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 .
Application Status
The preliminary amendment filed September 22, 2023 is acknowledged. Claims 1-9 are pending and under examination.
Drawings
The drawings are objected to because on sheet 3, “FIG. 3” is not oriented upright with respect to the rest of the figure. Rule 37 C.F.R. 1.84(p)(1) indicates that reference characters must be oriented in the same direction as the view so as to avoid having to rotate the sheet. The immunoblots are meant to be viewed such that the labels next to the arrows are upright.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the terms Opti-MEM®, Novocyte®, and Lipofectoamine®, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
Claim 1 recites a recombinant vector comprising polynucleotides encoding a HIF-1a inhibitor, a 2A peptide, and an anticancer cytokine. The genus of 2A peptides and cytokines are inherently all protein-based and therefore can be “encoded by a polynucleotide”. HIF-1a inhibitors include small molecules, other genes/proteins, antibodies and nucleic-acid based inhibitors, such as antisense oligonucleotides, miRNAs and siRNAs. Only protein-based and nucleic acid-based inhibitors can be “encoded by polynucleotides”, therefore the genus of HIF-1a inhibitors is limited to exogenous or heterologous proteins, antibodies, and nucleic acid-based inhibitors that only contain naturally-occurring nucleotides (i.e., not nucleotides with 2’-OMe sugars or phosphorothioate linkages).
It is noted that there no requirement for the 2A peptide coding sequence to be “operably linked” to the other two other coding sequences even in claim 2 that requires the 2A peptide sequence to be between the other coding sequences.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating lung and liver cancer using a recombinant vector encoding CYB5R3 and IL-21, does not reasonably provide enablement for 1) preventing cancer, 2) treatment of all cancers, 3) use of all HIF-1a inhibitors and 4) use of all the “anti-cancer” cytokines recited in claim 6. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Exemplary factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP 2164.01(a). All of these factors were considered, along with others, and a sufficient number are addressed below so as to create a prima facie case.
Nature of the Invention and Breadth of Claims
Claim 1 is drawn to a method of preventing or treating cancer by administering a bicistronic vector encoding an HIF-1a inhibitor and a cytokine with “anti-cancer” properties. Prevention is defined in the Specification as “all actions that inhibit a disease such as cancer or delay the onset of the disease” ([0033]). “Treatment is defined as “all actions in which symptoms such as a cancer disease are ameliorated or advantageously changed” ([0036]). The Specification defines “anti-cancer cytokine” as “a cytokine known to induce immune responses specific to cancer cells and cancer by activating T cells, B cells, NK cells, and the like in the body, and served to kill cancer cells through autoimmunity” and gives examples of anti-cancer cytokines ([0033]). The Specification does not define “HIF-1a inhibitor” and encompasses any means in which the expression or activity of the HIF-1a gene, mRNA, or protein is reduced. As noted in paragraph 7 above, the inhibitor must be genetically encoded, and therefore includes cellular proteins that inhibit the expression or activity of HIF-1a, antibodies that can inhibit the protein’s activity, RNAi-based nucleic acids that inhibit HIF-1a post-transcriptionally, or gene editing systems targeted to the HIF-1a locus, such as Cas9/gRNA systems.
Accordingly, enablement of the method requires one skilled in the art to reduce symptoms and/or prevent the onset of symptoms in the genus of cancers by expressing 1) HIF-1a inhibitors from a vector, thereby reducing HIF-1a expression and activity and 2) a cytokine from the genus of cytokines that have been shown previously to activate immune cels that can kill cancer cells.
Guidance in the Specification
The Specification provides prophetic lists of possible cancers ([0034]) and anticancer cytokines ([0033]). The Specification discloses a single HIF-1a inhibitor – cytochrome b5 reductase (CYB5R3), but does not disclose other genes/proteins that regulate HIF-1a or structures of antibodies that may inhibit HIF-1a activity in vivo, or the sequences of nucleic-acid inhibitors. The specification provides a set of working examples of recombinant vectors that encode CYB5R3 in combination with IL-2, IL-7, IL-12, IL-15, IL-21, IL-37, and GM-CSF ([0045]; Fig 2, 4) and measures the apoptotic-promoting potential of each combination in A549 cells, a lung cancer cell line (Fig 5). Expressing CYB5R3 in the A549 cell line resulted in a modest increase in apoptosis, while co-expressing the cytokine resulted in 50% increase in cell apoptosis over baseline. Interestingly though, administering CYB5R3 alone without a cytokine in H1299 cells, another lung cancer cell line, had no anti-cancer effects (Fig 5). Only when IL-21 was co-expressed with CYB5R3 was the recombinant vector effective at killing cancer cells.
The Specification provides no additional examples of expressing both proteins in other cancer cells types, or expressing CYB5R3 with an Interferon or with IL-18. The Specification does not provide any examples wherein the dual gene expression vector can prevent cancer. Accordingly, in light of the specification, it is highly unpredictable how or even if one skilled in the art could prevent any cancer, treat any cancer other than lung cancer, use any other HIF-1a inhibitor other than CYB5R3, or use IL-18 or IFNs in combination with CYB5R3 to treat cancer.
State of the Prior Art
Because each of the claimed elements in the method encompass a genus, each will be reviewed as they apply to enablement of the claimed invention.
Cancers are a heterogenous group of diseases whose only unifying feature is unregulated cell proliferation. The underlying genetic and metabolic causes of the uncontrolled cell division and the interactions with the tumor microenvironment differ amongst cancer types, and sometimes even within cancer types, such as breast cancer. It is well-established in the art that therapies for one cancer may not work to treat another type of cancer. This is true even for some established “anti-cancer” cytokines. For instance, Zaidi teaches that although IFN-gamma has been used to treat a variety of malignancies, IFN-gamma also has tumorigenic-promoting affects (Zaidi and Merlino, Clinical Cancer Research (2011), 17: 6118-6124; Abstract, Fig 2). Additionally, Fabbi described IL-18 treatment as a “double edge sword” because IL-18 has been shown to both promote tumor development and progression or enhance anti-tumor immunity and limit tumor growth in different preclinical models (Fabbi et al., Journal of Leukocyte Biology (2015), 97: 665-675). Specifically in lung cancer, the cell-type tested by Applicant, IL-18 was shown to enhance lung metastasis through induction of PD-1 on NK cells (Table 3), but suppress parental tumor growth via T cell responses (Table 1). Because Applicant did not test IL-18 together with CYB5R3 expression in lung cell lines, it is not predictable what effect the combination would have even in lung cancer. Finally, Hong teaches that granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes immune-independent tumor progression by supporting tumor microenvironments and stimulating tumor growth and metastasis (In-Sun Hong, Experimental & Molecular Medicine (2016) 48: e242). In summary, there is unpredictability in the field of cancer therapies regarding the roles and tumor-inhibiting ability of cytokines in different cancer types.
HIF-1a is a transcription factors that functions to upregulate genes necessary for cell survival in hypoxic (i.e., low oxygen levels) environments (Hayashi et al., Cancer Science (2019), 110: 1510-1517; Fig 1). Most tumor microenvironments are hypoxic and HIF-1a activation is through to be a hallmark of cancer cells (Abstract). Although HIF-1a-inhibiting proteins are known in the art including VHL, Rack1 and HSP90 (Section 3.1 and 3.3), the effect of inhibiting HIF-1a in cancer cells or anti-cancer immune cells for treating different cancers is a mixed bag. For instance, treating myeloma cells with a sulfonanilide that inhibits HIF-1a signaling increased apoptosis in cancer cells (Hose et al., Blood (2010), 116: 2987). Won demonstrated that overexpression of CYB5R3 in hepatocellular carcinoma cells reduced tumor growth (US 20160235821 A1; ([0101]-[0103]). However, downregulation of HIF-1a expression has also been shown to lead to increased proliferation of prostate cancer stem cells (Marhold et al., Molecular Cancer Research (2014), 13: 1-9; Fig 5). Additionally, Teng showed that HIF-1a-induced CBX2 transcription promotes pancreatic cancer progression (World Journal of Gastrointestinal Oncology (2021), 13: 1709-1724; Abstract). Even Applicant’s preferred HIF-1a inhibitor, CYB5R3, has been shown to correlate with low survival rates and promote colonization and metastasis formation in triple-negative breast cancer (Lund et al., Molecular and Cellular Proteomics (2015), 14: 2988-2999). Therefore, it is not predictable that the results shown in two lung cancer cell lines by Applicant could be recapitulated in different cancer cell types and in different cancer models.
Finally, there is no evidence in the art that antibodies directed to HIF-1a are effective in vivo when endogenously expressed. There is also no evidence in the art that expressing anti-cancer cytokines from an exogenous polynucleotide either alone or in combination with coding sequences of HIF-1a inhibitors can prevent cancer.
Thus, in view of the prior art, it would be highly unpredictable how or even if one skilled in the art could prevent any cancer, treat any cancer other than lung and liver cancer, use any other HIF-1a inhibitor other than CYB5R3, or use IL-18 or IFNs in combination with CYB5R3 to treat cancer.
Experimentation Required
In order to practice the invention, one skilled in the art would need to create vectors for the expression of the many upstream and downstream regulators of HIF-1a together with the genus of anti-cancer cytokines and systematically test every cell cancer line, in anti-cancer immune cells, and in cancer models at a variety of doses and administration schemes to determine which, if any, can decrease reduce cancer cell survival or slow proliferation. However, given the great degree of heterogeneity in cancer genetics and biology, it is unpredictable which cancers under which tumor environments would response to HIF-1a inhibition. As such, undue experimentation would need to be done by the skilled artisan to practice the invention in its entire claimed scope.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant, and the lack of working examples across the claimed scope, it is the conclusion that an undue experimentation would be required to practice the invention across its entire claimed scope.
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.
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 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Hinrichs (US 20210052647 A1, published February 25, 2021; cited on the PCT International Search Report) in view of Won (US 20160235821 A1; published August 18, 2016; cited on IDS filed 2/21/2025) and Sanchez-Hernandez (Sanchez-Hernandez et al., Gene Therapy (2018), 25: 439-449).
Regarding claims 1-3 and 6, Hinrichs teaches a recombinant cassette comprising the coding sequence for IL-21 (i.e., an anti-cancer cytokine) and the coding sequence for IL-15 (i.e., a second anti-cancer cytokine) connected by a “linker” (i.e., wherein the linker is inserted in between the two IL coding sequences) (Fig 1C). Hinrichs teaches one such linker is the cleavable linker Furin-P2A (i.e., a 2A peptide) (Table 5). Hinrichs teaches a retroviral vector in which the IL-21 coding sequence and the IL-15 is connected by a Furin 2A peptide coding sequence (Table 6B; SEQ ID NO 44; [0153]). Hinrichs teaches T cells transduced with the IL-21/15-P2A vector and then administered to CaSki-cell-derived tumor-bearing mice were effective at promoting tumor regression in ([0201]-[0207]; Fig 9). Hinrichs teaches the dual anti-cancer-cytokine expression method is effective treating hepatocellular carcinoma ([0114]). Therefore, Hinrichs teaches administering a vector for the co-expression of two anti-cancer proteins to a subject for the purpose of treating cancer.
Hinrichs does not teach including the coding sequence for a protein that inhibits HIF-1a.
Won teaches overexpression of CYB5R3 in cancer cells results in significant reduction of HIF-1a, which leads to inhibition of cancer cell grown in vitro and in vivo (Abstract). Won teaches a recombinant vector comprising the coding sequence of CYB5R3 (Figure 4A). Won demonstrates administering the recombinant vector to a hepatocellular carcinoma (i.e., liver cancer) cell line inhibited cell growth ([0101]-[0103]). Won teaches “to improve the therapeutic effect, combination of some drugs have been tried” ([0007]).
Sanchez-Hernandez teaches co-expression of two tumor suppressor genes separated by a p2A peptide sequence and delivered by lentiviral vector (page 441, ¶4) is an effective gene therapy treatment for cancers (Fig 3). Sanchez-Hernandez teaches expressing both genes has an additive effect for reducing cancer cell viability (Fig 3).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have substituted the IL-15 coding sequence in Hinrich’s retroviral vector for Won’s CYB5R3 coding sequence. It would have amounted to the simple substitution of the coding sequence of one known anti-cancer protein for another by known means to yield predictable results. The skilled artisan would have predicted that the coding sequence of CYB5R3 could be cloned into Hinrich’s retroviral vector because 1) Won teaches providing the coding sequence in another recombinant vector and it is evident from all three cited references that cloning genes encoding anti-cancer proteins into vectors for delivery to cells is routine in the art. Additionally, it would have been entirely predictable that providing both IL-21 and CYB5R3 would reduce HCT116 cancer cell proliferation because Hinrichs teaches the cytokines are effective for treating hepatocellular carcinoma and Won demonstrates reduced HCT116 growth upon CYB5R3 expression. The skilled artisan would have been motivated to combine the CYB5R3 and IL-21 coding sequences into a single vector for cancer treatment since 1) it’s easier to administer a single vector, 2) Won teaches that finding effective combinations of drugs is a goal of the pharmaceutical industry and 3) Sanchez-Hernandez teaches that co-expressing known anti-cancer proteins in cancer cells can have an additive effect for reducing cancer cell growth.
Regarding claim 4, Won teaches the sequence of CYB5R3 is SEQ ID NO 1 ([0057]), which is recited on page 8, and which is 100% identical to SEQ ID NO 5 of the examined application.
Regarding claim 5, Hinrichs teaches the sequence of Furin 2A peptide is RAKRSGSGATNFSLLKQAGDVEENPGP (SEQ ID NO 11) (Table 5), which comprises a sequence that is 100% identical to SEQ ID NO 5 of the examined application (underlined above).
Regarding claims 7-8, Hinrichs teaches the recombinant vector is a retroviral vector, as indicated above for claim 1.
Regarding claim 9, as indicated above for claim 1, Hinrichs teaches the dual-cytokine-vector therapy is useful for treating hepatocellular carcinoma (i.e., liver cancer) and Won demonstrates CYB5R3 overexpression reduces growth of a liver cancer cell line.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10973884 in view of Hinrichs (US 20210052647 A1, published February 25, 2021; cited on the PCT International Search Report) and Sanchez-Hernandez (Sanchez-Hernandez et al., Gene Therapy (2018), 25: 439-449).
Patented claim 1 recites A method for treating cancer comprising a step of administering a vector containing a polynucleotide encoding cytochrome b5 reductase 3 (CYB5R3) protein or a cell containing the vector to a subject in need of cancer treatment; wherein the CYB5R3 protein is overexpressed and inhibits hypoxia-inducible factor 1 (HIF-1) in cancer cells of the subject, and wherein the cancer is one or more cancers selected from the group consisting of colorectal cancer, liver cancer, stomach cancer, breast cancer, pancreatic cancer, prostate cancer, lung cancer, and kidney cancer. Patented claim 2 recites the CYB5R3 protein consists of the amino acid sequence represented by SEQ. ID. NO: 1, which is 100% identical to SEQ ID NO 1 of the examined application. Patented claims 3-4 recites wherein the vector is a linear DNA, a plasmid DNA, or a recombinant virus vector, including a retrovirus, adenovirus, adeno-associated virus, herpes simplex virus, lentivirus, vaccinia virus.
The patented claims do not recite the vector also comprising the coding sequence for an anti-cancer cytokine and a 2A peptide.
Hinrichs teaches a recombinant cassette comprising the coding sequence for IL-21 (i.e., an anti-cancer cytokine) and the coding sequence for IL-15 (i.e., a second anti-cancer cytokine) connected by a “linker” (Fig 1C), the cleavable linker Furin-P2A with a sequence that is 100% identical to SEQ ID NO 5 of the examined application ([0057]). Hinrichs teaches cells transduced with the IL-21/15-P2A vector and then administered to tumor-bearing mice were effective at promoting tumor regression in ([0201]-[0207]; Fig 9). Hinrichs teaches the dual anti-cancer-cytokine expression method is effective treating hepatocellular carcinoma ([0114]).
Sanchez-Hernandez teaches co-expression of two tumor suppressor genes separated by a p2A peptide sequence and delivered by lentiviral vector (page 441, ¶4) is an effective gene therapy treatment for cancers (Fig 3). Sanchez-Hernandez teaches expressing both genes has an additive effect for reducing cancer cell viability (Fig 3).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have added the coding sequence for IL-21 to the patented vector and separated it by the 2A peptide coding sequence as taught in Hinrichs for the purpose of treating cancer. It would have amounted to the simple combination of elements by known means to yield predictable results. The skilled artisan would have predicted that the coding sequence of IL-21 and the 2A peptide could be added to the patented vector because Hinrichs and Sanchez-Hernandez both teach that cloning anti-cancer genes for co-expression during gene therapy is routine in the art. Additionally, it would have been entirely predictable that providing both IL-21 and CYB5R3 would reduce cancer cell proliferation because Hinrichs teaches the cytokines are effective for treating a cancer because CYB5R3 is a known anti-cancer protein expression. The skilled artisan would have been motivated to combine the CYB5R3 and IL-21 coding sequences into a single vector for cancer treatment since it’s easier to administer a single vector, and Sanchez-Hernandez teaches co-expression of anti-cancer proteins can lead to additive effects for reducing cancer cell growth.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635