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Mitochondrial localization of muc1

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Title: Mitochondrial localization of muc1.
Abstract: The invention provides methods of identifying and making compounds that inhibit the interaction between MUC1 and either or both of HSP70 and HSP90. Also embraced by the invention are in vivo and in vitro methods of inhibiting such an interaction. ...


Inventor: Donald W. KUFE
USPTO Applicaton #: #20120071704 - Class: 600 1 (USPTO) - 03/22/12 - Class 600 
Surgery > Radioactive Substance Applied To Body For Therapy



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The Patent Description & Claims data below is from USPTO Patent Application 20120071704, Mitochondrial localization of muc1.

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RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 12/064,425, filed Feb. 21, 2008, which is a national phase application under 35 U.S.C. §371 of International Application No. PCT/US2006/032906, filed Aug. 21, 2006, which claims priority to U.S. provisional application Ser. No. 60/710,166, filed Aug. 22, 2005, the entire contents of which are hereby incorporated by reference. The entire text of each of the above-referenced disclosures are specifically incorporated herein by reference without disclaimer.

TECHNICAL FIELD

This invention relates to the regulation of cell growth, and more particularly to regulation of cancer cell growth.

BACKGROUND

The MUC1 protein is overexpressed by greater than 800,000 of the 1.3 million tumors diagnosed in the United States each year.

SUMMARY

The inventors have found that MUC1 binds to the HSP70 and HSP90 chaperones and that this binding is important for targeting of MUC1 to the mitochondria, where it attenuates stress-induced apoptosis. MUC1 binds to HSP70 and HSP90 independently, and c-Src is involved in MUC1-HSP90 binding. The invention includes methods for identifying compounds useful for inhibiting the interaction between MUC1 and HSP70 or HSP90. Such compounds can be useful for directly promoting apoptosis of MUC1-expressing cancer cells, for enhancing the efficacy of genotoxic chemotherapeutic agents against such cancer cells, and as anti-cancer prophylactic agents. Also included in the invention are methods of inhibiting the interaction between HSP70 or HSP90 and MUC1 in which cells (e.g., carcinoma cells such as breast carcinoma cells) are contacted with compounds that inhibit the interaction between MUC1 and HSP70 or HSP90. While the experiments described herein were generally performed with human MUC1, MUC1-binders, and cells, it is understood that the methods described herein can be performed with corresponding molecules from any of the mammalian species recited below.

The invention includes methods of identifying compounds that inhibit binding of MUC1 to HSP70. The methods include: (a) providing a MUC1 test agent; (b) providing a HSP70 test agent that binds to the MUC1 test agent; (c) contacting the MUC1 test agent with the HSP70 test agent in the presence of a test compound under conditions that permit the binding of the MUC1 test agent with the HSP70 test agent in absence of the test compound; and (d) determining whether the test compound inhibits binding of the MUC1 test agent to the HSP70 test agent. The contacting can be carried out in a cell-free system or it can occur in a cell.

The invention also includes methods of identifying compounds that inhibit binding of MUC1 to HSP90. The methods include: (a) providing a MUC1 test agent, e.g., a phosphorylated MUC1 test agent; (b) providing a HSP90 test agent that binds to the MUC1 test agent; (c) contacting the MUC1 test agent with the HSP90 test agent in the presence of a test compound under conditions that permit the binding of the MUC1 test agent with the HSP70 test agent in absence of the test compound; and (d) determining whether the test compound inhibits binding of the MUC1 test agent to the HSP90 test agent. The contacting can be carried out in a cell-free system or it can occur in a cell. The HSP90 test agent is phosphorylated by c-Src. In some embodiments, the contacting is performed in the presence of c-Src.

Also featured by the invention are methods of generating compounds that inhibit the interaction between MUC1 and HSP70 of HSP90. The methods include: (a) providing the three-dimensional structure of a molecule containing the cytoplasmic domain of MUC1 or HSP70 or HSP90 (e.g., the substrate binding domain of HSP70 or HSP90); (b) designing, based on the three dimensional structure, a compound containing a region that inhibits the interaction between MUC1 and HSP70 or the interaction between MUC1 and HSP90; and (c) producing the compound.

Another embodiment of the invention is a process of manufacturing a compound. The process includes: (a) performing the method described in the previous paragraph; and (b) after determining that the compound inhibits the interaction between MUC1 and HSP70 or MUC1 and HSP90, manufacturing the compound.

In another aspect, the invention provides in vivo methods of inhibiting binding of MUC1 to HSP70 or HSP90 in a cancer cell that expresses MUC1. The methods include: (a) identifying a subject as having a cancer that expresses MUC1 or is suspected to express MUC1; and (b) administering to the subject a compound or, where the compound is a polypeptide, a nucleic acid containing a nucleic acid sequence encoding the polypeptide, the nucleic acid sequence being operably linked to a transcriptional regulatory element (TRE), wherein the compound inhibits binding of HSP70 or HSP90 to the cytoplasmic domain of MUC1. The compound can be a peptide fragment of (a) MUC1, (b) HSP70, or (c) HSP90. Thus, the compound can be a peptide fragment of the cytoplasmic domain of MUC1. The compound can be a peptide fragment that includes all or part of amino acids 46-72 of SEQ ID NO:1. It can be or include all or part of the substrate binding domain of HSP70 or HSP90. Moreover, the compound can be an antibody, or an antibody fragment, that binds to the cytoplasmic domain of MUC1. Alternatively, the compound can be a small molecule, e.g., a small molecule that is or contains a nucleic acid aptamer. The subject can be a human subject. The cancer cell can be, e.g., a breast cancer, lung cancer, colon cancer, pancreatic cancer, renal cancer, stomach cancer, liver cancer, bone cancer, hematological cancer, neural tissue cancer, melanoma, ovarian cancer, testicular cancer, prostate cancer, cervical cancer, vaginal cancer, or bladder cancer cell. The TRE can be a DF3 enhancer.

Also embraced by the invention are methods of killing a cancer cell. The methods can include, before, after, or at the same time as performing the methods described in the previous paragraph, exposing the subject to one or more genotoxic agents. The genotoxic agents can be, for example, one or more forms of ionizing radiation and/or one or more chemotherapeutic agents. The one or more chemotherapeutic agents can be, for example, cisplatin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide, verampil, podophyllotoxin, tamoxifen, taxol, transplatinum, 5-fluorouracil, vincristin, vinblastin, methotrexate, or an analog of any of the aforementioned.

“Polypeptide” and “protein” are used interchangeably and mean any peptide-linked chain of amino acids, regardless of length or post-translational modification. The MUC1 and MUC1-binder molecules and test agents used in any of the methods of the invention can contain or be wild-type proteins or can be variants that have one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, 12, 15, 20, 25, 30, 35, 40, or 50) conservative amino acid substitutions. Conservative substitutions typically include substitutions within the following groups: glycine and alanine; valine, isoleucine, and leucine; aspartic acid and glutamic acid; asparagine, glutamine, serine and threonine; lysine, histidine and arginine; and phenylalanine and tyrosine. All that is required is that: (i) such variants of MUC1 have at least 25% (e.g., at least: 30%; 40%; 50%; 60%; 70%; 75%; 80%; 85%; 90%; 95%; 97%; 98%; 99%; 99.5%, or 100% or even greater) of the ability of wild-type MUC1-C to bind to HSP70 or HSP90; and (ii) such variants of a MUC1-binder have at least 25% (e.g., at least: 30%; 40%; 50%; 60%; 70%; 75%; 80%; 85%; 90%; 95%; 97%; 98%; 99%; 99.5%, or 100% or even greater) of the ability of the relevant wild-type MUC1-binder to bind to MUC1-C.

As used herein, a “MUC1-binder” is HSP70 or HSP90.

As used herein, a “MUC1-binder test agent” contains, or is, (a) the full-length, wild-type MUC1-binder, (b) a part of the MUC1-binder that is shorter than the full-length MUC1-binder, or (c) (a) or (b) but with one or more (see above) conservative substitutions. “Parts of a MUC1-binder” include fragments as well deletion variants (terminal as well internal deletions) of the MUC1-binder. Deletion variants can lack one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid segments (of two or more amino acids) or non-contiguous single amino acids. MUC1-binder test agents can include internal or terminal (C or N) irrelevant amino acid sequences (e.g., sequences derived from other proteins or synthetic sequences not corresponding to any naturally occurring protein). These added irrelevant sequences will generally be about 1 to 50 (e.g., two, four, eight, ten, 15, 20, 25, 30, 35, 40, or 45) amino acids in length. MUC1-binder test agents other than full-length wild-type MUC1-binder molecules will have at least 50% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or 100% or more) of the ability of the full-length wild-type MUC1-binder to bind to the cytoplasmic domain of MUC1.

As used herein, a “MUC1 test agent” contains, or is, (a) full-length, wild-type mature MUC1, (b) a part of MUC1 that is shorter than full-length, wild-type, mature MUC1, or (c) (a) or (b) but with one or more (see above) conservative substitutions. “Parts of a MUC1” include fragments (e.g., MUC1-C or the cytoplasmic domain (CD) of MUC1) as well as deletion variants (terminal as well internal deletions) of MUC1. Deletion variants can lack one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid segments (of two or more amino acids) or non-contiguous single amino acids. MUC1 test agents can include internal or terminal (carboxy or amino) irrelevant amino acid sequences (e.g., sequences derived from other proteins or synthetic sequences not corresponding to any naturally occurring protein). These added irrelevant sequences will generally be about 1 to 50 (e.g., two, four, eight, ten, 15, 20, 25, 30, 35, 40, or 45) amino acids in length. MUC1 test agents other than full-length, wild-type, mature MUC1 will have at least 50% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or 100% or more) of the ability of the full-length, wild-type, mature MUC1-binder to bind to HSP70 or HSP90. Both MUC1 test agents and parts of a MUC1 can be phosphorylated, e.g., on a tyrosine residue.

As used herein, “operably linked” means incorporated into a genetic construct so that expression control sequences effectively control expression of a coding sequence of interest.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

Other features and advantages of the invention, e.g., inhibiting survival of cancer cells, will be apparent from the following description, from the drawings and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a representation of the pOZ-N-MUC1 vector. To construct this vector, MUC1-C was cloned into the retroviral pOZ-N vector downstream of the Flag-HA epitopes.

FIG. 1B is a reproduction of an SDS-PAGE gel of proteins purified from HeLa cells stably expressing pOZ-N-MUC1 (MUC1) or the empty vector (Control) by immunoprecipitation with anti-Flag and separation of the precipitated proteins by glycerol gradient centrifugation. Proteins in the corresponding gradient fractions were analyzed by SDS-PAGE and Coomassie blue staining MUC1-associated proteins with apparent masses of 70 and 90 kDa are highlighted with arrows.

FIGS. 1C and 1D are MALDI-TOF-MS spectra of 70 and 90 kDa immunoprecipitated proteins. FIG. 1C depicts the analysis of the 70 kDa protein with peptides corresponding to HSP70 shown with an asterisk. FIG. 1D depicts the analysis of the 90 kDa protein with peptides corresponding to HSP90 shown with an asterisk.

FIGS. 2A and 2B are series of immunoblots of immunoprecipitated lysates. FIG. 2A depicts immunoblots of lysates from HCT116/MUC1 cells subjected to immunoprecipitation with anti-MUC1-N or a control mouse IgG. The precipitates were analyzed by immunoblotting with the indicated antibodies (anti-HSP70, anti-HSP90, or anti-MUC1-N). FIG. 2B depicts immunoblots of immunoprecipitated lysates from HCT116 cells stably expressing Flag-MUC1-CD subjected to immunoprecipitation with anti-MUC1-N or a control mouse IgG. The precipitates were analyzed by immunoblotting with the indicated antibodies (anti-HSP70, anti-HSP90, or anti-MUC1-N).

FIG. 2C depicts the amino acid sequence of MUC1-CD (SEQ ID NO:1). The c-Src phosphorylation site at Y-46 and the θ-catenin binding domain are highlighted.

FIG. 2D is a series of immunoblots of adsorbates of recombinant HSP70 or HSP 90 incubated with GST, GST-MUC1-CD, GST-MUC1-CD (1-45) and GST-MUC1-CD (46-72) bound to glutathione beads. The adsorbates were immunoblotted with the indicated antibodies (HSP70 and HSP90). Input lanes show total amounts of HSP70 and HSP90 proteins added to the reactions. Loading of the GST proteins was assessed by Coomassie blue staining.

FIG. 2E is a series of immunoblots of HSP90 binding to MUC1-CD. The indicated GST-MUC1-CD fusion proteins were incubated with c-Src and ATP for 20 minutes at 30° C. HSP90 was then added for 1 hour at 4° C. The adsorbates were analyzed by immunoblotting with anti-HSP90. Loading of the GST proteins was assessed by Coomassie blue staining.

FIG. 3A is a series of immunoblots of immunoprecipitated lysates of 293 cells transiently transfected with MUC1 or MUC1 (Y46F) in the presence and absence of c-Src. Anti-MUC1-N and control IgG immunoprecipitates were immunoblotted with the indicated antibodies.

FIG. 3B is a bar graph depicting the intensities of the signals in FIG. 3B as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 3C is a series of immunoblots of HCT116/MUC1 cell lysates immunoprecipitated with anti-c-Src. The cells were untreated prior to lysis or treated with 20 ng/ml HRG for 10 minutes or with 10 mM PP2 for 1 hour and then HRG.

FIG. 3D is a series of immunoblots of HCT116/MUC1 cell lysates immunoprecipitated with anti-MUC1-N. The cells were untreated prior to lysis or treated with 20 ng/ml HRG for 10 minutes or with 10 mM PP2 or 1 mM GA for 1 hour and then HRG. Anti-MUC1-N immunoprecipitates were immunoblotted with the indicated antibodies.

FIG. 3E is a bar graph depicting the intensities of the signals in FIG. 3D as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 3F is a series of immunoblots of anti-HSP90 immunoprecipitates of lysates of HCT116/vector, HCT116/MUC1 and HCT116/MUC1 (Y46F) cells that were untreated or treated with HRG for 10 minutes. Anti-HSP90 immunoprecipitates were immunoblotted with the indicated antibodies.

FIG. 3G is a bar graph depicting the intensities of the signals in FIG. 3F as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 4A is a series of immunoblots of lysates of MCF-7 cells immunoprecipitated with anti-MUC1-N. Cells were untreated or treated with HRG for 10 minutes. Anti-MUC1-N immunoprecipitates were immunoblotted with the indicated antibodies.

FIG. 4B is a bar graph depicting the intensities of the signals in FIG. 4A as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 4C is a series of immunoblots of lysates of MCF-7 cells immunoprecipitated with anti-HSP-90. Cells were untreated or treated with HRG for 10 minutes. Anti-HSP-90 immunoprecipitates were immunoblotted with the indicated antibodies.

FIG. 4D is a bar graph depicting the intensities of the signals in FIG. 4C as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 4E is a series of immunoblots of lysates of ZR-75-1 cells immunoprecipitated with anti-MUC1-N. Cells were untreated or treated with HRG for 10 minutes. Anti-MUC1-N immunoprecipitates were immunoblotted with the indicated antibodies.

FIG. 4F is a bar graph depicting the intensities of the signals in FIG. 4E as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 4G is a series of immunoblots of lysates of ZR-75-1 cells immunoprecipitated with anti-HSP-90. Cells were untreated or treated with HRG for 10 minutes. Anti-HSP-90 immunoprecipitates were immunoblotted with the indicated antibodies.

FIG. 4H is a bar graph depicting the intensities of the signals in FIG. 4G as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 5A is a series of immunoblots of whole cell lysates (WCL) and cell membrane (CM) preparations of HCT116/MUC1 cells immunoprecipitated with anti-MUC1-N. The cells were left untreated or stimulated with HRG for 10 minutes.

FIG. 5B is a bar graph depicting the intensities of the signals in FIG. 5A as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 5C is a series of immunoblots of cytosolic fractions of HCT116/MUC1 cells immunoblotted with anti-MUC1-C and anti-θ-actin. The cells were left untreated or stimulated with HRG for 10 minutes. The cytosolic fractions were also immunoblotted with antibodies against the cell membrane-associated PDGFR, ER-associated BAP31 and mitochondria-associated Tom20 proteins. Whole cell lysate (WCL) was included as a control.

FIG. 5D is a bar graph depicting the intensities of the signals in FIG. 5C as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 5E is a series of immunoblots of anti-HSP90 precipitates from cytosolic fractions immunoblotted with anti-MUC1-C and anti-HSP90. The cells were left untreated or stimulated with HRG for 10 minutes.

FIG. 5F is a bar graph depicting the intensities of the signals in FIG. 5E as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 5G is a series of immunoblots of anti-Flag precipitates from HCT116/Flag-MUC1-CD cells that were untreated or treated with HRG for 10 minutes. Anti-Flag precipitates were immunoblotted with the indicated antibodies.

FIG. 5H is a bar graph depicting the intensities of the signals in FIG. 5G as assessed by densitometric scanning. The fold-increase in MUC1-HSP90 binding is expressed as the mean±SEM of three separate experiments compared to that obtained with the MUC1 control (assigned a value of 1). The asterisk denotes p<0.05 as compared to control.

FIG. 6A is a series of immunoblots of purified mitochondria from HCT116/MUC1 cells that were treated with HRG for 10 minutes or with PP2 for 1 hour and then HRG. Purified mitochondria were subjected to immunoblotting with the indicated antibodies. Whole cell lysate (WCL) was included as a control. The amount of WCL loaded in the lane represents 0.06% of the total protein used to purify the mitochondrial fraction.

FIG. 6B is a series of immunoblots of purified mitochondria from HCT116/MUC1 cells that were treated with HRG for 10 minutes or with GA for 1 hour and then HRG. Purified mitochondria were subjected to immunoblotting with the indicated antibodies. Whole cell lysate (WCL) was included as a control. The amount of WCL loaded in the lane represents 0.06% of the total protein used to purify the mitochondrial fraction.

FIG. 6C is a series of immunoblots of mitochondrial or whole cell fractions of HCT116/MUC1 cells that were treated with 1 mM GA for the indicated times. Purified mitochondria (left) and whole cell lysates (right) were immunoblotted with the indicated antibodies.

FIG. 7A is a series of immunoblots of purified mitochondria from HCT116/MUC1 cells that were untreated or treated with 60 mg/ml trypsin for 15 minutes at 4° C. Mitochondria were also first incubated in hypotonic buffer before exposure to trypsin. Digestion of the proteins was analyzed by immunoblotting with the indicated antibodies.

FIG. 7B is a series of immunoblots of purified mitochondria from HCT116/MUC1 cells that were treated with 0.5% or 1.0% digitonin (DIG) for 15 minutes at 4° C. Lysates were immunoblotted with the indicated antibodies.

FIG. 7C is a series of immunoblots of purified mitochondria from HCT116/MUC1 cells that were treated with 0.5% digitonin for 1 minute at 4° C., diluted with buffer, and then digested with 60 mg/ml trypsin for 15 minutes at 4° C. Digestion of the proteins was analyzed by immunoblotting with the indicated antibodies.

FIG. 8 is a depiction of a proposed pathway for targeting of MUC1 to mitochondria by HRG/ErbB receptor/c-Src signaling and the HSP70/HSP90 complex. TOM, translocase of the mitochondrial outer membrane. TIM, translocase of the mitochondrial inner membrane.

DETAILED DESCRIPTION

MUC1 is a mucin-type glycoprotein that is expressed on the apical borders of normal secretory epithelial cells (Kufe et al., 1984). MUC1 forms a heterodimer following synthesis as a single polypeptide and cleavage of the precursor into two subunits in the endoplasmic reticulum (Ligtenberg et al., 1992). The cleavage may be mediated by an autocatalytic process (Levitan et al., 2005). The >250 kDa MUC1 N-terminal (MUC1 N-ter, MUC1-N) subunit contains variable numbers of 20 amino acid tandem repeats that are imperfect with highly conserved variations and are modified by O-linked glycans (Gendler et al., 1988; Siddiqui et al., 1988). MUC1-N is tethered to the cell surface by dimerization with the ˜23 kDa C-terminal subunit (MUC1 C-ter, MUC1-C), which includes a 58 amino acid extracellular region, a 28 amino acid transmembrane domain and a 72 amino acid cytoplasmic domain (CD; SEQ ID NO:1) (Merlo et al., 1989). The human MUC1 sequence is

The human MUC1-C sequence is:

(SEQ ID NO: 5) GSVVVQLTLAFREGTINVHDVETQFNQYKTEAASRYNLTISDVSVSDVP FPFSAQSGAGVPGWGIALLVLVCVLVALAIVYLIALAVCQCRRKNYGQL DIFPARDTYHPMSEYPTYHTHGRYVPPSSTDRSPYEKVSAGNGGSSLSY

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stats Patent Info
Application #
US 20120071704 A1
Publish Date
03/22/2012
Document #
13231663
File Date
09/13/2011
USPTO Class
600/1
Other USPTO Classes
514 44/R, 514 193, 4241741, 514 194, 514 195, 424/111, 424649, 514 34, 514 199, 514 33, 604 20
International Class
/
Drawings
19


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