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
Amendments
In the reply filed 09/30/2025, Applicant has amended claims 1 and 10, newly canceled claims 6-7 and 13, and added new claims 22-23.
Claim Status
Claims 1, 3-5, 8-12 and 15-23 are pending.
Claims 15-19 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. The election was made without traverse in the reply filed on 05/31/2023.
Claims 1, 3-5, 8-12 and 20-23 are considered on the merits.
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 1, 3-5, 11-12 and 20-21 stand rejected under 35 U.S.C. 103 as being unpatentable over Jarde et al (Cell Stem Cell. October 1, 2020; 27: 646–662. Prior art of record) in view of Sato et al., (Scientific Reports. May 22, 2020; 10:8308, p. 1-15. Prior art of record).
It is noted that the prior rejection of claims 1, 3-5, 11-12 and 20-21 has been maintained. The following rejection is edited to address the amendment to claim 1.
With respect to claim 1, Jarde teaches a method of culturing single intestinal epithelial cells or intestinal crypts (see e.g., p. e4, “Single cell organoid culture” and “Organoid culture” sections), thus teaches the preamble a method of culturing intestinal cells or tissue.
Jarde teaches the single intestinal epithelial cells are isolated by FACS and cultured in vitro in a culture medium comprising R-spondin 1, CHIR, WNT-3a (i.e., agents for activating Wnt signaling), and neuregulin 1 (NRG1, an EGF family ligand) (see e.g., p. e4, “Single cell organoid culture” section).
Jarde teaches “NRG1 treatment dramatically increased (by 50%) the ability of Lgr5-GFPhigh, Lgr5-GFPmed, and Lgr5-GFPlow cells to form organoids compared to EGF (Figure 6H)” (p. 657, left col, line 2), and organoids treated with NRG1 exhibit a dramatic increase in complexity with multiple buds, which are similar to in vivo crypt domains (Figures 7D and 7E) (p. 657, left col, last para), thus teaches the culturing results in the formation of intestinal organoids.
Jarde teaches NRG1 treatment promotes stem cell proliferation evidenced by expression of the stem cell markers Lgr5 and Olfm4 being upregulated in NRG1-treated tissues (Figure 7F) (p. 657, left col, last para), thus teaches the intestinal organoids express OLFM4 and LGR5.
However, Jarde does not teach the culture medium comprises Epiregulin.
Nevertheless, Jarde acknowledges they “did not evaluate the function of other members of the EGF family of ligands. It is possible that these ligands, in conjunction with NRG1, contribute to supporting intestinal tissue regeneration following injury” (p. 659, right col, “Limitations of Study” section, line 3). Regarding EGF family of ligands, Jarde teaches in “Introduction” that the ligands include EGF, epiregulin, and neuregulin (NRG) 1-4 (p. 647, left col, para 2). It is noted that Jarde has evaluated the function of EGF in conjunction with NRG1 in supporting intestinal tissue regeneration (see e.g., Fig 1F, Fig 6H and Fig 7D-7E, “EGF+NRG1” group). Thus, Jarde clearly contemplates evaluating other EGF family ligands, including epiregulin, in conjunction with NRG1 in supporting intestinal tissue regeneration following injury.
Regarding epiregulin supporting intestinal tissue regeneration following injury, Sato teaches “Immediately after irradiation exposure, the production of EGF family proteins is markedly upregulated in the intestinal epithelial cells and surrounding stromal cells to promote epithelial regeneration. To mimic the in vivo situation, we added epiregulin to the organoid culture of irradiated crypt epithelial cells” (p. 3, last 4 lines, also see p. 13, “Organoid culture” and Fig 5D-5E), thus suggests epiregulin is upregulated in vivo following injury to promote intestinal tissue regeneration. Sato teaches the culture medium for intestinal organoid assay comprises RspoI (i.e., R-spondin 1) and CHIR-99021 (the same agents used by Jarde for activating Wnt signaling), EGF and Epiregulin (p. 13, “Organoid culture”).
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 of culturing intestinal cells or tissue in vitro in culture medium comprising an agent for activating Wnt signaling and NRG1 for intestinal organoids formation disclosed by Jarde, by combining an additional EGF family ligand Epiregulin in the culture medium as suggested by Jarde and taught by Sato with a reasonable expectation of success. Since Jarde suggests to evaluate other EGF family ligands, including Epiregulin, in conjunction with NRG1 in supporting intestinal tissue regeneration following injury (Jarde, p. 659, right col, “Limitations of Study” section, and “Introduction”, p. 647, left col, para 2), and since Sato suggests Epiregulin is upregulated in vivo following injury to promote intestinal tissue regeneration and reduces to practice culturing intestinal cells in vitro in culture medium comprising Epiregulin in an intestinal organoid assay (p. 3, last 4 lines, also see p. 13, “Organoid culture” and Fig 5D-5E), one of ordinary skill in the art would have had a reason to combine Epiregulin in the culture medium of Jarde in order to evaluate the function of Epiregulin in conjunction with NRG1 in supporting intestinal tissue regeneration following injury (Jarde, p. 659, right col, “Limitations of Study” section, line 3). Furthermore, since both media of Jarde and Sato comprise the same agents for activating Wnt signaling (R-spondin 1 and CHIR, see Jarde, p. e4, “Single cell organoid culture” section and Sato, p. 13, “Organoid culture”), and both Jarde and Sato teach the presence of active Wnt signaling is required for intestinal tissue regeneration (e.g., Jarde, p. 654, right col, end of para 1; Sato, end of p. 3-p. 4 and Fig 5D-5E, it is noted that Sca1-negative cells have higher regeneration efficiency and higher Wnt signaling since YAP target genes (such as Sca1) are inversely correlated with Wnt target genes, see Sato abstract and p. 2, end of last full para), one of ordinary skill in the art would have had a reasonable expectation of success in combining Epiregulin in conjunction with NRG1, in the medium comprising an agent for activating Wnt signaling, to support regeneration of intestinal tissue following injury.
Regarding the culture medium not comprising EGF, Jarde teaches the small intestine organoids “treated with NRG1 and without EGF were much larger” and “EGF was no longer required, demonstrating that NRG1 can substitute for EGF” (p. 649, left col, para 1, lines 4 & 8, see Fig 1E-1G for NRG1 only), and “similar phenotypes were observed when single cells were supplemented with NRG1 in the absence of EGF (Figure S7E)” (p. 657, left col, para 1, line 7). Thus, Jarde explicitly teaches NRG1 can substitute for EGF and teaches a culture medium supplemented with NRG1 in the absence of EGF. Accordingly, one of ordinary skill in the art would have appreciated that the culture medium comprising an agent for activating Wnt signaling, NRG1 and Epiregulin as suggested by Jarde in view of Sato would not have comprised EGF.
With respect to claim 3, directed to the intestinal organoids being intestinal enteroids, enteroids are known to be organoids derived from the small intestine and the specification recites “intestinal epithelial organoids, which are commonly referred to as enteroids” (p. 3, line 4). As discussed supra, Jarde teaches culturing with NRG1 promotes single cells to form intestinal organoid and these single cells are epithelial cells isolated from small intestinal tube (p. e4, “Single cell organoid culture” section), and Sato teaches culturing intestinal crypt epithelial cells in organoid culture (p. 13, “Organoid culture”), thus teaches the intestinal organoids are small intestinal epithelial organoids (i.e., enteroids).
With respect to claim 4, directed to culturing resulting in stem cell maintenance, and claim 5, directed to the cells being stem cells, as discussed supra, Jarde teaches culturing intestinal stem cells (Lgr5-GFPhigh) with NRG1 results in more organoids and increased overall cell numbers (Fig 6H, and Fig S7E in page 40) and “these results clearly demonstrate that NRG1 promotes a proliferative signature in stem and progenitor cells and induces these cells to express higher levels of stem cell markers” (p. 657, left col, para 2, line 1), and Sato teaches the culturing Sca1--negative Lgr5-derivatives (i.e., intestinal stem cells) with Epiregulin results in regeneration of Lgr5hi intestinal stem cells (see p. 4 and Fig 5F and legend), thus teaches culturing intestinal stem cells with NRG1 and Epiregulin results in stem cell maintenance.
With respect to claim 11 directed to culture medium further comprising an R-spondin and Noggin, and claim 12 limiting the R-spondin being R-spondin 1, Jarde teaches a single cell organoid culture medium further comprises “100 ng/mL Noggin and 1 ug/mL R-spondin 1” (p. e4, “Single cell organoid culture” section, line 6), and Sato teaches the organoid assay medium comprises RspoI (i.e., R-spondin 1) and Noggin (p. 13, “Organoid culture”).
With respect to claim 20 directed to the agent capable of activating Wnt signaling being Wnt3A, as stated supra, Jarde teaches the medium for culturing intestinal cells comprises Wnt3A that is capable of activating Wnt signaling (p. e4, “Single cell organoid culture” section, line 8).
With respect to claim 21 directed to the intestinal organoids having a budded morphology with putative crypt-like domains budding off of a central lumen, Jarde teaches the “organoids treated with NRG1 and without EGF were much larger, with buds composed of numerous rapidly proliferating cells” (p. 649, 1st para) and “organoids treated with NRG1 exhibit a dramatic increase in complexity with multiple buds, which are similar to in vivo crypt domains” (p. 657, left col, last para, see Fig 1F, Fig 4H and Fig 7D for examples of organoids having a budded morphology with putative crypt-like domains budding off of a central lumen).
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.
Response to Traversal:
Applicant’s arguments filed on 09/30/2025 are acknowledged.
Applicant first argues that no combination of cited references teaches a culture medium that both (i) lacks EGF and (ii) contains NRG1 in combination with EREG as now recited in amended claim 1. Specifically, Jarde used NRG1 as a substitute for EGF but did not teach combining NRG1 with EREG, nor did it disclose the beneficial effects of such a combination in an EGF-free setting. Sato disclosed EREG supplementation, but always in the context of EGF-containing media (Remarks, p. 8-9).
Applicant's arguments have been fully considered, but they are not persuasive.
In response to Applicant’s argument that Jarde does not introduce EREG in an EGF-free setting, Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, as Applicant has acknowledged, Jarde explicitly teaches NRG1 as a substitute for EGF (p. 647, last paragraph titled “NRG1 Can Substitute for EGF and Promote Robust Proliferation of Intestinal Organoids”), i.e., Jarde teaches a culture medium supplemented with NRG1 in the absence of EGF (p. 657, left col, para 1, line 7). Thus, Jarde teaches an EGF-free culture medium that both (i) lacks EGF and (ii) contains NRG1. In regard to introducing epiregulin (EREG) into this medium, Jarde recognizes the limitation that they “did not evaluate the function of other members of the EGF family of ligands” and suggests that “It is possible that these ligands, in conjunction with NRG1, contribute to supporting intestinal tissue regeneration following injury” (p. 659, right col, “Limitations of Study” section, line 3. Emphasis added), and teaches in “Introduction” that the EGF ligands include EGF, epiregulin, and neuregulin (NRG) 1-4 (p. 647, left col, para 2. Emphasis added). Thus, Jarde alone makes obvious an EGF-free culture medium that lacks EGF and contains NRG1, and further combines epiregulin in order to evaluate the function of an EGF ligand, such as epiregulin, in conjunction with NRG1, in supporting intestinal tissue regeneration following injury.
Furthermore, Sato suggests epiregulin is upregulated in vivo following intestinal injury to promote intestinal tissue regeneration and reduces to practice an intestinal organoid culture medium containing epiregulin, in conjunction with an EGF ligand (“EGF”, p. 13, para. “Organoid culture” and p. 3, last 4 lines). Thus, Jarde suggests introducing epiregulin in an EGF-free culture medium that lacks EGF and contains NRG1, and Sato reduces to practice a culture medium containing epiregulin, in conjunction with an EGF ligand (“EGF”).
In response to Applicant’s argument that Sato discloses epiregulin in the context of EGF-containing media and the unpredictable biology of intestinal stem-cell niche makes outcomes of EGF-free culture non-predictable (Remarks, p. 8-9), as stated supra, Jarde has explicitly taught NRG1 as a substitute for EGF, e.g., Jarde teaches the small intestine organoids “treated with NRG1 and without EGF were much larger” and “EGF was no longer required, demonstrating that NRG1 can substitute for EGF” (p. 649, left col, para 1, lines 4 & 8, see Fig 1E-1G for NRG1 only), and “similar phenotypes were observed when single cells were supplemented with NRG1 in the absence of EGF (Figure S7E)” (p. 657, left col, para 1, line 7). Thus, Jarde teaches NRG1 can substitute for EGF (and is even better than EGF) in culturing intestinal organoids. Accordingly, one of ordinary skill in the art would have had a predictably reasonable expectation of success in combining epiregulin with NRG1 to obtain similar or better culture outcome of intestinal organoids as compared to Sato’s epiregulin with EGF.
Applicant further argues that Applicant has shown unexpected results such that the experiments recited in the application demonstrate for the first time that a culture medium containing a Wnt activator, NRG1, and EREG, without exogenous EGF, can support the formation and maintenance of intestinal organoids expressing OLFM4 and LGR5 with crypt-like morphology (Remarks, end of p. 9 – p. 10).
Applicant's arguments have been fully considered, but they are not persuasive because Applicant does not specifically point out the experiments demonstrating the unexpected results. Thus, there is no factually supported objective evidence in the record supporting Applicant’s argument.
Claims 8-9 stand rejected under 35 U.S.C. 103 as being unpatentable over Jarde et al (Cell Stem Cell. 2020; 27: 646–662, published on October 1, 2020. Prior art of record) in view of Sato et al., (Scientific Reports. May 22, 2020; 10:8308, p. 1-15. Prior art of record), as applied to claim 1 above, and further in view of Fordham et al (Cell Stem Cell. 2013; 13: 734–744. Prior art of record).
Claim 8 is directed to the intestinal tissue or cells being human intestinal tissue or cells. Claim 9 further limits the human intestinal tissue being fetal intestinal tissue.
As discussed supra, Jarde in view of Sato teach a method of culturing intestinal cells to form intestinal organoids. Jarde and Sato teach the cells are isolated from mice (Jarde, p. e4, “Organoid culture” and “Single cell organoid culture” sections, and Sato, p. 12, last two sections). Jarde teaches human small intestinal tissues from adult patients are collected following surgery (p. e4, “Human small intestinal tissue” section) and are used for immunofluorescent analysis for NRG1 expression (see supplemental Fig S3B).
However, Jarde and Sato do not teach the tissue or cells used in culturing is human intestinal tissue or cells, nor teach human fetal intestinal tissue.
Fordham teaches a method for culturing human fetal intestinal tissue in vitro to make fetal enterospheres (title, abstract). Fordham teaches “fetal human intestinal tissue at around gestational week 10 was dissected and dissociated” to be cultured into formation of “human Fetal Enterospheres (hFEnS). hFEnS are highly proliferative and can be passaged repeatedly by mechanical dissociation for over 2 months” (p. 735, right col, para 2). Fordham does a transplantation study and finds the FEnS can differentiate into intestinal tissues in an injury model, and teaches hFEnS comprise a population of expandable fetal enteric progenitors from human that can be used as a transplantable source and have the potential to be used in regenerative medicine (p. 742, right col, para 2, lines 1&7).
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 of culturing mouse intestinal tissue/cells to form intestinal organoids suggested by Jarde in view of Sato, by substituting the mouse intestinal tissue/cells with human fetal intestinal tissue as taught by Fordham with a reasonable expectation of success. Since Fordham teaches human fetal enterospheres are highly proliferative that serve as a transplantable source and can be used in regenerative medicine (see Fordham p. 742, right col, para 2, lines 1&7), one of ordinary skill in the art would have had a reason to substitute the mouse tissue with human fetal intestinal tissue in order to obtain expandable, transplantable human Fetal Enterospheres for use in regenerative medicine. Furthermore, as stated supra, since Jarde teaches that both human and mouse small intestine express NRG1, there would have been a reasonable expectation of success in substituting mouse with human cells in the method of Jarde.
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.
Response to Traversal:
Applicant’s arguments filed on 09/30/2025 are acknowledged and have been discussed above.
Claim 10 stands rejected under 35 U.S.C. 103 as being unpatentable over Jarde et al (Cell Stem Cell. 2020; 27: 646–662, published on October 1, 2020. Prior art of record) in view of Sato et al., (Scientific Reports. May 22, 2020; 10:8308, p. 1-15. Prior art of record), as applied to claim 1 above, and further in view of Matrigel-Wikipedia (Wikipedia. December 9, 2019, downloaded from https://en.wikipedia.org/w/index.php?title=Matrigel&oldid=930001942, downloaded on 7/25/23. Prior art of record).
Claim 10 is directed to the culturing being in a 3D scaffold comprising laminin, nidogen, collagen, hepatic sulfate proteoglycans, and TGF-β.
As discussed supra, Jarde in view of Sato teach a method of culturing intestinal cells to form intestinal organoids. Both Jarde and Sato teach the culturing is in Matrigel that solidifies during culturing at 37°C (Jarde, p. e4, “Organoid culture” and “Single cell organoid culture”, and Sato, p. 13, “Organoid culture”), thus teach culturing intestinal cells/tissue in Matrigel, which solidifies to form a 3D scaffold.
However, Jarde and Sato do not specifically teach the scaffold comprising laminin, nidogen, collagen, hepatic sulfate proteoglycans and TGF-β.
Matrigel-Wikipedia teaches that Matrigel is a basement membrane matrix that is commercially available and can be used as a 3D scaffold for cell culture (p. 1, para 1 and para “metastasis model”). Matrigel-Wikipedia teaches Matrigel comprises “laminin, nidogen, collagen, hepatic sulfate proteoglycans and growth factors like TGF-β” (p. 2, para “constituents”).
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 appreciated that the method of culturing intestinal cells/tissue in a 3D scaffold Matrigel as suggested by Jarde in view of Sato would have been in a 3D scaffold comprising laminin, nidogen, collagen, hepatic sulfate proteoglycans and TGF-β as evidenced by Matrigel-Wikipedia.
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.
Response to Traversal:
Applicant’s arguments filed on 09/30/2025 are acknowledged and have been discussed above.
Claims 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Jarde et al (Cell Stem Cell. 2020; 27: 646–662, published on October 1, 2020. Prior art of record) in view of Sato et al., (Scientific Reports. May 22, 2020; 10:8308, p. 1-15. Prior art of record), as applied to claim 1 above, and further in view of RnD System (Information sheet of Recombinant Human Epiregulin. Published on 2/6/2018. Downloaded from https://www.rndsystems.com/products/recombinant-human-epiregulin-protein_1195-ep, downloaded on 1/5/2026. P. 1).
Claim 22 is directed to the culture medium comprising EREG at a concentration between 0.1 ng/mL and 5 ng/mL. Claim 23 is directed to being about 1 ng/mL.
However, Sato uses epiregulin at a concentration of 500 ng/mL (p. 13, para “Organoid culture”), but Jarde and Sato are silent on using EREG at the claimed concentration in claims 22-23.
RnD System teaches the ED50 of recombinant human epiregulin (EREG) is 0.125 - 0.75 ng/mL, measured in a cell proliferation assay (see p. 1, section “Specifications”, row “Activity”, and section “DATA”, left panel “Bioactivity”).
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 of culturing intestinal cells/tissue in a culture medium comprising EREG as suggested by Jarde in view of Sato, by substituting the concentration of EREG with a concentration between 0.1 ng/mL and 5 ng/mL, about 1 ng/mL, as suggested by RnD System with a reasonable expectation of success. Since RnD System teaches the ED50 of recombinant human EREG is 0.125 - 0.75 ng/mL measured in a cell proliferation assay (see p. 1, section “Specifications”, row “Activity”, and section “DATA”, left panel “Bioactivity”), one of ordinary skill in the art would have had a reason to substitute with the claimed lower concentration as suggested by RnD System in order to support intestinal organoid culture with a lower amount of agents.
Furthermore, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is a routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
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.
Response to Traversal:
Applicant’s arguments filed on 09/30/2025 are acknowledged and have been discussed above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631