(12) United States Patent (10) Patent N0.: US 7,723,289 B2 Barnea (45) Date of Patent: *May 25, 2010

US007723289B2

(54) PIF TETRAPEPTIDES Marketletter, Sep. 13, 1999, 2 pages.* Barnea, Embryo-Maternal Dialogue.‘ Linking Pregnancy Recogni (75) Inventor: Eytan R. Barnea, Cherry Hill, NJ (US) tion and Proliferation Control, Rochester Trophoblast Conference (73) Assignee: BioIncept, LLC, Cherry Hill, NJ (US) 2000, under the auspices of the Trophoblast Conference and SIEP, the Society for the Investigation of Early Pregnancy, Rochester, NY. * Notice: Sub'ectJ to any disclaimer, the term of this Ripka et al., Peptidomimetic design, 1998, Curr. Op. Chem. Biol. patent is extended or adjusted under 35 2:441-452. U.S.C. 154(b) by 960 days. Hrbuy et al., Synthesis of oligopeptide and peptidomimetic libraries, 1997, Curr. Op. Chem. Biol. 1:114-119. This patent is subject to a terminal dis Hruby et al., Conformational and topographical considerations in claimer. designing agonist peptidomimetics from peptide leads, 2000, Curr. (21) App1.No.:11/110,990 Med. Chem. Sept. 7(9): 945-970. Barnea et al., Progress in characterization ofpre-implantation factor (22) Filed: Apr. 20, 2005 in embryo cultures and in vivo, 1999, Am. J. Reprod. Immunol. 00. Barnea, The Embryo.‘ a privileged entity in a privileged site.‘ lessons (65) Prior Publication Data learntfrom embryonal development, 1997, Early Pregnancy: Biol. & Med, 3:77-80. US 2008/0003178 A1 Jan. 3, 2008 Barnea, Current Progress in Early Pregnancy Investigation and the Steps Ahead Part I, 2000, Early Pregnancy Biology & Medicine, Related US. Application Data 4: 1-4 (SIEP Publ @ www.carlypregnancyorg). Barnea et al., Embryo-maternal signaling prior to implantation, (63) Continuation-in-part of application No. 10/971,760, 2001, in Obstetrics & Gynecology, Section 2 Human ?led on Oct. 22, 2004. ReproductioniAnatomy, Physiology, Embryology, Munteanu Ed. (Romanian Academy of Science Publishers), pp. 112-117. (60) Provisional application No. 60/513,370, ?led on Oct. Roussev et al., Embryonic origin of preimplantation factor (PIF).‘ 22, 2003. biological activity and partial characterization, 1996, Mol. Human Reprod., 2, No. 11:883-887. (51) Int. Cl. Barnea, En I/lsion the ?eld of Early Pregnancy Investigation, 1995, A61K 38/00 (2006.01) Early Pregnancy: Biol. & Med, 1:169-170. (52) US. Cl...... 514/2;424/184.1;424/278.1; Rayburn, Embryonic Medicine and Therapy, 1999, (Jauniaux, E., 530/330 Barnea, E.R., Edwards, R.G., eds.) The New England Journal of Medicine Book Review, 340(19):1519. (58) Field of Classi?cation Search ...... None Barnea, Keynote Editorial: New Frontiers in Early Pregnancy Inves See application ?le for complete search h1story. tigation, 1995, Early Pregnancy: Biol. & Med. 1:1-3. (56) References Cited Barnea et al., Editorial: Re?ections on early pregnancy.‘ organizing chaos or organized chaos?, 1996, Early Pregnancy: Biol. & Med. U.S. PATENT DOCUMENTS 2:77-79. Barnea et al., Use ofLymphocyte Platelet Binding Assay for Detect 5,279,941 A * 1/1994 Lessey ...... 435/721 ing a Preimplantation Factor.‘ A Quantitative Assay, 1994, Am. J. 5,646,003 A 7/1997 Barnea et a1. Reprod. Immunol. 32:133-138. 5,981,198 A 11/1999 Barnea et a1. Boklage, Survival probability of human conceptions from fertiliza 6,585,979 B1 7/2003 Berman tion to term, Int J Fertil Mar-Apr. 1990, 35(2): 75, 79-80, 81-94. 2003/0099643 A1 5/2003 June et a1. Barnea et al., Immune System (IS) and Proliferation Control (PC) 2005/0064520 A1 3/2005 Barnea et a1. from Embryo to Adulthood.‘ Roles of Preimplantation Factor (PIF) 2008/0269137 A1 10/ 2008 Barnea and Developmental Proteins (DPs), 2001, Renaissance Congress of 2009/0081225 A1 3/ 2009 Barnea the 21‘’ Century: The Woman and Child Before, During and After Pregnancy, A Global union of Scienti?c Congresses, under the high FOREIGN PATENT DOCUMENTS patronage of the President of the Italian Republic, 5”’ SIEP World Conference, 15’ International Congress of the Mediterranean Society W0 W0 9526982 A2 * 10/1995 of Reproduction and Neonatology, 4th International Congress of the W0 WO 02053092 A2 * 7/2002 International Society for New Technology in Gynecology, Reproduc W0 W0 03/004601 A 1/2003 W0 WO 2004/053086 A 6/2004 tion and Neonatology, Rome, Italy. W0 WO 2005/040196 A2 5/2005 (Continued) OTHER PUBLICATIONS Primary ExamineriMichael Szperka (74) Attorney, Agent, or FirmiPepper Hamilton LLP Rose et al., Manual of Clinical Laboratory Immunology, 5th edition, 1997, ASM Press, pp. 20-48.* (57) ABSTRACT Janeway et al., Immunobiology, 3rd edition. 1997, Garland Publish ing Inc., pp. 7:25 and 9:31.* Peptides and peptidomimetics capable of enhance endome Goodnow CC., Lancet. Jun. 30, 2001;357(9274):2115-21.* trial receptivity, blocking activated but not basal immunity, Skyler, JS, et al. Diabetes Care. 2005;28:1068-1076.* inhibiting cell proliferation and creating a TH2 type cytokine PoZZilli, P., et a1. Diabetol. 2000;43:1000-1004.* bias are disclosed. The peptides and mimetics are based upon Dong, V.M., et a1. Ped Transplant . . . 1999;161:181-189.* the C-terminal tetrapeptide of PIF peptides. Also disclosed Bell, JJ et al. J. Immunol. 2008;180:1508-1516.* are methods of using these peptides and peptidomimetics for Kraus, TA, and Mayer, L. Curr. Opin. Gastroenterol. 2005;21:692 696* therapeutic and diagnostic purposes. Schroeder, RA, et al. J. Surg. Sci. Res. 2003;111:109-119.* Chaouat, J. Reprod. Fert. 1990, 89:447-458.* 6 Claims, 23 Drawing Sheets Tangri et al., J. Immunol., 1994, 152:4903-4911.* (20 of 23 Drawing Sheet(s) Filed in Color) US 7,723,289 B2 Page 2

OTHER PUBLICATIONS Gonzalez et al., Immunomodulatory features of preimplantation fac tors (PIF) from mouse embryos, 2002, 11th World Conference on Coulam et al., Preimplantation Factor (PIF) Predicts Subsequent Human Reproduction, June, Montreal, Canada. Pregnancy Loss, 1995, Am. J. Reprod. Immunol. 34:88-92. Paidas et al, Pregnancy Implantation Factor (PIF) Activity is Corre Barnea et al., Embryonic Signals, in JauniauX, l997, JauniauX, E., lated with a Pro-In?ammatory Response, 2002, 23rd Annual Society Barnea, E.R., Edwards, R.G. (eds.) Embryonic Medicine and for Maternal-Fetal Medicine Conference, San Francisco, CA Therapy, pp. 63-75 (Oxford University Press). (abstract). Barnea, Underlying mechanisms and treatment of early pregnancy Barnea et al., Identi?cation and Validation of an Assay for failure, 200l, Ferti Magazine, Ferti.Net Worldwide Fertility Net Preimplantation Factor (PIF), 1994, Second World Conference on work, Apr. 1-4. Implantation and Early Pregnancy in Humans, May, Atlantic City, NJ Navot et al., Poor oocyte quality rather than implantation failure as (abstract). a cause ofage-related decline in female fertility, Lancet Jun. 8, 1991: Gardner et al., Culture of viable human blastocysts in de?ned sequen 337(8754):l375-l377 (abstract). tial serum-free media, 1998, Human Reprod. June: 13, Suppl 3: Mirhashemi, Cancer and Pregnancy, 2002, (Barnea, E.R., Jauniaux, 148-159. E., Schwartz, P.E., eds.) New England J Med Book Review, Jun. 13, Barnea et al., Preimplantation Signalling by the Embryo, 3rd World 346(24): 1921. Conference on Early Pregnancy, Oct. 3-6, 1996 (abstract). Roussev et al., A Novel Bioassay for Detection of Preimplantation Raghupathy, The l-type immunity is incompatible with successful Factor (PIF), 1995, Am J Reprod. Immunol. 33:68-73. pregnancy, l997, Immunol. Today 18: 478 (abstract). Wegmann et al., Bidirectional cytokine interactions in the maternal Roussev et al., Development and Validation of an Assay for Measur ing Preimplantation Factor (PIF) ofEmbryonal Origin, 1996, Am. J. fetal relationship: is successful pregnancy a TH2 phenomenon? Reprod. Immunol. 35:281-287. l993, Immunol. Today 14, 353-356 (abstract). Cavanagh et al, The puri?cation of early-pregnancy factor to homo Barnea et al., 2000, Maternal ImmuneResponse to Trophoblast, GTD geneity from human platelets and identi?cation as chaperonin 10, and Cancer, In: Shoenfeld, Y. and Gerhwin, M.E. (eds) Cancer and 1994, Eur. J. Biochem. 222: 551-560 (abstract). Autoimmunity, pp. 343-350, Elsevier Science B.V. Publishers. Piccinni et al., Production of IL-4 and leukemia inhibitory factor by Barnea et al., Identi?cation and Validation of an Assay for T cells of the cumulus oophorus: a favorable microenvironment for Preimplantation Factor (PIF), 1994, Society for Gynecologic Inves pre-implantation embryo development, 200 1, Eur. J. Immunol., Aug: tigation 415’ Meeting, April, Chicago, IL (abstract). 31(8), 2431-2437(abstract). Roussev et al., Clinical Validation of Preimplantation Factor (PIF) Wickramasinghe et al., Blood and bone marrow changes in malaria, Assay, 1994, Second World Conference on Implantation and Early 2000, Baillieres Best. Pract. Res. Clin. Haematol. June:l3(2), 277 Pregnancy in Humans, May, Atlantic City, NJ (abstract). 299 (abstract). Roussev et al., 1994, A Novel Bioassayfor Detection ofPreimplanta Romagnani, Lymphokine production by human T cells in disease tion Factor (PIF), American Society of Reproductive Immunology, states, 1994, Annu. Rev. Immunol. 12, 227-257 (abstract). XVI Annual Meeting, June, Philadelphia, PA (abstract). Chaouat et al., IL-l0 prevents naturally occurring fetal loss in the Coulam et al., Preimplantation Factor (PIF) Predicts Subsequent CBA X DBN2 mating combination, and local defect in IL-l0 pro Pregnancy Loss, 1994, The American Fertility Society 50th Annual duction in this abortion-prone combination is corrected by in vivo Meeting, November, San Antonio, TX (abstract). injection ofIFN-tau, 1995, J. ofImmunol. 154, 4261-4268 (abstract). Roussev et al., Embryonic Origin of Preimplantation Factor (PIF), Ho et al., Distribution of Thl and Th2 cell populations in human 1995, Society for Gynecological Investigation 42” Meeting, Chi peripher and decidual T cells from normal and anembryonic preg cago, IL (abstract). nancies, 200l, Fertil. Steril. Oct:76(4): 797-803 (abstract). Barnea et al., Partial Characterization of Embryo-Derived Wu et al., Increase in the production of interleukin-l0 early after Preimplantation Factor (PIF), 2006, Ninth World Congress on implantation is related to the success of pregnancy, 2001, Am. J. Human Reproduction, May, Philadelphia, PA (abstract). Reprod. Immunol. Dec:46(6): 386-392 (abstract). Barnea et al., Preimplantation Factor (PIF): Current Developments, Choudhury et al., Human reproductive failure I: Immunological fac 1996, Third World Conference on Early PregnancyiAn Interdisci tors, 2000, Hum. Reprod. Update 7:ll3-l34. plinary Approach, October, Atlantic City, NJ (abstract). Heyner, Growth factors in preimplantation development: role of insu lin and insulin-like growth factors, 1997, Early Preg. Biol and Med 3: Barnea et al., 1998, Partial Characterization of Mammalian Preimplantation Factor in Culture and In J/ivo, Fourth International 153 - l 63. Meeting Mechanisms in Local Immunity: and Joint Meeting Fourth Abbas et al., Functional diversity of helper T lymphocytes, 1996, Meeting of Alps Adria Society for Immunology of Reproduction Nature 383: 787-793. Taubes, Malaria Parasite Outwits the Immune System, 2000, Science (AASIR), September, Opatija, Croatia (abstract). 290: 435. Barnea, Preimplantation Factor.‘ A speci?c embryo viability factor, Barnea et al., Implantation, 2001, in Obstetrics & Gynecology, Sec 1999, The First National Congress on Human Assisted Reproduction tion 2 Human Re productioniAnatomy, Physiology, Embryology, with International Participation under the patronage of the Romanian Munteanu Ed. (Romanian Academy of Science Publishers), pp. 1 17 Academy, Timisoara, Romania (abstract). I23 (TOC only). Gonzales et al., Preimplantation factor (PIF) could be a portion of Barnea et al., Evolution offeto-placental unit, in Obstetrics & Gyne CD2 or a homologue peptide, 2001, 57th Annual Meeting of the cology, 2001, Section 2 Human Re productioniAnatomy, Physiol American Society for Reproductive Medicine, Orlando, FL ogy, Embryology, Munteanu Ed. (Romanian Academy of Science (abstract). Publishers), pp. 170-175. Barnea, Safeguards established at conception in?uence peri and Morgan et al., Approaches to the Discovery of Non-Peptide Ligands postnatal life.‘ Roles of Preimplantation Factor (PIF) and Develop for Peptide Receptors and Peptidases, 1989, Annual Reports Medici mental Proteins (DPs), 200 I, World Congress of Perinatal Medicine, nal Chem.24: 243-252. Parallel Scienti?c SIEP Meeting, Sep. 23-27, Barcelona, Spain Ripka et al., Peptidomimetic design, 1998, Curr Opin in Chem Biol. (abstract). 2:441-452. Barnea, Novel Preimplantation Factors (PIF) and Developmental Hruby et al., Synthesis of oligopeptide and peptidomimetic libraries, Peptides (DPs) are involved in safeguarding pregnancy, 2002, The l997, Curr Opin in Chem Biol. l:ll4-l l9. Fetus as a Patient, Budapest, Hungary (abstract). Hruby et al., Conformational and Topographical Considerations in Gonzales et al., Preimplantation factors (PIF) embryo-derived Designing Agonist Peptidomimetics from Peptide Leads, 2000, Cur immunomodulatory peptides.‘ possible implicationsfor maternal rec rent Medicinal Chem. 7:945-970. ognition and allograft tolerance, 2002, 22nd Annual Meeting of the Stewart et al., Preimplantation Development of Mammalian Embryo American Society for Reproductive Immunology, Chicago, IL and Its Regulation by Growth Factors, l997, Dev. Genetics 21:91 (abstract). 101. US 7,723,289 B2 Page 3

Gonzalez et al. “Preimplantation Factor (PIF) May Modulate Mater Recognition and Allograft Tolerance” 2002, American Journal of nal Cellular Immunity (CD2)” 1998, SIEP, The Society for the Inves Reproductive Immunology, vol. 47, No. 6, p. 347. tigation of Early Pregnancy, BioIncept, Inc., BBRI, Boston Biomedi Schumacher et al. Primer on the Rheumatic Diseases, 10”‘ edition, cal Research Institute, p. 68-69. 1993, Arthritis Foundation, pp. 86-89 and 100-105. Barnea, Insight into Early Pregnancy Events: The Emerging Role of Barnea et al. “Applying Embryo-Derived Immune Tolerance to the the Embryo, 2004, Am. J. Reprod. Immunol. 51:319-322. Treatment of Immune Disorders” 2007, Annals of the New York Academy of Sciences, 1110: 602-618. Gonzalez et al. “Preimplantation Factors (PIF) Embryo-Derived Immunomodulatory Peptides: Possible Implications for Maternal * cited by examiner

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