(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 WO 2013/072763 A3 23 May 2013 (23.05.2013) W P O P C T

(51) International Patent Classification: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/4164 (2006.01) A61P 25/00 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, A61K 9/70 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (21) International Application Number: NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, PCT/IB20 12/002797 RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (22) International Filing Date: TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 16 November 2012 (16.1 1.2012) ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 61/560,577 16 November 201 1 (16. 11.201 1) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant: NOMETICS INC. [CA/CA]; Parteq, 1625 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Biosciences Complex, Queen's University, Queen's Univer TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, sity Biosciences Complex, Kingston, ON K7L 3N6 (CA). ML, MR, NE, SN, TD, TG). (72) Inventor: ENSCORE, David, J.; 105 Travertine Trail, Al- Published: pharetta, GA 30022 (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every (88) Date of publication of the international search report: kind of national protection available): AE, AG, AL, AM, 15 August 2013 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,

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© (54) Title: NON-SENSITIZING TRANSDERMAL CLONIDINE PATCH (57) Abstract: Disclosed herein are non sensitizing clonidine transdermal patches and methods of treatment using the same. The transdermal patches do not contain LUE92, acetaldehyde and polyethylene terephthalate, which are either irritants to skin, or pre - cursors or irritants to skin. The transdermal patches do not elicit an allergic response in the skin of a subject . PCT/IB20 12/002797

A . CLASSIFICATION OF SUBJECT MATTER IPC: A61K 31/4164 (2006.01) . A 6IK 9/70 (2006.01) . A 6IP 25/00 (2006.01) 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) IPC: A61K 31/4164 (2006.01 ) , A61K 9/70 (2006.01 ) , A61P 25/00 (2006.01 )

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

Electronic database(s) consulted during the international search (name of database(s) and, where practicable, search terms used) Canadian Patent Database, google. ca, (Keywords: clonidine, LlIE, acetaldehyde, polyethylene terephthalate, PET)

C . DOCUMENTS CONSIDERED TO BE RELEVANT

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

CN 1186659 A (ZHENG, M . ET AL.) 08 July 1998 (08-07-1998) 1-18, 21-23 espacenet translation to englisli *entire document*

CN 191 1222 A; (WU, R. ET AL.) 14 February 2007 (14-02-2007) 1-4, 6-7, 9-1 1, 13-16, 18, 21-23 espacenet translation to englisli *entire document* 1-4, 6, 9-1 1, 13-16, 18, 21, 23 CN 10101 1391 A ; (ZHIHUI, C. ET AL.) 08 August 2007 (08-08-2007) espacenet translation to englisli *entire document*

U S 4765974 B (TOKUDA, S. ET AL.) 23 August, 1988 (23-08-1988) 1-3, 6, 9-10, 13, 23 ♦abstract, column 1, line 63-, column 2, line 45; column 4, lines 18-19; examples 1, 2*

EP 427877 Al; (LOKUDA, S.) 22 May 1991 (22-05-1991) ♦abstract, page 1, lines 4-6; page 3, line 9-26; page 5, line 11-12; page 7, line 56-57; page 8 line 1-8*

[x] 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 conflict with the application but citecTto understand document defining the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance document of particular relevance the claimed invention cannot be earlier application or patent but published on or after the international considered novel or cannot be considered to involve an inventive filing date step when the document is taken alone document which may throw doubts on priority claim(s) or which is document of particular relevance the claimed invention cannot be cited to establish the publication date of another citation or other considered to involve an inventive step when the document is special reason (as specified) combined with one or more other such documents such combination being obvious to a person skilled the art document referring to an oral disclosure use. exhibition or other means document member of the same patent family document published prior to the international filing date but later than the priority date claimed Date of the actual completion of the international search Date of mailing of the international search report

19 March 20 1 ( 19-03-20 13) 09 April 2013 (09-04-2013) Name and mailing address of the ISA/CA Authorized officer Canadian Intellectual Property Office Place du Portage I, C I 14 - 1st Floor, Box PCT Lily Y u (819) 934-0070 50 Victoria Street Gatineau, Quebec K1A 0C9 Facsimile No.: 001-819-953-2476

Form PCT/ISA/210 (second sheet ) (July 2009) Page 4 of 7 . PCT/IB20 12/002797

Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of the 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] Claim Nos. : 24-49 because they relate to subject matter not required to be searched by this Authority, namely :

Claims 24-49 relate to a method of medical treatment, which the International Search Authority is not required to search under Ar ticle 17(2)a(I) and Rule 39. 1 (iv) of the Patent Cooperation Treaty Regulations. This authority has nevertheless conducted a search based on the alleged therapeutic effect derived from the use of a transdermal patch comprising compound of formula I, wherein the patch does not contain LUE92, acetaldehyde and/or polyethylene terephthalate

2 . [ ] Claim 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. [ ] Claim 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 :

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

2 . [ ] As all searchable claims could be searched without effort justifying 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 claim Nos. :

4 . [ ] 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 bv claim Nos. :

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)) (July 2009) Page 2 of 7 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

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

US 4822617 Bl; (PANOZ, D. ,E.) 18 April 1989 (18-04-1989) 1-3, 6, 7, 9-10, 13-15, 18, 21-23 ♦abstract, column 1, lines 10-15, 35-43; column 2, line65- column 3, line 54; column 5, lines 8- 15, 65-68; column 6, line 1-5; claim 1*

US 2009 0062754 Al; (TANG, J.) 05 March 2009 (05-03-2009) 19, 20 abstract, paragraphs [0009]-[0010], [0026]-[0027], [0065], [0085]-[0088], claims 1, 5, 6, 8 and 16*

US 420121 1 B; (CHANDRASEKARAN , S. ET AL) 06 (06-05-1980) 19, 20 ♦abstract, column 2, line 4-column 3, line 15; column 4, line 50-column 6, line 8; claims, 1-4, 8 and 9*

MAIBACH, H.; Clonidine: Iritant and allergic contact dermatitis assays.; Contact Dermatitis: Vol. 12 pp 192-195; 1985; ISSN: 1600-0536 *cited by Applicant* *Entire document*

BENEZRA, C ; Stracture-activitv relationships of skin haptens with a closer look at compounds used in transdermal devices.; Journal of Controlled Release.; Vol. 15 page267-270; 1991. ISSN: 0168-3659 *page 269, column 2, line 10- page270, column 1, line 8*

ZHANG, Y. EL AL.; Adjuvants to prolong the local anesthetic effects of coated microneedle products.; International Journal of Pharmaceutics; Vol. 439, page 187-192; 25 September 2012; ISSN: 0378-5173 ♦abstract, page 191, 2nd column, line 15-29*

Form PCL ISA 210 (continuation of second sheet) (July 2009) Page 5 of 7 Information on patent family members PCT/IB20 12/002797

Patent Document Publication Patent Family Publication Cited in Search Report Date Member(s) Date

CN1 186659A 08 July 1998 (08-07-1998) None

CN191 1222A 14 February 2007 (14-02-2007) None

CN10101 1391A 08 August 2007 (08-08-2007) None

US4765974A 23 August 1988 (23-08-1988) None

EP0427877A1 22 May 1991 (22-05-1991 ) CA2002761A1 10 May 1991 (10-05-1991 ) CA2002761 C 09 March 1999 (09-03-1999) EP0427877B1 16 June 1993 (16-06-1993) JP1287024A 17 November 1989 (17-1 1-1989) JP2524190B2 14 August 1996 (14-08-1996) US5175052A 29 December 1992 (29-12-1992)

US4822617A 18 April 1989 (18-04-1989) AT39326T 15 January 1989 (15-01-1989) BE896578A1 16 August 1983 (16-08-1983) CH661446A5 3 1 July 1987 (31-07-1987) DE3475692D1 26 January 1989 (26-01-1989) EP01 17027A1 29 August 1984 (29-08-1984) EP01 17027B1 2 1 December 1988 (21-12-1988) IE830094L 18 July 1984 (18-07-1984) IE54286B1 16 August 1989 (16-08-1989) JP59155268A 04 September 1984 (04-09-1984) JP4042025B 10 July 1992 (10-07-1992) PH23952A 23 January 1990 (23-01-1990)

US2009062754A1 05 March 2009 (05-03-2009) AU2008297001A1 12 March 2009 (12-03-2009) CA2698495A1 12 March 2009 (12-03-2009) CN101842065A 22 September 2010 (22-09-2010) EP2190392A1 02 June 2010 (02-06-2010) JP2010538064A 09 December 2010 (09-12-2010) KR20 100063 11OA 10 June 2010 (10-06-2010) MX2010002452A 15 October 2010 (15-10-2010) NZ584320A 30 March 2012 (30-03-2012) WO2009032184A1 12 March 2009 (12-03-2009)

Form PCT/ISA/210 (patent family annex ) (July 2009) Page 6 of 7 US420121 1A 06 May 1980 (06-05-1980) AR218037A1 15 May 1980 (15-05-1980) ATA905877A 15 (15-1 1-1980) AT362884B 25 (25-06-1981 ) AU512328B2 02 (02-10-1980) AU2846277A 08 (08-03-1979) BE862585A1 02 May 1978 (02-05-1978) BG29866A3 16 (16-02-1981 ) CA1089362A1 11 November 1980 ( 1 1-1 1-1980) CH646876A5 28 December 1984 (28-12-1984) CS216917B2 3 1 December 1982 (31-12-1982) DD135566A5 16 (16-05-1979) DE2755661A1 25 (25-01-1979) DE2755661 C2 22 May 1986 (22-05-1986) DK387777A 13 January 1979 (13-01-1979) DK159375B 08 October 1990 (08-10-1990) DK159375C 18 March 1991 (18-03-1991 ) ES245891 U 0 1 (01-06-1980) ES245891Y 16 (16-12-1980) ES472073A1 16 March 1979 (16-03-1979) FI772754A 13 January 1979 (13-01-1979) FR2397190A1 09 (09-02-1979) FR2397190B1 15 October 1982 (15-10-1982) GB1577259A 22 October 1980 (22-10-1980) GR61591A1 02 December 1978 (02-12-1978) HU179397B 28 October 1982 (28-10-1982) IE46069L 12 January 1979 (12-01-1979) IE46069B1 09 February 1983 (09-02-1983) IL52839A 30 (30-09-1979) IL52839D0 3 1 October 1977 (31-10-1977) IT1 104643B 2 1 October 1985 (21-10-1985) JP54020129A 15 February 1979 (15-02-1979) JP62014526B 02 April 1987 (02-04-1987) LU78845A1 06 September 1979 (06-09-1979) MX154722A 07 December 1987 (07-12-1987) NL7710213A 16 January 1979 (16-01-1979) NL189800B 0 1 March 1993 (01-03-1993) NL189800C 02 August 1993 (02-08-1993) N0772955A 15 January 1979 (15-01-1979) NZ185000A 3 1 August 1979 (31-08-1979) PH16059A 09 June 1983 (09-06-1983) PL204853A1 10 September 1979 (10-09-1979) PL1 13984B1 3 1 (31-01-1981 ) PT67128A 0 1 November 1977 (01-1 1-1977) PT67128B 16 March 1979 (16-03-1979) R075336A1 30 December 1980 (30-12-1980) SE7709731A 13 January 1979 (13-01-1979) SE7709731 L 13 January 1979 (13-01-1979) SU1005650A3 15 March 1983 (15-03-1983) YU166578A 20 March 1985 (20-03-1985) YU41594B 3 1 October 1987 (31-10-1987) ZA7705848A 30 August 1978 (30-08-1978)

Form PCT/ISA/210 (extra sheet) (July 2009) Page 7 of 7