DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 28 May 2026 has been entered.
Claim Status
Claim 1 is 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.
Claim Interpretation
The amendment to claim 1, “in a multiparallel bioreactor for growing adherent cells”, does not further limit the claim as written. The claim already required the functional limitation where adherent cells are present and grown in a multiparallel bioreactor. Furthermore, the statement “for growing adherent cells” is an intended use statement which does not add additional structure to the process of producing a virus. Thus, the current amendment to claim 1 does not alter the scope of the claim nor add additional limitations to the claim. MPEP 2111.04 states examples of claim language that may raise a question as to the limiting effect of the language in a claim are, for example, “adapted for” and the determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps"). In In re Giannelli, 739 F.3d 1375, 1378, 109 USPQ2d 1333, 1336 (Fed. Cir. 2014).
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, 4, 9-10, 12-13, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Reiter et al. (CN 101100657 A, published 09 January 2008, IDS ref.) in view of Sousa et al. (Biotechnol. Prog., 2015, Vol. 31, No. 6), Thomas et al. (WO 2016/116769 A1, of record), and Kapre et al. (WO 2013/154928, of record).
The IDS reference, CN 101100657 A, is presented in Chinese, US 2005/0181495 A1 was used for reference purposes as the English equivalent.
This is a new rejection. A response to Applicant’s traversal regarding the previous rejection follows the rejection below.
Regarding claims 1, 4, 9-10, and 12-13, Reiter teaches methods of production of viral antigen on a culture of adherent cells bound to a microcarrier (Abstract). Reiter teaches the method utilizes anchorage-dependent cells selected from the group of adherent cells, VERO (claim 10), BHK, CHO (claim 9), RK, RK44, RK13, MRC-5, MDCK, CEF, or diploid monolayer cells (para. [0018]). Reiter teaches the culture of adherent cells bound to a microcarrier are grown to confluence and infected with a virus after increase of cell density and microcarrier concentration of cell biomass of the confluent cell culture (para. [0020]). Reiter teaches the microcarrier utilized is preferably selected from a group of microcarriers to include polyethylene (para. [0025]). Reiter teaches it is within the knowledge of one skilled in the art to select the respective microcarrier type, the microcarrier concentration in the starting culture, the adherent cells susceptible to the virus, and the medium and optimal growth conditions, like oxygen concentration, supplements of the medium, temperature, pH, pressure, stirring speed and feeding control, to obtain a confluent cell culture biomass which can be used to obtain a cell biomass having increased cell density and microcarrier concentration (para. [0027]). Reiter teaches in an example of influenza virus production, the peak area corresponds to the total antigen concentration at the end of the lytic cycle at day 3 after infection (para. [0055]), which suggests the produced virus was collected after 3 days post infection. Reiter teaches the virus in selected from the group of Influenza virus, Ross River Virus, Hepatitis A Virus, Vaccinia Virus, recombinant Vaccinia Virus, Herpes Simplex Virus, Japanese encephalitis Virus, West Nile Virus, Yellow Fever Virus, chimeric Yellow Fever Virus, Rhinovirus, and Reovirus (para. [0026]). Reiter teaches production of defective Vaccinia Virus, Vaccinia Virus WR or defective Vaccinia Virus vD4-ZG#2 (para. [0063]). Reiter teaches it is within the knowledge of one skilled in the art to select an adherent host cell and the virus susceptible to this host to obtain increased virus yield of the desired virus (para. [0026]).
Reiter does not teach a multiparallel bioreactor and is silent to the impeller speed of the bioreactor.
However, Thomas teaches the use of stirred tank bioreactor systems, such as a stirred tank culture array exemplified by the commercially available AMBR systems (p. 13, lines 23-26). The bioreactor array of Thomas reads as a multiparallel bioreactor. Thomas teaches their bioreactors are useful because they permit precise control of certain physiochemical parameters including, pH and oxygen (p. 13, lines 26-29). Thomas teaches the impeller of the bioreactor may be set to rotate at a speed of about 10-600 rpm (p. 14, lines 14-19). Thomas teaches 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 and the speed of rotation may be set or adjusted in order to impart some level or levels of mechanical stress to cells (p. 14, lines 19-22).
Additionally, Sousa teaches anchorage-dependent cell cultures used for the production of viruses, viral vectors, and vaccines (Abstract). Sousa teaches one promising solution is to grow cells on microcarriers suspended in a bioreactor (Abstract). Sousa teaches mixing time and microcarrier suspension can be quantified by means of simple engineering correlations (p. 1602). Sousa teaches microcarrier suspension experiments were performed to determine the minimum agitation rates that would fully suspend the microcarriers (p. 1602). Sousa teaches estimations of shear stress under stirred conditions as results of flow through Kolmogorov eddies can be determined using known equations (p. 1602). Sousa teaches the hydrodynamic parameters include kinematic viscosity, which is the turbulent energy dissipation in the impeller zone and the viscosity of the fluid; turbulent energy dissipation rate, which is determined from the power input of the impeller, diameter of the bioreactor, and density of the medium (p. 1602). Sousa teaches other variables include energy dissipation throughout a stirred bioreactor volume, which is determined by an equation where working volume and impeller diameter (p. 1603).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the multiparallel bioreactor of Thomas in view of Sousa in the method of Reiter with a reasonable expectation of success because multiparallel bioreactors allow for multiple culture comparisons simultaneously. One would be motivated to utilize the multiparallel bioreactor of Thomas in view of Sousa in the method of Reiter because Thomas teaches their bioreactors are useful because they permit precise control of certain physiochemical parameters including, pH and oxygen. Additionally, Reiter teaches it is within the knowledge of one skilled in the art to select the respective microcarrier type, the microcarrier concentration in the starting culture, the adherent cells susceptible to the virus, and the medium and optimal growth conditions, like oxygen concentration, supplements of the medium, temperature, pH, pressure, stirring speed and feeding control, to obtain a confluent cell culture biomass which can be used to obtain a cell biomass having increased cell density and microcarrier concentration. The teachings of Reiter regarding the many result-effective variables for culturing cells in a bioreactor and in view of Thomas and Sousa would motivate one of ordinary skill to look to the multiparallel bioreactor in order to determine ideal conditions resulting in reproducible yields of virus.
Regarding the limitation directed to the impeller speed of claims 1 and 12-13. The impeller speed taught by Thomas, 10 – 600 rpm, reads on the impeller speed range from 300 rpm to 1200 rpm (claim 1), 300-1000 rpm (claim 12), and 300-487 rpm (claim 13). Additionally, Thomas teaches 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).
Therefore, it would have been obvious to one of ordinary skill in the art to select the specific impeller speed 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 and Sousa because Sousa teaches the impeller speed can be determined using known equations which are quantified by means of simple engineering correlations.
Regarding the limitation directed to harvesting the virus, antigen, vector, or particle after at least 3 days (claim 1) and at 3-10 days (claim 4). Reiter teaches in an example of influenza virus production, the peak area corresponds to the total antigen concentration at the end of the lytic cycle at day 3 after infection, which suggests the harvesting of said virus would be done after 3 days.
Additionally, Kapre teaches 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 teaches, in a preferred embodiment, the system comprises a plurality of incubation chambers stacked in parallel (multiparallel bioreactor) (p. 7, lines 6-7). Kapre teaches 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).
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. 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.
Additionally, 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 reads as at least 3 days and falls within the range of 3- 10 days. The time frame required to harvest the viruses would have been a routine matter of optimization on the part of the artisan of ordinary skill, said artisan recognizing the time required to harvest the viruses depends on the quantity of cells, type of cells being utilized, and the virus being developed. A holding of obviousness over the cited claims is therefore clearly required. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages. See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382.; See also M.P.E.P. § 2144.05 (II)(A).
Therefore, the teachings Reiter in view of Thomas, Sousa, and Kapre render obvious the limitations of claim 1.
Regarding claim 17, Reiter in view of Thomas and Sousa are silent to wherein the adherent cells are grown in a closed-loop manufacturing system.
However, Kapre teaches 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 in the method of Reiter in view of Thomas and Sousa 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 28 May 2026 have been fully considered but they are not persuasive.
Regarding the remarks that the Office fails to understand the patentable feature of claim 1 on page 6 of the response, these remarks are merely the argument of counsel and is unsupported by evidence or declarations of those skilled in the art. Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See M.P.E.P. § 2129 and § 2144.03 for a discussion of admissions as prior art. Counsel's arguments cannot take the place of objective evidence. In re Schulze, 145 USPQ 716 (CCPA 1965); In re Cole, 140 USPQ 230 (CCPA 1964); and especially In re Langer, 183 USPQ 288 (CCPA 1974). See M.P.E.P. § 716.01(c) for examples of attorney statements that are not evidence and that must be supported by an appropriate affidavit or declaration.
Furthermore, the rejections of record and the rejections present in this office action address all of the limitations of the claims.
Regarding the remarks directed to the inventors conducting experiments as disclosed in the instant specification, these experiments and calculations are similar to that discussed in the above rejections. The methods described are found to be a matter of routine experimentation.
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, which do not include all of the references of said rejection, are not persuasive.
Additionally, the impeller speed is considered a variable which would be determined by routine optimization and/or experimentation. Thomas provides an example of such variability in this result effective variable and 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.
Claims 2 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Reiter et al. (CN 101100657 A, published 09 January 2008, IDS ref.) in view of Thomas et al. (WO 2016/116769 A1, of record), Sousa et al. (Biotechnol. Prog., 2015, Vol. 31, No. 6), and Kapre et al. (WO 2013/154928, of record) as applied to claims 1, 4, 9-10, 12-13, and 17 above, and further in view of Miller et al. (US 2012/0156772, of record).
This is a new rejection. All traversals were addressed in the response to traversal above.
Regarding claim 2, Reiter teaches the microcarrier utilized is preferably selected from a group of microcarriers to include polyethylene (para. [0025]). Reiter teaches it is within the knowledge of one skilled in the art to select the respective microcarrier type, the microcarrier concentration in the starting culture, the adherent cells susceptible to the virus, and the medium and optimal growth conditions, like oxygen concentration, supplements of the medium, temperature, pH, pressure, stirring speed and feeding control, to obtain a confluent cell culture biomass which can be used to obtain a cell biomass having increased cell density and microcarrier concentration (para. [0027]).
Reiter teaches the microcarrier may comprise polyethylene, however, does not specify the polyethylene is a PET chip.
Miller teaches 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 teaches growing adherent cells such as Chinese hamster ovary (CHO) cells, Madin-Darby canine kidney (MDCK) cells, and Vero cells (para. [0065]). Miller teaches 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 teaches 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 read as a process of producing a virus and/or viral antigen. Miller teaches the carrier may be made of a polymer and polymers comprise polyester, such as polyethylene terephthalate (PET) (para. [0045]). Miller teaches the shape of the carrier may be polygonal, which reads as a chip (para. [0041]). Therefore, Miller teaches the carrier comprises a PET chip.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the PET of Miller in the method of Reiter with a reasonable expectation of success because both Reiter and Miller teach methods for culturing adherent cells on microcarriers in a bioreactor. Additionally, it would have been obvious to one of ordinary skill in the art to utilize the PET chip taught my Miller in the method of Reiter with a reasonable expectation of success because, absent evidence of criticality, there are only 4 commonly used types of polyethylene carriers, low-density polyethylene (LDPE), high-density polyethylene (HDPE), polyethylene terephthalate glycol-modified (PETG), and polyethylene terephthalate (PET), and one of ordinary skill would immediately envision the choice of LDPE, HDPE, PETG, or PET. MPEP 2144.08.II.4(a) states that a genus may be so small that, when considered in light of the totality of the circumstances, it would anticipate the claimed species or subgenus. For example, it has been held that a prior art genus containing only 20 compounds and a limited number of variations in the generic chemical formula inherently anticipated a claimed species within the genus because “one skilled in [the] art would... envisage each member” of the genus. In re Petering, 301 F.2d 676, 681, 133 USPQ 275, 280 (CCPA 1962) (emphasis in original).
Regarding claim 14, Miller teaches 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 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.
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.
Claims 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Reiter et al. (CN 101100657 A, published 09 January 2008, IDS ref.) in view of Thomas et al. (WO 2016/116769 A1, of record), Sousa et al. (Biotechnol. Prog., 2015, Vol. 31, No. 6), and Kapre et al. (WO 2013/154928, of record) as applied to claims 1, 4, 9-10, 12-13, and 17 above, and further in view of Luitjens et al. (US 2011/0207202, of record).
This is a new rejection. All traversals were addressed in the response to traversal above.
Regarding claim 8, Reiter teaches the virus in selected from the group of Influenza virus, Ross River Virus, Hepatitis A Virus, Vaccinia Virus, recombinant Vaccinia Virus, Herpes Simplex Virus, Japanese encephalitis Virus, West Nile Virus, Yellow Fever Virus, chimeric Yellow Fever Virus, Rhinovirus, and Reovirus (para. [0026]). Reiter teaches production of defective Vaccinia Virus, Vaccinia Virus WR or defective Vaccinia Virus vD4-ZG#2 (para. [0063]). Reiter teaches it is within the knowledge of one skilled in the art to select an adherent host cell and the virus susceptible to this host to obtain increased virus yield of the desired virus (para. [0026]).
However, Reiter teaches the method wherein the virus is a Vaccinia virus or modified Vaccinia virus, yet, is 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 teaches 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 teaches 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 teaches 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 in the method of Reiter in view of Thomas, Sousa, and Kapre because Luitjens teaches 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 in the method of Reiter in view of Thomas, Sousa, and Kapre because both Thomas and Luitjens teaches culturing cells in an agitated bioreactor with an impeller speed between 300 and 1200 rpm and Thomas and Kapre 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 Reiter in view of Thomas, Sousa, and Kapre because Luitjens teaches adenoviral vectors and methods for propagating same in host cells are well-known in the art.
Regarding claim 11, Reiter teaches growing adherent cells, but is silent to HEK293 cells.
However, Luitjens teaches 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.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Reiter et al. (CN 101100657 A, published 09 January 2008, IDS ref.) in view of Thomas et al. (WO 2016/116769 A1, of record), Sousa et al. (Biotechnol. Prog., 2015, Vol. 31, No. 6), Kapre et al. (WO 2013/154928, of record), and Miller et al. (US 2012/0156772, of record) as applied to claims 2 and 14 above, and further in view of Chang et al. (TW 1233449 B, of record).
This is a new rejection. All traversals were addressed in the response to traversal above.
Chang is in the Chinese language. A machine translation is provided. Citations are made to the machine translation.
Regarding claim 16, Reiter in view of Thomas, Sousa, Kapre, and Miller are silent to wherein the PET strips comprise interwoven fibers.
However, Chang teaches 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 teaches 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 Reiter in view of Thomas, Sousa, Kapre, and Miller 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 Reiter in view of Thomas, Sousa, Kapre, and Miller because Chang teaches 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.
Claims 23 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Reiter et al. (CN 101100657 A, published 09 January 2008, IDS ref.) in view of Thomas et al. (WO 2016/116769 A1, of record), Sousa et al. (Biotechnol. Prog., 2015, Vol. 31, No. 6), and Kapre et al. (WO 2013/154928, of record) as applied to claims 1, 4, 9-10, 12-13, and 17 above, and further in view of Li et al. (mAbs, 2010, of record).
This is a new rejection. All traversals were addressed in the response to traversal above.
Regarding claims 23, Reiter in view of Thomas, Sousa, and Kapre 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 teaches cell culture processes for monoclonal antibody production. Li teaches 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 teaches [cell] culture operating parameter optimization (see section Bioreactor Optimization and Scale Up, para. 1). Li teaches a typical stirred tank bioreactor is equipped with temperature, pressure, agitation, pH and dissolved oxygen controls. Li teaches 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.
Therefore, to a person having ordinary skill in the art it would have been prima facie obvious to utilize the operating parameter optimization of Li in the method of Reiter in view of Thomas, Sousa, and Kapre 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 Reiter in view of Thomas, Sousa, and Kapre 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, Reiter in view of Thomas, Sousa, and Kapre are 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 teaches 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 teaches 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).
Therefore, to a person having ordinary skill in the art it would have been prima facie obvious to utilize the metabolite monitoring taught by Li in the method of Reiter in view of Thomas, Sousa, and Kapre 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 Reiter in view of Thomas, Sousa, and Kapre 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.
Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Reiter et al. (CN 101100657 A, published 09 January 2008, IDS ref.) in view of Thomas et al. (WO 2016/116769 A1, of record), Sousa et al. (Biotechnol. Prog., 2015, Vol. 31, No. 6), Kapre et al. (WO 2013/154928, of record), and Li et al. (mAbs, 2010, of record) as applied to claims 23 and 26 above, and further in view of Tomaskova et al. (J Virol, 2011, of record).
This is a new rejection. All traversals were addressed in the response to traversal above.
Regarding claims 24-25, Reiter in view of Thomas, Sousa, Kapre, and Li 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 teaches hypoxia induces the gene expression and extracellular transmission of persistent lymphocytic choriomeningitis virus (LCMV) (Abstract). Tomaskova teaches LCMV to infect HeLa cells to demonstrate the effects of hypoxia on viral replication (Results, Hypoxia enhances expression of LCMV genes). Tomaskova teaches 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 teaches 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 teaches 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 meet the DO levels of less than about 40% and less than about 10% to increase viral production.
Therefore, it would have been obvious to a person of ordinary skill in the art to culture cells in hypoxic conditions of Tomaskova for use in the method of Reiter in view of Thomas, Sousa, Kapre, and Li because Tomaskova teaches lower oxygen levels increase viral replication in certain species of virus. One would be motivated to culture cells in hypoxic conditions of Tomaskova for use in the method of Reiter in view of Thomas, Sousa, Kapre, and Li because Tomaskova teaches 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 for use in the method of Reiter in view of Thomas, Sousa, Kapre, and Li because Tomaskova teaches 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.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Reiter et al. (CN 101100657 A, published 09 January 2008, IDS ref.) in view of Thomas et al. (WO 2016/116769 A1, of record), Sousa et al. (Biotechnol. Prog., 2015, Vol. 31, No. 6), and Kapre et al. (WO 2013/154928, of record) as applied to claims 1, 4, 9-10, 12-13, and 17 above, and further in view of Sanfeliu et al. (Biotechnol Bioeng, 1999, of record).
This is a new rejection. All traversals were addressed in the response to traversal above.
Regarding claim 27, Reiter in view of Thomas, Sousa, and Kapre 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 teaches the effect of glutamine depletion on the death of attached Chinese hamster ovary (CHO) cells (see abstract). Sanfeliu teaches 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 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.
Therefore, to a person having ordinary skill in the art it would have been prima facie obvious to utilize the teachings of Sanfeliu in the method of Reiter in view of Thomas, Sousa, and Kapre to increase glutamine levels without the addition of media. One would have been motivated to utilize CHO cells in the method of Reiter in view of Thomas, Sousa, and Kapre 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 in the method of Reiter in view of Thomas, Sousa, and Kapre 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.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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