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 amended claims filed August 17, 2023 are acknowledged. Claims 18-23 are canceled. Claims 3, 9, 12, and 24-26 are amended. Claims 1-17 and 24-26 are pending and under examination herein.
Specification
The use of the terms “ALFA®” and “NANOBODY®”, which are a trade name or a mark 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.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 112(b)
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 7 and 12-15 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 7 contains the trademark/trade name “ALFA®” (NanoTag Biotechnologies GmbH). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a synthetic epitope tag having a specific amino acid sequence and, accordingly, the identification/description is indefinite.
Claim 12 recites the limitation “the programmable bacterial cells” (plural). There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which the claim depends, recites that the system comprises “a programmable bacteria cell” (singular), but not multiple programmable bacterial cells.
Claims 13-15, which depend from claim 12, are similarly rejected.
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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
(1)
Claims 1-5, 9, and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Park (Science Translational Medicine (2020) 12(559): eaaz1863; cited in IDS) in view of Chien (Current Opinion in Systems Biology (2017) 5: 1-8; cited in IDS), Din (Nature (2016) 536: 81-85; cited in IDS), and Chang (Nature Chemical Biology (2018) 14: 317-324; cited in IDS).
Park teaches that a major challenge for chimeric antigen receptor (CAR) T cell therapy
for solid tumors is that there are few antigens whose expression is strictly confined to tumors, which “poses considerable safety concerns and potentially narrows the therapeutic window for their application against solid tumors” (e.g., Abstract; Introduction). Park states, “In addition to the shared expression of solid tumor antigens on normal tissue, most of these antigens also have heterogeneous and nonuniform expression patterns in tumors, limiting the potential for effective and durable antitumor responses” (Introduction). To address these challenges, Park evaluated a combination approach comprising (1) an oncolytic virus (OV) which selectively infects and drives tumor-specific expression of a proof-of-concept CAR-targetable tumor antigen (a truncated nonsignaling variant of CD19, “CD19t”), and (2) a CD19-specific CAR T cell, which was tested in human solid tumor xenograft models (e.g., Abstract; Introduction; Methods). Park states that engineered oncolytic viruses are a promising treatment modality for solid tumors because “[t]hese viruses exhibit tumor selectivity, desirable immunogenic properties, and targeted transgene delivery to tumors” and exert immune-stimulating effects systemically and in the local tumor microenvironment (e.g., Introduction).
Park discloses that the oncolytic virus effectively delivered CD19t antigen to solid tumor cells in vitro and that CD19-CAR T cells demonstrated anti-tumor activity against CD19t-infected tumors in vitro and in vivo (e.g., Results; Figures 1-3). Park also discloses that infiltration of endogenous T cells into the tumor site was amplified by the combination of the CD19t-expressing oncolytic virus and the CD19-CAR T cells (e.g., Results; Figure 6). Park concludes that “this antigen delivery method can be clinically translated for solid tumor types that lack amenable tumor antigens for safe and effective targeting by CD19-CAR T cells” (e.g., Discussion). Regarding future directions in which this work may be taken, Park discloses, “Although the introduction of de novo tumor targets distinguishes our approach from other studies combining OV with CAR T cells, we plan to further modify these OV to express checkpoint pathway inhibitors, cytokines, and chemokines to augment CAR T cell trafficking to tumors and their antitumor activities”, and further, “Although we performed these proof-of-concept studies using CD19t as a target, this approach has the potential to introduce other targets, including nonhuman species-specific antigens, which may also further enhance the antitumor efficacy by eliciting host immunity to foreign proteins” (Discussion at page 7).
Park notes that although they observed minimal vaccinia or mCD19t expression in normal tissues after intratumoral delivery of OVm19t, the OV has the potential to infect normal cells, leading to unwanted expression of CD19t antigen (Discussion at page 8). Park also states that “immunogenicity against vaccinia virus may limit the opportunity for repeat injections of OV19t” (Discussion at page 8).
In contrast to the instant claims, the combination system disclosed by Park does not comprise a programmable bacteria cell comprising a synchronized lysis circuit and a nucleic acid sequence encoding an antigen recognized by the CAR T cell. Further, while Park notes the potential for the combination strategy of their disclosure to be used for targeting other targets (e.g., nonhuman species-specific antigens), Park does not disclose CAR T cells targeting, e.g., a form of super-folding green fluorescent protein (sfGFP).
Chien reviews engineering strategies that have advanced bacterial cancer therapies. Chien teaches that bacteria naturally localize to tumor by entering through the extensive tumor vasculature and colonizing the necrotic core, evading immune surveillance by macrophages and neutrophils (page 2). Chien further teaches, “Since bacteria can grow to a higher density in tumor environments than in healthy tissue, quorum (density) sensing can be used as a tumor sensitive switch” (page 3; Figure 2C). Chien summarizes work by Din, who “engineered a circuit termed the synchronized lysis circuit (SLC) in which a lysis gene, as well as production of a therapeutic compound, was regulated by quorum sensing. The growth of SLC bacteria would trigger rhythmic bacterial death (Figure 2C). The SLC circuit led to reduction in tumor activity in vitro and in vivo, where it slowed tumor growth while controlling bacterial growth. Additionally, mice were healthier when treated with the lysis circuit bacteria than from bacteria with a constitutively produced therapeutic. Dynamic circuits such as these capable of driving periodic drug delivery may have unique implications, as the timing of drug administration has recently been shown to be important to therapeutic efficacy and chemoresistance development” (Chien at page 4; Figure 2). The SLCs taught by Din comprise a quorum sensing gene, a lysis gene (gene E), a promoter (e.g., tac or luxI), and a terminator (e.g., T0 or T1), as well as a gene encoding a superfolder GFP (sfGFP) (e.g., Din at pages 81-82; Figure 1A-1B; Supplementary Information; Extended Data Figure 5), relevant to claims 1-2. Din further describes the addition of a cytotoxic payload (Haemolysin E, encoded by hlyE) to the circuit and teaches that the SLC bacteria were capable of releasing HlyE at the level to kill cervical cancer cells in vitro (e.g., page 2; Figures 1 and 3). Din notes that they previously established “that oral delivery of these bacterial strains led to safe and efficient colonization of hepatic colorectal metastases … , and that mice tolerated repeated dosing without overt adverse effects” (page 84).
Relevant to claims 12-14, Chien further teaches that the species and strain of bacteria used are an important consideration (page 4). Chien teaches that bacteria of the genera Salmonella, Escherichia, Bifidobacteria, and others have been used for engineered bacterial therapies. After S. typhimurium, E. coli is the next most commonly used model organism in cancer therapeutics, since E. coli has non-pathogenic variants naturally found in the human gut, some of which have a positive health effect when given (e.g., pages 4-5). Chien discloses that E. coli Nissle 1917 is the most commonly used probiotic strain (pages 4-5).
Chang describes the engineering of CAR T cells to respond to diverse soluble ligands such as the CD19 ectodomain and GFP variants in order to broaden the utility of CARs in disease treatment (e.g., Abstract; Introduction). Chang discloses that soluble CD19 ligands stimulated CD19 CAR-expressing primary human CD4+ T cells to produce immunostimulatory cytokines (e.g., Results). Chang further generated green fluorescent protein (GFP)-binding CARs against monomeric super folder GFP (sfGFP) and homodimeric sfGFP linked by a disulfide bond introduced by a D117C substitution (relevant to claims 1 and 3-5) to determine the role of multimericity of the soluble ligand in triggering CAR activation (e.g., Results; Figure 1). Chang observed that Jurkat cells (T cells) expressing a single GFP-CAR construct were activated by dimeric sfGFP but not by monomeric sfGFP (Results; Figure 1). Chang concludes that their work provides the first demonstration of CARs that are specifically engineered to respond to freely soluble ligands and stimulate T cell effector function (e.g., Discussion).
In view of the teachings above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the combination approach of Park by substituting a tumor-targeting bacteria cell or cells (e.g., of the genus Salmonella or Escherichia) expressing a synchronized lysis circuit in place of the oncolytic virus. The skilled artisan would have been motivated to do so because Chien teaches that bacteria such as Salmonella and Escherichia colonize to tumors naturally, and further, because Din provides that these probiotic bacterial strains may be administered orally and under a repeated dosing regimen without overt adverse effects. One would further have been motivated to incorporate a SLC regulated by quorum sensing in the probiotic bacteria cell(s) because Chien teaches that the SLC circuit simultaneously reduced tumor activity and controlled bacterial growth, and that mice treated with lysis circuit bacteria were healthier than those treated with constitutively active therapeutic bacteria. There would have been a reasonable expectation of success because both the OV taught by Park and the SLC bacteria described by Chien and Din are capable of specifically targeting tumors and expressing nucleic acids that encode an exogenous antigen in combination with a therapeutic compound.
The skilled artisan would have been further motivated to make a system wherein the programmable bacteria cell(s) encodes a synthetic antigen such as sfGFP because, as taught by Park, it was a known problem in the field of CAR T cell therapy that identifying antigens that are truly confined to tumors remains a great challenge that poses safety and efficacy-related concerns. The use of a synthetic antigen would alleviate these safety concerns because the CAR would not target normal cells, which lack endogenous expression of sfGFP. There would have been a reasonable expectation of success because Din provides a proof-of-concept that sfGFP can be expressed in SLC bacteria, and Chang provides a proof-of-concept that a CAR construct specific for sfGFP can be generated and specifically target GFP-expressing cells.
(2)
Claims 1 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Park (Science Translational Medicine (2020) 12(559): eaaz1863; supra) in view of Chien (Current Opinion in Systems Biology (2017) 5: 1-8; supra), Din (Nature (2016) 536: 81-85; supra), and Chang (Nature Chemical Biology (2018) 14: 317-324; supra) as applied to claims 1-5, 9, and 12-14 above, and further in view of Gotzke (Nature Communications (2019) 10: 4403; cited in IDS) and Bao (biomolecules (2021) 11(2): 238).
The teachings of Park are recited in the 35 U.S.C. § 103 rejection above.
While Park notes the potential for the combination strategy of their disclosure to be used for targeting other targets (e.g., nonhuman species-specific antigens), Park does not disclose CAR T cells targeting an ALFA® tag protein.
The teachings of Chien, Din, and Chang, with respect to programmable bacteria comprising a SLC, are discussed above.
Gotzke describes the “ALFA-tag”, a small protein which Gotzke reports has utility in a variety of life sciences applications (e.g., Abstract). The “ALFA-tag” was inspired by an artificial peptide reported to form a stable α-helix in solution and its sequence was selected in part based on its absence in common eukaryotic model systems (e.g., page 2). Gotzke determined via immunofluorescence experiments that the “ALFA-tag” does not seem to impair the physiological behavior of tagged proteins of interest (e.g., page 2). Gotzke further characterized a single domain antibody (NANOBODY®) “NbALFA” specific for the “ALFA-tag” and generated a weakened version (“NbALFAPE”) which could be used for applications such as the specific enrichment of cells under physiological conditions, e.g., CAR-modified T cells (e.g., Abstract; Results). Gotzke discloses that 71.8-97.7% enrichment of CD62L+ lymphocytes, most of which were CD3+ T cells, could be achieved by passing human peripheral blood mononuclear cells (PBMCs) through an ALFA® SelectorPE column pre-charged with an ALFA-tagged single-domain antibody recognizing CD62L (e.g., page 6).
Bao reviews the application of single-domain antibodies (nanobodies®) in CAR-T therapy. According to Bao, “Nanobodies have been widely applied as the antigen binding domain of CAR-T due to their small size, optimal stability, high affinity, and manufacturing feasibility. The nanobody-based CAR structure has shown a proven function in more than ten different tumor-specific targets. After being transduced in Jurkat cells, natural killer cells, or primary T cells, the resulting nanobody-based CAR-T or CAR-NK cells demonstrate anti-tumor effects both in vitro and in vivo. Interestingly, anti-BCMA CAR-T modulated by a single nanobody or bi-valent nanobody displays comparable clinical effects with that of single-chain variable fragment (scFv)-modulated CAR-T” (Abstract).
Based on the further teachings of Gotzke and Bao, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the combination approach of Park by substituting a tumor-targeting bacteria cell or cells expressing a synchronized lysis circuit in place of the oncolytic virus (based on the further teachings of Chien, Din, and Chang), wherein the programmable bacteria cell(s) encodes an “ALFA-tag” antigen and the CAR T cell comprises a single-domain antibody targeting said antigen. The skilled artisan would have been motivated to use an “ALFA-tag” as an antigen because it’s a small, synthetic protein (and therefore, could be easily expressed in bacteria and would not be endogenously expressed, overcoming challenges described by Park), and because a corresponding single-domain antibody specific for the ALFA-tag can be incorporated into a chimeric antigen receptor (as suggested by Gotzke and Bao). There would have been a reasonable expectation of success because Bao teaches that single-domain antibodies have widely been applied as antigen-binding domains in CAR-T cells, and because Din provides a proof-of-concept that a synthetic antigen can be expressed by a SLC bacteria.
(3)
Claims 1, 9-10, 16-17, 24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Park (Science Translational Medicine (2020) 12(559): eaaz1863; supra) in view of Chien (Current Opinion in Systems Biology (2017) 5: 1-8; supra), Din (Nature (2016) 536: 81-85; supra), and Chang (Nature Chemical Biology (2018) 14: 317-324; supra) as applied to claims 1-5, 9, and 12-14 above, and further in view of Slaney (Cancer Research (2014) 74(24): 7168-7174).
The teachings of Park are recited in the 35 U.S.C. § 103 rejection above.
While Park notes that their OVs may be modified to express cytokines or chemokines to augment CAR T cell trafficking to tumors and their antitumor activities, Park does not expressly teach expressing nucleic acids encoding one of IL-12, CXCL9, and CXCL16.
The teachings of Chien, Din, and Chang, with respect to programmable bacteria comprising a SLC, are discussed above.
Slaney teaches that in the cancer setting, the presence of tumor-infiltrating lymphocytes has been reported to correlate well with positive clinical outcomes (e.g., Introduction). Slaney further teaches that trafficking of T cells to the tumor microenvironment is critical for the success of adoptive T cell therapies, but a lingering problem in the field is the need to effectively target a higher frequency of T cells to the tumor microenvironment, overcoming challenges associated with immunosuppression and aberrant vasculature (e.g., Abstract; Introduction). Pertinent to claims 9-10, 16, and 24, Slaney discloses that increased expression of CXCL9 (a ligand for CXCR3, expressed on T cells) by tumor cells resulted in increased infiltration of CXCR3+ cytotoxic T lymphocytes (CTLs) and enhanced anti-tumor response in murine cancer models (page 7169). In addition, Slaney discloses that expression of CXCR6 (the receptor for CXCL16) is upregulated upon activation of naïve T cells, and that mice lacking CXCR6 have reduced T cell infiltration in mammary tumors and impaired tumor regression (page 7169), suggesting that CXCL16 expression in tumors would also serve to traffic activated T cells to the tumor microenvironment. Slaney also teaches that local delivery of IL-12 to the tumor site enhance intratumoral T-cell infiltration and local proliferation by decreasing immunosuppression and enhancing antigen presentation (page 7171).
In view of the further teachings of Slaney, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the combination approach of Park by substituting a tumor-targeting bacteria cell or cells expressing a synchronized lysis circuit in place of the oncolytic virus (based on the further teachings of Chien, Din, and Chang), wherein the tumor-targeting bacteria cell(s) further comprise a nucleic acid encoding a cytokine such as IL-12, CXCL9, or CXCL16. The skilled artisan would have been motivated to do so because Slaney teaches that the presence of tumor-infiltrating lymphocytes in the tumor microenvironment improves clinical outcomes, and intratumoral expression of IL-12, CXCR9, and CXCL16 increase trafficking of T cells (e.g., CAR T cells) to the tumor microenvironment to facilitate anti-tumor activity. There would have been a reasonable expectation of success because those of ordinary skill in the art would have recognized the suitability of targeting expression of one or more of these cytokines to the tumor microenvironment to facilitate cancer treatment, and furthermore, Din provides a proof-of-concept that an additional therapeutic protein in combination with an antigen (sfGFP) can be expressed by a SLC bacteria.
(4)
Claims 1 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Park (Science Translational Medicine (2020) 12(559): eaaz1863; supra) in view of Chien (Current Opinion in Systems Biology (2017) 5: 1-8; supra), Din (Nature (2016) 536: 81-85; supra), and Chang (Nature Chemical Biology (2018) 14: 317-324; supra) as applied to claims 1-5, 9 and 12-14 above, and further in view of Stritzker (Bioengineered Bugs (2010) 1(2): 139-145).
The teachings of Park are recited in the 35 U.S.C. § 103 rejection above.
In contrast to the instant claims, the combination system disclosed by Park does not comprise a programmable bacteria cell (or cells) comprising a synchronized lysis circuit and a nucleic acid sequence encoding an antigen recognized by the CAR T cell, wherein the programmable bacteria cell(s) is an E. coli Nissle cell having an msbB gene knockout.
The teachings of Chien, Din, and Chang, with respect to programmable bacteria comprising a SLC, are discussed above.
Stritzker teaches that despite the utility of bacteria for tumor therapy based on their specific colonization of tumors, even non-pathogenic bacteria induced immune system responses which can be devastating for a cancer patient (e.g., Abstract). Spritzker investigated a msbB-mutant of the probiotic E. coli Nissle 1917 strain, which is unable to myristoylate lipid A, a lipid that serves as an anchor of LPS in the Gram-negative outer membrane and that activates TLR4 and can lead to septic shock (e.g., Abstract; Introduction). Stritzker observed that knockout of the msbB gene resulted in no differences in bacterial replication in vitro, lower activation of (i.e., production of TNF-α and IL-6 by) murine macrophages, and decreased toxicity in immunocompetent BALB/c mice compared to wild-type EcN (e.g., Abstract; Results; Figures 2A, 3, 4). Further, Stritzker observed that the msbB-knockout mutants still selectively colonized tumors at high concentrations (e.g., Abstract; Results; Figure 5). Stritzker concludes that the msbB-mutant EcN strain is particularly useful for tumor therapy as it has probiotic activity, does not express any protein toxins, and has a higher tumor-to-background ratio than that observed for Salmonella strains (e.g., Discussion, pages 141-142).
Based on the additional teachings of Stritzker, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the combination approach of Park by substituting a tumor-targeting bacteria cell or cells expressing a synchronized lysis circuit in place of the oncolytic virus (based on the further teachings of Chien, Din, and Chang), wherein the tumor-targeting bacteria cell(s) is an EcN strain having a msbB gene knockout. The skilled artisan would have been motivated to do so because Stritzker teaches that in comparison to the wild-type EcN strain, the msbB knockout strain of EcN induced less toxicity and pro-inflammatory cytokine activation. There would have been a reasonable expectation of success because the EcN msbB knockout strain replicates normally in culture and retains the ability to specifically colonize tumors, like the wild-type strain.
Allowable Subject Matter
Claims 6, 8, 11, and 25 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643