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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 4 February 2010 (04.02.2010) WO 2010/013279 A3

(51) International Patent Classification: celle (AV) (IT). LA RANA, Giovanna [IT/IT]; Via M . A61K 47/48 (2006.01) A61P 29/00 (2006.01) Schipa, 64, 1-80122 Napoli (IT). SASSO, Oscar [IT/IT]; Corso Umberto I, 259, 1-80034 Marigliano (NA) (IT). (21) International Application Number: SARNELLI, Giovanni [IT/IT]; Via Napoli, 27, 1-80078 PCT/IT2009/000341 Pozzuoli (NA) (IT). RUSSO, Roberto [IT/IT]; Via del (22) International Filing Date: Priorato, 39, 1-80135 Napoli (IT). NIEDDU, Maria 29 July 2009 (29.07.2009) [IT/IT]; Via dei Mille, 3 1, 1-07100 Sassari (SS) (IT). CIRILLO, Carla [IT/IT]; Via Giuseppe Verdi, 40, (25) Filing Language: Italian 1-81030 Orta di Atella (CE) (IT). DE LUCIA, Salvatore (26) Publication Language: English [IT/IT]; Via Frazione Cagni, 12, 1-8201 1 Forchia (BN) (IT). (30) Priority Data: NA2008A000047 29 July 2008 (29.07.2008) rr (74) Agent: SARPI, Maurizio; Studio Ferrario, Via Collina, 36, 1-00187 Roma (IT). (71) Applicant (for all designated States except US): STEW¬ ART ITALIA SRL [IT/IT]; Corso G. Matteotti, 10, (81) Designated States (unless otherwise indicated, for every 1-2012 1 Milano (IT). kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (72) Inventors; and CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (71) Applicants : RIMOLI, Maria Grazia [IT/IT]; Via San DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, Nullo, 64, 1-80014 Giugliano (NA) (IT). CALIGNANO, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, Antonio [IT/IT]; Corso Amedeo di Savoia, 239, 1-801 36 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, Napoli (NA) (IT). CUOMO, Rosario [IT/IT]; Via Martiri ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, delle Foibe, 11, 1-81 100 Caserta (IT). BOATTO, Gian- NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, piero [IT/IT]; Via delle Magnolie 43/B, 1-07100 Sassari SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (IT). TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors; and (84) Designated States (unless otherwise indicated, for every (75) Inventors/ Applicants (for US only): ABIGNENTE, En¬ kind of regional protection available): ARIPO (BW, GH, rico [IT/IT]; Via Cilea, 112, 1-80127 Napoli (IT). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, MELISI, Daniela [IT/IT]; Via Lago di Viverone, 71, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 1-74 100 Taranto (IT). CURCIO, Annalisa [IT/IT]; Via TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Roma, 105, 1-80058 Torre Annunziata (NA) (IT). LUON- ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, GO, Elvira [IT/IT]; Via Piesco, 18, 1-83030 Torre Ie No- MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM,

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(54) Title: GALACTOSYLATED PRO-DRUGS OF NON-STEROIDAL ANTI-INFLAMMATORIES WITH IMPROVED PHARMACOKINETIC CHARACTERISTICS AND REDUCED TOXICITY OF THE STARTING DRUG

(57) Abstract: Pro-drugs of all non-steroidal anti-inf lammatories with free acid function derivatized with an ester group, which have the general structural formula given below (I) where A is: , , benorylate, ibufenac, , indomethacin, , , , , , , , , meclof enamic acid, , , and where in the ester group R can be a sugar (amongst which aldose, or ketose pentose, or esose selected from a group of D- and L- enantioiuers of ribose, glucose, galactose, mannose, arabinose, xilose, allose, altrose, gulose, idose and talose and substituted derivatives thereof, such as , galactosamine, iV-acetyl glucosamine, iV-acetyl galactosamine, N- acetyl ribosamine), a disaccharide, a trisaccharide or an oligosaccharide. τ < T T

According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K A61P

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practical, search terms used) EPO-Internal , WPI Data, COMPENDEX, EMBASE, BIOSIS

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No

WO 98/35973 A (OREAL [FR]; DALKO MARIA 3,9-17 [FR]; GALEY JEAN BAPTISTE [FR]) 20 August 1998 (1998-08-20) the whole document figure 1 ; example 1 1,2

HANESSIAN S ET AL: "One-step 3,10-17 stereocontrolled synthesis of [alpha]-anomeric carboxylic acid esters from unprotected glycosyl donors: A water-soluble aspirin pro-drug analogue" SYNTHESIS 2002 GEORG THIEME VERLAG DE, no. 14, 2002, pages 1959-1968, XP002527135 the whole document page 1962; compound 11

/

Further documents are listed in the continuation of Box C See patent family annex

Special categories of cited documents later document published after the international filing date or priority date and not in conflict with the application but ' document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention Ξ' earlier document but published on or after the international document of particular relevance, the claimed invention filing date cannot be considered novel or cannot be considered to . ' document which may throw doubts on priority cla ιm(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance, the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu¬ other means ments, such combination being obvious to a person skilled " document published prior to the international filing date but in the art later than the priority date claimed document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

26 October 2009 24/03/2010

Name and mailing address of the ISA/ Authorized officer European Patent Office, P B 5818 Patentlaan 2 NL - 2280 HV Rijswijk TeI (+31-70) 34 0-2040, Fax (+31-70) 340-3016 Orl ando , Michel e

Form PCT/ISA/210 (second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 2004/002457 A (A & D BIOSCIENCE INC 1-3,7-17 [US]; HOLICK MICHAEL F [US]; RAMANATHAN HALASYA [) 8 January 2004 (2004-01-08) the whole document paragraphs [0048] - [0059]

US 2005/215487 A l (HOLICK MICHAEL F [US] 1-3,7-17 ET AL) 29 September 2005 (2005-09-29) the whole document paragraphs [0077] - 10088]

CN 1 513 861 A (UNIV CHINA OCEANOGRAPHY) 1-3,7-17 21 OuIy 2004 (2004-07-21) abstract & DATABASE WPI Week 200470 Thomson Scientific, London, GB; AN 2004-710642 & CN 1 513 861 A (UNIV CHINA OCEANOGRAPHY) 2 1 July 2004 (2004-07-21) abstract

ZHAO ET AL: "A facile enzymatic process 1-3,7-17 for the preparation of ibuprofen ester prodrug in organic media" JOURNAL OF MOLECULAR CATALYSIS. B , ENZYMATIC, ELSEVIER, AMSTERDAM, NL, vol. 36, no. 1-6, 1 November 2005 (2005-11-01), pages 47-53, XP005105115 ISSN: 1381-1177 the whole document page 48; figure SCHEMEl

ZHAO X ET AL: "Pharmacological activity 1-3,7-17 and hydrolysis behavior of novel ibuprofen glucopyranoside conjugates" EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 41, no. 11, 1 November 2006 (2006-11-01), pages 1352-1358, XP024993925 ISSN: 0223-5234 [retrieved on 2006-11-01] the whole document page 1353; figure SCHEMEl V-

Form PCT/ISA/21 0 (continuation of second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim N o

Y NA WANG ET AL: "Regi oselective Enzymatic 1-3 ,7-17 Synthesi s of Non-Steroidal Ant i -Infl ammatory Drugs Containing Glucose i n Organic Media" BIOTECHNOLOGY LETTERS , KLUWER ACADEMIC PUBLISHERS, DO, vol . 27, no . 11 , 1 June 2005 (2005-06-01 ) , pages 789-792 , XP019230862 ISSN: 1573-6776 the whole document page 790; figure SCHEMEl

Y MISHRA ASHUTOSH ET AL: "Synthesi s , 7 characterization and pharmacological eval uati on of ami de prodrugs of ketorol ac" EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol . 43, no. 1 1 , 26 September 2007 (2007-09-26) , pages 2464-2472, XP002527136 ISSN : 0223-5234 abstract

Y TSUNEMATSU H ET AL: "SYNTHESIS AND THE 8 STEREOSELECTIVE ENZYMATIC HYDROLYSIS OF FLURBIPROFEN-BASIC AMINO ACID ETHYL ESTERS" JOURNAL OF DRUG TARGETING, HARWOOD ACADEMIC PUBLISHERS GMBH , DE , vol . 2 , no . 6 , 1 January 1995 (1995-01-01 ) , pages 517-525 , XP000923073 ISSN: 1061-186X the whole document figure 1

T CURCIO ANNALISA ET AL: "Galactosyl prodrug of ketorol ac : synthesi s , stabi l ity, and pharmacol ogical and pharmacokinetic eval uati ons . " JOURNAL OF MEDICINAL CHEMISTRY 25 JUN 2009, vol . 52, no. 12, 25 June 2009 (2009-06-25) , pages 3794-3800 , XP002552183 ISSN: 1520-4804

-/~

Form PCT/ISA/210 (continuation o f second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No

A BONINA F P ET AL: "Pharmacokinetic and pharmacodynamic profile of tri ethylene glycol indomethacin ester as a new oral prodrug" JOURNAL OF CONTROLLED RELEASE, ELSEVIER, AMSTERDAM, NL, vol. 41, no. 3 , 1 September 1996 (1996-09-01), pages 187-193, XP004037584 ISSN: 0168-3659

WO 2004/032971 A (BIOTECHNOLOGIE GESELL SCHAFT M [DE]; ORLANDO MICHELE [DE]; HEMBERGER J ) 22 April 2004 (2004-04-22) claims

BONINA F ET AL: "Synthesis and in vitro chemical and enzymatic stability of g lycosyl 3 '-azi do-3 '-deoxythymi d ine derivatives as potential anti-HIV agents" EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 2002 ELSEVIER NL, vol. 16, no. 3 , 2002, pages 167-174, XP002552184

BONINA F ET AL: "Glycosyl derivatives of dopamine and L-dopa as anti -Parkinson prodrugs: synthesis, pharmacological activity and in vitro stability studies" JOURNAL OF DRUG TARGETING, HARWOOD ACADEMIC PUBLISHERS GMBH, DE, vol. 11, no. 1 , 1 January 2003 (2003-01-01), pages 25-36, XP008095477 ISSN: 1061-186X

Form PCT/ISA/210 (continuation of second sheet) (April 2005) INTERNATIONAL SEARCH REPORT

Box No. Il 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. Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely:

2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically:

3. I I 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 No. Ill 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 additional sheet

1. As all required additional search fees were timely paid by the applicant, this international search report covers all searchable I HnimQ

2. As all searchable claims could be searched without effort justifying an additional fees, this Authority did not invite payment of additional fees.

3. As 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. v No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.:

see add . sheet

Remark on Protest The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee. The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation.

No protest accompanied the payment of additional search fees.

Form PCT/ISA/210 (continuation of first sheet (2)) (April 2005) International Application No. PCT/IT2009 /000341

FURTHER INFORMATION CONTINUED FROM PCT/ISA/ 210

This International Searching Authority found multiple (groups of) inventions in this international application, as follows:

1 . claims: 1 , 2 , 7-9 (complete); 3 , 10-17 (in part)

Galactosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, , sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, , flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

2. cl aims : 3, 10-17 ( i n part)

Ribosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

3 . claims: 3 , 10-17 (in part)

Glucosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

4. cl aims : 3, 10-17 ( i n part)

Mannosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

5 . claims : 3 , 10-17 (in part) International Application No. PCT/IT2009 /000341

FURTHER INFORMATION CONTINUED FROM POT/ISA/ 210

Arabinosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meciofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

6 . claims: 3 , 10-17 (in part)

Xylosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

7 . claims: 3 , 10-17 (in part)

Allosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

8 . claims: 3 , 10-17 (in part)

Altrosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

9 . claims: 3 , 10-17 (in part) International Application No. PCT/IT2009 /000341

FURTHER INFORMATION CONTINUED FROM PCT/ISA/ 210

Gulosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

10. claims: 3 10-17 (in part)

Idosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

11. claims: 3 , 10-17 (in part)

Talosylated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

12. claims: 3 , 10-17 (in part)

Glucosamine- or N-acetyl-glucosamine-conjugated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

13. claims: 3 , 10-17 (in part) International Application No. PCT/IT2009 /000341

FURTHER INFORMATION CONTINUED FROM POT/ISA/ 210

Galactosamine- or N-acetyl-galactosamine conjugated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

14. claims: 3 , 10-17 (in part)

N-acetyl-ribosamine-conjugated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

15. claims: 4 (complete); 3 , 10-17 (in part)

D isacchari de-conjugated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

16. claims: 5 (complete); 3 , 10-17 (in part)

Tri sacchari de-conjugated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same.

17. claims: 6 (complete); 3 , 10-17 (in part) International Application No. PCT/IT2009 /000341

FURTHER INFORMATION CONTINUED FROM PCT/ISA/ 210

0 igosacchari de-conjugated derivatives of non-steroidal antiinflammatory drugs having a free acid function: aspirin, diflunisal, benorilate, ibufenac, diclofenac, indometacin, sulindac, ketorolac, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, wherein the oligosaccharide contains 4-10 residues. Use thereof in the preparation of a medicament for pain therapy or inflammation and pharmaceutical compositions comprising the same. Patent document Publication Patent family Publication cited in search report date member(s) date

WO 9835973 20-08-1998 AU 6625698 A 08-09- 1998 BR 9807157 A 25-04- 2000 CA 2280185 A l 20-08- 1998 DE 69814058 D l 05-06- 2003 DE 69814058 T2 19-02- 2004 EP 0968221 A l 05-01- 2000 ES 2198046 T3 16-01- -2004 FR 2759370 A l 14-08- 1998 JP 3753188 B2 08-03- 2006 JP 2000510163 T 08-08- 2000 US 6255297 B l 03-07- 2001 ZA 9801122 A 20-08- 1998

WO 2004002457 A 08-01-2004 CA 2490190 A l 08-01-2004 EP 1578402 A2 28-09-2005

us 2005215487 A l 29-09-2005 NONE

CN 1513861 A 21-07-2004 NONE

WO 2004032971 A 22-04-2004 AT 409048 T 15-10-2008 AU 2003273413 A l 04-05-2004 EP 1549350 A l 06-07-2005 ES 2314238 T3 16-03-2009 US 2006100163 A l 11-05-2006

Form PCT/ISA/21 0 (patent family annex) (April 2005)