` DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 2, 8, and 24-26 are currently amended, claims 3, 5-7, 15, and 18-22 were previously cancelled, claims 1-2, 4, 8-14, 16-17, and 23-27 have been considered on their merits. All arguments have been considered.
Withdrawn Rejections
The claim objection has been withdrawn in view of Applicant’s amendment.
The claim rejections under 35 U.S.C. § 112(b) have been withdrawn in view of Applicant’s amendments.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4, 9-10, 12-14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. (US 2012/0156772, of record) in view of Thomas et al. (WO 2016/116769, of record) and Kapre et al. (WO 2013/154928, of record).
This rejection is repeated with regard to claims 1-2, 4, 9-10, 12-14, and 17 for the same reasons of record as set forth in the Official action mailed 07 May 2025. Response to Applicant’s traversal follows the reiterated rejection below.
Regarding claim 1, Miller et al. teach a cell culture system using one or more small multidimensional polymer carriers which will be seeded with adherent cells to be grown in an agitated bioreactor (para. [0059] and [0061]). Miller et al. teach adding the carriers with inoculum in a bioreactor, adding culture medium, suspending the carriers in the medium, and allowing the cells to grow on the carriers (para. [0062]). Miller et al. teach these carriers can be commercially used for culturing cell lines and these cell lines can be used for developing vaccines (virus antigens/virus particles) (para. [0065]). The development of vaccines taught by Miller et al. read as a process of producing a virus and/or viral antigen.
Miller et al. are silent to the bioreactor being a multiparallel bioreactor and to a specific impeller speed between 300 rpm to 1200 rpm.
However, Thomas et al. teach the use of a multiparallel bioreactor for culturing cells at specific impeller speeds of about 10 - 600 rpm (p. 13, lines 23-32). It would have been obvious to one of ordinary skill in the art to utilize the multiparallel bioreactor of Thomas et al. for use in the method of Miller because a multiparallel bioreactors allow for multiple culture comparisons simultaneously. One would be motivated to utilize the multiparallel bioreactor of Thomas et al. for use in the method of Miller because Thomas et al. teach their bioreactors are useful because they permit precise control of certain physiochemical parameters including, pH and oxygen (p. 13, lines 26-29). One would have a reasonable expectation of success in utilize the multiparallel bioreactor of Thomas et al. for use in the method of Miller because both references teach culturing cells in an agitated bioreactor.
The impeller speed, 10 – 600 rpm, reads on the impeller speed range from 300 rpm to 1200 rpm. Additionally, Thomas et al. teach one of skill will appreciate that depending on the size of the reactor and volume of fluid to be stirred the speed of rotation may vary (p. 14, lines 16-22). It would have been obvious to one of ordinary skill in the art to select the specific impeller speed of Thomas et al. for use in the method of Miller et al. because where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation: selecting a specific impeller speed, is prima facie obvious (see M.P.E.P. § 2144.05). One would have had a reasonable expectation of successfully selecting an impeller speed based on the size of the bioreactor and volume of fluid in said bioreactor based on the teachings of Thomas et al.
Miller et al. suggests the use of their carrier and culture system to produce vaccines, however, Miller et al. is silent to a specific embodiment where these vaccines are produced. Miller et al. in view of Thomas et al. is silent to treating the adherent cells on the carrier with at least one virus, virus agent, viral vector, or virus particle and to harvesting the virus, virus agent, viral vector, or virus particle after at least 3 days after the transfer of the adherent cells on the carrier into the multiparallel bioreactor.
However, Kapre et al. teach methods of producing bulk quantities of virus from a population of mammalian cells in vitro (p. 1, lines 9-11). The methods set forth includes using a closed loop system with one or more incubation vessels each of which contains at least one permeable matrix comprising a porous polymeric material; where adherent host cells are seeded onto the matrix material, inoculating the host cells with a live virus, allowing the virus to replicate within the host cells, and harvesting the host cells infected with the live virus (Summary of Invention, p. 6, lines 1-11 and p. 7 lines 8-9). Kapre et al. teach, in a preferred embodiment, the system comprises a plurality of incubation chambers stacked in parallel (multiparallel bioreactor) (p. 7, lines 6-7). Kapre et al. teach the time period needed for culturing virus-infected cells to generate replicated virus is preferably from two days to two weeks (p. 15, lines 3-10).
Thus, to a person having ordinary skill in the art it would have been prima facie obvious to utilize the method of producing virus from a population of adherent cells of Kapre et al. in the method of Miller et al. in view of Thomas et al. because to produce viruses in an adherent cell it is necessary to first infect a host cell and allow incubation time for the viruses to replicate. The end result is to produce viruses; therefore, harvesting the virus would be the last step of this process. This reads on treating the adherent cells on the carrier with at least one virus, virus antigen, viral vector, or virus particle and harvesting the virus, virus antigen, viral vector, or virus particle after the transfer of the adherent cells on the carrier into the multiparallel bioreactor. One would be motivated to utilize the methods of Kapre et al. with the method of Miller et al. in view of Thomas et al. because while Miller et al. does not specifically teach how bulk quantities of virus are produced, Miller et al. does teach their carriers can be commercially used for culturing cell lines and these cell lines can be used for developing vaccines (virus antigens/virus particles) (Miller et al., para. [0065]). One would have a reasonable expectation of success in utilize the methods of Kapre et al. with the method of Miller et al. in view of Thomas et al. because both Kapre et al. and Miller et al. in view of Thomas et al. teach similar methods of culturing adherent cells in multiparallel bioreactors.
Regarding the virus harvesting time frame, where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists: selecting the specific virus harvesting time window, is obvious (see M.P.E.P. § 2144.05). One would have had a reasonable expectation of successfully selecting the harvesting time window which falls inside a larger time window due to the variables of the conditions of the culturing environment and variations with the species of adherent cells being grown. The time period taught by Kapre et al. reads as at least 3 days.
Therefore, the teachings of Miller et al. in view of Thomas et al. and Kapre et al. are obvious over the limitations of claim 1.
Regarding claim 2, Miller et al. teach the carrier may be made of a polymer and polymers comprise polyester, such as polyethylene terephthalate (PET) (para. [0045]). Miller et al. teach the shape of the carrier may be polygonal, which reads as a strip (para. [0041]). Therefore, Miller et al. teach the carrier comprises a PET strip.
Regarding claim 4, Miller et al. in view of Thomas et al. is silent to a process wherein the adherent cells are harvested 3-10 days after the transfer of the adherent cells on the carrier into the multiparallel bioreactor.
However, Kapre et al. teach the time period for harvesting adherent cells is preferably is from two days to two weeks (Description of the Invention, p. 15, lines 9-10). Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to modify the method of Miller et al. in view of Thomas et al. to specifically harvest adherent cells 3-10 days after the transfer of the adherent cells on the carrier to the container of the multiparallel bioreactor. This conclusion of obviousness is based on the rationale that where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists: selecting the specific harvesting time window, is obvious (see M.P.E.P. § 2144.05). One would have had a reasonable expectation of successfully selecting the harvesting time window which falls inside a larger time window due to the variables of the conditions of the culturing environment and variations with the species of adherent cells being grown.
Regarding claims 9 and 10, Miller et al. teach growing adherent cells such as Chinese hamster ovary (CHO) cells, Madin-Darby canine kidney (MDCK) cells, and Vero cells (para. [0065]).
Regarding claims 12 and 13, Miller et al. is silent to a specific impeller speed between 300 rpm to 1000 rpm and 300 rpm to 487 rpm.
However, Thomas et al. teach the use of a multiparallel bioreactor for culturing cells at specific impeller speeds of about 10 - 600 rpm (p. 13, lines 23-32). Selecting the multiparallel bioreactor of Thomas et al. for use in the method of Miller et al. would have been prima facie obvious because Thomas et al. teach one of skill will appreciate that depending on the size of the reactor and volume of fluid to be stirred the speed of rotation may vary (p. 14, lines 16-22). The impeller speed, 10 – 600 rpm, reads on the impeller speed range from 300 rpm to 1000 rpm and ranges from 300 rpm to 487 rpm. Additionally, selecting the specific impeller speed of Thomas et al. for use in the method of Miller et al. would have been prima facie obvious because where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation: selecting a specific impeller speed, is prima facie obvious (see M.P.E.P. § 2144.05). One would have had a reasonable expectation of successfully selecting an impeller speed because Thomas et al. teach, based on the size of the bioreactor and volume of fluid in said bioreactor and multiparallel bioreactors are useful because they permit precise control of certain physiochemical parameters including, pH and oxygen (p. 13, lines 26-29)
Regarding claim 14, Miller et al. teach carrier dimensions are at least about 0.2mm in length and 0.2mm in width and height range of about 0.012 mm to 0.5 mm (para. [0008]). Miller et al is silent to a specific growth area of PET strips ranging from about 10 cm2 to about 15 cm2, or about 13.9 cm2.
However, selecting the specific growth area of the PET strip would have been prima facie obvious. This conclusion of obviousness is based on the rationale that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation: selecting a specific growth area of the PET strip based on the size of the container of the bioreactor, is prima facie obvious (see M.P.E.P. § 2144.05). One would have had a reasonable expectation of successfully selecting the specific growth area of the carrier based on the size of the container of the bioreactor with a reasonable expectation of success because this is a matter of routine optimization.
Regarding claim 17, Miller et al. in view of Thomas et al. is silent to wherein the adherent cells are grown in a closed-loop manufacturing system.
However, Kapre et al. teach methods of producing bulk quantities of inactivated virus from a population of adherent cells using a closed loop system (Summary of Invention, p. 6, lines 1-11). Thus, to a person having ordinary skill in the art it would have been prima facie obvious to utilize the teachings of Kapre et al. in the method of Miller et al. in view of Thomas et al. with a reasonable expectation of success because a closed-loop system offers a reduced risk of contamination from environmental sources and would improve batch-to-batch consistency. One would be motivated to use a closed-loop system because of the reduced risk of contamination.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments filed 06 November 2025 have been fully considered but they are not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, at page 9 of the response, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Applicant argues the combination of Miller, Thomas, and Kapre does not establish a prima facie case of obviousness, the examiner has not successfully demonstrated that there is any motivation to combine nor a reasonable expectation of success, regarding the method of claim 1. However, the reiterated rejection above clearly discusses motivation and reasonable expectations of success for all combinations of references.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, all of the arguments directed to Thomas and Kapre, which do not include all of the references of said rejection, are not persuasive.
In response to applicant's argument, at page 10 of the response, that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., Applicant’s specification at para. [0004]) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding the arguments directed to the impeller rpm, as indicated in the rejection above, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation: selecting a specific impeller speed, is prima facie obvious (see M.P.E.P. § 2144.05). While the combination of references is discussed in the rejection, routine optimization provides appropriate motivation for a prima facie case of obviousness.
Regarding the arguments directed to Kapre and the utilization of porous matrix, these are not persuasive because the method for producing virus of Kapre was the purpose of the reference, not the matrix on which the cells are cultured. The carrier of Miller would not impede the flow, as the carriers of Miller are suspended in the culture media.
Regarding the arguments throughout the response directed to the individual references not correcting the deficiencies of the preceding references, these are not persuasive because, as indicated above, the references utilized are shown to not be deficient.
Claims 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. (US 2012/0156772, of record) in view of Thomas et al. (WO 2016/116769, of record) and Kapre et al. (WO 2013/154928, of record) and in further view of Luitjens et al. (US 2011/0207202, of record).
This rejection is repeated with regard to claims 8 and 10 for the same reasons of record as set forth in the Official action mailed 07 May 2025. Response to Applicant’s traversal follows the reiterated rejection below.
Regarding claim 8, Miller et al. in view of Thomas et al. and Kapre et al. are silent to wherein the virus, virus antigen, viral vector, or virus particle is, or derived from a modified vaccinia virus Ankara (MVA), Vascular Stomatitis Virus (VSV), adeno-associated virus (AAV), lentivirus, retrovirus, and adenovirus.
However, Luitjens et al. teach a method for producing recombinant adenovirus serotype 35 (rAd35) by infecting cells with rAd35, culturing the infected cells with a perfusion system to propagate the rAd35, and harvesting the rAd35 (column 4, lines 1-9). Luitjens et al. teach the person skilled in the art knows how to find the optimal agitation, pH, temperature, dissolved oxygen concentrations of the cell culturing medium and are in principle not critical and depend on the type of cell chosen (column 8, lines 3-17). Luitjens et al. teach the optimal agitation is between 50-300 rpm (column 8, lines 14-15). This reads on the vector is a viral vector, or is derived from adenovirus.
Thus, to a person having ordinary skill in the art it would have been prima facie obvious to utilize teachings of Luitjens et al. in the method of Miller et al. in view of Thomas et al. and Kapre et al. because Luitjens et al. teach adenoviral vectors and methods for propagating same in host cells are well-known in the art (column 6, lines 32-52). One would be motivated to use teachings of Luitjens et al. in the method of Miller et al. in view of Thomas et al. and Kapre et al. because both Thomas et al. and Luitjens et al. teach culturing cells in an agitated bioreactor with an impeller speed between 300 and 1200 rpm and Thomas et al. and Kapre et al. teach appropriate impeller speed is an important variable when optimizing culture conditions for increased yields. There would have been a reasonable expectation of successfully using adenovirus rAd35 in the method of Miller et al. in view of Thomas et al. and Kapre et al. because Luitjens et al. teach adenoviral vectors and methods for propagating same in host cells are well-known in the art.
Regarding claim 11, Miller et al. teach growing adherent cells, but is silent to HEK293 cells.
However, Luitjens et al. teach HEK293 were known to be producer cells for rAd335 (column 5, lines 24-25) and HEK293 cells are known in the art to be adherent cells. It is well known in the art HEK293 cells are commonly used in biological production systems and are functional equivalents to CHO, MDCK and Vero cells. It would have been prima facie obvious to substitute HEK293 cells for CHO, MDCK and/or VERO cells because they were all known as equivalents in the field of adherent cells for biological production systems, and one would have had a reasonable expectation that the HEK293 cells would have worked in the same manner. Substitution of one known element for another known element, the elements having equivalent effect, is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See M.P.E.P. § 2143(I).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments filed 06 November 2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, all of the arguments directed to Luitjens, which do not include all of the references of said rejection, are not persuasive.
Regarding the arguments throughout the response directed to the individual references not correcting the deficiencies of the preceding references, this is not persuasive because, as indicated above, the references utilized are shown to not be deficient.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. (US 2012/0156772, of record) in view of Thomas et al. (WO 2016/116769, of record) and Kapre et al. (WO 2013/154928, of record) and further in view of Chang et al. (TW 1233449 B, of record).
This rejection is repeated with regard to claim 16 for the same reasons of record as set forth in the Official action mailed 07 May 2025. Response to Applicant’s traversal follows the reiterated rejection below.
Chang is in the Chinese language. A machine translation is provided. Citations are made to the machine translation.
Regarding claim 16, Miller et al. in view of Thomas et al. and Kapre et al. are silent to wherein the PET strips comprise interwoven fibers.
However, Chang et al. teach the mass culture of cells, production of viruses and microorganisms using animal cells as hosts, and animal cell expression systematic production of recombinant proteins, monoclonal antibodies, in vitro culture of tissue engineering and other applications related to animal cell culture (lines 161-167). Chang et al. teach the carrier in the culture entity can be a fibrous woven or non-woven microporous carrier, a polymer foamed porous hydrophilic carrier, a ceramic porous hydrophilic carrier, or other common hydrophilic porous carriers (lines 161-167). For clarity of the record, woven reads as a synonym of interwoven.
Thus, to a person having ordinary skill in the art it would have been prima facie obvious to utilize PET strips comprising interwoven fibers in the method of Miller et al. in view of Thomas et al. and Kapre et al. because interwoven fibers provide an increased surface area, and provide additional relief surfaces for the adhesive cells to attach and proliferate. One would have been motivated to utilize PET strips because adhesive cells require adhesion prior to proliferation and woven fiber carriers are used to protect from shear forces from the agitated bioreactor. There would have been a reasonable expectation of success choosing PET strips with interwoven fibers as the carrier in the method of Miller et al. in view of Thomas et al. and Kapre et al. because Chang et al. teach in disclosed culture system is effective for proliferation and even distribution of the cells (lines 358-364).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments filed 06 November 2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, all of the arguments directed to Chang, which do not include all of the references of said rejection, are not persuasive.
Regarding the argument on page 15 of the response, directed to the equivalence between woven and interwoven fabrics, as indicated in the rejection above, interwoven and woven are synonyms. The instant specification does not define or even utilize the term “interwoven” and therefore was presumed to be using the two words interchangeably, the PET strips in the specification at para. [0033] and [0043] are referred to as woven PET strips, while the limitation of claim 16 refers to the PET strips comprising interwoven fibers. Therefore, because Chang refers to woven carriers, one would conclude the woven carriers of Chang and the instant specification both comprise interwoven fibers.
Regarding the arguments throughout the response directed to the individual references not correcting the deficiencies of the preceding references, this is not persuasive because, as indicated above, the references utilized are shown to not be deficient.
Claims 23 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. (US 2012/0156772, of record) in view of Thomas et al. (WO 2016/116769, of record) and Kapre et al. (WO 2013/154928, of record) and further in view of Li et al. (mAbs, 2010, of record).
This rejection is repeated with regard to claims 23 and 26 for the same reasons of record as set forth in the Official action mailed 07 May 2025. Response to Applicant’s traversal follows the reiterated rejection below.
Regarding claims 23, Miller et al. in view of Thomas et al. and Kapre et al. are silent to wherein one or more multiparallel bioreactor conditions are monitored or adjusted by the multiparallel bioreactor, wherein the one or more multiparallel bioreactor conditions comprise pH, temperature, dissolved oxygen (DO), and cell density.
However, Li et al. teach cell culture processes for monoclonal antibody production. Li et al. teach optimization of key variables in this technology; such as, cell lines capable of synthesizing the required molecules at high productivities that ensure low operating cost; culture media and bioreactor culture conditions that achieve both the requisite productivity and meet product quality specifications; appropriate on-line and off-line sensors capable of providing information that enhances process knowledge; and good understanding of culture performance at different scales to ensure smooth scale-up (Abstract).
Li et al. teach [cell] culture operating parameter optimization (see section Bioreactor Optimization and Scale Up, para. 1). Li et al. teach a typical stirred tank bioreactor is equipped with temperature, pressure, agitation, pH and dissolved oxygen controls. Li et al. teach biological parameters are used for determining the physiological state of the culture and include viable cell concentration, viability and a variety of intracellular and extra-cellular measurements (see section Bioreactor Optimization and Scale Up, para. 1). Viable cell concentration reads as cell density. Thus, to a person having ordinary skill in the art it would have been prima facie obvious to utilize the operating parameter optimization of Li et al. in the method of Miller et al. in view of Thomas et al. and Kapre et al. with a reasonable expectation of success because these features are standard features of a bioreactor and monitoring bioreactor conditions are standard practice. One would have been motivated to include these features in the method of Miller et al. in view of Thomas et al. and Kapre et al. for the purpose of optimization. This reads as one or more multiparallel bioreactor conditions are monitored or adjusted by the multiparallel bioreactor, wherein the one or more multiparallel bioreactor conditions comprise pH, temperature, dissolved oxygen (DO), and cell density.
Regarding claim 26, Miller et al. in view of Thomas et al. and Kapre et al. is silent to wherein consumption and production of one or more multiparallel bioreactor metabolites are monitored by the multiparallel bioreactor, wherein the one or more multiparallel bioreactor metabolites comprise glutamine, NH4, carbon dioxide, oxygen, glucose, and lactate.
However, Li et al. teach cell culture metabolites such as glucose, lactate, and glutamine are commonly measured using enzymatic biosensors specific to the measured analyte (see section Bioreactor Optimization and Scale Up, para. 10-17). Biosensors specific to measured analyte reads as metabolites are monitored by the bioreactor. Li et al. teach in addition to the quantification of metabolites common instrumentation for bioreactors also measure carbon dioxide, oxygen, and ammonium (see section Bioreactor Optimization and Scale Up, para. 10). Thus, to a person having ordinary skill in the art it would have been prima facie obvious to utilize the metabolite monitoring taught by Li et al. in the method of Miller et al. in view of Thomas et al. and Kapre et al. because measuring the metabolites of a cell culture are necessary to monitor the substrate level, culture performance, and product quality attributes. One would have been motivated to measure the metabolites in the method of Miller et al. in view of Thomas et al. and Kapre et al. for the purpose of optimization. This reads as consumption and production of one or more multiparallel bioreactor metabolites are monitored by the multiparallel bioreactor, wherein the one or more multiparallel bioreactor metabolites comprise glutamine, NH4, carbon dioxide, oxygen, glucose, and lactate.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments filed 06 November 2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, all of the arguments directed to Li, which do not include all of the references of said rejection, are not persuasive.
Regarding the arguments throughout the response directed to the individual references not correcting the deficiencies of the preceding references, this is not persuasive because, as indicated above, the references utilized are shown to not be deficient.
Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. (US 2012/0156772, of record) in view of Thomas et al. (WO 2016/116769, of record), Kapre et al. (WO 2013/154928, of record), and Li et al. (mAbs, 2010, of record) and further in view of Tomaskova et al. (J Virol, 2011, of record).
This rejection is repeated with regard to claims 24 and 25 for the same reasons of record as set forth in the Official action mailed 07 May 2025. Response to Applicant’s traversal follows the reiterated rejection below.
Regarding claims 24-25, Miller et al. in view of Thomas et al., Kapre et al. and Li et al. are silent to wherein the cells are incubated at a reduced DO level of less than about 40% DO to increase viral production or wherein the cells are incubated at the reduced DO level of less than about 10% DO to increase viral production.
However, Tomaskova et al. teach hypoxia induces the gene expression and extracellular transmission of persistent lymphocytic choriomeningitis virus (LCMV) (Abstract). Tomaskova et al. teach LCMV to infect HeLa cells to demonstrate the effects of hypoxia on viral replication (Results, Hypoxia enhances expression of LCMV genes). Tomaskova et al. teach hypoxia enhances gene expression, production of extracellular infectious virions, and in vitro transmission of an RNA virus replicating in the cytoplasm (Introduction, para. 4). Tomaskova et al. teach HeLa cells were infected with LCMV, then incubated for 48 hours in moderate hypoxia (2% O2) and normoxia (21% O2) (see Results, Hypoxia enhances expression of LCMV genes). Tomaskova et al. teach both DNA and RNA genome viruses take advantage of hypoxic conditions to improve replication and viral particle assembly phases (Discussion para. 1 and 2). Therefore, the 2% oxygen level of Tomaskova et al. meet the DO levels of less than about 40% and less than about 10% to increase viral production.
Thus, it would have been obvious to a person of ordinary skill in the art to culture cells in hypoxic conditions of Tomaskova et al. for use in the method of Miller et al. in view of Thomas et al., Kapre et al., and Li et al. because Tomaskova et al. teach lower oxygen levels increase viral replication in certain species of virus. One would be motivated to culture cells in hypoxic conditions of Tomaskova et al. for use in the method of Miller et al. in view of Thomas et al., Kapre et al., and Li et al. because Tomaskova et al. teach lower oxygen levels increase viral replication in certain species of virus and hypoxia-inducible factor (HIF) modulates gene expression of the viruses that pass through a DNA stage, contain hypoxia-responsive promoter elements, and replicate in the nucleus (Abstract). One would have had a reasonable expectation of success in culturing cells in hypoxic conditions of Tomaskova et al. for use in the method of Miller et al. in view of Thomas et al., Kapre et al. and Li et al. because Tomaskova et al. teach hypoxia increases viral production.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments filed 06 November 2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, all of the arguments directed to Tomaskova, which do not include all of the references of said rejection, are not persuasive.
Regarding the arguments throughout the response directed to the individual references not correcting the deficiencies of the preceding references, this is not persuasive because, as indicated above, the references utilized are shown to not be deficient.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. (US 2012/0156772, of record) in view of Thomas et al. (WO 2016/116769, of record), Kapre et al. (WO 2013/154928, of record), and Li et al. (mAbs, 2010, of record) and further in view of Sanfeliu et al. (Biotechnol Bioeng, 1999, of record).
This rejection is repeated with regard to claim 27 for the same reasons of record as set forth in the Official action mailed 07 May 2025. Response to Applicant’s traversal follows the reiterated rejection below.
Regarding claim 27, Miller et al. in view of Thomas et al., Kapre et al., and Li et al. are silent to wherein the glutamine level increases without media addition after treating the cells with at least one vector that produces a biological agent.
However, Sanfeliu et al. teach the effect of glutamine depletion on the death of attached Chinese hamster ovary (CHO) cells (see abstract). Sanfeliu et al. teach using anchorage dependent Chinese hamster ovary (CHO) cell line expressing γ-IFN transfected with a plasmid containing human bcl2 (hbcl-2) (Abstract). This reads on treating the cells with at least one vector that produces a biological agent. The CHO cells of Sanfeliu et al. were able to grow in media devoid of glutamine due to endogenous glutamine synthetase activity. The cells synthesize glutamine from glutamic acid in the medium (Abstract). This reads on glutamine level increases without media addition. Thus, to a person having ordinary skill in the art it would have been prima facie obvious to utilize the teachings of Sanfeliu et al. in the method of Miller et al. in view of Thomas et al., Kapre et al., and Li et al. to increase glutamine levels without the addition of media. One would have been motivated to utilize CHO cells in the method of Miller et al. in view of Thomas et al., Kapre et al., and Li et al. because CHO cells can synthesize glutamine, increasing the glutamine level without media addition. There would have been a reasonable expectation of success using the CHO cells described in Sanfeliu et al. in the method of Miller et al. in view of Thomas et al., Kapre et al., and Li et al. because the CHO cells can synthesize glutamine due to endogenous glutamine synthetase activity.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments filed 06 November 2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, all of the arguments directed to Sanfeliu, which do not include all of the references of said rejection, are not persuasive.
Regarding the arguments throughout the response directed to the individual references not correcting the deficiencies of the preceding references, this is not persuasive because, as indicated above, the references utilized are shown to not be deficient.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631