PATENT COOPERATION TREATY From the INTERNATIONAL SEARCHING AUTHORITY i PCT 100004 China 7th Floor, Scitech Place, No. Wai Ave. Chao Yang District, Beijing WRITTEN OPINION OF THE INTERNATIONAL SEARCHING AUTHORITY UNITALEN ATTORNEYS AT LAW (PCT Rule 43bis.1) Date of mailing (day/montivear) 28 December 2016 Applicants or agents file reference FOR FURTHER ACTION OP160744 See paragraph 2 below International application No. International fling date (day/month/vear) [Priority dae (day/monsh/year) PCTICN2016/099852 23 September 2016 24 September 2015, ‘ifiation (IPC) or both national classification ae IPC WG.O1}i: AIK 31/131(2006.01i_A6IP 9/10(2006.01)i Tniernatonal Patent C AGIK 31/1 Applicant INNOLIFE CO.,LTD. 1. This opinion contains indications relating o the Following items: Z] Box No.1 Basis of the opinion Box No.l Priority [7] Box No. IL Non-establshment of opinion with regard to novelty, inventive step and industrial applicability Box No. IV Lack of unity of invention [7] Box No. V_Reasoned statement under Rule 43bis.1(a)) with regard to novelty, inventive step and industrial applicability; tations and explanations supporting suc sta Box No. VI Certain documents cited Box No. VI Certain defects in the international application Box No. VII Certain observations on the international application FURTHER ACTION If a demand for intemational preliminary examination is made, this opinion will be considered to be a writen opinion of the International Preliminary Examining Authority (IPEA”) except that this dees not apply where the applicant chooses an Authority ‘other than this one to be the IPEA and the chosen IPEA has notified the Intemational Bureau under Rule 66.Lbis(b) that writen ‘opinions of this international Searching Authority will nt be so considered, IF this opinion is, as provided above, considered to be a written opinion of the IPEA, the applicant is invited to submit the IPEA, ‘written reply together, whe PCTIISA/220 or before the expiration of 22 months from the priority date, For further options, see Form PCTIISA/220, e appropriate, with amendments, before the expiration of 3 months from the date of mailing of Form ihichever expires ater. ‘Name and mailing adress ofthe ISA7] Date of completion ofthis opinion] Avthorized oficer STATE INTELLECTUAL PROPERTY OFFICE OF THE ated) PR.CHINA JIANG,Wei China 6, Xitucheng Re. Jimen Bridge, Haidian District, Beijing 100088 Facsimile No (86—10) 62019451 Telephone No, (86-10)62088437 Form PCT/SA/37 (Cover sheet) Guly 2011)WRITTEN OPINION OF THE Intemational application No, INTERNATIONAL SEARCHING AUTHORITY PCT/CN2016/099852 Box No. Basis of the opinion 1. With regard tothe language, this opinion has been established on the basis of [7] the intersational application in dhe language in which it was filed, a translation of the international application inte which is the language of a translation furnished forthe purposes of international search (Rules 12.3(a) and 23.100) ‘This opinion has been established taking into account the retifeation of an obvious mistake authorized by or notified to this Authority under Rule 91 (Rule 43bis.1(4). 3. With regard to any mueceotide and/or amino acid sequence disclosed in the international application, this opinion has been established on the basis ofa sequence listing filed or furnished: a (eeans) on paper 7] in electronic form b. Gime) 7] inthe international application as filed together with the international application in eletronic form subsequently to this Authority for the purposes of search 4 In addition, in the ease that more than one version or copy of a sequence listing has been filed or furnished, the required slatements thatthe information in the subsequent or additional copies i identical to that in the application as filed or does ‘ot go beyond the application as filed, as appropriate, were furnished. 5. Additional comments Fon PCT/ISA/37 (Box No.) Guly 2011)WRITTEN OPINION OF THE International application No, INTERNATIONAL SEARCHING AUTHORITY Po TeNamanene Box No. II Non-establishment of opinion with regard to novelty, inventive step and industrial applicability Te questions whether the claimed invention appears to be novel, to involve an inventive step (to be non obvious), orto be industrially applicable have not been examined in respect of: the entire international application. 7] chims Nos. 1-24, 33.35 because [7] the said international application, othe said clsims Nos, _1-24, 33-35 _ relate t the following subject matter which does ‘not require an international earch (specifi): (1) The subject mater of claims 1-24 and 33-35 relates to a method of treatment of the human or animal body by therapy andl therefore does not warrant an international search according to the criteria set ‘out in Rule 39.1(iv). Thus, the search is based on the subject matter that could reasonably be expected, to be claimed later in the procedure, and the corresponding claims, namely use of a composition comprising a copper chelating tetramine in the manufacturing of a medicament for repairing and regenerating ischemic tissue. the description, claims or drawings (indicate particular elements below) or sad claims Nos. are s0-unelear that no meaningful opinion could be formed (specify: the claims, o suid claims Nos are so inadequately supported by the description that no meaningful opinion could be Formed (specify: no international search report has been established for ssid claims Nos. ‘4meaningful opinion could not be formed without the sequence listing; the applicant didnot, within the prescribed ime limit Fumisha sequence listing on paper complying with the standard provided for in Annex Cot the Administrative Instructions, and such listing was not available tothe International Searching Authority in a form and manner acceptable tit fumish a sequence listing in cletronic form complying with the standard provided for in Annex C of the Administrative Instructions, and such listing was not available tothe International Searching Authority in a form and manner acceptable ay the required Inte furnishing fee forthe fumishing ofa sequence listing in esponse to an invitation under Rule 13¢er 1) orb). See Supplemental Box for further detail Fon PCT/ISA/237 (Box No. ID Guly 2011)WRITTEN OPINION OF THE Intemational application No, INTERNATIONAL SEARCHING AUTHORITY PCT/CN2016/099852 Box No, Vv Ressoned statement under Rule 43b/.1(a)i) with regard to novelty, inventive step and industrial applicability; citations and explanations supporting such statement 1. Statement Novelty (N) Claims YES Claims No Inventive step (18) Claims YES Claims No Ivlstral applicability (A) Claims yes Claims No Citations ae explanations U1} 1 Citations: 2] Di: ZHANG, Lin, eal, Cardiovascular Diabetology, 2013, 12 : 123 {3} D2: SHAO, Tongxian etal, Journal of Luoyang Medical College, 2000, 18(1): 15 [4] D3: WO 20040179571 04 March 2004 (04.03.2004) [5] D4: CN 103467577 25 December 2013 (25.12.2013) [6] DS: US 2014171508A. 19 June 2014 (19.06.2014) (7] IL Explanations {8} 1. Novelty [9] D1 discloses diabetes causes cardiomyopathy through a copper-mediated mechanism that incorporates ‘myocardial copper deficiency, whereas triethylenetetramine(TETA) treatment prevents this response (see abstract), [10] 2 discloses copper content in ischemic myocardium of rabbits tended to reduce, complementing copper has certain effect on correcting myocardial ischemia (see page 16, conclusions). [11] D8 discloses 1 method of teating ischemic cardiomyopathy, comprising administering to a human an amount of trientine of a trientine type copper chelation agent to lower the copper values content of said tissue (see claims 5 and 10), [12] D4 discloses the use of copper-bearing nano-biological materials in the manufacturing of a medicament for Uucating lower limbs ischemic diseases (see claim 1), [13] DS discloses methods and pharmaceutical compositions for preconditioning the CNS to neuroprotect against, minimize and/or prevent the effects of ischemia by stimulating and stabilizing HIF. therapeutic agents include copper chelators (see description, paragraphs [0019] and [0021]). the 14] None of the cited documents discloses all echnical novel and comply with PCT Article 33(2) atures of claims 1-38. Therefore, claims 1-38 are [15] 2ulnventive step: [16] D1 discloses trientine is used for treating diabetic cardiomyopathy by increasing myocardial copper level D1 is considered to be the closest prior art. The difference between the subject-matter of claims 1, 29 (or 33 and D1 is that claims 1, 29 and 33 treat ischemic tissue injury. The problem to be solved by the present invention is to provide a new use of trientine. However, D2 discloses complementing copper has certain effect on correcting myocardial ischemia. A person skilled in the art can easily think in terms of using trientine to inerease copper level in ischemic myocardium, and to treat ischemie cardiomyopathy which belongs to ischemic tissue injury. Therefore, claims 1, 29 and 33 do not meet the requirement of the Article 33(3) PCT with respect to inventive step. Though relate to different therapeutic mechanism, they are all used for repairing and regenerating isch ischemic tissue injury. Therefore, based on D1 and D2, claims 2-5, 30-31 and 34-35 also do not meet the requirement of the Article 33(3) PCT Foun PCT/ISA/237 (Box No. V) Gly 2011)WRITTEN OPINION OF THE Intemational application No, INTERNATIONAL SEARCHING AUTHORITY POnCiaiNose: ‘Reasoned statement under Rule 430/1(a\) with regard to novelty, inventive step and industrial applicability; BoxNo-V citations and explanations supporting such statement [17] Additional technical features of depensient claims 6-7 and 17 are routine selection in the art. Additional technical features of dependent claims 8-9 are disclosed in D2 (see page 16, conclusions) and DI (see: abstract). Claims 10-14 and 32 further define the composition comprises a copper ion, claim 15 further define administering a copper ion to the individual, It is obvious for a person skilled in the art to increase copper level in ischemic tissue through using copper ion, and the effect of treating ischemic tissue Injury can be expected on the basis of D2. In addition, trientine isa well-know copper chelator, and dihydrochloride is a common pharmaceutically acceptable salt of trientine. Therefore, the compositions defined in claims 11-14 are able to be produced by common experiment. Dependent claims 16 and 18-24 relate to therapeutic regimens or administration dosages, these features merely present in the course of administration do not enable the use to possess an inventive step. Claims 6-24 and 32 therefore do not comply with PCT Article 33(3). [18] The difference between the subject-matter of claim 25 and D1 is the composition comprising a copper ion A person skilled in the art can easily think in terms of using trientine and copper ion to inerease copper level for treating diabetic cardiomyopathy. Therefore, claim 25 does not meet the requirement of the Article 33(3) PCT with respect to inventive step. Likewise, additional technical features of dependent claims 26-28 are disclosed in D1 (see abstract), or are routine selection in the art. Therefore, claims 26-28 also do not comply with PCT Article 3303). [19] The difference between the subject-matter of claim 37 and D1 is that claim 37 teats ischemic tissue injury Likewise, based on D1 and D2, claim 37 do not meet the requirement of the Article 33(3) PCT. Claims 38 ‘and 36 further define the kit or composition used for treating ischemic tissue injury comprises a copper ion, However, Itis obvious for a person skilled in the art to increase copper level in ischemic tissue by using copper ion, and the effect of creating ischemic tissue injury can be expected on the basis of D2, (Claims 38 and 36 therefore do not comply with PCT Article 33(3), (20) 3.dnduser 1 applicability: [21] The subject matter of claims 1-38 can be made or used in the industry, and thus meets the requirements of Article 33(4) Pt Foun PCT/ISA/237 (Box No. V) Gly 2011)