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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 response filed August 26, 2025 has been received and entered into the application file. All arguments have been fully considered.
Claims 1-3, 5-6, 8-10, 12, 16, 18-24, and 26-28 from the claim set filed August 26, 2025 are pending. Claims 8-10 and 21-22 are withdrawn. Claims 4, 7, 11, 13-15, 17, 25, and 29 are cancelled. Claims 1, 16, and 24 are currently amended. Thus, claims 1-3, 5-6, 12, 16, 18-20, 23-24, and 26-28 are being examined on the merits herein.
Rejection(s) Withdrawn
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.
RE: Claims 1-3, 5-6, 16, 18-20, 24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Boehringer (WO 2018/178063 A1, published October 4, 2018; cited in the Incoming Written Opinion of the International Searching Authority filed June 10, 2021; IDS filed December 22, 2021) in view of Zhang (US 2003/0008375 A1, published January 9, 2003; cited in the Incoming Written Opinion of the International Searching Authority filed June 10, 2021; IDS filed December 22, 2021).
Applicant filed amendments now requiring independent claims 1, 16, and 24 to be a method of treating cells for cell therapy. As noted in Applicant remarks, Boehringer and Zhang do not teach a method, per se, of treating cells for cell therapy. As such, the previously filed rejections are withdrawn.
RE: Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Boehringer in view of Zhang, and further in view of Vericel (US 2016/0317584 A1, published November 3, 2016; cited in the Incoming Written Opinion of the International Searching Authority filed June 10, 2021; IDS filed December 22, 2021).
RE: Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Boehringer in view of Zhang, and further in view of Pfizer (WO 2017/085602 A1, published May 26, 2017, cited in the Incoming Written Opinion of the International Searching Authority filed June 10, 2021; IDS filed December 22, 2021).
RE: Claims 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Boehringer in view of Zhang, and further in view of Grayson (Grayson, et al., Biotechnology and Bioengineering (2011) 108(5): 1-21; cited in the Incoming Written Opinion of the International Searching Authority filed June 10, 2021; IDS filed December 22, 2021).
For the reasons discussed above, the obviousness rejection over Boehringer and Zhang is withdrawn, and thus the obviousness rejections that are based on the same basis are likewise withdrawn. However, Applicant amendment has necessitated new grounds of rejection, as set forth below.
New ground(s) of Rejection, necessitated by Amendment
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.
Claims 1-3, 12, 16, 18 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Roy (WO 2018/075940 A1, published 4/26/2018; IDS filed 12/22/2021; cited in the Incoming Written Opinion of the International Searching Authority filed 6/10/2021).
In regards to claims 1 and 16:
In regards to a method of treating cells for cell therapy, Roy teaches immunotherapy using adoptive T cell transfer (ACT) is a highly promising approach in treating cancers, infectious and autoimmune diseases, as well as for transplantation associated problems (p1, lines 22-25). Roy teaches of CAR-T cell therapy (p2, line 17). Roy teaches current T cell expansion methods using suspension cultures, is non-physiological and requires very high dosages of cytokines and does not recapitulate the cell-cell communication required for efficient T cell expansion (p2, lines 5-7). Roy teaches new bioprocess engineering methods to efficiently expand CAR-T populations, in terms of numbers, cell quality and potency, is critically needed to enable broad clinical use of this promising therapy (p3, lines 4-6). Roy teaches what is needed is a synthetic microenvironment capable of mimicking T cell niches within secondary lymphoid organs such as lymph nodes, the anatomical location where natural T cell activation and expansion take place in the body. Roy teaches the system should take advantage of 3D microcarriers which are widely used for adherent cells in industry practice but not for suspension cells- that can be functionalized with antibodies to promote suspension cell (i.e., T cell) activation and expansion. The system should provide suspension cells with improved potency and efficacy (p3, lines 15-24).
Thus, Roy teaches a method of treating T cells for cell therapy and teaches the system provides improved potency and efficacy.
Briefly, Roy teaches a method of expanding, activating, and/or transfecting suspension cells, the method comprising: obtaining a blood sample from a patient; isolating suspension cells from the blood sample; introducing the suspension cells to a bioreactor comprising a porous microcarrier; activating the suspension cells; expanding the suspension cells; optionally transfecting the suspension cells; preparing the suspension cells for transfusion into the patient; and transfusing the suspension cells into the patient (p5, lines 23-28).
In regards to a perfusion chamber, Roy teaches functionalized microcarriers were used in combination with modem bioreactors to create 3D niches where T cells are stimulated to expand with anti-CD3 and anti-CD28 antibodies while remaining in close cell-cell contact. The high surface density of these microcarriers encouraged high cell density and efficient signaling, while cytokine requirements, media usage, and bioreactor footprint were reduced (p22, Example 1).
Roy teaches the bioreactor comprises a closed bioreactor and an open bioreactor with the closed bioreactor comprising a stirred-type bioreactor, a bag bioreactor and a perfusion bioreactor (p5, lines 1-5). Roy teaches the methods according to the disclosure can combine the LN-like niche with perfusion bioreactors to affect dynamic culture and flow perfusion and thus improve expansion efficacy (time and cell numbers), product quality, scalability, and cost effectiveness (p11, lines 26-29). Further, Roy teaches perfusion bioreactors minimize high shear and can deliver fresh nutrients and cytokines continuously while imposing fluid mechanical forces on cells in a controlled manner. In cultures with microcarriers, the high cell density requires frequent media exchanges, in which case the application of perfusion has significant benefit. In some embodiments of the present disclosure, stirred-tank type ambrTM micro-bioreactor systems (TAP Biosystems) that allows bioprocess optimization at microscale (10- 15 ml) are used, mimicking the core characteristics of classical bioreactors, but with reduced use of media and growth factors. Other embodiments can use the CartiGen perfusion bioreactor system (model C9-x, Instron), optionally without employing the compression feature due to the unknown effects of the associated mechanical stimuli. In either embodiment, fresh media can be perfused using a common flow loop in a varying flow rate, closely mimicking the physiological interstitial flow rate, ranging from 0.1-2.0 μm/s 25 (p13, lines 22-31 – p14, lines 1-4).
Thus, Roy teaches a perfusion chamber and further teaches a perfusion chamber with a working volume of 10-15 mL, i.e., a volume of 50 mL or less.
In regards to introducing a media comprising at least about 3x10^6 cells/mL (i.e., claim 1) into a perfusion chamber having a volume of 50 mL or less, Roy teaches a cell culture media with a cell density of 2.5x10^6 cells/mL (p29, lines 5-8). Examiner notes the sole difference between the cell density of Roy and the instant application comprises only the routine optimization of cell density. Said optimization would have been obvious and well-within the purview of the ordinarily skilled artisan at the time of filing. Examiner notes Roy teaches a smaller working volume, i.e., 10-15 mL, as compared to the larger working volume, i.e., 50 mL or less, of the instant application. As Roy uses a smaller volume, so does Roy use a slightly lesser cell density. Additionally, Examiner notes Roy teaches microcarriers allow for high density cell culture; typically, about two orders of magnitude higher cell densities (up to 2x 108 cells/mL, compared to 2-3x 106/mL cells without microcarrier) (p12, lines 10-22).
As a POSITA will appreciate, cell density is a result effective variable based on multiple parameters such as volume size, time spent in culture, the type of cells used, etc. Absent any teaching of criticality or unexpected results by the Applicant, it would be obvious that one of ordinary skill in the art would recognize that cell density is a result effective variable and Examiner notes that the optimization of cell density/concentration would have been prima facie obvious to one of ordinary skill in the art at the time of filing. Generally, differences in parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05).
In regards to perfusing the cells by: measuring at least one parameter of the cells or the media, the at least one parameter selected from pH, optical density, dissolved oxygen concentration, temperature and light scattering; determining, in response to the measurement of the at least one parameter, a cell state associated with at least one of metabolic activity of the cells, average size of the cells and density of the cells in the media, Roy teaches of assessing cell culture fold change (i.e., changes in cell density) and phenotype via flow cytometry (i.e., measuring light scattering) and chemotaxis assay. Fold change (i.e., cell density) was quantified using a Countess automatic cell counter (measures light scattering). Roy teaches media was added after day 3, every 1-2 days based on media color (i.e., light scattering affecting media color) (p33, lines 13-17). Thus, Roy teaches of determining the density of the cells in the media via the measurement of light scattering.
In regards to introducing a volume effective to treat the cells for cell therapy of at least one additive selected from a transducing agent, a pH control agent, and a cell activator into the perfusion chamber, Roy teaches of transducing the T cells (p33, line 20) using a VSV-G pseudotyped lentivirus with a chimeric antigen receptor as the genetic payload (i.e., transducing for cell therapy) and teaches adding the appropriate amount of virus to achieve an MOI of 5 or 15 (i.e., a volume effective to treat the cell for cell therapy) based on starting cell number (i.e., the volume effective of the additive [transducing agent] is selected in response to the cell state [cell density]) (p34, lines 3-6).
In regards to withdrawing cell waste and byproducts from the perfusion chamber, Roy teaches of frequent media exchanges which inherently consists of withdrawing cell waste and byproducts from the perfusion chamber (p13, lines 24-26).
In regards to harvesting the treated cells, Roy teaches the use of microcarrier-based expansion allows, upon completion of culture, close to 100% cell harvesting (p12, lines 18-27). Roy further teaches (claim 45) of cell separation, purification, packaging, preservation, storage, shipping and transport, et. Thus, Roy teaches of harvesting the treated cells.
In regards to claim 16, Examiner notes claim 16 differs from claim 1 in that claim 16 states “introducing a media comprising at least about 0.5x10^6 cells/mL”. As discussed supra, Roy teaches a cell culture media with a cell density of 2.5x10^6 cells/mL (p29, lines 5-8).
Thus, the claims are obvious and are properly rejected.
In regards to claim 2, Roy teaches a cell culture media with a cell density of 2.5x10^6 cells/mL (p29, lines 5-8). Examiner notes the sole difference between the cell density of Roy and the instant application comprises only the routine optimization of cell density. Said optimization would have been obvious and well-within the purview of the ordinarily skilled artisan at the time of filing. Additionally, Examiner notes Roy teaches microcarriers allow for high density cell culture; typically, about two orders of magnitude higher cell densities (up to 2x 108 cells/mL, compared to 2-3x 106/mL cells without microcarrier) (p12, lines 10-22).
As a POSITA will appreciate, cell density is a result effective variable based on multiple parameters such as volume size, time spent in culture, the type of cells used, etc. Absent any teaching of criticality or unexpected results by the Applicant, it would be obvious that one of ordinary skill in the art would recognize that cell density is a result effective variable and Examiner notes that the optimization of cell density/concentration would have been prima facie obvious to one of ordinary skill in the art at the time of filing. Generally, differences in parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05).
Thus, the claim is obvious and is properly rejected.
In regards to claim 3, Roy teaches in some embodiments of the present disclosure, stirred-tank type ambrTM micro-bioreactor systems (TAP Biosystems) that allows bioprocess optimization at microscale (10- 15 ml) are used, mimicking the core characteristics of classical bioreactors, but with reduced use of media and growth factors. Other embodiments can use the CartiGen perfusion bioreactor system (model C9-x, Instron), optionally without employing the compression feature due to the unknown effects of the associated mechanical stimuli. In either embodiment, fresh media can be perfused using a common flow loop in a varying flow rate, closely mimicking the physiological interstitial flow rate, ranging from 0.1-2.0 μm/s 25 (p13, lines 22-31 – p14, lines 1-4).
Thus, the claim is obvious and is properly rejected.
In regards to claim 12, Roy teaches a high viability. As is shown in Fig 8B, the cells of Roy have at least about 75% viability or higher. I.e., the harvested, treated cells have a viability of at least about 75% or higher.
Thus, the claim is obvious and is properly rejected.
In regards to claim 18, Roy teaches a final media volume of 2 mL (p33, lines 10-12) indicating that the perfusion chamber may accommodate a volume of 2.5 mL or less.
Thus, the claim is obvious and is properly rejected.
In regards to claim 23, Roy teaches of assessing cell culture fold change (i.e., changes in cell density) and phenotype via flow cytometry (i.e., measuring light scattering) and chemotaxis assay. Fold change (i.e., cell density) was quantified using a Countess automatic cell counter (measures light scattering). Roy teaches media was added after day 3, every 1-2 days based on media color (i.e., light scattering affecting media color) (p33, lines 13-17). Thus, Roy teaches of determining the density of the cells in the media via the measurement of light scattering.
Thus, the claim is obvious and is properly rejected.
Claims 5-6, 19-20, 24, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Roy in view of Janas (Janas, et al., BioProcess International (2015), Perfusion’s Role in Maintenance of High-Density T-Cell Cultures, retrieved on 1/20/2026 from https://www.bioprocessintl.com/bioreactors/perfusion-s-role-in-maintenance-of-high-density-t-cell-cultures; PTO 892).
In regards to claims 5 and 19, Roy does not teach wherein the additive comprises the pH control agent.
Janas teaches of perfusion’s role in the maintenance of high-density T-cell cultures. Janas teaches T-cell therapy is a rapidly growing field (p1, last paragraph-p2 1st paragraph). Janas teaches generating enough cells for anticancer T-cell therapy can present logistical and technical difficulties (p2, 2nd paragraph). Janas teaches, as such, cell therapy manufacturers have adopted many principles of the bioprocess industry, including the use of bioreactors for cell cultivation. Janas teaches the combination of rocking agitation and perfusion media exchange allows high cell concentrations to be reached and that using such bioreactors, a therapeutic dose of T-cells can be generated by a single 1L culture for either TILs or CAR-T cells (p2, 2nd paragraph).
Janas further teaches the culture conditions in bioreactors must be optimized for primary T cells to be infused into patients, as for example, at the end of T-cell therapy cultures, cell populations must be viable (p2, 3rd paragraph). Janas teaches of studying the impact of media perfusion on high density T-cell cultures and further teaches of analyzing the impact of perfusion on cell growth and viability, as well as its role in controlling key metabolites and growth factors (p2, 5th paragraph).
Janas teaches of initiating perfusion once cell density is greater than 2x10^6 cells/mL (Table 1). Janas teaches of recording the number of total viable cells and cell viability every day (Figure 1). Janas teaches with perfusion, cells continued to expand throughout the entire bioreactor period, ultimately reaching densities of 20x10^6 viable cells/mL. These results demonstrate an absolute requirement for media perfusion to expand healthy T-cell cultures to the large cell numbers required for therapy (p4, Results, 1st and 2nd paragraph).
Janas teaches of a pH control function. Janas teaches of bags containing an embedded pH optical sensor. A reservoir of 0.1 M NaOH was connected to such bags through an additional pump unit (p3, 3rd paragraph). Janas teaches of measuring pH from culture supernatants using either a BioProfile 400 bioanalyzer or a YSI 7100MBS bioanalyzer (p4, 1st paragraph). Janas teaches of measuring pH in the T-cell cultures (Fig 2) and teaches of determining in response to the pH measurement, the lactate and ammonia concentrations (i.e., metabolic activity) of the T-Cells (Fig 2). Janas further teaches of studying lactic acid concentrations in correlation with pH. Janas teaches at 20mM of lactic acid (pH 6.6), growth was inhibited, and at 30 mM of lactic acid (pH less than 6.6) both growth inhibition and a loss of cell viability occurred (Fig 3). Janas summarized that perfusion strategies should be set to ensure that lactate levels remain below that concentration (and therefore pH levels remain above 6.6) (p5, last paragraph).
Thus, Janas teaches of measuring pH, determining in response to the pH measurement a cell state associated with a metabolic activity and introducing a volume effective to treat the cells for cell therapy of a pH control agent, the volume effective selected responsive to the cell state (i.e., the pH needs to remain above 6.6).
Further, Janas teaches of using CO2 and a 0.1 M NaOH reservoir attached to the bioreactor to maintain pH at 7.1-7.2, which Janas teaches is considered optimal for proliferation of primary T cells (p6, 2nd paragraph).
Thus, both Janas and Roy teach of high-cell density perfusion of T cells for cell therapy, with Janas teaching a specific pH range to maintain for optimal proliferation of primary T cells and Roy teaching a method of perfusion with improved potency and efficacy. Therefore, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Janas and Roy. A POSITA would have been so motivated in order to have the most effective high-cell density perfusion with improved potency and efficacy (as taught by Roy) with optimal pH levels for primary T cell proliferation (as taught by Janas). A POSITA would have had a reasonable expectation of success in combining said teachings due to both Roy and Janas studying perfusion in regards to high-cell density T cell cultures for cell therapy.
Thus, the claims are obvious and are properly rejected.
In regards to claim 6, Janas teaches a perfusion rate of 500 mL/day for cell densities of 2-10 x 10^6 cells/mL (Table 2). Janas further teaches for experiments with a pH-control function, a bag, i.e., a perfusion bag, containing an embedded pH optical sensor was used. Janas further teaches a reservoir of 0.1 M NaOH was connected to the perfusion bags (p3, Cell Expansion Culture System). Janas does not teach a flow rate in terms of VVD nor does Janas per se teach a flow rate for the introduction of the at least one additive, i.e., the pH control agent. However, as Janas teaches a set perfusion rate and teaches the pH control agent was added to the bag with the set perfusion rate, it is inherent that the pH control agent was added at a rate of 500 mL/day. To determine the VVD for 500mL/day, the daily flow rate is divided by the working volume of the bioreactor. Janas teaches a 1000mL bioreactor (Table 2). Thus, Janas teaches 0.5 VVD (i.e., 500/1000). Therefore, Janas teaches wherein the at least one additive is introduced at a flow rate of 5 VVD or less.
Thus, the claim is obvious and is properly rejected.
In regards to claim 20, Roy and Janas teach the method of claim 19. Further, Janas teaches using CO2 and a 0.1 M NaOH reservoir attached to the bioreactor, we maintained the pH at 7.1–7.2, which is considered optimal for proliferation of primary T cells (p6, 2nd paragraph). This reads on the limitations of claim 20.
Thus, the claim is obvious and is properly rejected.
In regards to claim 24, as discussed supra, Roy and Janas teach introducing a media comprising at least about 0.5 x 10^6 cells/mL into a perfusion chamber having a volume of 50 mL or less for a method of treating cells for cell therapy. Additionally, and as discussed supra, Janas teaches of introducing a pH control agent, i.e., introducing a first volume of at least one additive [pH control agent] into the perfusion chamber.
Further, Janas teaches introducing IL-2 (i.e., a cell activator) into the perfusion media. Janas teaches, for example, at a perfusion rate of 500 mL/day using media supplemented with 20 ng/mL of Il-2, the total IL-2 amount would be 10 micrograms/day. Janas teaches culturing with a perfusion bag for nine days (p3, Cell Expansion System Culture). Thus, Janas teaches introducing a first volume of at least one additive (i.e., IL-2, a cell activator) into the perfusion chamber; after a first predetermined period of time (i.e., daily) introducing a second volume of the at least one additive (i.e., IL-2, added daily and thus after the first day a second volume of media with IL-2 is perfused). Janas teaches of waste withdrawal (p4, last paragraph) and further teaches of daily checks of the supernatant samples from the bioreactor cultures (Fig 2). I.e., Janas teaches of daily adding IL-2 via the perfusion media and also of daily removal of cell waste and byproducts. This reads on after a first predetermined period of time introducing a second volume of the IL2; and after a second predetermined period of time, withdrawing cell waste and byproducts from the perfusion chamber. Janas teaches daily adding IL-2 (a predetermined period of time) and the daily removal of waste and byproducts (a predetermined period of time).
As discussed supra, Janas and Roy teach harvesting the treated cells.
Thus, the claim is obvious and is properly rejected.
In regards to claim 26, the limitations of said claims (cell density and perfusion chamber volume) have been discussed supra and noted as being taught by Roy and Janas. As such, the claim is properly rejected.
In regards to claims 27 and 28, Roy and Janas do not teach the required limitations per se. Examiner notes the limitations of claim 27 read on a controlled cell culture protocol in a perfusion system in which hour zero would be first stimulating cells via a cell activator/ transducing agent/pH control agent, then boosting the activation/transduction/pH an hour later (hour 1) by adding a second volume of activator/transducer/pH agent, and flushing waste an hour later (hour 2) to maintain viability. As discussed supra, Janas teaches a protocol of providing IL-2 daily, i.e., a predetermined time of every day. Janas does not teach a predetermined time of less than an hour. In addition, Janas teaches perfusion rates need to be optimized for growing T cells in bioreactors and further teaches determining optimal conditions for T cells grown in bioreactors will be key to the establishment of an emerging T-cell therapy industry (p8 bottom of the page -p9 top of the page).
Thus, Examiner notes that absent any teaching of criticality by the Applicant concerning the first predetermined period of time being less than about 1 hour (claim 27) or less than about 1 minute (claim 28), it would be obvious that one of ordinary skill in the art would recognize said predetermined period of time is a result effective variable. Further, it would be obvious to a POSITA that the at least one additive could be added and after that, in less than a minute, or within 30 seconds for example, the second volume of additive could be added since doing so would prevent oversaturation. In addition, Examiner notes the types of cells being grown in the bioreactor and the agent added to the bioreactor would all play roles in determining the “predetermined period of time”. Thus, said limitations are a result effective variable. “[W[here 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. “In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05).
Thus, the claims are obvious and are properly rejected.
Conclusion
No claim is allowed.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633