# US 11,441,110 B2 · Plug flow tubular bioreactor, system containing the same and method for production of virus > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,441,110 B2 - Document ID: US11441110B2 - Status: Granted - Kind: B2 - Application number: 16/092,610 - Filed: 2016-05-06 - Published: 2019-04-25 - Granted: 2022-09-13 - Earliest claimed: 2016-05-06 - Assignees: Max-Planck-Gesellschaft zur Forderung der Wissenschaften e.V. - Applicants: Max-Planck-Gesellschaft Zur FöRderung Der Wissenschaften E.V. - Inventors: Felipe Tapia; Yvonne Genzel; Udo Reichl - Web page: https://patentgrep.com/patent/US11441110B2 ## CPC - C12M 23/06: {Tubular (C12M23/08, C12M23/16 take precedence)} - C12M 23/28: {disposable or single use} - C12M 23/44: {Multiple separable units; Modules} - C12M 29/00: {Means for introduction, extraction or recirculation of materials, e.g. pumps (pumps per se F04B)} - C12M 41/00: {Means for regulation, monitoring, measurement or control, e.g. flow regulation (controlling or regulating chemical, physical or physicochemical processes B01J19/0006; heating or cooling apparatus for laboratory use B01L7/00; electro optical investigation of individual particles, flow cytometers G01N15/14; automatic analysis G01N35/00; controlling or regulating in general G06N)} - C12M 41/12: {of temperature (controlling the temperature of chemical or physical processes B01J19/0013, heating or cooling apparatus for laboratory use B01L7/00)} - C12M 41/26: {of pH} - C12M 41/34: {of gas} - C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) - C12M: APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; {APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS} - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) ## Abstract The present invention relates in a first aspect to a plug flow tubular bioreactor having an integral or multi-part tube adapted for cultivation, and, optionally, infection, viral transduction, or transfection of eukaryotic cells. In a further aspect, the present invention relates to a plug flow tubular bioreactor system comprising the plug flow tubular bioreactor according to the present invention. Further, the present invention relates to a method for preparing virus particles, vectors, cells or other molecules including toxic molecules using the plug flow tubular bioreactor or the system according to the present invention. Finally, the present invention relates to the use of a plug flow tubular bioreactor for the preparation of virus particles, vectors including viral vectors, cells including modified cells or other molecules including toxic molecules. ## Claims ### Claim 1 A method for preparing one or more of virus particles, vectors other than viral vectors, viral vectors, whole virus, unmodified cells, modified cells, non-toxic molecules, and toxic molecules by cultivation of eukaryotic cells, comprising: a) cultivation of infected, virally transduced, or transfected and/or induced eukaryotic cells in a plug flow tubular bioreactor adapted for infection, viral transduction, or transfection of eukaryotic cells for a time sufficient to allow production of one or more of virus particles, vectors other than viral vectors, viral vectors, and non-toxic or toxic molecules, and b) controlling a pH value and/or the oxygen concentration at a beginning of passage and during passage of a mixture of cells and means for infection, viral transduction or transfection. ### Claim 2 (depends on 1) The method according to claim 1, for production of whole virus, comprising admixing eukaryotic cells and infecting virus in a means for admixing the eukaryotic cells and the infecting virus to form a mixture and, thereafter, introducing said mixture into the plug flow tubular bioreactor through a feeding line. ### Claim 3 (depends on 1) The method according to claim 1, wherein processing is performed so as to produce viral vectors. ### Claim 4 (depends on 1) The method according to claim 1, wherein the eukaryotic cells are admixed or treated with an inducing agent for inducing or activating expression of toxic molecules in said eukaryotic cells to form an admixture and, thereafter, introducing said admixture into the plug flow tubular bioreactor. ### Claim 5 (depends on 1) The method according to claim 1, wherein the plug flow tubular bioreactor has an integral or multi-part tube with at least one inlet and at least one outlet whereby the at least one inlet is present at a first end of the tube and the at least one outlet is present at a second end of the tube, wherein the plug flow tubular bioreactor is adapted for cultivation of eukaryotic cells, and wherein a ratio of a length to a diameter of the tube is at least 5000:1. ### Claim 6 (depends on 5) The method according to claim 5, wherein the plug flow tubular bioreactor further comprises one or more additional inlets and outlets positioned along the length of the tube of the plug flow tubular bioreactor for supplying one or more of air, nutrients, and medium. ### Claim 7 (depends on 5) The method according to claim 5, wherein the tube is at least partly of a hollow fiber. ### Claim 8 (depends on 1) The method according to claim 1, wherein the plug flow tubular bioreactor is configured for single use. ### Claim 9 (depends on 5) The method according to claim 5, wherein the plug flow tubular bioreactor further comprises at least one inlet port for connecting the at least one inlet of the plug flow tubular bioreactor to a feed line for introducing cells, and means for infection, viral transduction, or transfection of said cells, and at least one discharge port for connecting the at least one outlet of the plug flow tubular bioreactor with a discharge line. ### Claim 10 (depends on 1) The method according to claim 1, wherein the plug flow tubular bioreactor is part of a plug flow bioreactor system comprising a module for holding the eukaryotic cells to be cultured and i) infected, virally transduced and or transfected and/or ii) induced or activated for expression of molecules including toxic molecules in the tubular bioreactor; a module for admixing the eukaryotic cells and i) means for infection, viral transduction, or transfection of the eukaryotic cells and/or ii) means for induction or activation of expression of molecules including toxic molecules; and at least one pump for allowing plug flow of said mixture through the tubular bioreactor. ### Claim 11 (depends on 10) The method according to claim 10, wherein the plug flow bioreactor system further comprises a control module for control of at least the flow of a) the mixture of cells through the plug flow tubular bioreactor and admixing performed using the module for admixing, and b) the temperature of the plug flow tubular bioreactor. ### Claim 12 (depends on 10) The method according to claim 10, wherein the plug flow bioreactor system further comprises means for introducing at least one of air, nutrients, medium, pH-adjusting components, inducers of production into a feed line connected to the tube and/or into the tube. ### Claim 13 (depends on 10) The method according to claim 10, wherein the plug flow bioreactor system further comprises a container containing a virus stock or nucleic acid based compounds. ### Claim 14 (depends on 10) The method according to claim 10, wherein the plug flow bioreactor system further comprises a medium stock reservoir, and/or at least one further pump for introducing medium stock into the plug flow tubular bioreactor. ### Claim 15 (depends on 1) The method according to claim 1, wherein the plug flow bioreactor system further comprises means for controlling at least the pH and/or oxygen concentration of a medium containing the cells and i) the means for infection, viral transduction or transfection or ii) the means allowing induction or activation of expression of molecules including toxic molecules when introduced into the plug flow tubular bioreactor. ### Claim 16 (depends on 1) The method according to claim 1, wherein the plug flow tubular bioreactor is a coiled tubular bioreactor.