and teaches the beads are exemplified as DYNABEADS® M-450 CD3/CD28 T (e.g., p. 41 and 48). Dynabeads Info evidences that the Dynabeads are monosized having a diameter of 4.5 μm with coefficient of variation (CV) <5% (see downloaded website information, p. 6, “Uniformity”). Thus, June as evidenced by Dynabeads Info teaches step a (ii) supplying a 3D bioreactor (i.e., a gas permeable bag) comprising a plurality of solid geometrical structures (i.e., magnetic beads such as DYNABEADS® M-450) having outer surfaces for coating (i.e., coated with anti-CD3/anti-CD28 mAb), wherein 90% or more of said solid geometrical structures have a volume that does not vary by more than +/- 10.0% (i.e., the beads are monosized having a diameter with coefficient of variation (CV) <5%).
Regarding step b, as stated supra, June teaches the gas permeable bag comprising anti-CD3/anti-CD28 mAb coated magnetic beads, thus teaches coating said 3D bioreactor (comprising the magnetic beads) with antibodies.
Regarding step c, June teaches the T cells are incubated with the anti-CD3/anti-CD28 mAb coated magnetic beads (see Fig 1B above) and teaches cell surface proteins may be ligated by allowing paramagnetic beads to which anti-CD3 and anti-CD28 are attached (3x28 beads) to contact the T cells (e.g., p. 48), thus teaches binding T-cells to said antibodies.
Regarding step d, June teaches “addition of anti-CD3/CD28 coated paramagnetic beads for positive selection and activation of T cells” (e.g., p. 6), thus teaches activating said T-cells (by the 3x28 beads).
Regarding step e, June teaches “Lentiviral vector was added at the time of cell activation” (e.g., p. 6 and see Fig 1B above), thus teaches transducing the antibody bound T-cells by a transduction reagent (i.e., a lentiviral vector).
Regarding step f, June teaches at Day 5, the transduced T cells are transferred from gas permeable bags to WAVE bioreactor for expansion (see Fig 1B above), thus teaches removing said transduced T-cells from said 3D bioreactor (i.e., the gas permeable bags) and transferring to a T-cell expansion bioreactor (i.e., WAVE bioreactor) wherein said transduced T-cells undergo expansion.
With respect to claim 3, as stated supra, June teaches the transduced T cells are removed from the gas permeable bags and transferred to WAVE bioreactor for expansion, followed by harvest the expanded T cells, thus teaches said transduced T-cells that are removed from said 3D bioreactor (i.e., the gas permeable bags) are prevented from transferring back into said 3D bioreactor.
With respect to claim 4 directed to the 3D bioreactor comprising biocompatible material, as stated supra, June teaches the T cells are cultured in the gas permeable bags and can further be expanded (see e.g., Fig 1B above), thus teaches the 3D bioreactor (i.e., the gas permeable bags) comprises biocompatible material.
With respect to claim 14 directed to the T cells being transduced with lentivirus vectors, as stated supra, June teaches “Lentiviral vector was added at the time of cell activation” (e.g., p. 6 and see Fig 1B above), thus teaches the T cells are transduced with lentivirus vectors.
Accordingly, June as evidenced by Dynabeads Info anticipates instant claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Ling et al., (US 2021/0355420 A1. Cited in IDS 12/11/2025) in view of Bajgain et al., (Mol Ther Methods Clin Dev. 2014:1:14015, p. 1-9).
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With respect to claim 1, Ling teaches a method for processing and manufacturing CAR T cells for cancer treatment using a 3D bioprocessor including a plurality of spheres and a plurality of rods interconnecting the spheres (e.g., abstract and [0010]). Ling teaches “In addition to cell isolation, the bioprocessor has potential for T cell activation and transduction when the spherical beads surfaces are coated with antibodies like anti-CD3, CD28 to stimulate the T cells” (Example 1, “Sphere and Rod Design for the Cell Expansion”, [0046]), thus teaches a method for separating, activating, transducing and expansion of T-cells.
Regarding step a (ii), as stated supra, Ling teaches a 3D bioprocessor including a plurality of spheres and a plurality of rods interconnecting the plurality of spheres (e.g., [0010] and Fig 6a attached). From Fig 6a attached, it is clear that the spheres and the rods are uniform in size. Ling teaches the fixed structure has “substantial uniformity” and “the designs form a repeatable and non-random mesh structure” (e.g., [0022]). Thus, Ling teaches step a (ii) supplying a 3D bioreactor comprising a plurality of solid geometrical structures (i.e., a plurality of spheres and rods) having outer surfaces for coating (e.g., the spherical beads surfaces are coated with antibodies like anti-CD3, CD28), wherein 90% or more of said solid geometrical structures have a volume that does not vary by more than +/- 10.0% (i.e., have substantial uniformity and non-random mesh structure).
Regarding step b, as stated supra, Ling teaches the spherical beads surfaces are coated with antibodies like anti-CD3, CD28 ([0046]), thus teaches coating said 3D bioreactor with antibodies.
Regarding step c, Ling teaches “Whereas certain cells will flow through and not be captured by the bioprocessor, antibodies specific for one of the population of cells will capture the population, which is isolated, or separated from other population” ([0023]) and teaches isolation of T cells by using antibodies specific for these cell types ([0028]), thus teaches binding T-cells to said anti-CD3 and CD28 antibodies.
Regarding step d, Ling teaches activation occurs by T-cell receptors binding to the one or more biotinylated antibodies including anti-CD3 antibody and anti-CD28 antibody ([0027]) and the bioprocessor has potential for T cell activation and transduction when the spherical beads surfaces are coated with antibodies like anti-CD3, CD28 to stimulate the T cells ([0046]), thus teaches activating said T-cells.
Regarding step e, as stated supra, Ling teaches the bioprocessor has potential for T cell activation and transduction ([0046]) and teaches the current manufacturing comprise activating T cells with the CD3/CD28 antibodies and then the T cells are transduced with lentiviral vectors (e.g., [0008] and see Fig 1 for gene delivery after activation/expansion). Thus, Ling teaches transducing the antibody bound T-cells by a transduction reagent (e.g., lentiviral vectors).
Regarding step f directed to expansion, Ling teaches the 3D bioprocess can be used for manufacturing clinical scale T cells (see Example 4). Ling teaches the 3D bioprocess has a total surface area of about 25.49 cm2 ([0050]) and theoretically, a 3D bioprocess with a surface area of 250 cm2 is needed for clinical application ([0051], i.e., at least 10 of these 3D bioprocesses).
However, Ling does not teach removing the transduced T-cells from the 3D bioreactor and transferring to a T-cell expansion bioreactor wherein said transduced T-cells undergo expansion in claim 1 step f.
Nevertheless, Ling acknowledges that the current manufacturing approaches comprise after activation (i.e., step d) and transduction (i.e., step e), the T-cells are moved into a large bioprocessor bag for further expansion (related to step f), but the approaches have disadvantages such as relying on manual interactions and open system ([0006] and [0008]).
Bajgain teaches a method for expanding clinically relevant cell numbers ex vivo using containers having gas-permeable membrane as a closed system in an automated manner, allowing an easy translation of preclinical protocols into the good manufacturing practice (e.g., abstract and see Fig 7 for automated collection of cells in a closed G-Rex system).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising expanding transduced T cells in multiple 3D bioprocesses to obtain clinical scale T cells suggested by Ling, by substituting with removing the transduced T-cells from the 3D bioreactor and transferring to a T-cell expansion bioreactor (such as a closed G-Rex system) for expansion as summarized by Ling and suggested by Bajgain with a reasonable expectation of success. Since Ling suggests multiple bioprocesses are needed to obtain clinically relevant cell numbers ([0050-0051]) and acknowledges the approaches for transferring T cells to a large bioprocessor bag for further expansion with disadvantages of manual interactions and open system ([0006] and [0008]), and since Bajgain teaches a method for expanding clinically relevant cell numbers ex vivo using a closed G-Rex system in an automated manner (e.g., abstract and see Fig 7), one of ordinary skill in the art would have had a reason to substitute with removing the transduced T-cells from the 3D bioreactor of Ling and transferring to a closed G-Rex system for expansion and automated collection as suggested by Bajgain in order to obtain clinically relevant numbers and GMP quality of T cells without the disadvantages of multiple bioprocesses, manual interactions and open system.
With respect to claim 2, Ling teaches the structure is enclosed by a wall that facilitates liquid perfuse through the mesh structure ([0045]) and if the surface of the bioprocess is immobilized with anti-CD3 antibodies, then the T cells perfusion through the 3D bioprocess can bind the anti-CD3 antibodies ([0050]), and teaches using patients' PBMC sample as the input ([0050-0051]), thus teaches the binding of T-cells to the antibodies comprises perfusing said 3D bioreactor with PBMCs.
With respect to claim 3, as stated supra, Ling in view of Bajgain make obvious removing the transduced T-cells from the 3D bioreactor and transferring to a T-cell expansion bioreactor, such as a closed G-Rex system for further expansion and collection. Accordingly, one of ordinary skill in the art would have expected that the transduced T-cells that are removed from the 3D bioreactor are prevented from transferring back into the 3D bioreactor.
With respect to claim 4, Ling teaches the 3D bioprocessor is made of a material that is biocompatible such as polycaprolactone (e.g., [0042]).
With respect to claim 14, as stated supra, Ling teaches the bioprocessor has potential for T cell activation and transduction ([0046]) and the current manufacturing approaches comprise transducing T cells with lentiviral vectors (e.g., [0008]), thus suggests the T-cells are transduced with lentivirus vectors.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Ling et al., (US 2021/0355420 A1. Cited in IDS 12/11/2025) in view of Bajgain et al., (Mol Ther Methods Clin Dev. 2014:1:14015, p. 1-9), as applied to claim 1 above, and further in view of Hu et al., (Biomaterials. 2009; 30: 5785-5792).
Claim 5 is directed to the geometrical structure outer surfaces being initially coated with poly(p-xylylene) prior to coating with the antibodies.
As stated supra, Ling teaches the 3D bioprocessor is made of a biocompatible material such as polycaprolactone (PCL) (e.g., [0042]). Ling teaches the method provides a coating on the bioprocessor surface area, then provides a protein, e.g., avidin or streptavidin, to attach to the coating, followed by providing one or more biotinylated antibodies immobilized on the protein (e.g., [0010]). Thus, Ling teaches the geometrical structure outer PCL surfaces are initially coated with a coating and avidin, prior to coating with the biotinylated antibodies.
However, Ling is silent on the initial coating being poly(p-xylylene).
Hu teaches a method of using reactive polymer coatings on poly (ε-caprolactone) (PCL) scaffolds (e.g., abstract). Hu teaches PCL is a frequently used biocompatible scaffold material, but lacks active functional groups for covalent linkage (p. 5786, left col, para 3). Hu applies chemical vapor deposition of poly[(4-amino-p-xylylene)-co-(p-xylylene)] (PPX–NH2) to PCL surfaces to present a layer of amine groups (i.e., initially coating the PCL surface with substituted poly(p-xylylene), related to claim 5), and these aminated PCL surfaces are conjugated to biotin and then immobilized with avidin to tether biotinylated adenovirus (e.g., p. 5786, right col, para 2.5, similar to the teaching of Ling). Hu teaches this surface modification should be able to custom-tailor bioconjugation for different applications (abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising initially coating the PCL bioreactor surfaces with a coating and avidin prior to coating with biotinylated antibodies suggested by Ling in view of Bajgain, by choosing poly(p-xylylene) as the initial coating as suggested by Hu with a reasonable expectation of success. Since Ling teaches using polycaprolactone (PCL) to make the bioreactor (e.g., [0042]) and teaches the bioreactor surface is initially coated with a coating then attached with avidin followed by providing biotinylated antibodies (e.g., [0010]), and since Hu teaches PCL lacks functional groups for covalent linkage and reduces to practice initially coating with substituted poly(p-xylylene) on the PCL surface, then conjugated to biotin and then avidin followed by providing a biotinylated reagent (a virus in Hu’s case), one of ordinary skill in the art would have had a reason to choose substituted poly(p-xylylene) as suggested by Hu to initially coat the PCL bioreactor surface prior to coating with biotinylated antibodies of Ling in view of Bajgain in order to modify the biocompatible PCL with amine groups for covalent linkage of custom-tailor bioconjugations for coating the bioreactor with antibodies.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claim 6-8 and 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Ling et al., (US 2021/0355420 A1. Cited in IDS 12/11/2025) in view of Bajgain et al., (Mol Ther Methods Clin Dev. 2014:1:14015, p. 1-9), as applied to claim 1 above, and further in view of Bangs Lab (Streptavidin Coated Microspheres Product Data Sheet 721. published on 07/05/2023. Downloaded from https://bangslabs.com/wp-content/uploads/PDS721_BLISACoated-1.pdf, downloaded on 09/08/2026, p. 1-3) and Cohn et al., (Colloids Surf B Biointerfaces. 2015; 134: 1-7).
Claim 6-8 and 10-13 are directed to coating the bioreactor with antibody labelled particles with the claimed structures.
However, Ling and Bajgain are silent on coating the bioreactor with antibody labelled particles as recited in claims 6-8 and 10-13.
Nevertheless, as stated supra, Ling teaches that the bioreactor is coated with biotinylated antibody selected from the group consisting of anti-CD3 antibody and anti-CD28 antibody (e.g., reference claim 6, related to instant claim 13). Ling acknowledges that the 3D bioprocessor comprising a plurality of spheres and rods provides a high surface-to-volume ratio to increase reactivity between cells and the bioprocessor surfaces (e.g., [0009] and [0022]).
Regarding antibody labelled particles, Bangs Lab teaches commercially available streptavidin coated microspheres that may be coated with biotinylated antibodies (i.e., antibody labelled particles. See e.g., p. 1, last section “Attachment of Biotinylated IgG” and the figure in page 1 for attaching biotinylated antibodies with the streptavidin coated microspheres), related to claim 6 and claims 10-12. Bangs Lab teaches the streptavidin coated microspheres can be silica-streptavidin having a diameter of 0.5 µm and 1.0 µm (see p. 3, right col. “Silica – Streptavidin”), related to claims 7 and 8.
Regarding coating the bioreactor with antibody labelled particles, as stated supra, Ling teaches the 3D bioreactor is made of a biocompatible material such as polycaprolactone (PCL) (e.g., [0042]). Cohn teaches antibodies can be immobilized on hydrophobic polycaprolactone (PCL) fibers via hydrophobic interactions (e.g., abstract and p. 4, right col., para 3.3. “Anti-CD20 immobilization”, also see Fig 6 for schematic diagram of antibody immobilization on PCL surfaces).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising coating the bioreactor surfaces with antibodies such as anti-CD3 and CD28 antibodies suggested by Ling in view of Bajgain, by substituting with coating the bioreactor surfaces with antibody labelled particles as suggested by Bangs Lab and Cohn with a reasonable expectation of success. Since Ling teaches that the bioreactor comprises a plurality of spheres to provide a high surface-to-volume ratio to increase reactivity between cells and the bioreactor surfaces (e.g., [0022]), since Bangs Lab reduces to practice silica-based antibody coated particles (p. 1 and 3), and since Cohn teaches antibodies may be immobilized on hydrophobic PCL (the material used by Ling) via hydrophobic interactions (e.g., abstract), one of ordinary skill in the art would have had a reason to substitute with coating the bioreactor surfaces with antibody labelled particles in order to increase surface-to-volume ratio of the bioreactor to increase reactivity between cells and the bioreactor surfaces to more efficiently select and activate T cells. Furthermore, since Cohn teaches antibodies may be immobilized on PCL surfaces via hydrophobic interactions, and since the antibody labelled particles of Bangs Lab are coated with antibodies on the outer surfaces and Ling’s bioreactor is made of PCL, one of ordinary skill in the art would have had a reasonable expectation of success in immobilizing the antibody labelled particles of Bangs Lab on the bioreactor surfaces of Ling, i.e., coating the 3D bioreactor with antibody labelled particles.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-8 and 10-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of US Patent Nos: 11,447,731 (‘731), 11,912,971 (‘971), 11,149,244 (‘244), or 11,492,580 (‘580) in view of Ling et al., (US 2021/0355420 A1. Cited in IDS 12/11/2025), Bajgain et al., (Mol Ther Methods Clin Dev. 2014:1:14015, p. 1-9), Bangs Lab (Streptavidin Coated Microspheres Product Data Sheet 721. published on 07/05/2023. Downloaded from https://bangslabs.com/wp-content/uploads/PDS721_BLISACoated-1.pdf, downloaded on 09/08/2026, p. 1-3), Cohn et al., (Colloids Surf B Biointerfaces. 2015; 134: 1-7) and Hu et al., (Biomaterials. 2009; 30: 5785-5792). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patent claims of ‘731 and ‘971 recite a 3D bioreactor for growth of cells (thus being biocompatible) comprising a plurality of voids having a surface area for cell expansion, said plurality of voids having a diameter D, a plurality of pore openings between said voids having a diameter d, such that D>d and wherein: (a) 90% or more of said voids have a selected void volume (V) that does not vary by more than +/−10.0%; and (b) 90% or more of said pore openings between said voids have a value of d that does not vary by more than +/−10.0%; wherein said bioreactor has a coating of a substituted or unsubstituted poly(p-xylylene) and polydopamine is applied to said poly(p-xylylene) coating wherein said polydopamine is capable of binding an additional layer or layers for cell culturing, further including a tetrameric protein attached to said polydopamine coating, further including a biotinylated antibody immobilized on said tetrameric protein, wherein said biotinylated antibody comprises anti-CD-3 antibody and anti-CD28 antibody (one of ordinary skill in the art would have immediately expected that the bioreactor coated with anti-CD3/CD28 antibodies would be obviously used in separating, activating and expanding T cells), related to instant claims 1, 4, 5 and 13.
Patent claims of ‘244 recite a method for T cell activation and expansion (thus being biocompatible) comprising: supplying a 3D bioreactor of biocompatible polymeric material comprising a plurality of voids having a surface area for cell expansion, said plurality of voids having a diameter D, a plurality of pore openings between said voids having a diameter d, such that D>d and wherein: (a) 90% or more of said voids have a selected void volume (V) that does not vary by more than +/−10.0%; and (b) 90% or more of said pore openings between said voids have a value of d that does not vary by more than +/−10.0%; providing a polydopamine coating on said bioreactor surface area for cell expansion; providing a tetrameric protein attached to said polydopamine coating; providing one or more biotinylated antibodies immobilized on said tetrameric protein; flowing T-cells through said bioreactor having T-cell receptors where said T-cell receptors bind to said one or more biotinylated antibodies and are activated; exposing the activated T-cells to a perfusion media containing a signaling molecule to promote T-cell expansion, wherein said biotinylated antibody comprises anti-CD3 antibody and anti-CD28 antibody, related to instant claims 1, 4, 5 and 13.
Patent claims of ‘580 recite a method for activating and expanding T cells comprising supplying a 3D bioprocessor comprising a plurality of spheres and a plurality of rods interconnecting the plurality of spheres, the plurality of rods assisting in providing spacing between the plurality of spheres that are adjacent to each other; providing a coating on a surface area of the 3D bioprocessor, the surface area including the plurality of spheres and the plurality of rods; providing a protein attached to the coating; providing one or more biotinylated antibodies immobilized on the protein; flowing cells through the 3D bioprocessor, wherein the cells bind to the one or more biotinylated antibodies, wherein the cells comprise T-cells, wherein receptors of the T-cells bind to the one or more biotinylated antibodies and are activated and further comprising exposing the activated T-cells to a perfusion media containing a signaling molecule to promote T-cell expansion, wherein the one or more biotinylated antibody is selected from the group consisting of: anti-CD3 antibody, anti-CD28 antibody, wherein the 3D bioprocessor is formed from a material that is biocompatible, wherein the plurality of spheres and the plurality of rods form a repeatable and non-random mesh structure, wherein the plurality of spheres and the plurality of rods form a fixed structure of substantial uniformity (one of ordinary skill in the art would have immediately expected that the bioreactor comprising spheres and rods in a substantial uniformity and form non-random mesh would likely have size variation below +/- 10% as instantly claimed), related to instant claims 1, 4 and 13.
However, the patent claims are silent on transducing T cells with lentivirus vectors or transferring transduced T cells to a bioreactor for expansion, nor teach coating the bioreactor with antibody labelled particles. Further, claims of ‘580 are silent on the bioreactor being initially coated with poly(p-xylylene) in instant claim 5.
Ling teaches a method for separating, activating, transducing and expansion of CAR T cells for cancer treatment using a 3D bioprocessor including a plurality of spheres and a plurality of rods interconnecting the spheres (e.g., abstract and [0010], also see Example 1, “Sphere and Rod Design for the Cell Expansion”, [0046]). Ling teaches the bioprocessor has potential for T cell activation and transduction ([0046]) and the current manufacturing approaches comprise transducing T cells with lentiviral vectors (e.g., [0008]), thus suggests the T-cells are transduced with lentivirus vectors, related to instant claims 1 and 14. Ling teaches the structure is enclosed by a wall that facilitates liquid perfuse through the mesh structure ([0045]) and if the surface of the bioprocess is immobilized with anti-CD3 antibodies, then the T cells perfusion through the 3D bioprocess can bind the anti-CD3 antibodies ([0050]), and teaches using patients' PBMC sample as the input ([0050-0051]), thus teaches the binding of T-cells to the antibodies comprises perfusing said 3D bioreactor with PBMCs, related to instant claim 2. Ling acknowledges that the current manufacturing approaches comprise after activation and transduction, the T-cells are moved into a large bioprocessor bag for further expansion, but the approaches have disadvantages such as relying on manual interactions and open system ([0006] and [0008]), related to instant claims 1 and 3.
Bajgain teaches a method for expanding clinically relevant cell numbers ex vivo using containers having gas-permeable membrane as a closed system in an automated manner, allowing an easy translation of preclinical protocols into the good manufacturing practice (e.g., abstract and see Fig 7 for automated collection of cells in a closed G-Rex system).
Bangs Lab teaches commercially available streptavidin coated microspheres that may be coated with biotinylated antibodies (i.e., antibody labelled particles. See e.g., p. 1, last section “Attachment of Biotinylated IgG” and the figure in page 1 for attaching biotinylated antibodies with the streptavidin coated microspheres), related to claim 6 and claims 10-12. Bangs Lab teaches the streptavidin coated microspheres can be silica-streptavidin having a diameter of 0.5 µm and 1.0 µm (see p. 3, right col. “Silica – Streptavidin”), related to claims 7 and 8.
Regarding coating the bioreactor with antibody labelled particles, as stated supra, Ling teaches the 3D bioreactor is made of a biocompatible material such as polycaprolactone (PCL) (e.g., [0042]). Cohn teaches antibodies can be immobilized on hydrophobic polycaprolactone (PCL) fibers via hydrophobic interactions (e.g., abstract and p. 4, right col., para 3.3. “Anti-CD20 immobilization”, also see Fig 6 for schematic diagram of antibody immobilization on PCL surfaces).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the patent method or have used the patent apparatus, by combining transducing the T cells with a lentivirus vector encoding a CAR and combining transferring transduced T cells to a bioreactor for expansion as suggested by Ling and Bajgain, and substituting with coating the bioreactor surfaces with antibody labelled particles as suggested by Bangs Lab and Cohn with a reasonable expectation of success. Since Ling teaches transduction of T cells with lentiviral vector encoding a CAR for cancer therapy and acknowledges the approaches for transferring T cells to a large bioprocessor bag for further expansion with disadvantages of manual interactions and open system ([0006] and [0008]), and since Bajgain teaches a method for expanding clinically relevant cell numbers ex vivo using a closed G-Rex system in an automated manner (e.g., abstract and see Fig 7), one of ordinary skill in the art would have had a reason to combine a transduction step and transferring to a closed G-Rex system for expansion and automated collection as suggested by Ling and Bajgain in order to obtain clinically relevant numbers and GMP quality of CAR-T cells without the disadvantages of multiple bioprocesses, manual interactions and open system. Furthermore, since Ling teaches that the bioreactor comprises a plurality of spheres to provide a high surface-to-volume ratio to increase reactivity between cells and the bioreactor surfaces (e.g., [0022]), since Bangs Lab reduces to practice silica-based antibody coated particles (p. 1 and 3), and since Cohn teaches antibodies may be immobilized on hydrophobic PCL (such as the material used by Ling) via hydrophobic interactions (e.g., abstract), one of ordinary skill in the art would have had a reason to substitute with coating the bioreactor surfaces with antibody labelled particles in order to increase surface-to-volume ratio of the bioreactor to increase reactivity between cells and the bioreactor surfaces to more efficiently select and activate T cells.
Furthermore, regarding the bioreactor being initially coated with poly(p-xylylene), Hu teaches a method of using reactive polymer coatings on poly (ε-caprolactone) (PCL) scaffolds (e.g., abstract). Hu teaches PCL is a frequently used biocompatible scaffold material, but lacks active functional groups for covalent linkage (p. 5786, left col, para 3). Hu applies chemical vapor deposition of poly[(4-amino-p-xylylene)-co-(p-xylylene)] (PPX–NH2) to PCL surfaces to present a layer of amine groups (i.e., initially coating the PCL surface with substituted poly(p-xylylene), related to instant claim 5), and these aminated PCL surfaces are conjugated to biotin and then immobilized with avidin to tether biotinylated adenovirus (e.g., p. 5786, right col, para 2.5, similar to the biotinylated antibodies in patent claims). Hu teaches this surface modification should be able to custom-tailor bioconjugation for different applications (abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the patent method of ‘580, by choosing poly(p-xylylene) as the initial coating as suggested by Hu with a reasonable expectation of success. Since the patent claims recite providing a coating on a surface area of the 3D bioprocessor for binding of avidin and biotinylated antibodies and the bioprocessor is made of polycaprolactone (PCL), and since Hu teaches PCL lacks functional groups for covalent linkage and reduces to practice initially coating with substituted poly(p-xylylene) on the PCL surface, then conjugated to biotin and then avidin followed by providing a biotinylated reagent (a virus in Hu’s case), one of ordinary skill in the art would have had a reason to choose substituted poly(p-xylylene) as suggested by Hu to initially coat the PCL bioreactor surface prior to coating with avidin and biotinylated antibodies in order to modify the biocompatible PCL with amine groups for covalent linkage of custom-tailor bioconjugations for coating the bioreactor with antibodies.
Since the instant application claims are obvious over cited patent claims, in view of Ling, Bajgain, Bangs Lab, Cohn and Hu, said claims are not patentably distinct.
Provisional Double Patenting Rejections
Claims 1-8 and 10-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims of Application No: 18/640,078 (‘078) in view of Ling et al., (US 2021/0355420 A1. Cited in IDS 12/11/2025) and Bajgain et al., (Mol Ther Methods Clin Dev. 2014:1:14015, p. 1-9). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims recite a 3D bioreactor comprising: a. a plurality of voids having a diameter D and a plurality of pore openings between said voids having a diameter d, including a void surface area for coating, wherein 90% or more of said voids have a selected void volume (V) that does not vary by more than +/−10.0% and 90% or more of said pore openings between said voids have a value of d that does not vary by more than +/−10.0%; or b. a plurality of solid geometrical structures having outer surfaces for coating, wherein 90% or more of said solid geometrical structures have a volume (V) that does not vary by more than +/−10.0%; and c. a coating of antibody labelled particles on said 3D bioreactor void surface area or on said outer surfaces of said geometrical outer surfaces, wherein said 3D bioreactor comprises biocompatible material, wherein said void surface area or said geometrical structure outer surfaces are initially coated with substituted or unsubstituted poly(p-xylylene), β-casein or polydopamine, wherein said antibody labelled particles comprise silica particles, wherein said antibody labelled particles have a particle diameter of 10 nm to 10.0 μm, wherein said antibody labelled particles comprise particles coated with a biotin binding molecule wherein said biotin binding molecule is coated with biotinylated antibodies, wherein said biotin molecule comprises a tetrameric protein, wherein said tetrameric protein comprises avidin, streptavidin or de-glycosylated native avidin protein, wherein said biotinylated antibodies are selected from the group consisting of anti-CD3 antibody, anti-CD22 antibody, anti-CD25 antibody and anti-CD28 antibody, a method for coating the bioreactor, further including flowing T-cells through said 3D bioreactor, wherein said T-cells bind to said biotinylated antibodies which T-cells are activated and transduced to CAR T-cells, wherein said T-cells are transduced with lentivirus vectors, related to instant claims 1, 4-8 and 10-14.
However, copending claims are silent on transferring transduced T cells to a bioreactor for expansion in instant claims 1 and 3, nor recite perfusing with PBMCs in instant claim 2.
Ling teaches a method for separating, activating, transducing and expansion of CAR T cells for cancer treatment using a 3D bioprocessor including a plurality of spheres and a plurality of rods interconnecting the spheres (e.g., abstract and [0010], also see Example 1, “Sphere and Rod Design for the Cell Expansion”, [0046]). Ling teaches the structure is enclosed by a wall that facilitates liquid perfuse through the mesh structure ([0045]) and if the surface of the bioprocess is immobilized with anti-CD3 antibodies, then the T cells perfusion through the 3D bioprocess can bind the anti-CD3 antibodies ([0050]), and teaches using patients' PBMC sample as the input ([0050-0051]), thus teaches the binding of T-cells to the antibodies comprises perfusing said 3D bioreactor with PBMCs, related to instant claim 2. Ling acknowledges that the current manufacturing approaches comprise after activation and transduction, the T-cells are moved into a large bioprocessor bag for further expansion, but the approaches have disadvantages such as relying on manual interactions and open system ([0006] and [0008]), related to instant claims 1 and 3.
Bajgain teaches a method for expanding clinically relevant cell numbers ex vivo using containers having gas-permeable membrane as a closed system in an automated manner, allowing an easy translation of preclinical protocols into the good manufacturing practice (e.g., abstract and see Fig 7 for automated collection of cells in a closed G-Rex system).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the copending method and have used the apparatus, by combining perfusing PBMCs for T cell binding and combining transferring transduced T cells to a bioreactor for expansion as suggested by Ling and Bajgain with a reasonable expectation of success. Since Ling reduces to practice perfusing PBMCs for T cell separation and activation, and acknowledges the approaches for transferring T cells to a large bioprocessor bag for further expansion but with disadvantages of manual interactions and open system ([0006] and [0008]), and since Bajgain teaches a method for expanding clinically relevant cell numbers ex vivo using a closed G-Rex system in an automated manner (e.g., abstract and see Fig 7), one of ordinary skill in the art would have had a reason to combine the perfusion of PBMCs and transferring the transduced CAR-T cells to a closed G-Rex system for expansion and automated collection as suggested by Ling and Bajgain in order to obtain clinically relevant numbers and GMP quality of CAR-T cells from PBMCs without the disadvantages of manual interactions and open system.
Since the instant application claims are obvious over cited application claims, in view of Ling and Bajgain, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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