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  Modified peptides as therapeutic agentsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain StructureThe Patent Description & Claims data below is from USPTO Patent Application 20070049532. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. application Ser. No. 10/645,761, filed Aug. 18, 2003, which is a continuation of U.S. application Ser. No. 09/428,082, filed Oct. 22, 1999, which claims the benefit of U.S. Provisional Application No. 60/105,371, filed Oct. 23, 1998, which are incorporated by reference herein. BACKGROUND OF THE INVENTION [0002] Recombinant proteins are an emerging class of therapeutic agents. Such recombinant therapeutics have engendered advances in protein formulation and chemical modification. Such modifications can protect therapeutic proteins, primarily by blocking their exposure to proteolytic enzymes. Protein modifications may also increase the therapeutic protein's stability, circulation time, and biological activity. A review article describing protein modification and fusion proteins is Francis (1992), Focus on Growth Factors 3:4-10 (Mediscript, London), which is hereby incorporated by reference. [0003] One useful modification is combination with the "Fc" domain of an antibody. Antibodies comprise two functionally independent parts, a variable domain known as "Fab", which binds antigen, and a constant domain known as "Fc", which links to such effector functions as complement activation and attack by phagocytic cells. An Fc has a long serum half-life, whereas an Fab is short-lived. Capon et al. (1989), Nature 337: 525-31. When constructed together with a therapeutic protein, an Fc domain can provide longer half-life or incorporate such functions as Fc receptor binding, protein A binding, complement fixation and perhaps even placental transfer. Id. Table 1 summarizes use of Fc fusions known in the art. TABLE-US-00001 TABLE 1 Fc fusion with therapeutic proteins Fusion Therapeutic Form of Fc partner implications Reference IgG1 N-terminus of Hodgkin's disease; U.S. Pat. No. CD30-L anaplastic lymphoma; T- 5,480,981 cell leukemia Murine Fc.gamma.2a IL-10 anti-inflammatory; Zheng et al. (1995), J. transplant rejection Immunol. 154: 5590-600 IgG1 TNF receptor septic shock Fisher et al. (1996), N. Engl. J. Med. 334: 1697-1702; Van Zee, K. et al. (1996), J. Immunol. 156: 2221-30 IgG, IgA, TNF receptor inflammation, U.S. Pat. No. 5,808,029, IgM, or IgE autoimmune disorders issued Sep. 15, (excluding 1998 the first domain) IgG1 CD4 receptor AIDS Capon et al. (1989), Nature 337: 525-31 IgG1, N-terminus anti-cancer, antiviral Harvill et al. (1995), IgG3 of IL-2 Immunotech. 1: 95-105 IgG1 C-terminus of osteoarthritis; WO 97/23614, published OPG bone density Jul. 3, 1997 IgG1 N-terminus of anti-obesity PCT/US 97/23183, filed leptin Dec. 11, 1997 Human Ig CTLA-4 autoimmune disorders Linsley (1991), J. Exp. C.gamma.1 Med. 174: 561-9 [0004] A much different approach to development of therapeutic agents is peptide library screening. The interaction of a protein ligand with its receptor often takes place at a relatively large interface. However, as demonstrated for human growth hormone and its receptor, only a few key residues at the interface contribute to most of the binding energy. Clackson et al. (1995), Science 267: 383-6. The bulk of the protein ligand merely displays the binding epitopes in the right topology or serves functions unrelated to binding. Thus, molecules of only "peptide" length (2 to 40 amino acids) can bind to the receptor protein of a given large protein ligand. Such peptides may mimic the bioactivity of the large protein ligand ("peptide agonists") or, through competitive binding, inhibit the bioactivity of the large protein ligand ("peptide antagonists"). [0005] Phage display peptide libraries have emerged as a powerful method in identifying such peptide agonists and antagonists. See, for example, Scott et al. (1990), Science 249: 386; Devlin et al. (1990), Science 249: 404; U.S. Pat. No. 5,223,409, issued Jun. 29, 1993; U.S. Pat. No. 5,733,731, issued Mar. 31, 1998; U.S. Pat. No. 5,498,530, issued Mar. 12, 1996; U.S. Pat. No. 5,432,018, issued Jul. 11, 1995; U.S. Pat. No. 5,338,665, issued Aug. 16, 1994; U.S. Pat. No. 5,922,545, issued Jul. 13, 1999; WO 96/40987, published Dec. 19, 1996; and WO 98/15833, published Apr. 16, 1998 (each of which is incorporated by reference). In such libraries, random peptide sequences are displayed by fusion with coat proteins of filamentous phage. Typically, the displayed peptides are affinity-eluted against an antibody-immobilized extracellular domain of a receptor. The retained phages may be enriched by successive rounds of affinity purification and repropagation. The best binding peptides may be sequenced to identify key residues within one or more structurally related families of peptides. See, e.g., Cwirla et al. (1997), Science 276: 1696-9, in which two distinct families were identified. The peptide sequences may also suggest which residues may be safely replaced by alanine scanning or by mutagenesis at the DNA level. Mutagenesis libraries may be created and screened to further optimize the sequence of the best binders. Lowman (1997), Ann. Rev. Biophys. Biomol. Struct. 26: 401-24. [0006] Other methods compete with phage display in peptide research. A peptide library can be fused to the carboxyl terminus of the lac repressor and expressed in E. coli. Another E. coli-based method allows display on the cell's outer membrane by fusion with a peptidoglycan-associated lipoprotein (PAL). Hereinafter, these and related methods are collectively referred to as "E. coli display." Another biological approach to screening soluble peptide mixtures uses yeast for expression and secretion. See Smith et al. (1993), Mol. Pharmacol. 43: 741-8. Hereinafter, the method of Smith et al. and related methods are referred to as "yeast-based screening." In another method, translation of random RNA is halted prior to ribosome release, resulting in a library of polypeptides with their associated RNA still attached. Hereinafter, this and related methods are collectively referred to as "ribosome display." Other methods employ chemical linkage of peptides to RNA; see, for example, Roberts & Szostak (1997), Proc. Natl. Acad. Sci. USA, 94: 12297-303. Hereinafter, this and related methods are collectively referred to as "RNA-peptide screening." Chemically derived peptide libraries have been developed in which peptides are immobilized on stable, non-biological materials, such as polyethylene rods or solvent-permeable resins. Another chemically derived peptide library uses photolithography to scan peptides immobilized on glass slides. Hereinafter, these and related methods are collectively referred to as "chemical-peptide screening." Chemical-peptide screening may be advantageous in that it allows use of D-amino acids and other unnatural analogues, as well as non-peptide elements. Both biological and chemical methods are reviewed in Wells & Lowman (1992), Curr. Opin. Biotechnol. 3: 355-62. [0007] In the case of known bioactive peptides, rational design of peptide ligands with favorable therapeutic properties can be completed. In such an approach, one makes stepwise changes to a peptide sequence and determines the effect of the substitution upon bioactivity or a predictive biophysical property of the peptide (e.g., solution structure). Hereinafter, these techniques are collectively referred to as "rational design." In one such technique, one makes a series of peptides in which one replaces a single residue at a time with alanine. This technique is commonly referred to as an "alanine walk" or an "alanine scan." When two residues (contiguous or spaced apart) are replaced, it is referred to as a "double alanine walk." The resultant amino acid substitutions can be used alone or in combination to result in a new peptide entity with favorable therapeutic properties. [0008] Structural analysis of protein-protein interaction may also be used to suggest peptides that mimic the binding activity of large protein ligands. In such an analysis, the crystal structure may suggest the identity and relative orientation of critical residues of the large protein ligand, from which a peptide may be designed. See, e.g., Takasaki et al. (1997), Nature Biotech. 15: 1266-70. Hereinafter, these and related methods are referred to as "protein structural analysis." These analytical methods may also be used to investigate the interaction between a receptor protein and peptides selected by phage display, which may suggest further modification of the peptides to increase binding affinity. [0009] Conceptually, one may discover peptide mimetics of any protein using phage display and the other methods mentioned above. These methods have been used for epitope mapping, for identification of critical amino acids in protein-protein interactions, and as leads for the discovery of new therapeutic agents. E.g., Cortese et al. (1996), Curr. Opin. Biotech. 7: 616-21. Peptide libraries are now being used most often in immunological studies, such as epitope mapping. Kreeger (1996), The Scientist 10(13): 19-20. [0010] Of particular interest here is use of peptide libraries and other techniques in the discovery of pharmacologically active peptides. A number of such peptides identified in the art are summarized in Table 2. The peptides are described in the listed publications, each of which is hereby incorporated by reference. The pharmacologic activity of the peptides is described, and in many instances is followed by a shorthand term therefor in parentheses. Some of these peptides have been modified (e.g., to form C-terminally cross-linked dimers). Typically, peptide libraries were screened for binding to a receptor for a pharmacologically active protein (e.g., EPO receptor). In at least one instance (CTLA4), the peptide library was screened for binding to a monclonal antibody. TABLE-US-00002 TABLE 2 Pharmacologically active peptides Binding partner/ Form of protein of Pharmacologic peptide interest.sup.a activity Reference intrapeptide EPO receptor EPO-mimetic Wrighton et al. (1996), disulfide- Science 273: 458-63; bonded U.S. Pat. No. 5,773,569, issued Jun. 30, 1998 to Wrighton et al. C-terminally EPO receptor EPO-mimetic Livnah et al. (1996), cross-linked Science 273: 464-71; dimer Wrighton et al. (1997), Nature Biotechnology 15: 1261-5; International patent application WO 96/40772, published Dec. 19, 1996 linear EPO receptor EPO-mimetic Naranda et al. (1999), Proc. Natl. Acad. Sci. USA, 96: 7569-74; WO 99/47151, published Sep. 23, 1999 linear c-Mpl TPO-mimetic Cwirla et al. (1997) Science 276: 1696-9; U.S. Pat. No. 5,869,451, issued Feb. 9, 1999; U.S. Pat. No. 5,932,946, issued Aug. 3, 1999 C-terminally c-Mpl TPO-mimetic Cwirla et al. (1997), cross-linked Science 276: 1696-9 dimer disulfide- stimulation of Paukovits et al. (1984), linked dimer hematopoiesis Hoppe-Seylers Z. ("G-CSF-mimetic") Physiol. Chem. 365: 303-11; Laerum et al. (1988), Exp. Hemat. 16: 274-80 alkylene- G-CSF-mimetic Bhatnagar et al. (1996), linked dimer J. Med. Chem. 39: 3814-9; Cuthbertson et al. (1997), J. Med. Chem. 40: 2876-82; King et al. (1991), Exp. Hematol. 19: 481; King et al. (1995), Blood 86 (Suppl. 1): 309a linear IL-1 receptor inflammatory and U.S. Pat. No. 5,608,035; autoimmune diseases U.S. Pat. No. 5,786,331; ("IL-1 antagonist" or U.S. Pat. No. 5,880,096; "IL-1ra-mimetic") Yanofsky et al. (1996), Proc. Natl. Acad. Sci. 93: 7381-6; Akeson et al. (1996), J. Biol. Chem. 271: 30517-23; Wiekzorek et al. (1997), Pol. J. Pharmacol. 49: 107-17; Yanofsky (1996), PNAs, 93: 7381-7386. linear Facteur stimulation of Inagaki-Ohara et al. thymique lymphocytes (1996), Cellular Immunol. serique (FTS) ("FTS-mimetic") 171: 30-40; Yoshida (1984), Int. J. Immunopharmacol, 6: 141-6. intrapeptide CTLA4 MAb CTLA4-mimetic Fukumoto et al. (1998), disulfide Nature Biotech. 16: 267-70 bonded exocyclic TNF-.alpha. receptor TNF-.alpha. antagonist Takasaki et al. (1997), Nature Biotech. 15: 1266-70; WO 98/53842, published Dec. 3, 1998 linear TNF-.alpha. receptor TNF-.alpha. antagonist Chirinos-Rojas ( ), J. Imm., 5621-5626. intrapeptide C3b inhibition of complement Sahu et al. (1996), J. disulfide activation; autoimmune Immunol. 157: 884-91; bonded diseases Morikis et al. (1998), ("C3b-antagonist") Protein Sci. 7: 619-27 linear vinculin cell adhesion processes- Adey et al. (1997), cell growth, differentiation, Biochem. J. 324: 523-8 wound healing, tumor metastasis ("vinculin binding") linear C4 binding anti-thrombotic Linse et al. (1997), J. protein (C4BP) Biol. Chem. 272: 14658-65 linear urokinase processes associated with Goodson et al. (1994), receptor urokinase interaction with Proc. Natl. Acad. Sci. 91: its receptor (e.g., 7129-33; International angiogenesis, tumor cell application WO invasion and metastasis); 97/35969, published ("UKR antagonist") Oct. 2, 1997 linear Mdm2, Hdm2 Inhibition of inactivation of Picksley et al. (1994), p53 mediated by Mdm2 or Oncogene 9: 2523-9; hdm2; anti-tumor Bottger et al. (1997) J. ("Mdm/hdm antagonist") Mol. Biol. 269: 744-56; Bottger et al. (1996), Oncogene 13: 2141-7 linear p21.sup.WAF1 anti-tumor by mimicking Ball et al. (1997), Curr. the activity of p21.sup.WAF1 Biol. 7: 71-80 linear farnesyl anti-cancer by preventing Gibbs et al. (1994), Cell transferase activation of ras oncogene 77: 175-178 linear Ras effector anti-cancer by inhibiting Moodie et al. (1994), domain biological function of the Trends Genet 10: 44-48 ras oncogene Rodriguez et al. (1994), Nature 370: 527-532 linear SH2/SH3 anti-cancer by inhibiting Pawson et al (1993), domains tumor growth with Curr. Biol. 3: 434-432 activated tyrosine Yu et al. (1994), Cell kinases; treatment of 76: 933-945; Rickles et al. SH3-mediated disease (1994), EMBO J. 13: states ("SH3 antagonist") 5598-5604; Sparks et al. (1994), J. Biol. Chem. 269: 23853-6; Sparks et al. (1996), Proc. Natl. Acad. Sci. 93: 1540-4; U.S. Pat. No. 5,886,150, issued Mar. 23, 1999; U.S. Pat. No. 5,888,763, issued Mar. 30, 1999 linear p16.sup.INK4 anti-cancer by mimicking Fahraeus et al. (1996), activity of p16; e.g., Curr. Biol. 6: 84-91 inhibiting cyclin D-Cdk complex ("p16-mimetic") linear Src, Lyn inhibition of Mast cell Stauffer et al. (1997), activation, IgE-related Biochem. 36: 9388-94 conditions, type I hypersensitivity ("Mast cell antagonist") linear Mast cell treatment of inflammatory International application protease disorders mediated by WO 98/33812, published release of tryptase-6 Aug. 6, 1998 ("Mast cell protease inhibitors") linear HBV core treatment of HBV viral Dyson & Muray (1995), antigen (HBcAg) infections ("anti-HBV") Proc. Natl. Acad. Sci. 92: 2194-8 linear selectins neutrophil adhesion; Martens et al. (1995), J. inflammatory diseases Biol. Chem. 270: 21129-36; ("selectin antagonist") European patent application EP 0 714 912, published Jun. 5, 1996 linear, calmodulin calmodulin antagonist Pierce et al. (1995), cyclized Molec. Diversity 1: 259-65; Dedman et al. (1993), J. Biol. Chem. 268: 23025-30; Adey & Kay (1996), Gene 169: 133-4 linear, integrins tumor-homing; treatment International applications cyclized- for conditions related to WO 95/14714, published integrin-mediated cellular Jun. 1, 1995; WO events, including platelet 97/08203, published aggregation, thrombosis, Mar. 6, 1997; WO wound healing, 98/10795, published osteoporosis, tissue Mar. 19, 1998; WO repair, angiogenesis (e.g., 99/24462, published May for treatment of cancer), 20, 1999; Kraft et al. and tumor invasion (1999), J. Biol. Chem. ("integrin-binding") 274: 1979-1985 cyclic, linear fibronectin and treatment of inflammatory WO 98/09985, extracellular and autoimmune published Mar. 12, matrix conditions 1998 components of T cells and macrophages linear somatostatin treatment or prevention of European patent and cortistatin hormone-producing application 0 911 393, tumors, acromegaly, published Apr. 28, 1999 giantism, dementia, gastric ulcer, tumor growth, inhibition of hormone secretion, modulation of sleep or neural activity linear bacterial antibiotic; septic shock; U.S. Pat. No. 5,877,151, lipopolysaccharide disorders modulatable by issued Mar. 2, 1999 CAP37 linear or pardaxin, antipathogenic WO 97/31019, published cyclic, mellitin 28 Aug. 1997 including D- amino acids linear, cyclic VIP impotence, WO 97/40070, published neurodegenerative Oct. 30, 1997 disorders linear CTLs cancer EP 0 770 624, published May 2, 1997 linear THF-gamma2 Burnstein (1988), Biochem., 27: 4066-71. linear Amylin Cooper (1987), Proc. Natl. Acad. Sci., 84: 8628-32. linear Adrenomedullin Kitamura (1993), BBRC, 192: 553-60. cyclic, linear VEGF anti-angiogenic; cancer, Fairbrother (1998), rheumatoid arthritis, Biochem., 37: 17754-17764. diabetic retinopathy, psoriasis ("VEGF antagonist") cyclic MMP inflammation and Koivunen (1999), Nature autoimmune disorders; Biotech., 17: 768-774. tumor growth ("MMP inhibitor") HGH fragment treatment of obesity U.S. Pat. No. 5,869,452 Echistatin inhibition of platelet Gan (1988), J. Biol. aggregation Chem., 263: 19827-32. linear SLE SLE WO 96/30057, published autoantibody Oct. 3, 1996 GD1alpha suppression of tumor Ishikawa et al. (1998), metastasis FEBS Lett. 441 (1): 20-4 antiphospholipid endothelial cell activation, Blank et al. (1999), Proc. beta-2- antiphospholipid Natl. Acad. Sci. USA 96: glycoprotein-I syndrome (APS), 5164-8 (.beta.2GPI) thromboembolic antibodies phenomena, thrombocytopenia, and recurrent fetal loss linear T Cell Receptor diabetes WO 96/11214, published beta chain Apr. 18, 1996. Antiproliferative, antiviral WO 00/01402, published Jan. 13, 2000. anti-ischemic, growth WO 99/62539, published hormone-liberating Dec. 9, 1999. anti-angiogenic WO 99/61476, published Dec. 2, 1999. linear Apoptosis agonist; WO 99/38526, published treatment of T cell- Aug. 5, 1999. associated disorders (e.g., autoimmune diseases, viral infection, T cell leukemia, T cell lymphoma) linear MHC class II treatment of autoimmune U.S. Pat. No. 5,880,103, diseases issued Mar. 9, 1999. linear androgen R, proapoptotic, useful in WO 99/45944, published p75, MJD, DCC, treating cancer Sep. 16, 1999. huntingtin linear von Willebrand inhibition of Factor VIII WO 97/41220, published Factor; Factor interaction; anticoagulants Apr. 29, 1997. VIII linear lentivirus LLP1 antimicrobial U.S. Pat. No. 5,945,507, issued Aug. 31, 1999. linear Delta-Sleep sleep disorders Graf (1986), Peptides Inducing Peptide 7: 1165. linear C-Reactive inflammation and cancer Barna (1994), Cancer Protein (CRP) Immunol. Immunother. 38: 38 (1994). linear Sperm- infertility Suzuki (1992), Comp. Activating Biochem. Physiol. Peptides 102B: 679. linear angiotensins hematopoietic factors for Lundergan (1999), J. hematocytopenic Periodental Res. conditions from cancer, 34(4): 223-228. AIDS, etc. linear HIV-1 gp41 anti-AIDS Chan (1998), Cell 93: 681-684. linear PKC inhibition of bone Moonga (1998), Exp. resorption Physiol. 83: 717-725. linear defensis (HNP- antimicrobial Harvig (1994), Methods 1, -2, -3, -4) Enz. 236: 160-172. linear p185.sup.HER2/neu, C- AHNP-mimetic: anti-tumour Park (2000), Nat. erbB-2 Biotechnol. 18: 194-198. linear gp130 IL-6 antagonist WO 99/60013, published Nov. 25, 1999. linear collagen, other autoimmune diseases WO 99/50282, published joint, cartilage, Oct. 7, 1999. arthritis-related proteins linear HIV-1 envelope treatment of neurological WO 99/51254, published protein degenerative diseases Oct. 14, 1999. linear IL-2 autoimmune disorders WO 00/04048, published (e.g., graft rejection, Jan. 27, 2000; WO rheumatoid arthritis) 00/11028, published Mar. 2, 2000 .sup.aThe protein listed in this column may be bound by the associated peptide (e.g., EPO receptor, IL-1 receptor) or mimicked by the associated peptide. The references listed for each clarify whether the molecule is bound by or mimicked by the peptides. [0011] Peptides identified by peptide library screening have been regarded as "leads" in development of therapeutic agents rather than as therapeutic agents themselves. Like other proteins and peptides, they would be rapidly removed in vivo either by renal filtration, cellular clearance mechanisms in the reticuloendothelial system, or proteolytic degradation. Francis (1992), Focus on Growth Factors 3: 4-11. As a result, the art presently uses the identified peptides to validate drug targets or as scaffolds for design of organic compounds that might not have been as easily or as quickly identified through chemical library screening. Lowman (1997), Ann. Rev. Biophys. Biomol. Struct. 26: 401-24; Kay et al. (1998), Drug Disc. Today 3: 370-8. The art would benefit from a process by which such peptides could more readily yield therapeutic agents. SUMMARY OF THE INVENTION [0012] The present invention concerns a process by which the in vivo half-life of one or more biologically active peptides is increased by fusion with a vehicle. In this invention, pharmacologically active compounds are prepared by a process comprising: [0013] a) selecting at least one peptide that modulates the activity of a protein of interest; and [0014] b) preparing a pharmacologic agent comprising at least one vehicle covalently linked to at least one amino acid sequence of the selected peptide. The preferred vehicle is an Fc domain. The peptides screened in step (a) are preferably expressed in a phage display library. The vehicle and the peptide may be linked through the N- or C-terminus of the peptide or the vehicle, as described further below. Derivatives of the above compounds (described below) are also encompassed by this invention. [0015] The compounds of this invention may be prepared by standard synthetic methods, recombinant DNA techniques, or any other methods of preparing peptides and fusion proteins. Compounds of this invention that encompass non-peptide portions may be synthesized by standard organic chemistry reactions, in addition to standard peptide chemistry reactions when applicable. [0016] The primary use contemplated is as therapeutic or prophylactic agents. The vehicle-linked peptide may have activity comparable to--or even greater than--the natural ligand mimicked by the peptide. In addition, certain natural ligand-based therapeutic agents might induce antibodies against the patient's own endogenous ligand; the vehicle-linked peptide avoids this pitfall by having little or typically no sequence identity with the natural ligand. [0017] Although mostly contemplated as therapeutic agents, compounds of this invention may also be useful in screening for such agents. For example, one could use an Fc-peptide (e.g., Fc-SH2 domain peptide) in an assay employing anti-Fc coated plates. The vehicle, especially Fc, may make insoluble peptides soluble and thus useful in a number of assays. [0018] The compounds of this invention may be used for therapeutic or prophylactic purposes by formulating them with appropriate pharmaceutical carrier materials and administering an effective amount to a patient, such as a human (or other mammal) in need thereof. Other related aspects are also included in the instant invention. [0019] Numerous additional aspects and advantages of the present invention will become apparent upon consideration of the figures and detailed description of the invention. BRIEF DESCRIPTION OF THE FIGURES [0020] FIG. 1 shows a schematic representation of an exemplary process of the invention. In this preferred process, the vehicle is an Fc domain, which is linked to the peptide covalently by expression from a DNA construct encoding both the Fc domain and the peptide. As noted in FIG. 1, the Fc domains spontaneously form a dimer in this process. [0021] FIG. 2 shows exemplary Fc dimers that may be derived from an IgG1 antibody. "Fc" in the figure represents any of the Fc variants within the meaning of "Fc domain" herein. "X.sup.1" and "X.sup.2" represent peptides or linker-peptide combinations as defined hereinafter. The specific dimers are as follows: Continue reading... Full patent description for Modified peptides as therapeutic agents Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Modified peptides as therapeutic agents patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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