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 .
DETAILED ACTION
Election/Restriction
Applicant’s election of species of different containers in claims 65-68 and PBMCs as APCs in claims 95-98, in the reply filed on 12/18/2025, is acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction/election requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
The requirement is still deemed proper and is therefore made FINAL.
Claims 73-76 and 99 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Status
Claims 30-32, 50, 65-68, 70, 73-76, 81-82, 84, 91-100, 107 and 121 are pending.
Claims 73-76 and 99 are withdrawn.
Claims 30-32, 50, 65-68, 70, 81-82, 84, 91-98, 100, 107 and 121 are considered on the merits.
Priority
This application is a 371 of PCT/US21/30623 (filed on 05/04/2021), which claims benefits from provisional applications 63/162,441 (filed on 03/17/2021), 63/146,405 (filed on 02/05/2021), 63/023,666 (filed on 05/12/2020) and 63/019,917 (filed on 05/04/2020). The priority claim of the instant application has been granted and the earliest benefit date is 05/04/2020 from the application 63/019,917.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/09/2024, 01/30/2025, 03/27/2025 and 07/17/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g., [001111], [001264]). Applicant is required to amend or delete the embedded hyperlink and/or other form of browser-executable code. For example, “www” can be replaced with “world wide web” and “http” can be replaced with “hypertext transfer protocol” as the URL code. See MPEP § 608.01.
Claim Objections
Claims 31, 68, 70, 81 and 94 are objected to because of the following informalities:
Claim 31, the second wherein clause, recites the number of APCs in step (c) is greater than the number of APCs in step (b). This seems to contain typographic errors since step (c) is directed to harvesting TILs but not culturing TILs. It is recommended to change the limitation to “wherein the number of APCs in the culture medium in step (b) is greater than the number of APCs in the culture medium in step (a)”.
Claim 68 recites the phase “or about 2 cell layers; or” in the end, which contains typographic error. It is recommended to change to “or about 2 cell layers”.
Claim 70 recites a list of cell layers to choose from, but misses a conjunction before the last option. It is recommended to add an “or” before “about 4 cell layers”.
Claim 81 recites the phrase “a first population of TILs” in lines 2-3. It is recommended to change to “the first population of TILs”.
Claim 94 recites the phrase “harvested TIL population” in line 2. It is recommended to change to “the harvested TIL population”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 70, 81, 82, 84, 95, 96 and 107 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 70 recites the limitation “the second gas-permeable surface area” in line 2. There is insufficient antecedent basis for this limitation in the claim because base claim 30 is silent on a second gas-permeable surface area. It is recommended to change its dependency to claim 65.
Claim 81 recites the limitations “the first container” in line 3 and “the first gas-permeable surface area” in line 5. There is insufficient antecedent basis for the limitations in the claim because base claim 30 is silent on a first container or a gas-permeable surface area. Claims 82 and 84 are rejected as being dependent from claim 81 but not resolving the ambiguity.
Claim 95 recites the limitation “the antigen-presenting cells” in line 2. There is insufficient antecedent basis for this limitation in the claim because base claim 30 recites antigen-presenting cells in both step (a) and step (b), thus it is not clear which antigen-presenting cells this limitation is referring to. Claim 96 is rejected as being dependent from claim 95 but not resolving the ambiguity.
Claim 107 recites the limitation “the IL-2 concentration” in line 2. There is insufficient antecedent basis for this limitation in the claim because base claim 30 recites IL-2 in both step (a) and step (b), thus it is not clear which IL-2 this limitation is referring to.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 30, 65-68, 91, 95-97 and 107 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Jin et al., (J Immunother. 2012;35:283–292. IDS 10/09/2024).
With respect to claim 30, Jin teaches a method for expanding tumor infiltrating lymphocytes (TILs) to numbers needed for patient treatment (abstract), thus teaches the preamble a method for expanding TILs into a therapeutic population of TILs.
Regarding step (a) and step (b), directed to a priming first expansion and a rapid second expansion, Jin teaches a two-step TIL rapid expansion protocol (REP) comprising a first step of expansion in one G-Rex100 flask, followed by dividing the expanded cells into 3 G-Rex100 flasks and performing a second step of expansion (p. 285, last para – p. 286, first para, also see p. 287, last para “TIL REP Using Serial Culture in G-Rex100 Flasks”). The flow chart in Fig 6 demonstrates the two-step REP comprising culturing from Day 0 – Day 7, the first expansion in one flask “A” (equivalent to the claimed step (a)), and culturing from Day 7 – Day 14, the second expansion in three flasks “A1, A2, A3” (equivalent to the claimed step (b), see discussion below).
Furthermore, regarding step (a) a priming first expansion, Jin teaches 5 x 106 TILs harvested after the initial TIL culture (i.e., a first population of TILs) are cultured in a G-Rex100 flask in a cell culture medium comprising 3000 IU/mL of IL-2, 30 ng/mL of anti-CD3 (also known as OKT-3, see Table 4) and irradiated allogeneic PBMCs at a TIL:PBMC ratio of 1 to 100 to produce expanded TILs (i.e., a second population of TILs) (p. 285, last para – p. 286, first para. Note that PBMCs are equivalent to claimed APCs). Jin teaches the first step of expansion is performed for about 7 days (p. 286, first para, see Fig 6). Jin teaches after the first step of expansion, the population of TILs is greater in number than input (see Table 5 comparing Day 7 to Day 0 having about 160-fold increase), thus Jin teaches step (a).
Regarding step (b) a rapid second expansion, Jin teaches the TILs obtained from the first step are suspended and divided into three G-Rex100 flasks (it is noted that the PBMCs and anti-CD3 antibodies are divided together with the TILs) and more fresh media with IL-2 (3000 IU/mL) are added to each flask for a second step of expansion (p. 286, first para, see Fig 6), thus teaches the TILs are cultured in a cell culture medium comprising IL-2, OKT-3 (anti-CD3) and APCs (PBMCs). Jin teaches the second step of expansion is performed for about 7 days and the cells are harvested on day 14 of the two-step REP culture (p. 286, first para, see Fig 6, equivalent to the third population of TILs). Jin teaches the second expansion can produce sufficient quantities of TILs for clinical therapy (p. 289, right col, para 1), thus teaches the third population of TILs is a therapeutic population of TILs. Thus, Jin teaches step (b).
Regarding step (c) harvesting the TILs, Jin teaches the therapeutic population of TILs is harvested (see Fig 6 and Tables 5-6).
With respect to claim 65, as stated supra, Jin teaches the step of the priming first expansion is performed in a first container (e.g., in one G-Rex100 flask “A”, see Fig 6 and p. 286, first para) comprising a first gas-permeable surface (i.e., a gas-permeable bottom, p. 285, last para), and the step of the rapid second expansion is performed in a second container (e.g., in three G-Rex100 flasks “A1, A2, A3”, see Fig 6 and p. 286, first para) comprising a second gas-permeable surface (p. 285, last para).
With respect to claim 66, as stated supra, Jin teaches the first container being one G-Rex100 flask and the second container being three G-Rex100 flasks, thus teaches the second container is larger than the first container.
With respect to claims 67-68 and 97 directed to the number and cell layers of APCs/PBMCs in the priming first expansion, as a first matter, the specification defines that “The terms "about" and "approximately" mean within a statistically meaningful range of a value. Such a range can be within an order of magnitude” ([00726]). As stated supra, Jin teaches 5 x 106 TILs are cultured in a G-Rex100 flask with a 100 cm2 gas-permeable silicon bottom, and teaches irradiated allogeneic PBMCs are provided at a TIL:PBMC ratio of 1 to 100 (p. 285, last para), thus teaches the total number of APCs/PBMCs being added to the priming first expansion is about 5 x 108, being within the claimed range in claim 97. In regard to cell layers, by comparing the gas-permeable surface area (i.e., 100 cm2) and the area of one PBMC (8-10 µm in diameter, the cell area being about 50 µm2-78 µm2), each cell layer has about 2 x108 - 1.3 x108 PBMCs, thus the APCs/PBMCs are layered onto the first gas-permeable surface area at an average thickness of about 2.5 to about 3.8 cell layers (i.e., 5 x 108 / 2 x108 - 1.3 x108), being within the claimed range in claims 67-68.
With respect to claim 91, Jin teaches in the step of the rapid second expansion (Day 7 – Day 14), on Day 11, 150mL of AIM-V with IL-2 (3000 IU/mL) was added to each flask (see Fig 6 legend), thus teaches after 4 days, the cell culture medium is supplemented with additional IL-2.
With respect to claim 95 and claim 96, as stated supra, Jin teaches the TILs are cultured with irradiated allogeneic PBMCs at a TIL:PBMC ratio of 1 to 100 (p. 285, last para – p. 286, first para), thus teaches the antigen-presenting cells (APCs) are PBMCs and the PBMCs are irradiated and allogeneic.
With respect to claim 107 directed to the IL-2 concentration being about 10,000 IU/mL to about 5000 IU/mL, Jin teaches a cell culture medium comprising 3000 IU/mL of IL-2 (p. 285, last para), within the claimed range. Note that the term “about” is defined as “a range can be within an order of magnitude” ([00726]).
Accordingly, Jin anticipated instant claims.
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.
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 31-32, 70, 81-82, 84 and 98 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al., (J Immunother. 2012;35:283–292, IDS 10/09/2024) in view of Sadeghi et al (J Immunological Methods. 2011; 364: 94-100).
Claims 31-32, 70, 81-82, 84 and 98 are directed to APCs/PBMCs in the rapid second expansion being greater in numbers/cell layers than those in the priming first expansion.
However, Jin is silent on supplementing additional APCs/PBMCs in the second step of expansion, thus is silent on the APCs/PBMCs in the rapid second expansion being greater in numbers/cell layers than those in the priming first expansion.
Nevertheless, Jin refers to using WAVE bioreactors in TIL rapid expansion for the entire REP process (p. 291, left col, last full para).
Sadeghi teaches a large-scale expansion method of TILs using WAVE bioreactor system for adoptive cell transfer therapy in the clinic (abstract). Sadeghi teaches the method comprises removing tumor tissue from patients (p. 95, right col, para 2.1), and culturing tumor fragments in a plate to grow and pool TILs (p. 95, right col, para 2.2 “Isolation of TILs”, equivalent to Jin’s initial TIL culture). Sadeghi teaches “TILs from 4 different donors were subsequently pre-activated and expanded using the bioreactor and static culture conditions in parallel” (p. 95, right col, end of para 2.2, also see below, equivalent to instant step (a) and Jin’s first step of expansion in the two-step REP). Sadeghi teaches in the WAVE bioreactor, “a combination of pre-expanded TILs (50–100x106, pre-expanded in average for 10 days in T-flasks), 200-fold of irradiated (55 Gy) PBMCs, agonistic anti-CD3 antibody and IL-2 was added to each culture bag” (p. 96, left col, para 2.5), thus teaches a rapid expansion step which is equivalent to instant step (b) and Jin’s second step of expansion in the two-step REP. Sadeghi teaches the cell culture medium is supplemented with IL-2, anti-CD3 antibody (OKT-3) and 200-fold of irradiated PBMCs (i.e., APCs) in this step.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for expanding TILs comprising a rapid second expansion supplemented with additional IL-2 disclosed by Jin, by combining supplementing 200-fold of irradiated PBMCs (i.e., APCs) in this step as taught by Sadeghi with a reasonable expectation of success. Since both Jin and Sadeghi teach using irradiated PBMCs as feeder cells to expand TILs (Jin p. 285, left col, last para; Sadeghi p. 95, left col, para 2), and since Sadeghi reduces to practice supplementing 200-fold of irradiated PBMCs in the equivalent Jin’s second expansion to obtain a large amount of TILs for adoptive cell transfer therapy in the clinic (Sadeghi abstract), one of ordinary skill in the art would have had a reason to combine supplementing 200-fold of irradiated PBMCs as taught by Sadeghi in the rapid second expansion step of Jin in order to produce sufficient quantities of TILs for clinical therapy (Jin, p. 289, right col, para 1). Furthermore, since Jin teaches the PBMCs are provided at a TIL:PBMC ratio of 1 to 100 in the first step of expansion (i.e., step (a)) (p. 285, last para) and since Sadeghi teaches the PBMCs are provided at a 200-fold ratio to TILs in the equivalent second step of expansion of Jin (i.e., step (b) (p. 96, left col, para 2.5), one of ordinary skill in the art would have understood that the method suggested by Jin in view of Sadeghi would have had the number of APCs added in the rapid second expansion (200-fold) being greater than, e.g., being about 2:1 to, the number of APCs added in the priming first expansion (100-fold) in claims 31 and 32, the cell layers in the rapid second expansion being about 5 to about 7.6 cell layers (since the APCs/PBMCs being about 2.5 to about 3.8 cell layers in the priming first expansion, see above), within the claimed range in claim 70, the ratio of the average number of layers in the priming first expansion to that in the rapid second expansion being about 1:2, within the claimed ranges in claims 81, 82 and 84, and the total number of PBMCs added in the rapid second expansion being about 10 x 108 (since the total number of PBMCs added to the priming first expansion being about 5 x 108, see above), within the claimed range in claim 98. Note that the term “about” is defined as “a range can be within an order of magnitude” ([00726]).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 50 and 100 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al., (J Immunother. 2012;35:283-292. IDS 10/09/2024) in view of Bajgain et al. (Molecular Therapy - Methods & Clinical Development. 2014; 1, 14015: p. 1-9. IDS 10/09/2024).
With respect to claim 50 directed to transferring the TILs to an infusion bag, however, Jin does not specifically teach a step of transferring the harvested TIL population to an infusion bag. Note that the specification does not provide a special definition for an “infusion bag”, thus an infusion bag is reasonably interpreted as a bag for storing reagent that can be used for infusion into patients.
Nevertheless, Jin teaches the aim of the study is to produce sufficient quantities of TILs for clinical therapy (title, p. 283, para 1 and p. 289, right col, para 1).
Bajgain follows up Jin’s method of using the G-Rex flasks in expanding T cells (abstract, p. 1, right col, para 1 and p. 2, left col, para 1). Bajgain teaches in order to harvest the cells expanded in G-Rex containers, the Wilson Wolf company developed the “GatheRex,” a semiautomated system that allows the operator to drain the excess media present in the culture and collect cells in a cell collection bag without risk of contamination (p. 4, last para – p. 5, 1st para, and p. 8, right col, section “Cell harvesting using the GatherRex”, see Fig 7 #16 for a cell collection bag, equivalent to the claimed infusion bag).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for expanding TILs for clinical therapy as suggested by Jin, by combining a step of transferring the harvested TIL population to an infusion bag as suggested by Jin and taught by Bajgain with a reasonable expectation of success. Since Jin teaches the aim of TIL expansion is to produce sufficient quantities of TILs for clinical therapy (title, p. 283, para 1 and p. 289, right col, para 1) and the most common administration route for TILs is via intravenous infusion (Official note taken), and since Bajgain teaches a method and an equipment “GatheRex” for collecting expanded TILs to a cell collection bag without risk of contamination (p. 4, last para – p. 5, 1st para), one of ordinary skill in the art would have had a reason to combine the step of collection as taught by Bajgain in the method of Jin in order to collect the expanded therapeutic population of TILs in an infusion bag for administering into patients.
With respect to claim 100 directed to the harvesting being performed using a membrane-based cell processing system, note that there is no special definition in the specification for “membrane-based cell processing system”, thus it is reasonably interpreted as a cell processing system comprising a membrane in one component. As stated supra, Jin in view of Bajgain suggests a method of expanding TILs comprising a step of harvesting the therapeutic population of TILs and transferring to an infusion bag.
Bajgain teaches harvesting is performed using the “GatheRex,” a semiautomated system that comprises a 0.2 um sterile filter to harvest cells without contamination (p. 8, right col, section “Cell harvesting using the GatherRex”, see Fig 7 #2 for a 0.2 um sterile filter. It is noted that this sterile filter comprises a 0.2 um-pore-size membrane). Thus, Bajgain teaches the harvesting is performed using a membrane-based cell processing system. Accordingly, one of ordinary skill in the art would have understood the method of expanding and harvesting TILs as suggested by Jin in view of Bajgain would have had a step of harvesting the therapeutic population of TILs using a membrane-based cell processing system as taught by Bajgain to collect TILs for clinical therapy without risk of contamination.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 92-94 and 121 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al., (J Immunother. 2012;35:283-292. IDS 10/09/2024) in view of Bajgain et al. (Molecular Therapy - Methods & Clinical Development. 2014; 1, 14015: p. 1-9. IDS 10/09/2024), as applied to claims 50 and 30 above, and further in view of Frank et al., (J ImmunoTherapy of Cancer. 2016; 4(Suppl 1):82, p. 20), Hege et al., (J ImmunoTherapy of Cancer. 2017; 5:22, p. 1-14. IDS 03/27/2025) and Maecker et al (BMC Immunology 2005, 6:17, p. 1-14).
Claims 92 is directed to the method further comprising cryopreserving the TILs using a cryopreservation process. Claim 93 is directed to the method further comprising a step of cryopreserving the infusion bag. Claim 94 is directed to the cryopreservation process being performed using a 1:1 ratio of harvested TIL population to cryopreservation media. Claim 121 is directed to the method further comprising a step of cryopreserving the harvested TILs and the steps of the priming first expansion through the cryopreservation being performed in 16 days or less.
However, Jin and Bajgain are silent on a step of cryopreserving the infusion bag, nor teach the cryopreservation process.
Regarding a step of cryopreserving the expanded and harvested TIL population using a cryopreservation process, Frank teaches after the steps of obtaining TILs by culturing tumor fragments and rapid expanding TILs in a G-Rex flask, the expanded TILs are cryopreserved (p. 20, “Method”), thus teaches claims 92 and 121. Frank teaches cryopreservation did not affect the measured phenotypic characteristics of TIL (p. 20, “Results” and “Conclusions”). Frank teaches cryopreservation is a beneficial process which allows the final cell product to be shipped in a safe manner with less time constraints (p. 20, “Background”).
Regarding cryopreserving the infusion bag comprising the T cells, Hege teaches a therapeutical population of T cells are harvested after expansion, and the final cell products were cryopreserved in sterile bags using a cryopreservation process (p. 4, left col), and cryopreserved T cells were thawed in a 37 °C water bath at the patient’s bedside and infused directly (p. 4, right col, para 1), thus teaches claim 93 cryopreserving the infusion bag using a cryopreservation process.
Regarding the cryopreservation process of lymphocytes (PBMCs) being performed using a 1:1 ratio to cryopreservation media, Maecker teaches 2x freezing media is first prepared, PBMCs are resuspended, and “an equal volume of chilled 2x freezing media was added to the cell suspension” (p. 10, right col, last para “Cryopreservation”). Thus, Maecker teaches claim 94 cryopreservation process of lymphocytes (PBMCs) being performed using a 1:1 ratio of harvested cell population to cryopreservation media.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for expanding, harvesting and transferring the TILs into an infusion bag suggested by Jin in view of Bajgain, by combining a step of cryopreserving the infusion bag using a cryopreservation process being performed using a 1:1 ratio of TIL to cryopreservation media as taught by Frank, Hege and Maecker with a reasonable expectation of success. Since Frank teaches cryopreservation is a beneficial process which allows the final cell product to be shipped in a safe manner with less time constraints (p. 20, “Background”), and cryopreservation did not affect the phenotypic characteristics of TILs (p. 20, “Results” and “Conclusions”), and since Hege teaches the expanded therapeutic T cells can be cryopreserved in the infusion bag and can be infused directly into patients after thaw at bedside (p. 4, right col, para 1), and since Maecker reduces to practice a common cryopreservation process performed using a 1:1 ratio of resuspended cells to cryopreservation media, one of ordinary in the art would have had a reason to combine a step of cryopreserving the infusion bag comprising the TILs using a cryopreservation process taught by Frank, Hege and Maecker in order to increase the availability of the therapeutic TILs to patients in a safe manner with less time constraints and to assure sterility of the TILs. Furthermore, one ordinary skill in the art would have understood that the method as suggested by Jin, in view of Bajgain, Frank, Hege and Maecker would have had a total duration from the priming first expansion through cryopreservation being in 16 days or less because Jin teaches a duration from the priming first expansion through harvesting being about 14 days.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 30-32, 50, 65-68, 70, 81-82, 84, 91-98, 100, 107 and 121 are rejected on the ground of nonstatutory double patenting as being unpatentable over patented claims in the following US patents in view Jin et al., (J Immunother. 2012;35:283-292. IDS 10/09/2024), Sadeghi et al (J Immunological Methods. 2011; 364: 94-100), Maecker et al (BMC Immunology 2005, 6:17, p. 1-14) and Bajgain et al. (Molecular Therapy - Methods & Clinical Development. 2014; 1, 14015: p. 1-9. IDS 10/09/2024). Although the claims at issue are not identical, they are not patentably distinct from each other.
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method for expanding TILs of cited patents makes obvious the method for expanding TILs of instant application.
Patented claims recite a method for expanding TILs comprising performing a first expansion, a second expansion, harvesting, transferring and cryopreserving the TILs in a total of up to 22 days.
However, cited patented claims are silent on several limitations such as the number and ratio of APCs in the steps, cryopreservation process, membrane-based cell processing system or an infusion bag.
Regarding the number, cell layers and ratio of APCs in the first expansion and second expansion, Jin teaches using PBMCs (i.e., APCs) at a TIL:PBMC ratio of 1 to 100 in the equivalent first step of expansion, which is about 5 x 108 PBMCs on a 100 cm2 gas-permeable surface area, i.e., being layered at an average thickness of about 2.5 to about 3.8 cell layers (p. 285, last para, see discussion above), Sadeghi teaches using 200-fold PBMCs in the equivalent second step of expansion (p. 96, left col, para 2.5). Thus, Jin and Sadeghi teach using PBMCs as APCs in both expansion steps in a ratio of about 2:1 in the second expansion to the first expansion.
Regarding a cryopreservation process using 1:1 ratio of harvested cells to cryopreservation media, Maecker teaches preparing 2x freezing media and “an equal volume of chilled 2x freezing media was added to the cell suspension” (p. 10, right col, last para), thus teaches using 1:1 ratio of cell suspension to freezing media.
Regarding a membrane-based cell processing system and an infusion bag, Bajgain teaches harvesting cells to a cell collection bag using “GatheRex” system without risk of contamination (p. 4, last para – p. 5, 1st para, see Fig 7 #2 for a 0.2 um sterile filter), thus teaches a cell processing system comprising a sterile filter, which comprises a 0.2 um-pore-size membrane.
Therefore, it would have been obvious for one of ordinary skill in the art to have modified the method for expanding TILs recited in patented claims, by combining the number, cell layers and ratio of APCs taught by Jin and Sadeghi, the cryopreservation process taught by Maecker, and the membrane-based cell processing system and infusion bag taught by Bajgain with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so in order to efficiently expand, harvest, cryopreserve and transport sterile TILs to provide adoptive cell therapy for patients with cancers.
Since the instant application claims are obvious over cited patent claims, in view of Jin, Sadeghi, Maecker and Bajgain, said claims are not patentably distinct.
The above rejection is made over the following US patents:
10,420,799 B2; 10,639,330 B2; 10,894,063 B2; 10,918,666 B2; 11,007,226 B2; 11,026,974 B2; 11,040,070 B2; 11,168,303 B2; 11,168,304 B2; 11,179,419 B2; 11,254,913 B2; 11,273,180 B2; 11,291,687 B2; 11,304,979 B2; 11,344,581 B2; 11,351,197 B2; 11,351,199 B2; 11,384,337 B2; 11,529,372 B2; 11,541,077 B2; 11,713,446 B2; 11,939,596 B2; 12,024,718 B2; 12,104,172 B2; 12,226,434 B2; 12,280,140 B2; 12,343,380 B2; 12,453,697 B2; 12,473,532 B2; 12,485,145 B2; 12,516,291 B2; 12,570,959 B2; 12,570,961 B2.
Claims 30-32, 50, 65-68, 70, 81-82, 84, 91-98, 100, 107 and 121 are rejected on the ground of nonstatutory double patenting as being unpatentable over patented claims in the following US patents in view Jin et al., (J Immunother. 2012;35:283-292. IDS 10/09/2024), Sadeghi et al (J Immunological Methods. 2011; 364: 94-100), Maecker et al (BMC Immunology 2005, 6:17, p. 1-14) and Bajgain et al. (Molecular Therapy - Methods & Clinical Development. 2014; 1, 14015: p. 1-9. IDS 10/09/2024). Although the claims at issue are not identical, they are not patentably distinct from each other.
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the method of treating cancer comprising expanding TILs of cited patents makes obvious the method of expanding TILs of instant application.
Patented claims recite a method for treating cancer comprising expanding TILs comprising performing a first expansion, a second expansion, harvesting, transferring and cryopreserving the TILs in a total of up to 22 days.
However, cited patented claims are silent on several limitations such as the number and ratio of APCs in the steps, cryopreservation process, membrane-based cell processing system or an infusion bag.
Regarding the number, cell layers and ratio of APCs in the first expansion and second expansion, Jin teaches using PBMCs (i.e., APCs) at a TIL:PBMC ratio of 1 to 100 in the equivalent first step of expansion, which is about 5 x 108 PBMCs on a 100 cm2 gas-permeable surface area, i.e., being layered at an average thickness of about 2.5 to about 3.8 cell layers (p. 285, last para, see discussion above), Sadeghi teaches using 200-fold PBMCs in the equivalent second step of expansion (p. 96, left col, para 2.5). Thus, Jin and Sadeghi teach using PBMCs as APCs in both expansion steps in a ratio of about 2:1 in the second expansion to the first expansion.
Regarding a cryopreservation process using 1:1 ratio of harvested cells to cryopreservation media, Maecker teaches preparing 2x freezing media and “an equal volume of chilled 2x freezing media was added to the cell suspension” (p. 10, right col, last para), thus teaches using 1:1 ratio of cell suspension to freezing media.
Regarding a membrane-based cell processing system and an infusion bag, Bajgain teaches harvesting cells to a cell collection bag using “GatheRex” system without risk of contamination (p. 4, last para – p. 5, 1st para, see Fig 7 #2 for a 0.2 um sterile filter), thus teaches a cell processing system comprising a sterile filter, which comprises a 0.2 um-pore-size membrane.
Therefore, it would have been obvious for one of ordinary skill in the art to have modified the method for treating cancer comprising expanding TILs recited in patented claims, by combining the number, cell layers and ratio of APCs taught by Jin and Sadeghi, the cryopreservation process taught by Maecker, and the membrane-based cell processing system and infusion bag taught by Bajgain with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so in order to efficiently expand, harvest, cryopreserve and transport sterile TILs to provide adoptive cell therapy for patients with cancers.
Since the instant application claims are obvious over cited patent claims, in view of Jin, Sadeghi, Maecker and Bajgain, said claims are not patentably distinct.
The above rejection is made over the following US patents:
10,130,659 B2; 10,166,257 B2; 10,272,113 B2; 10,363,273 B2; 10,463,697 B2; 10,517,894 B2; 10,646,517 B2; 10,925,900 B2; 11,007,225 B2; 11,013,770 B2; 11,058,728 B2; 11,083,752 B2; 11,202,803 B2; 11,202,804 B2; 11,220,670 B2; 11,241,456 B2; 11,266,694 B2; 11,273,181 B2; 11,293,009 B2; 11,311,578 B2; 11,357,841 B2; 11,364,266 B2; 11,369,637 B2; 11,401,507 B2; 11,433,097 B2; 11,517,592 B2; 11,969,444 B2; 11,998,568 B2; 12,121,541 B2; 12,226,522 B2; 12,495,791 B2; 12,553,029 B2; 12,570,959 B2.
Claims 30-32, 50, 65-68, 70, 81-82, 84, 91-98, 100, 107 and 121 are rejected on the ground of nonstatutory double patenting as being unpatentable over patented claims in the following US patents in view Jin et al., (J Immunother. 2012;35:283-292. IDS 10/09/2024), Sadeghi et al (J Immunological Methods. 2011; 364: 94-100), Maecker et al (BMC Immunology 2005, 6:17, p. 1-14) and Bajgain et al. (Molecular Therapy - Methods & Clinical Development. 2014; 1, 14015: p. 1-9. IDS 10/09/2024). Although the claims at issue are not identical, they are not patentably distinct from each other.
The subject matter claimed in the instant application is disclosed in the referenced patent as follows: the expanded/cryopreserved TILs produced by a method of expansion of cited patents makes obvious the method of expanding TILs of instant application.
Patented claims recite a population of expanded/cryopreserved TILs produced by a method of expansion comprising performing a first expansion, a second expansion, harvesting, transferring and cryopreserving the TILs in a total of up to 22 days.
However, cited patented claims are silent on several limitations such as the number and ratio of APCs in the steps, cryopreservation process, membrane-based cell processing system or an infusion bag.
Regarding the number, cell layers and ratio of APCs in the first expansion and second expansion, Jin teaches using PBMCs (i.e., APCs) at a TIL:PBMC ratio of 1 to 100 in the equivalent first step of expansion, which is about 5 x 108 PBMCs on a 100 cm2 gas-permeable surface area, i.e., being layered at an average thickness of about 2.5 to about 3.8 cell layers (p. 285, last para, see discussion above), Sadeghi teaches using 200-fold PBMCs in the equivalent second step of expansion (p. 96, left col, para 2.5). Thus, Jin and Sadeghi teach using PBMCs as APCs in both expansion steps in a ratio of about 2:1 in the second expansion to the first expansion.
Regarding a cryopreservation process using 1:1 ratio of harvested cells to cryopreservation media, Maecker teaches preparing 2x freezing media and “an equal volume of chilled 2x freezing media was added to the cell suspension” (p. 10, right col, last para), thus teaches using 1:1 ratio of cell suspension to freezing media.
Regarding a membrane-based cell processing system and an infusion bag, Bajgain teaches harvesting cells to a cell collection bag using “GatheRex” system without risk of contamination (p. 4, last para – p. 5, 1st para, see Fig 7 #2 for a 0.2 um sterile filter), thus teaches a cell processing system comprising a sterile filter, which comprises a 0.2 um-pore-size membrane.
Therefore, it would have been obvious for one of ordinary skill in the art to have modified the population of expanded/cryopreserved TILs produced by a method of expansion recited in patented claims, by combining the number, cell layers and ratio of APCs taught by Jin and Sadeghi, the cryopreservation process taught by Maecker, and the membrane-based cell processing system and infusion bag taught by Bajgain with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so in order to efficiently expand, harvest, cryopreserve and transport sterile TILs to provide adoptive cell therapy for patients with cancers.
Since the instant application claims are obvious over cited patent claims, in view of Jin, Sadeghi, Maecker and Bajgain, said claims are not patentably distinct.
The above rejection is made over the following US patents:
10,695,372 B2; 11,052,115 B2; 10,398,734 B2; 10,894,063 B2; 11,052,116 B2; 11,123,371 B2; 11,141,438 B2; 11,304,980 B2; 11,337,998 B2; 11,344,579 B2; 11,344,580 B2; 11,351,198 B2; 11,857,573 B2; 11,865,140 B2; 11,975,028 B2; 12,031,157 B2, 12,188,048 B2; 12,194,061 B2; 12,558,375 B2.
Provisional Double Patenting Rejections
Claims 30-32, 50, 65-68, 70, 81-82, 84, 91-98, 100, 107 and 121 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims in the following US Applications in view Jin et al., (J Immunother. 2012;35:283-292. IDS 10/09/2024), Sadeghi et al (J Immunological Methods. 2011; 364: 94-100), Maecker et al (BMC Immunology 2005, 6:17, p. 1-14) and Bajgain et al. (Molecular Therapy - Methods & Clinical Development. 2014; 1, 14015: p. 1-9. IDS 10/09/2024). Although the claims at issue are not identical, they are not patentably distinct from each other.
The subject matter claimed in the instant application is disclosed in the referenced applications as follows: the method for expanding TILs of cited patents makes obvious the method for expanding TILs of instant application.
Copending claims recite a method for expanding TILs comprising performing a first expansion, a second expansion, harvesting, transferring and cryopreserving the TILs in a total of up to 22 days.
However, cited copending claims are silent on several limitations such as the number and ratio of APCs in the steps, cryopreservation process, membrane-based cell processing system or an infusion bag.
Regarding the number, cell layers and ratio of APCs in the first expansion and second expansion, Jin teaches using PBMCs (i.e., APCs) at a TIL:PBMC ratio of 1 to 100 in the equivalent first step of expansion, which is about 5 x 108 PBMCs on a 100 cm2 gas-permeable surface area, i.e., being layered at an average thickness of about 2.5 to about 3.8 cell layers (p. 285, last para, see discussion above), Sadeghi teaches using 200-fold PBMCs in the equivalent second step of expansion (p. 96, left col, para 2.5). Thus, Jin and Sadeghi teach using PBMCs as APCs in both expansion steps in a ratio of about 2:1 in the second expansion to the first expansion.
Regarding a cryopreservation process using 1:1 ratio of harvested cells to cryopreservation media, Maecker teaches preparing 2x freezing media and “an equal volume of chilled 2x freezing media was added to the cell suspension” (p. 10, right col, last para), thus teaches using 1:1 ratio of cell suspension to freezing media.
Regarding a membrane-based cell processing system and an infusion bag, Bajgain teaches harvesting cells to a cell collection bag using “GatheRex” system without risk of contamination (p. 4, last para – p. 5, 1st para, see Fig 7 #2 for a 0.2 um sterile filter), thus teaches a cell processing system comprising a sterile filter, which comprises a 0.2 um-pore-size membrane.
Therefore, it would have been obvious for one of ordinary skill in the art to have modified the method for expanding TILs recited in copending claims, by combining the number, cell layers and ratio of APCs taught by Jin and Sadeghi, the cryopreservation process taught by Maecker, and the membrane-based cell processing system and infusion bag taught by Bajgain with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so in order to efficiently expand, harvest, cryopreserve and transport sterile TILs to provide adoptive cell therapy for patients with cancers.
Since the instant application claims are obvious over cited application claims, in view of Jin, Sadeghi, Maecker and Bajgain, said claims are not patentably distinct.
These are provisional nonstatutory double patenting rejections because the patentably indistinct claims in the copending applications have not in fact been patented.
The above rejection is made over the following US Applications:
17/147,080 (allowed); 17/147,412 (allowed); 17/290,705 (allowed); 17/415,175; 17/610,671; 17/771,723; 17/829,087; 17/838,127; 17/997,648; 18/262,365; 18/262,843; 18/551,138; 18/551,586; 18/560,898; 18/619,119; 18/690,067; 18/693,508; 18/832,493; 18/832,901; 18/881,030; 18/984,595; 19/011,427, 19/108,091.
Claims 30-32, 50, 65-68, 70, 81-82, 84, 91-98, 100, 107 and 121 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims in the following US Applications in view Jin et al., (J Immunother. 2012;35:283-292. IDS 10/09/2024), Sadeghi et al (J Immunological Methods. 2011; 364: 94-100), Maecker et al (BMC Immunology 2005, 6:17, p. 1-14) and Bajgain et al. (Molecular Therapy - Methods & Clinical Development. 2014; 1, 14015: p. 1-9. IDS 10/09/2024). Although the claims at issue are not identical, they are not patentably distinct from each other.
The subject matter claimed in the instant application is disclosed in the copending applications as follows: the method of treating cancer comprising expanding TILs of cited applications makes obvious the method of expanding TILs of instant application.
Copending claims recite a method treating cancer comprising expanding TILs comprising performing a first expansion, a second expansion, harvesting, transferring and cryopreserving the TILs in a total of up to 22 days.
However, cited copending claims are silent on several limitations such as the number and ratio of APCs in the steps, cryopreservation process, membrane-based cell processing system or an infusion bag.
Regarding the number, cell layers and ratio of APCs in the first expansion and second expansion, Jin teaches using PBMCs (i.e., APCs) at a TIL:PBMC ratio of 1 to 100 in the equivalent first step of expansion, which is about 5 x 108 PBMCs on a 100 cm2 gas-permeable surface area, i.e., being layered at an average thickness of about 2.5 to about 3.8 cell layers (p. 285, last para, see discussion above), Sadeghi teaches using 200-fold PBMCs in the equivalent second step of expansion (p. 96, left col, para 2.5). Thus, Jin and Sadeghi teach using PBMCs as APCs in both expansion steps in a ratio of about 2:1 in the second expansion to the first expansion.
Regarding a cryopreservation process using 1:1 ratio of harvested cells to cryopreservation media, Maecker teaches preparing 2x freezing media and “an equal volume of chilled 2x freezing media was added to the cell suspension” (p. 10, right col, last para), thus teaches using 1:1 ratio of cell suspension to freezing media.
Regarding a membrane-based cell processing system and an infusion bag, Bajgain teaches harvesting cells to a cell collection bag using “GatheRex” system without risk of contamination (p. 4, last para – p. 5, 1st para, see Fig 7 #2 for a 0.2 um sterile filter), thus teaches a cell processing system comprising a sterile filter, which comprises a 0.2 um-pore-size membrane.
Therefore, it would have been obvious for one of ordinary skill in the art to have modified the method for treating cancer comprising expanding TILs recited in copending claims, by combining the number, cell layers and ratio of APCs taught by Jin and Sadeghi, the cryopreservation process taught by Maecker, and the membrane-based cell processing system and infusion bag taught by Bajgain with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so in order to efficiently expand, harvest, cryopreserve and transport sterile TILs to provide adoptive cell therapy for patients with cancers.
Since the instant application claims are obvious over cited application claims, in view of Jin, Sadeghi, Maecker and Bajgain, said claims are not patentably distinct.
These are provisional nonstatutory double patenting rejections because the patentably indistinct claims in the copending applications have not in fact been patented.
The above rejection is made over the following US Applications:
16/969,362; 17/050,552 (allowed); 17/110,179 (allowed); 17/290,710 (allowed); 17/817,217 (allowed); 17/817,239 (allowed); 17/817,276 (allowed); 17/856,793 (allowed); 18/247,877; 18/247,878; 18/256,421; 18/256,853; 18/291,536; 18/474,824; 18/707,719; 18/745,958; 18/886,988; 18/996,872; 19/050,082.
Claims 30-32, 50, 65-68, 70, 81-82, 84, 91-98, 100, 107 and 121 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims in the following US Applications in view Jin et al., (J Immunother. 2012;35:283-292. IDS 10/09/2024), Sadeghi et al (J Immunological Methods. 2011; 364: 94-100), Maecker et al (BMC Immunology 2005, 6:17, p. 1-14) and Bajgain et al. (Molecular Therapy - Methods & Clinical Development. 2014; 1, 14015: p. 1-9. IDS 10/09/2024). Although the claims at issue are not identical, they are not patentably distinct from each other.
The subject matter claimed in the instant application is disclosed in the copending applications as follows: the expanded/cryopreserved TILs produced by a method of expansion of cited applications makes obvious the method of expanding TILs of instant application.
Copending claims recite a population of expanded/cryopreserved TILs produced by a method of expansion comprising performing a first expansion, a second expansion, harvesting, transferring and cryopreserving the TILs in a total of up to 22 days.
However, cited copending claims are silent on several limitations such as the number and ratio of APCs in the steps, cryopreservation process, membrane-based cell processing system or an infusion bag.
Regarding the number, cell layers and ratio of APCs in the first expansion and second expansion, Jin teaches using PBMCs (i.e., APCs) at a TIL:PBMC ratio of 1 to 100 in the equivalent first step of expansion, which is about 5 x 108 PBMCs on a 100 cm2 gas-permeable surface area, i.e., being layered at an average thickness of about 2.5 to about 3.8 cell layers (p. 285, last para, see discussion above), Sadeghi teaches using 200-fold PBMCs in the equivalent second step of expansion (p. 96, left col, para 2.5). Thus, Jin and Sadeghi teach using PBMCs as APCs in both expansion steps in a ratio of about 2:1 in the second expansion to the first expansion.
Regarding a cryopreservation process using 1:1 ratio of harvested cells to cryopreservation media, Maecker teaches preparing 2x freezing media and “an equal volume of chilled 2x freezing media was added to the cell suspension” (p. 10, right col, last para), thus teaches using 1:1 ratio of cell suspension to freezing media.
Regarding a membrane-based cell processing system and an infusion bag, Bajgain teaches harvesting cells to a cell collection bag using “GatheRex” system without risk of contamination (p. 4, last para – p. 5, 1st para, see Fig 7 #2 for a 0.2 um sterile filter), thus teaches a cell processing system comprising a sterile filter, which comprises a 0.2 um-pore-size membrane.
Therefore, it would have been obvious for one of ordinary skill in the art to have modified the population of expanded/cryopreserved TILs produced by a method of expansion recited in copending claims, by combining the number, cell layers and ratio of APCs taught by Jin and Sadeghi, the cryopreservation process taught by Maecker, and the membrane-based cell processing system and infusion bag taught by Bajgain with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so in order to efficiently expand, harvest, cryopreserve and transport sterile TILs to provide adoptive cell therapy for patients with cancers.
Since the instant application claims are obvious over cited application claims, in view of Jin, Sadeghi, Maecker and Bajgain, said claims are not patentably distinct.
These are provisional nonstatutory double patenting rejections because the patentably indistinct claims in the copending applications have not in fact been patented.
The above rejection is made over the following US Applications:
17/817,247 (allowed); 17/817,273 (allowed); 17/823,419 (allowed); 17/823,448 (allowed); 17/856,806.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631