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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/20/2026 has been entered.
Claims 86-88, 90, 91, 93, 94, 96 and 97 are pending in this application and were examined on their merits.
Terminal Disclaimer
The terminal disclaimer filed on 02/20/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US 11,827,907 has been reviewed and is accepted. The terminal disclaimer has been recorded.
The rejection of Claims 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97 and 98 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3,
4, 5, 6, 7, 8, 10, 21, 22 and 24 of U.S. Patent No. 11,827,907 in view of Rao et al. (WO
2016/130940 A1) in view of Lipinski (WO 2015/086598 A2), both of record, and Vela
(WO 2020/168230 A1), cited in the IDS, has been withdrawn due to the above Terminal Disclaimer.
The rejection of Claims 86-91 and 93-97 under 35 U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement has been withdrawn due to the Applicant’s amendments to the claims filed 02/20/2026.
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.
Claim(s) 86-88, 90, 91, 93, 94, 96 and 97 are rejected under 35 U.S.C. § 103 as being unpatentable over Rao et al. (WO 2016/130940 A1) in view of Lipinski (WO
2015/086598 A2), both of record, and Vela (WO 2020/168230 A1), cited in the IDS.
Rao et al. teaches a method for producing Enterovirus A comprising culturing
adherent Vero cells in a bioreactor in culture medium, inoculating the cells with
Enterovirus A under conditions in which the Enterovirus A infects the cells,
culturing/incubating the cells under conditions in which the infected cell produces the
virus and harvesting the produced virus (Pg. 99, Claims 1 and 3), and reading on
Claims 86, 87 and 88.
The Rao reference further teaches that the conditions in which Enterovirus A
infects cells are known in the art and depend on the type of cell, the type of Enterovirus,
the culture medium, cell density, viral density (e.g., MOI), cell growth rate and number of
cell passages (Pgs. 13-14, Paragraph [0060]).
The Rao reference further teaches that cell density at the time of infection may
impact viral production and an optimal cell density at viral inoculation may result in
increased specific productivity, volumetric productivity, and/or stability, as well as
reduced media consumption and/or contaminants in the harvest (Pg. 14, Paragraph
[0061] and Pg. 95, Paragraph [0342]).
The Rao reference further teaches that maintaining suitable oxygen levels in a
cell culture medium may promote cell growth and/or virus productivity by providing
oxygen for cellular respiration, embodiments wherein the density of oxygen in the
culture medium is maintained above 50% and that methods for maintaining and/or
measuring the density of oxygen (DO) in a culture medium are known in the art (Pg. 17,
Paragraph [0072]).
With regard to Claims 86 and 90, the Rao reference teaches methods wherein
the Vero cells are grown at a constant initial DO level, pH and temperature, wherein the
DO is controlled and measured (monitored over time, thus actively) within the culture medium in a bioreactor and DO is maintained by automated injection of air/oxygen (e.g. by a process controller) (Pg. 75, Paragraph [0267] and Pg. 76, Paragraph [0268] and Pgs. 77-78, Paragraph [0275] and Fig. 30b).
The Examiner notes Rao et al. utilizes an iCELLis)™ NANO bioreactor (Pg. 75,
Paragraph [0266]-[0267]) which is also disclosed in the instant disclosure, see the
Specification as published at Pg. 5, Paragraph [0062]).
Rao et al. does not teach a method wherein the host cells are grown within the
bioreactor under an average air flow rate of about 80-100 ml/min and an average
oxygen flow rate of about 0-30 ml/min, and at a constant initial dissolved oxygen
level of 80-100% in the culture medium,
reducing the airflow rate over time and increasing the oxygen flow rate over time
based on measured air parameters and infecting the host cells with virus when the
reducing airflow rate and the increasing oxygen flow rate are within 30 mL/min of each
other, as required by Claim 86;
wherein infecting the host cells in Claim 86, step d) comprises infecting the host
cells when the air flow rate and the oxygen flow rate into the bioreactor are equal, as
required by Claim 91;
wherein the infecting the host cells in Claim 86, step d) occurs at a multiplicity of infection (MOI) of 0.1 to 0.05. as required by Claim 93;
a method further comprising a step of incubating the host cells at a second
dissolved oxygen (dO2) level, pH, and temperature different from the initial dO2 level,
pH, and temperature during the growing the host cells of b), as required by Claim 94;
or wherein the first-initial (O2 level is 100%, and wherein the second dO2 level is
between 50 % to 20 %, as required by Claim 97.
Lipinski teaches a method of culturing Vero cells to produce a virus, wherein the
virus may be influenza virus or Japanese encephalitis virus (Pg. 7, Lines 9-26) and
wherein an iCELLis™ bioreactor is utilized to culture Vero cells at a DO of 50% and an
airflow rate of 30 mL/min (Pg. 15, Lines 16-24).
Vela teaches a method of producing virus in a bioreactor comprising the following
steps:
a) providing host cells in the bioreactor;
b) growing host cells in a constant initial (100% O₂ level, pH, and temperature,
Pg. 2, Paragraph [0004]);
c) decreasing the dO2 to 20-90% of initial oxygen level;
d) infecting the host cells with at least one virus or virus particle 2-24 hours after
step c);
e) incubating said host cells infected with said virus or virus particle to propagate
said virus; and
f) harvesting the virus (Pg. 16, Claim 1);
wherein the host cells are adherent cells (Pg. 16, Claim 2);
wherein the infection of the host cells with the virus is at multiplicity of infection
(MOI) of about 0.1 to 0.05 (Pg. 17, Claim 9);
wherein the virus is selected from a group consisting of VSV, adenovirus,
Influenza virus, Ross River virus, Hepatitis A virus, Vaccinia virus and recombinant
Vaccinia virus, Herpes Simplex virus, Japanese Encephalitis virus, Herpes Simplex
virus, West Nile virus, Yellow Fever virus, and chimeras thereof, as well as Rhinovirus
and Reovirus (Pg. 17 Claim 12);
and wherein the host cells are Vero cells (Pg. 17 Claim 16).
It would have been obvious to those of ordinary skill in the art to modify the method of Rao of producing virus from infected Vero cells wherein the cell culture is maintained at a constant initial dO2 of 100% which is actively monitored and adjusted automatically by a controller to use an average air flow rate and average oxygen flow rate as claimed to maintain said initial dO2, further to reduce the air flow rate and increase the oxygen flow rate to maintain the constant initial dO2 level based on the monitored air parameters and then infecting the cells when the reducing of the air flow rate and increasing of the oxygen flow rate are within 30mL/min of each other because the dissolved oxygen percentage in the culture and the air flow and oxygen flow rates (including the average thereof) vis-a-vis the time of infection in a method of producing virus from host cells in a bioreactor are result effective variables subject to routine optimization and experimentation. The oxygen density (DO) is recognized by the Rao reference as important as maintaining suitable oxygen levels in a cell culture medium may promote cell growth and/or virus productivity by providing oxygen for cellular respiration, Lipinski teaches culturing Vero cells in a bioreactor at a particular oxygen density and the same air flow rate as claimed and Vela teaches adjusting (decreasing) dissolved oxygen in a method of infecting Vero cells with virus for viral production. Thus, the prior art recognizes the oxygen density, and therefore the oxygen concentration and flow rate of oxygen into the bioreactor is a critical result-effective variable involved in cell growth and viral productivity.
As such, modification of the rate at which air/oxygen is introduced into the bioreactor during growth and inducing viral infection at a particular optimal point when the air flow rate and oxygen flow rate are within 30 mL/min of one another would have been obvious to the ordinary artisan absent any showing of unexpected results. Those of ordinary skill in the art would have been motivated to make this modification in order to optimize the cell growth rate and maximize viral production therein. There would have been a reasonable expectation of success in making this modification because all of the references are drawn to the same field of endeavor, that is, the bioreactor culturing of Vero cells for the production of virus.
It would have been further obvious to those of ordinary skill in the art to modify
the method of Rao, Lipinski and Vela of producing virus from infected Vero cells to
incubate the host cells at a second dissolved oxygen (dO2) level, pH, and temperature
different from the initial dO2 level, pH, and temperature used during the growing of the
host cells because the altering of known culture conditions such as temperature and pH
would have been an obvious result-effective adjustment of parameters by routine
experimentation. See the MPEP at 2144.05 II. A. While the references listed above do
not specifically teach the limitations of altering the temperature and pH (Vela teaching
altering the dO2) from the initial culture temperature and pH, one of ordinary skill in the
art would recognize culture temperature and pH as optimizable variables dependent on
desired culture parameters. This is motivation for someone of ordinary skill in the art to
practice or test the parameter values widely to find those that are functional or optimal
which then would be inclusive or cover that values as instantly claimed.
Absent any teaching of criticality by the Applicant concerning the difference in culture temperature and pH from initial, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (MPEP § 2144.05 (II)(B). Those of ordinary skill in the art would have been motivated to make this modification in order to optimize the cell culture conditions and maximize viral production therein. There would have been a reasonable expectation of success in making this modification because all of the references are drawn to the same field of endeavor, that is, the bioreactor culturing of Vero cells for the production of virus.
With regard to Claim 93, Vela teaches wherein the infection of the host cells with
the virus is at multiplicity of infection (MOI) of about 0.1 to 0.05 (Pg. 17, Claim 9).
With regard to Claim 96, Vela teaches wherein the virus is selected from a group
consisting of VSV, adenovirus, Influenza virus, Ross River virus, Hepatitis A virus,
Vaccinia virus and recombinant Vaccinia virus, Herpes Simplex virus, Japanese
Encephalitis virus, Herpes Simplex virus, West Nile virus, Yellow Fever virus, and
chimeras thereof, as well as Rhinovirus and Reovirus (Pg. 17 Claim 12).
With regard to Claim 97, Vela teaches growing host cells in a constant initial dO2
level, pH, and temperature and decreasing the dO2 to 20-90% of initial oxygen level
(Pg. 16, Claim 1). Thus, the prior art encompasses an embodiment wherein the initial
O₂ is 100% and the second dO2 is 20-50%.
Response to Arguments
Applicant’s arguments, see Remarks, filed 02/20/2026, with respect to the above withdrawn rejections have been fully considered and are persuasive. The remaining arguments have been considered only insofar as they apply to the current rejections.
The Applicant argues that the combination of cited prior art does not obviate the instant invention with a reasonable expectation of success (Remarks, Pg. 8, Lines 16-19).
This is not found to be persuasive for the reasoning provided both in the prior action and the rejections set forth above.
The Applicant argues that none of the cited references utilize a system that actively monitors and processes air flow and oxygen flow parameters to infect Vero cells with a virus (Remarks, Pg. 9, Lines 13-21).
This is not found to be persuasive for the following reasons, as discussed above, the Rao reference teaches methods of infecting Vero cells with a virus wherein the Vero cells are grown at a constant initial DO level, pH and temperature, wherein the DO is controlled and measured (monitored over time, thus actively) within the culture medium in a bioreactor and DO is maintained by automated injection of air/oxygen (e.g. by a process controller) (Pg. 75, Paragraph [0267] and Pg. 76, Paragraph [0268] and Pgs. 77-78, Paragraph [0275] and Fig. 30b) while Lipinski teaches a method of culturing Vero cells to produce a virus, wherein the virus may be influenza virus or Japanese encephalitis virus (Pg. 7, Lines 9-26) and wherein an iCELLis™ bioreactor is utilized to culture Vero cells at a DO of 50% and an airflow rate of 30 mL/min (Pg. 15, Lines 16-24). The rationale for finding obvious the combining of the teachings of the references as well as motivation to do so with a reasonable expectation of success are set forth above.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/Examiner, Art Unit 1653 03/03/2026
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