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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date 23 February 2006 (23.02.2006) (51) International Patent Classification: A61K 31/00 (2006.01) A61K 45/06 (2006.01) A61K 31/05 (2006.01) GOlN 33/569 (2006.01) A61K 31/353 (2006.01) A61P 31/18 (2006.01) PCT (10) International Publication Number W O 2006/019841 A3 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (21) International Application Number: PCT/US2005/024893 (22) International Filing Date: (25) Filing Language: (26) Publication Language: (30) Priority Data: 60/588,013 13 July 2005 (13.07.2005) English English 13 July 2004 (13.07.2004) US (71) Applicant (for all designated States except US): GOV¬ ERNMENT OF THE UNITED STATES OF AMER¬ ICA [US/US]; The Secretary, Department of Health of and Human, Services, National Cancer Institute, Office of Technology Transfer, national Institutes, of Health, 601 1 Executive Boulevard, Suite 325, Rockville, M D 20852-3804 (US). (72) Inventors; and (75) Inventors/Applicants (for US only): ZEICHNER, Steven [US/US]; 5404 Glenwood Road, Bethesda, M D 20817 (US). KRISHNAN, Vyjayanthi [IN/US]; 12449 Great Park Circle, #201, Germantown, M D 20876 (US). (74) Agents: CORLESS, Peter, F. et al.; Edwards & Angell, LLP, P.O. Box 55874, Boston, M A 02205 (US). Published: — with international search report — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (88) Date of publication of the international search report: 22 February 2007 For two-letter codes and other abbreviations, refer to the "G u id ance Notes o n Codes and Abbreviations" appearing at the b e g in ning of each regular issue of the PCT Gazette. (54) Title: TREATMENT OF VIRAL INFECTIONS WITH EGR 1 ACTIVATORS (57) Abstract: The invention relates to treatment of cells or humans carrying or infected with a virus capable of causing an im m u n odeficiency disease with particular compounds, including Egr 1 activators. A . CLASSIFICATION O F SUBJECT MATTER INV. A61K31/O0 A61P31/18 A61K31/05 . A61K31/353 A61K45/06 G01N33/569 According t International o Patent Classification (IPC) o r t both national classification o and IPC B . FIELDS SEARCHED Minimum documentation searched (classification system followed b y classification symbols) A61K Documentation searched other than minimum documentation t o the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name o f data base and, where practical, search terms used) EPO-Internal , CHEM ABS Data, WPI Data, PAJ , BIOSIS, MEDLINE, EMBASE, SCISEARCH C . DOCUMENTS CONSIDERED T O BE RELEVANT Category* Citation o f document, with indication, where appropriate, o f the relevant passages Relevant t o claim No. W O 99/56737 A (INSTITUT NATIONAL D E LA SANTE ET D E LA RECHERCHE MEDICALE ; SAVOURET,) 1 1 November 1999 (1999-11-11) page 1 , lines 5-9 page 5 , lines 19-22 page 8 , line 24 - page 9 , line 2 page 10 line 2 2 - page 11, line 1 page 14 lines 12-19 page 18 lines 25-28 page 2 4 lines 15-27 page 2 5 lines 7,8 table 3 page 29 l i nes 13-20 12 4-10 c l aims 1,2,11 -/-- Further documents * Special categories are listed i n the continuation : o f Box C . See patent family annex. o f cited documents "A" document defining the general state o f the art which is not considered t o b e o f particular relevance "E" earlier document filing date but published o n o r after the international "T" later document published after the international filing date o r priority date and not i n conflict with the application but cited t o understand the principle o r theory underlying the invention "X" document o f particular relevance; the claimed invention cannot b e considered novel o r cannot b e considered t o involve a n inventive step when the document is taken alone "Y" document o f particular relevance; the claimed invention cannot b e considered t o involve a n inventive step when the document is combined with one o r more other such docu¬ ments, such combination being obvious t o a person skilled in the art. "&" document member o f the same patent family search report "L" document which may throw doubts o n priority claim(s) o r which i s cited t o establish the publication date o f another citation o r other special reason (as specified) "O" document referring t o a n oral disclosure, other means use, exhibition o r filing date but "P" document published prior t the international o later than the priority date claimed Date o f the actual completion o f the international search Date o f mailing o f the international 2 9 August 2006 Name and mailing address o f the ISA/ European Patent Office, P.B. 5818 Patentlaan 2 N L - 2280 H V Rijswijk TeI. (+31-70) 340-2040, Tx. 3 1 651 epo nl, Fax: (+31-70) 340-3016 Form PCT/ISA/210 (second sheet) (April 2005) 8 Authorized officer DEC Cielen, El sie C(Continuation). Category* DOCUMENTS CONSIDERED T O B E RELEVANT Relevant t o claim No. Citation of document, with indication, where appropriate, of the relevant passages W O 01/12228 A (UNIVERSITY O F MARYLAND BIOTECHNOLOGY INSTITUTE; UNIVERSITY O F MARYLAND) 2 2 February 2001 (2001-02-22) page 3 , line 3 5 - page 4 , line 6 page 5 , line 2 9 - page 6 , line 19 page 10, lines 8-18 1 ,2,11, 12,16 3,11 ,12, 15,16 page 11, page 12, page 13, page 14, page 17, examples page 24, claims l i nes 16,17 l i nes 2-8,16-25 l i nes 13-17 l i n e 3 1 - page 15, l ine 25 l i nes 19-23 1-5 l i nes 7-14 1,4-6,8,12,14,20,21,32,35-37,39,43,45,51,5 1,2,11, 12,16 2,54 "Synergi stic inhibi tion o f HIV - 1 i n acti vated and resting peripheral blood mononuclear cel l s , monocyte-derived macrophages, and sel ected drug-resi stant i sol ates with nucleoside analogues combined wi t h a natural product, resveratrol " JAIDS, JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES , 25(3) , 246-255 CODEN: JJASFJ, 2000, XP000982355 abstract page 248, col umn 1 , last 251, col umn 1 , paragraph paragraph 1 - page HEREDIA, ALONSO ET AL: 3,11,12, 15,16 figures 1,2 page 252, column 2 , paragraph 2 page 253, column 1 , paragraph 3 - column 2 , paragraph 2 WO 03/054160 A (THE REGENTS OF THE UNIVERSITY OF CALI FORNIA; VERDIN, ERIC; JORDAN, ALB) 3 July 2003 (2003-07-03) page 1 . l ines 14-20 page 2 , l ines 11-21 page 3 , l ines 3-8 page 4 , l ines 6-25 page 12, l i nes 9-15 page 26, l i nes 26-31 page 29, l i n e 2 1 - page 30, l ine 1 7 c l aim 1 6 3,11,12, 15,16 -I- Form PCTΛSA/210 (continuation o f second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED T O BE RELEVANT with indication, where appropriate, o f the relevant passages Relevant Category* Citation o f document, to claim No. X MAHMOOD, N . ET AL: "Constituents o f Cuscuta reflexa are anti- HIV agents" ANTIVIRAL CHEMISTRY & CHEMOTHERAPY , 8(1), 70-74 CODEN: ACCHEH; ISSN: 0956-3202, 1997, XP008067586 abstract 1,2,5 4,6-10 page 70, col umn 2 , paragraphs compound 2 page 72, column 1 , paragraph 3 table 1 2,3 page 72, col umn 2 , paragraphs 1,2,4 RABBI MOHAMMED F ET AL: "Interl eukin-10 enhances tumor necrosi s factor-alpha activation of HIV-I transcripti on i n latently i nfected T cel l s " JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVI ROLOGY, vol . 19, no. 4 , 1 December 1998 (1998-12-01), 321-331, XP0 Θ 8067583 ISSN: 1077-9450 abstract page 322 col umn I paragraphs page 323 col umn I paragraph figure 1 page 326, column 1 , paragraph 2 , paragraph 1 pages 3,4 2 2 - column DE 4 3 40 438 A l (BACKHAUS, ERWIN, 42477 RADEVORMWALD, DE) 1 June 1995 (1995-06-01) column 1 , lines 25-32,57-63 claim 1 X W O 03/002126 A (UNIVERSITY O F PRETORIA; TOKYO FOOD TECHNO COMPANY LIMITED; APOSTOLIDES) 9 January 2003 (2003-01-09) page 1 , paragraph 2 page 2 , paragraph 1-3 page 3 , paragraph 2 page 7 , paragraph 2 page 8 , paragraph 4 claims 1,4-6,21,24-26 -/141,12, 16 Form PCT/ISA/210 (continuation o f second sheet) (April 2005) P T/ C(Continuation). Category* 2005/024893 DOCUMENTS CONSIDERED T O BE RELEVANT with indication, where appropriate, o f the relevant passages Citation o f document, Relevant to claim No. A VAN 1T WOUT ANGELIQUE B ET AL: "Cel l ular on o f gene expression upon human immunodefi c i ency v i rus type CD4+-T-cel l l ines . " JOURNAL O F VIROLOGY 1 i nfecti vol . 77, no. 2 , January 2003 (2003-01) pages 1392-1402, XP002396149 ISSN: 0Θ 22-538X abstract page 1394, col umn 1 , paragraph 1 - page 1395, column 1 , paragraph 1 page 1395, col umn 2 , paragraph 2 page 1399, col umn 2 , paragraph 5 page 1400, column 2 , paragraph 1 A "Antioxidants i nduce d i fferent phenotypes by a d i stinct modulation o f signal transduction. " FEBS LETTERS, DELLA RAGIONE FULVIO ET AL: vol . 532, no. 3 , 18 December 2002 (2002-12-18) 289-294, XP004398419 ISSN: 0014-5793 c i ted i n the appl ication abstract figure 4 page 292, col umn 1 , paragraph page 292, col umn 2 , paragraph PX pages 1 5 1-3,11, 16 P,A KRISHNAN VYJAYANTHI ET AL: "Host cel l gene expression during human immunodeficiency v i rus type I latency and reactivation and effects o f targeting genes that are differential l y expressed i n v i ral latency" JOURNAL OF VIROLOGY, vol . 78, no. 17, September 2004 (2004-09) , pages 9458-9473, XP0Θ 8067579 ISSN: Θ Θ22-538X abstract 5-10,12, 15 page 9459, col umn I paragraph 1 page 9468, col umn 2 paragraph 2 page 9469, col umn 1 , paragraph 2 page 9470, column 2 , l ast paragraph page 9471, col umn 1 l ast paragraph col umn 2 , paragraph 1 L WO - 2006/017346 A (GOVERNMENT OF THE UNITED STATES OF AMERICA, A S REPND HUMAN SERVICES OF) 1 6 February 2006 (2006-02-16) 1,2 figure 6 page 14, l i nes 6-15 page 34, l i ne 4 - page 35, page 43, l ines 16-29 l ine 3 Form PCT/ISA/210 (continuation o f second sheet) (April 2005) International Application No. PCT/ US2005/ 024893 FURTHER INFORMATION CONTINUED FROM PCT/ISA/ 210 This International Searching Authority found multiple (groups of) inventions in this international application, a s follows: 1 . claims: 1-12, 15-16 A method of treating or preventing HIV infection i n a subject comprising identifying the subject a s i n need of Egr 1 activation, and administration of a n effective amount of a n Egr 1 activator. A method of treating latently HIV-infected cells / modulating lytic replication i n a n HIV-infected cell i n a subject / reducing latent HIV reservoirs i n a n HIV-infected subject / increasing expression of p24 i n a latently HIV-infected cell / activating latent HIV-provirus i n a cell i n a subject, comprising administration t o the subject of a n effective amount of a n Egr 1 activator that i s taxifolin. A method of treating HIV infection i n a subject comprising identifying the subject a s i n need of Egr 1 activation, administration of a n effective amount of a n Egr 1 activator t o reactivate HIV replication i n infected cells, and further administration of a n effective amount of a n additional antiviral agent that i s a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, or other non-nucleoside antiviral agent. A method of preventing HIV infection i n a subject comprising identifying a subject a s i n need of reactivation of a replication process i n latent HIV-infected cells; administering t o the subject a n effective amount of a n Egr 1 activator t o reactivate the replication process; and administering t o the subject one or more HIV antiviral agents t o inhibit lytic replication i n the cells. 2 . claims: 13-14 A method of screening for a compound capable of activating latent HIV-infected cells comprising contacting a test compound with a n ACH-2 cell or Jl. 1 cell or Ul cell and determining the level of p24 expression. INTERNATIONAL SEARCH REPORT Box II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet) This International Search Report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. X Claims Nos.: because they relate t o subject matter not required t o b e searched by this Authority, namely: Although claims 1-12, 15 and 16 are directed to a method o f treatment o f the human/animal body, the search has been carried out and based on the alleged effects o f the compound/composition. 2. Claims Nos.: because they relate t o parts of the International Application that d o not comply with the prescribed requirements t o such a n extent that no meaningful International Search can b e carried out, specifically: 3. J Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box III Observations where unity of invention is lacking (Continuation of item 3 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: see addi tional sheet A s all required additional search fees were timely paid by the applicant, this International Search Report covers all searchable claims. 2. A s all searchable claims could be searched without effort justifying a n additional fee, this Authority did not invite payment of any additional fee. 3. A s only some of the required additional search fees were timely paid by the applicant, this International Search Report covers only those claims for which fees were paid, specifically claims Nos.: 4 . _γ _ No required additional search fees were timely paid by the applicant. Consequently, this International Search Report is restricted t o the invention first mentioned i n the claims; it is covered by claims Nos.: 1-12, 15-16 Remark o n Protest The additional search fees were accompanied by the applicant's protest. No protest accompanied the payment of additional search fees. Form PCT/ISA/21 0 (continuation of first sheet (2)) (January 2004) Patent document cited i n search report Publication date Patent family member(s) Publication date W O 9956737 A 11-11-1999 AT AU CA DE DE EP ES FR JP 245973 3528299 2331364 69909998 69909998 1075256 2205807 2778337 2002513754 281179 765724 6638500 2380924 60015568 1207907 T A Al Dl T2 Al T3 Al T T B2 15- Θ - 2003 8 23-11- 1999 11-11- 1999 04-0922-04- 2004 14-02- 2001 01-05- 2004 12-11- 1999 14-05- 2002 W O 0112228 22-02-2001 AT AU AU CA DE EP A Al Dl A2 15-11-2004 25-09-2003 13-03-2001 22-02-2001 09-12-2004 29-05-2002 09-07-2003 06-10-2004 W O 03054160 A 03-07-2003 AU EP NONE NONE NONE 2002361797 A l 1463822 A 2 D E 4340438 Al 01-06-1995 09-01-2003 16-02-2006 W O 03002126 W O 2006017346 A A Form PCTΛSA/210 (patent family annex) (April 2005)