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 .
Priority
Acknowledgement is made of Applicants’ claim for benefit to prior filed US Provisional
Application 62/950,177, filed on 12/19/2019.
Information Disclosure Statement
The Information Disclosure Statements filed 6/14/2022, 2/23/2023, and 12/16/2024 have been considered by the examiner.
Status of Claims
Claims 1-2, 5, 9, 11, 13, 16-19, 21-22, 25, 29, 31, 33 and 36-39 are under examination.
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.
Claims 1-2, 5, 9, 11, 13, and 16-19 rejected under 35 U.S.C. 103 as being unpatentable over Masquelier (WO 2019/006436 Al) in view of Shen (US 2014/0004568 Al) have been withdrawn in view of applicant’s amendment filed on 08/08/2025.
Rejections maintained:
Claims 1-2, 5, 9, 11, 13, and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Masquelier et al. (WO 2019/006436 Al) in view of Shen et al. (US 2014/0004568 Al) and in view of Sheu et al. (Molecular Therapy — Methods & Clinical Development, 2015).
Regarding claim 1, Masquelier teaches a method of automated production of genome edited cells the expansion of those cells (page 2, paragraph 0005). Masquelier teaches a downstream processing module and isolating the cells from the viral vector (page 19, paragraph 0083). Masquelier teaches the production and purification are performed in an automated multi-model cell processing in an instrument (page 62, paragraph 00226). Masquelier does not specifically teach the production of a viral vector in cells which include transducing a viral producer cell with a gene of interest and expanding the producer cell producing the vector. Masquelier teaches cell growth within the growth module may be monitored using various measures of cell density and physiological which are monitored via pH and oxygen sensors (page 52, paragraph 00197), but does not teach in response to monitoring automatically controlling flow rate of media to adjust the one or more parameters.
Shen teaches a method of using a cell to produce virus (page 6, claim 1). The cell of Shen is a viral producer cell which is infected or transfected with a virus and maintained during a production phase where the cells produce more of the virus (page 1, abstract). Shen further teaches the producer cells are grown and maintained (page 8, claim 20).
It would have been obvious to one of ordinary skill in the art to combine the automated production of genome editing of Masquelier with the production of a viral vector in a cell as taught by Shen. One of ordinary skill in the art would have been motivated to make this combination in order to scale up and ease workload. Masquelier further teaches motivation for automation because traditional benchtop devices do not scale and currently the methods and systems to create edited cell populations remain cumbersome (page 2, paragraph 0003). There would have been a reasonable expectation of success because the platform of Masquelier is supportive of cells and virus and further transduction. The viral producing methods of Shen therefore would be supported in the system of Masquelier.
Sheu teaches a large scale, partially closed system method for the manufacturing of clinical grade lentiviral vector suitable for the generation of induced pluripotent stem cells (page 1, abstract). Sheu et al. teach a system comprised of a computer interface and a tubing adapter panel containing peristaltic pumps, fluid sensors and tubing clamps placed at various locations to control fluid flow (page 2, column 2).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Masquelier et al. and Shen et al. for the automated production of a viral vector in a cell as with the teachings of Sheu et al. for fluid sensors and tubing clamps to control fluid flow. Sheu et al. provide motivation by teaching that the methods provide an opportunity for large-scale vector production have therefore been contemplated, and one of the most prominent concepts is a closed system hollow fiber bioreactor (page 2, right column). Sheu et al. teach vector particle titers, comparable to those attained in flask or cell factory cultures, can be achieved while eliminating the need for periodic enzymatic passaging. Sheu further teach the potential for automated, compact, and efficient production of lentiviral vector (page 4, discussion). One of skill in the art would have had a reasonable expectation of success at combining Masquelier et al., Shen et al., and Sheu et al. because both teach production and isolation of cells and viral particles. Sheu further teaches processes happening in internal modules decrease the chance of contamination since other open system cell factories and their manipulation are prone to contamination (page 4, left column).
Regarding claim 2, Shen teaches the viral producer cell is a mammalian cell(page 8, claim 12).
Regarding claim 5, Masquelier teaches the method is relevant for any kind of virus including adeno-associated virus (AAV), lentivirus, retrovirus, or baculovirus as vectors.
Regarding claim 9, Shen teaches that the mammalian cell is a Chinese hamster ovary cell (page 8, claim 12).
Regarding claim 11, Shen teaches the mammalian cell is a human embryonic kidney cell (page 8, claim 12).
Regarding claim 13, Shen teaches the cells can comprise insect cells (page 8, claim 14).
Regarding claim 16, Masquelier teaches cell growth within the growth module may be monitored using various measures of cell density and physiological which are monitored via pH and oxygen sensors (page 52, paragraph 00197). Masquelier teaches the system may include one or more temperature and pressure sensors (page 41, paragraph 00155).
Regarding claim 17, Masquelier teaches cell transformation or transfection by electroporation, lipofection, and other methods disrupting the membrane including optoporation, injection, microprecipitation, microinjection, liposomes, particle bombardment, sonoporation, laser-induced poration, bead transfection, calcium phosphate or calcium chloride co-precipitation, or DEAE-dextran-mediated transfection (page 44, paragraph 00166).
Regarding claim 18, Masquelier teaches a washing and eluting process while transferring cell materials between an elution vial and the first filtration module (page 64, paragraph 00234)
Regarding claim 19, Masquelier teaches the purification module, may remove unwanted components of the nucleic acid assembly mixture. Masquelier teaches the purification module may use membrane based separation techniques and filtration (page 56, paragraph 00210).
Claims 21-22, 25, 31, and 36-39 are rejected under 35 U.S.C. 103 as being unpatentable over Sheu et al. (Molecular Therapy — Methods & Clinical Development, 2015) in view of Masquelier (WO 2019/006436 Al).
Regarding claim 21, Sheu teaches a large scale, partially closed system method for the manufacturing of clinical grade lentiviral vector suitable for the generation of induced pluripotent stem cells (page 1, abstract). Sheu et al. teach a system comprised of a computer interface and a tubing adapter panel containing peristaltic pumps, fluid sensors and tubing clamps placed at various locations to control fluid flow (page 2, column 2). Sheu teaches cell factory cultures, can be achieved in the Quantum system by utilizing the large surface area of a hollow fiber bioreactor coupled with media perfusion to efficiently culture producer cells while eliminating the need for periodic enzymatic passaging (page 2, left column). Sheu teaches both three and four plasmid systems are in use, where the structural, polymerase, envelope and genes of interest are split up into multiple plasmids and transfected into a producer cell line (page 2, left column). Sheu does not teach transferring the expanded cell to a downstream processing module. Sheu does not teach the further purification of the viral vector, but states that that transduction efficiency could be affected by the presence of cellular debris and envelope protein, so further downstream processing beyond what they have presented may be required to increase vector purity (page 4, right column).
Masquelier teaches a method for automated production of genome edited cells the expansion of those cells (page 2, paragraph 0005). Masquelier teaches a downstream processing module and isolating the cells from the viral vector (page 19, paragraph 0083). Masquelier teaches the production and purification are performed in an automated multi-model cell processing in an instrument (page 62, paragraph 00226).
It would have been obvious to one of ordinary skill in the art to combine the teachings of an automated viral vector production system taught by Sheu with automated multi-module cell editing instruments of Masquelier to improve isolation and processing methods. There would be a reasonable expectation of success because Sheu notes the need for more processing and Masquelier is also working with isolation of cells and viral particles. Further the more processes happening in internal modules decreases the chance of contamination since other open system cell factories and their manipulation are prone to contamination as taught by Sheu (page 4, left column).
Regarding claims 22 and 31, Sheu teaches the packaging cell is a HEK 293T cell which is a mammalian cell (page 6, left column).
Regarding claim 25, Masquelier teaches the method is relevant for any kind of virus including adeno-associated virus (AAV), lentivirus, retrovirus, or baculovirus as vectors.
Regarding claim 36, Masquelier teaches cell growth within the growth module may be monitored using various measures of cell density and physiological which are monitored via pH and oxygen sensors (page 52, paragraph 00197). Masquelier teaches the system may include one or more temperature and pressure sensors (page 41, paragraph 00155). Shen teaches the sensors can be monitored and analyzed by a processing system of the automated multi-mode cell processing system (page 41, paragraph 00155). Masquelier further teaches the processing system can use the sensor data for measurements and adjust cell growth conditions accordingly(page 37, paragraph 00140).
Regarding claim 37, Masquelier teaches cell transformation or transfection electroporation, lipofection, and other methods disrupting the membrane including optoporation, injection, microprecipitation, microinjection, liposomes, particle bombardment, sonoporation, laser-induced poration, bead transfection, calcium phosphate or calcium chloride co-precipitation, or DEAE-dextran-mediated transfection (page 44, paragraph 00166).
Regarding claim 38, The combination of Sheu and Masquelier would induce further processing of producer cells. Masquelier teaches cells rendered electrocompetent can be eluted in the filtration module or cell wash and concentration module. Further Masquelier teaches the cells may be eluted using a wash solution. Masquelier teaches ion exchange columns which are elution columns for the elution of the expanded cells (page 53, paragraph 00199).
Regarding claim 39, Masquelier teaches the purification module, may remove unwanted components of the nucleic acid assembly mixture. Masquelier teaches the purification module may use membrane based separation techniques and filtration (page 56, paragraph 00210).
Claims 29 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Sheu et al (Molecular Therapy — Methods & Clinical Development, 2015) in view of Masquelier (WO 2019/006436 Al) as applied to claims 21-22, 25, 31, and 36-39 above, and further in view of Shen (US 2014/0004568 Al).
Regarding claim 29, Sheu teaches the packaging cell is a HEK 293T cell which is a mammalian cell (page 6, left column). Sheu does not teach the packaging cell is a Chinese hamster ovary cell (CHO). Shen teaches that the mammalian cell is a Chinese hamster ovary cell (page 8, claim 12). It would have been obvious to one of ordinary skill in the art prior to the filing of this application to replace the mammalian cell of Sheu with the mammalian CHO cell taught by Shen. One would have been motivated to make this substitution because Shen teaches that CHO cells have been well studied in production where work has been conducted to understand the impact of hyperosmotic stress on cell growth, viability, cell metabolism, and antibody production (page 2, paragraph 0030). Therefore, using CHO cells would require minimal experimentation because an understanding of changes in the cells' physiological state during the growth phase and viral productivity are known. There would be a reasonable expectation of success because both Sheu and Shen recite methods of cells to produce virus.
Regarding claim 33, Sheu teaches the packaging cell is a HEK 293T cell (page 6, left column). Sheu does not teach the packaging cell is an insect cell. Shen teaches the packaging cells comprise insect cells (page 8, claim 14). ). It would have been obvious to one of ordinary skill in the art prior to the filing of this application to replace the mammalian cell of Sheu with the insect cell taught by Shen. There would be a reasonable expectation of success because both Sheu and Shen recite methods of cells to produce virus.
Response to Arguments
Applicant's arguments filed 08/08/2025 have been fully considered but they are not persuasive.
Applicant’s arguments: Applicant argues Masquelier and Shen whether taken alone or in any combination, fail to disclosure or otherwise suggest all of the features of claim 1. Claim 1 has been amended to further highlight the deficiencies of the cited references. In particular, present claim 1 recites, in part:
_(g) monitoring one or more parameters during (a) through (c) with one or more sensors; and (h) in response to the monitoring, automatically controlling a flow rate of media to adjust the one or more parameters.
Masquelier is directed to an automated, multi-module cell editing instrument 100 to automate multiple nucleic acid sequences inside one or more cells. Masquelier at Abstract. The instrument 100 includes a growth vial 800 for cell growth. Id. At para. [00134]. The growth vial 800 receives a cell culture with enough media to assure proper aeration in the vial 800 for desired growth of the cell culture. Id. at para. [00135]. That is, Masquelier discloses a closed volume with a set amount of media for growing a desired cell culture. Therefore, Masquelier fails to disclose or otherwise suggest "automatically controlling a flow rate of media to adjust the one or more parameters," in the manner recited in present claim 1.
Shen fails to cure the deficiencies of Masquelier. Shen is cited for disclosing a method of using a cell to produce a virus. Office Action at pp. 3-4. Without acceding to the Office's Page
assertions regarding Shen, this reference nonetheless fails to disclose or otherwise suggest the above quoted recitations of present claim 1.
For at least the foregoing reasons, Masquelier and Shen do not disclose or otherwise suggest all of the features of present claim 1 and, thus, present claim 1 is patentably distinguished from the cited references. Since claims 2, 5, 9, 13, and 16-19 depend, either directly or indirectly, from independent claim 1, these claims include all the features of claim 1. Thus, claims 2, 5, 9, 13, and 16-19 are considered patentably distinguishable over the cited art due at least to their respective dependencies from independent claim 1 and for the further features recited therein. It is therefore requested that the outstanding rejection under 35 U.S.C. §103 be withdrawn.
Sheu in view of Masquelier Claims 21, 22, 25, 31, and 36-39 stand rejected under 35 U.S.C. § 103 as being allegedly unpatentable over Sheu (NPL: "Large-Scale Production of Lentiviral Vector in a Closed System Hollow Fiber Bioreactor, " Molecular Therapy - Methods & Clinical Development, UK, 2015, VOL. 2, PAGES 15020(1-7)) in view of Masquelier. OA, pp. 5-9. Applicant respectfully traverses this rejection because Sheu and Masquelier, either alone or in any combination, fail to disclosure or otherwise all of the features of claim 21. However, solely to expedite prosecution, present claim 21 has been amended to further highlight the deficiencies of the cited references.
Specifically, present claim 21 recites, in part:
(g) monitoring one or more parameters during (a) through (c) with one or more sensors; and (h) in response to the monitoring, automatically controlling a flow rate of media to adjust the one or more parameters.
Sheu is directed to a hollow fiber bioreactor with a plurality of pressure sensors, a plurality of inlets for receiving cells, reagents, wash fluid, and media, and a plurality of outlets. However, Sheu fails to disclose or otherwise suggest the above quoted recitations of claim 21. Indeed, Sheu is silent with respect to "automatically controlling a flow rate of media to adjust the one or more parameters," in the manner recited in claim 21.
Masquelier fails to cure the deficiencies of Sheu. Masquelier is cited for disclosing a downstream processing module. Office Action a p. 6. Without acceding to the Office's assertions regarding Masquelier, this reference nonetheless fails to disclose or otherwise suggest the above quoted recitations of claim 21.
Applicant argues, Sheu and Masquelier fail to disclose or otherwise suggest all of the features of present claim 21 and, thus, claim 21 is patentably distinguished from the cited references. Since claims 22, 25, 31, and 36-39 depend, either directly or indirectly, from independent claim 21, these claims include all the features of claim 21. Thus, claims 22, 25, 31, and 36-39 are considered patentably distinguishable over the cited art due at least to their respective dependencies from independent claim 21 and for the further features recited therein. It is therefore requested that the outstanding rejection under 35 U.S.C. §103 be withdrawn.
Examiner’s response: A new rejection to claim 1 has been applied above in regard to the amendment filed. The combination of Masquelier, Shen et al. and Sheu et al. make obvious the invention of claim 1. Sheu et al. teach a system comprised of a computer interface and a tubing adapter panel containing peristaltic pumps, fluid sensors and tubing clamps placed at various locations to control fluid flow (page 2, column 2), which encompass the limitations of automatically controlling flow rate which have been added to claim 1.
As previously recited Sheu et al. teach fluid sensors and tubing clamps placed at various locations to control fluid flow (page 2, column 2), which encompass the limitations of automatically controlling flow rate which have been added to claim 21.
Applicant's arguments filed 02/19/2026 have been fully considered but they are not persuasive.
Applicant’s arguments: Applicant argues Sheu et al. does not cure the deficiencies of Masquelier, and the combined teachings do not disclose or suggest automatically controlling a flow rate of media both (1) to adjust the one or more parameters, and (2) in response to the monitoring. Sheu et al. does not suggest methods directed to any particular use of fluid sensors, tubing clamps, or means of controlling fluid flow. Applicant argues Sheu et al. makes no disclosure or suggestion whatsoever of controlling fluid flow both (1) to adjust the one or more parameters, and (2) in response to the monitoring.
Applicant argues the tubing clamps of Sheu et al. which control the fluid flow can be assumed to adjust the fluid flow rate, but Sheu et al. does not disclose controlling the fluid flow in order to adjust a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, or an optical density. Sheu et al. also does not disclose controlling the fluid flow in response to monitoring by a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, or an optical density sensor.
Examiner’s response: Sheu et al. teach a system comprised of a computer interface and a tubing adapter panel containing peristaltic pumps, fluid sensors and tubing clamps placed at various locations to control fluid flow (page 2, column 2). Sheu et al. teach a closed system hollow fiber bioreactor. Sheu et al. teach the bioreactor contains two mutually exclusive feedback loops, an intracapillary (IC) loop, which flows through the fibers’ interiors, and an extracapillary (EC) loop, which flows through the space between the porous fibers. Sheu et al. teach metabolites and fresh nutrients are transported through the pores. Sheu et al. further teach each of these loops can be accessed independently through selective task programming. Sheu et al. further teach internal sensors alert the operator if the intra-tubular pressure (page 2, right column). Sheu et al. teach the method has the potential for automated, compact, and efficient production of lentiviral vector (page 4, Discussion).
Therefore Sheu et al. contemplate flow rate of media through automation of delivering nutrients and the feedback loops programming to adjust the one or more parameters and in response to sensor monitoring.
Masquelier further teaches cell growth within the growth module may be monitored using various measures of cell density and physiology which are monitored via pH and oxygen sensors (page 52, paragraph 00197). Therefore, the combination of Masquelier et al., Shen et al., and Sheu et al. as described above in regards to claim 1 make obvious controlling the fluid flow in order to adjust pH level, oxygen level, or optical density in response to sensor monitoring.
Applicant’s arguments: Applicant argues Masquelier solely describes monitoring the growth module with sensors, such as the oxygen, pH, temperature, or pressure sensors, but does not connect the monitoring to an automatic control of the fluid flow.
Sheu et al. does not cure the deficiency of Masquelier recited above, because Sheu et al. is also completely silent regarding any connection between monitoring and adjusting in the manner recited in the claim.
Shen also fails to cure the deficiencies of Masquelier and Sheu et al. Shen fails to disclose or otherwise suggest the above quoted recitations of present claim 1.
Examiner’s response: Masquelier does not teach automatically controlling flow rate of media to adjust the one or more parameters in response to sensors monitoring the conditions. As described above Sheu et al. teach a system comprised of a computer interface and a tubing adapter panel containing peristaltic pumps, fluid sensors and tubing clamps placed at various locations to control fluid flow (page 2, column 2). Sheu et al. teach a closed system hollow fiber bioreactor to create a controlled environment. Sheu et al. teach feedback loops in which fresh nutrients are transported through the pores when signaled. Sheu et al. further teaches the loops can be accessed independently through programming. Sheu et al. teach the method has the potential for automated, compact, and efficient production of lentiviral vector (page 4, Discussion). Therefore Sheu et al. contemplate automated flow rate of media, delivering nutrients, and the feedback loops programmed to adjust the one or more parameters in response to sensor monitoring.
Furthermore, the combination of Masquelier et al., Shen et al., and Sheu et al. as described above in regards to claim 1 make obvious a method which includes monitoring one or more parameters with one or more sensors; and in response to the monitoring, automatically controlling a flow rate of media to adjust the one or more parameters, wherein the one or more sensors comprise a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor, and the one or more parameters comprise a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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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/C.L.M./Examiner, Art Unit 1638
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights