PCT/US2020/065149 22.03.2021
`
`PATENT COOPERATION TREATY
`
`From the INTERNATIONAL SEARCHING AUTHORITY
`
`To: WILSON SONSINI GOODRICH & ROSATI
`
`STEPHANIE S. DUSABAN GONZALES
`
`650 PAGE MILL ROAD
`PALO ALTO, CA 94304
`
`PCT
`
`NOTIFICATION OF TRANSMITTAL OF
`THE INTERNATIONAL SEARCH REPORT AND
`THE WRITTEN OPINION OF THE INTERNATIONAL
`SEARCHING AUTHORITY, OR THE DECLARATION
`
`MAR 22 2021
`
`
`
`
`(PCT Rule 44.1)
`
`
`(dayimonthiyear)
`
`
`
`Applicant’s or agent’s file reference
`46682-709601
`
`
`
`International application No.
`International filing date
`PCT/US 20/65149
`(day/month/year)
`
`
`Applicant SYDNEXIS, INC.
`
`FOR FURTHER ACTION _
`
`See paragraphs ! and 4 below
`paragrap
`
`-
`15 December 2020 (15.12.2020)
`
`1.
`
`The applicant is hereby notified that the international search report and the written opinion of the International Searching
`Authority have been established and are transmitted herewith.
`Filing of amendments and statement underArticle 19;
`The applicantis entitled, if he so wishes, to amendthe claimsof the international application (see Rule 46):
`When? The timelimit for filing such amendments is normally two months from the date of transmittal of the international
`search report.
`How?__Directly to the International Bureau preferably through ePCT,or on paperto:
`The International Bureau of WIPO, 34, chemin des Colombettes, 1211 Geneva 20, Switzerland
`
`
`
`Telephone No. PCT Helpdesk: 571-272-4300
`
`Authorized officer
`
`Lee Young
`
`
`
`
`
`
`
`
`
`
`
`
`
`For more detailed instructions, see the PCT Applicant's Guide, International Phase, paragraphs 9.004 — 9.011.
`
`2. C] The applicant
`is hereby notified that no international search report will be established and that the declaration under
`
`
`Article 17(2)(a) to that effect and the written opinion of the International Searching Authority are transmitted herewith.
`3. [J With regard to anyprotest against paymentof(an) additional fee(s) under Rule 40.2, the applicantis notified that:
`
`
`the protest together with the decision thereon has been transmitted to the International Bureau together with any request
`
`
`to forward the texts of both the protest and the decision thereon to the designated Offices.
`no decision has been madeyet onthe protest;
`the applicant will be notified as soon as a decision is made.
`
`4. Reminders
`
`
`
`The applicant may submit comments on an informal basis on the written opinion of the International Searching Authority to
`the International Bureau. These comments will be madeavailable to the public after international publication. The International
`
`
`Bureau will send a copy of such comments to all designated Offices unless an international preliminary examination report has
`
`
`been or is to be established.
`
`
`
`
`Shortly after the expiration of 18 months from the priority date, the international application will be published by the
`International Bureau. Ifthe applicant wishes to avoid or postpone publication, a notice ofwithdrawal ofthe international application,
`
`
`orof the priority claim, must reach the International Bureau before the completion of the technical preparations for international
`
`
`publication (Rules 90d/s.1 and 90dis.3).
`
`
`Within 19 months from the priority date, but only in respect of some designated Offices, a demand for international preliminary
`
`
`examination must befiled if the applicant wishes to postponethe entry into the national phase until 30 months from the priority
`
`
`date (in some Offices evenlater); otherwise, the applicant must, within 20 months from the priority date, perform the prescribed
`
`
`acts for entry into the national phase before those designated Offices.
`In respect of other designated Offices, the time limit of
`
`
`30 months(orlater) will apply even if no demand is filed within 19 months. For details about the applicable time limits, Office
`
`
`by Office, see www. wipo.int/pct/en/texts/time_limits.html and the PCT Applicant's Guide, National Chapters.
`
`
`Within 22 monthsfrom the priority date, the applicant may requestthat a supplementary international search be carried out
`
`
`by a different International Searching Authoritythat offers this service (Rule 45bis.1). The procedure for requesting supplementary
`
`
`international search is described in the PCT Applicant's Guide, International Phase, paragraphs 8.006-8.032.
`Name and mailing address of the ISA/US
`Mail Stop PCT, Attn: ISA/US
`Commissioner for Patents
`P.O. Box 1450, Alexandria, Virginia 22313-1450
`Facsimile No. 571-273-8300
`Form PCT/ISA/220 (revised January 2020)
`
`

`

`PCT/US2020/065149 22.03.2021
`
`PATENT COOPERATION TREATY
`
`PCT
`INTERNATIONAL SEARCH REPORT
`
`(PCT Article 18 and Rules 43 and 44)
`
`Applicant’s or agent’s file reference
`
`FOR FURTHER ACTION
`
`46682-709601
`
`International application No.
`PCT/US 20/65149
`
`Applicant
`SYDNEXIS, INC.
`
`see Form PCT/ISA/220 as well as, where applicable, item 5 below.
`
`Internationalfiling date (day/month/year)
`15 December 2020 (15.12.2020)
`
`(Earliest) Priority Date (day/month/year)
`16 December 2019 (16.12.2019)
`
`This internationalsearch report has been preparedbythis International Searching Authority and is transmitted to the applicant according
`to Article 18. A copy is being transmitted to the International Bureau.
`This international search report consists of a total of «
`sheets.
`C] It is also accompanied by a copyof eachprior art documentcited in this report.
`
`Basis of the report
`
`a. With regard to the language, the international search was carried out on the basis of:
`x] the international application in the language in which it was filed.
`whichis the language of
`| a translation of the international application into
`a translation furnished for the purposes of intemmational search (Rules 12.3(a) and 23.1(b)).
`
`This intemational search report has been established taking into accountthe rectification of an obvious mistake authorized
`by or notified to this Authority under Rule 91 (Rule 43 .6is(a)).
`
`With regard to any nucleotide and/or amino acid sequence disclosed in the international application, see Box No. I.
`
`Certain claims were found unsearchable (see Box No. II).
`
`Unity of invention is lacking (see Box No. HI).
`
`. With regard to the title,
`x] the text is approved as submitted by the applicant.
`[_] the text has been established by this Authority to read as follows:
`
`b. [] noneofthe figures is to be published with the abstract.
`
`With regard to the abstract,
`[X<]
`the text is approved as submitted by the applicant.
`the text has been established, according to Rule 38.2, by this Authority as it appears in Box No. 1V. The applicant may,
`within one month from the date of mailing of this international search report, submit commentsto this Authority.
`
`With regard to the drawings,
`a.
`the figure of the drawings to be published with the abstract is Figure No. 4
`as suggested by the applicant.
`as selected by this Authority, because the applicantfailed to suggest a figure.
`CT]
`CJ as selected by this Authority, because this figure better characterizes the invention.
`
`Form PCT/ISA/210 (first sheet) (July 2019)
`
`

`

`PCT/US2020/065149 22.03.2021
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US 20/65149
`
`Box No.II
`
`Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)
`
`This international search report has not been establishedin respect of certain claims underArticle 17(2)(a) for the following reasons:
`1.[] Claims Nos.:
`because they relate to siibyect matter not required to be searched by this Authority, namely:
`
`3.
`
`Claims Nos.: 4-6, 10-18, 33-42, 53-64, 82-100, 102
`because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
`
`Box No. HT
`
`Observations where unity of invention is lacking (Continuation of item 3 of first sheet)
`
`This Intemational Searching Authority found multiple inventions in this international! application, as follows:
`‘
`
`2, [| Claims Nos.:
`because theyrelate to parts of the international application that do not comply with the prescribed requirements to such an
`extent that no meaningful international search canbe carried out, specifically:
`
`No protest accompanied the payment of additional search fees.
`
`As all required additional search fees were Limelypaid by the applicant, this intemational searchreport coversall searchable
`claims.
`
`As all searchable claims could be searched withouteffort justifying additional fees, this Authority did not invite payment of
`additional fees.
`
`As only someof 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.:
`
`[] Norequired 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.:
`
`Remark on Protest
`
`The additional search fees were accompanied by the applicant’s protest and, where applicable, the
`paymentofa protestfee.
`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.
`
`Form PCT/ISA/210 (continuation offirst sheet (2)) July 2019)
`
`

`

`PCT/US2020/065149 22.03.2021
`
`INTERNATIONAL SEARCH REPORT
`
`Intemational application No.
`PCT/US 20/65149
`
`A.
`
`CLASSIFICATION OF SUBJECT MATTER
`
`IPC -
`
`A61K 31/5575; A61K 47/26; A61K 47/44 (2021.01)
`
`CPC - A61K 31/5575; AG1K 47/14; A61K 47/26
`
`According to International Patent Classification (IPC) or to both national classification and IPC
`.
`FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`See Search History document
`
`Documentation searched other than minimum documentation to the extent that such documentsare includedin the fields searched
`See Search History document
`
`Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
`See Search History document
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category*
`
`Citation of document, with indication, where appropriate, of the relevant passages
`
`US 2018/0193326 A1(Sydnexis,Inc.) 12 July 2018 (12.07.2018); entire document, especially
`abstract, [0003], (0045), [0097], [0187], pg 33 TABLE 1-5, pg 34 TABLE 7
`
`Relevant to claim No.
`
`1-3, 7-9, 19-22, 27-29,
`30/(20-22, 27-29),
`31/(30/(20-22, 27-29)),
`32/(31/(30/(20-22, 27-
`29))), 43-46, 49-52, 65-
`
`23-26, 30/(23-26),
`31(30/(23-26)),
`32/(31(30/(23-26))), 47-
`48
`
`US 2008/0021106 A1 (Petit, || et al.) 24 January 2008 (24.01.2008); entire document, especially|23-26, 30/(23-26),
`claim 1, claim 10-11
`31/(30/(23-26)),
`32/(31/(30/(23-26))), 47-
`48
`
`US 2018/0325888 A1 (Nevakar Inc.) 15 November 2018 (15.11.2018); entire document
`
`US 2004/0136915 A1 (Dugger,Ill et al.) 15 July 2004 (15.07.2004); entire document
`
`1-3, 7-9, 19-32, 43-52, 65
`-81, 101
`
`1-3, 7-9, 19-32, 43-52, 65
`-81, 101
`
`being obvious to a person skilled in the art
`
`Further documentsare listed in the continuation of Box C.
`Special categories of cited documents:
`documentdefining the generalstate ofthe art which is not considered
`to be of particular relevance
`document cited by the applicant in the international application
`earlier application orpatentbut published onor after the international
`filing date
`throw doubts on priority claim(s) or which
`document which may
`is cited to establish t ©publication date of anothercitation or other
`special reason (as specified)
`documentreferringto an oral disclosure, use, exhibition or other means
`documentpublishedpriorto the internationalfiling date but later than
`the priority date claimed
`Date of the actual completion of the international search
`
`“T”
`
`[| See patent family annex.
`later document published after the internationalfiling date or priority
`date andnot in conflict with the application but cited to understand
`the principte or theory underlying the invention
`“xX” document of particular relevance; the claimed invention cannot be
`considered novel or cannotbe considered to involve an inventive step
`whenthe documentis taken alone
`“Y” document of particular relevance, the claimed invention cannot
`be considered to involve an inventive step when the documentis
`combined with one or more other such documents, such combination
`
`“&” document memberofthe same patent family
`
`Date of mailing of the international search report
`
`MAR 22 2021
`
`Authorized officer
`
`Lee Young
`
`Telephone No. PCT Helpdesk: 571-272-4300
`
`15 February 2021
`
`Name and mailing address of the ISA/US
`Mail Stop PCT, Attn: ISA/US, Commissioner for Patents
`P.O. Box 1450, Alexandria, Virginia 22313-1450
`Facsimile No. 571-273-8300
`Form PCT/ISA/210 (second sheet) (July 2019)
`
`

`

`PCT/US2020/065149 22.03.2021
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US 20/65149
`
`C (Continuation).
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`
`-81, 101
`
`Category*
`
`Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`A
`
`US 2007/0254914 A1 (Wu et al.) 01 November 2007 (01.11.2007); entire document
`
`1-3, 7-9, 19-32, 43-52, 65
`
`Form PCT/ISA/210 (continuation of second sheet) (July 2019)
`
`

`

`PCT/US2020/065149 22.03.2021
`
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`
`PATENT COOPERATION TREATY
`
`
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`(PCT Rule 435is.1)
`
`(day/month/year)
`
`FAQ 9 2 2021
`
`
`
` PCT
`
`To: STEPHANIE S. DUSABAN GONZALES
`WILSON SONSINI GOODRICH & ROSATI
`
`
`650 PAGE MILL ROAD
`
`PALO ALTO, CA 94304
`
`
`
`
`
`Date ofmailing
`
`
`
`Applicant’s or agent’s file reference
`46682-709601
`
`
`
`Iniernaiional Alling date (day/month/year)
`International application Nu,
`Priority date (day/month/year)
`
`
`
`15 December 2020 (15.12.2020)
`PCT/US 20/65149
`16 December 2019 (16.12.2019)
`
`
`Intemational Patent Classification (IPC) or both national classification and IPC
`iPC - A61K 31/5575; AG1K 47/26; AG1K 47/44 (2021.01)
`
`
`
`
`
`
`
`FOR FURTHER ACTION
`See paragraph 2 below
`
`CPC - A61K 31/5575; A61K 47/14; A61K 47/26
`
`Applicant SYDNEXIS, INC.
`
`1, This opinion contains indicationsrelating to the following items:
`ix] Box No.I
`Basis of the opinion
`[| Box No.
`Priority
`x]
`Box No.
`Non-establishment of opinion with regard to novelty, inventive step and industrial applicability
`Box No.
`Lack of unity ofinvention
`
`Box No.
`
`Box No. VI
`
`Reasoned statement under Rule 43 is. 1(a)(i) with regard to novelty, inventive step and industrial applicability;
`citations and explanations supporting such statement
`Certain documents cited
`
`Box No. VII Certain defects in the international application
`[| Box No. VIII] Certain observations on the international application
`
`FURTHER ACTION
`
`If a demand for international preliminary examination is made, this opinion will be considered to be a written opinion of the
`International Preliminary Examining Authority (““IPEA”) except that this does not apply where the applicant chooses an Authority
`other than this one to be the IPEA and the chosen IPEA hasnotified the International Bureau under Rule 66.1dis(b) that written
`opinions of this International Searching Authority will not be so considered.
`If this opinion is, as provided above, consideredto be a written opinion of the IPEA, the applicantis invited to submit to the IPEA
`a written reply together, where appropriate, with amendments, before the expiration of 3 months fromthe date of mailing of Form
`PCT/ISA/220 or before the expiration of 22 months from the priority date, whichever expireslater.
`Forfurther options, see Form PCT/ISA/220.
`
`
`
`Name and mailing address of the ISA/US|Date of completionof this opinion Authorized officer
`
`
`Mail Stop PCT, Attn: ISA/US
`
`Lee Young
`
`Commissionerfor Patents
`
`
`15 February 2021
` PCT Help Desk
`
`P.O. Box 1450, Alexandria, Virginia 22313-1450
`
`Facsimile No. 571-273-8300
`Telephone No. 571-272-4300
`
`Form PCT/ISA/237 (coversheet) (revised January 2019)
`
`

`

`PCT/US2020/065149 22.03.2021
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`Intemational application No.
`PCT/US 20/65149
`
`Box No. J
`
`Basis of this opinion
`
`b.
`
`
`
`
`
`
`
`2. ) This opinion has been established taking into accountthe rectification of an obvious mistake authorized by or notified to
`this Authority under Rule 91 (Rule 43dis.1(b)).
`
`
`3. C] With regard to any nucleotide and/or amino acid sequencedisclosedin the international application, this opinion has been
`established on the basis of a sequencelisting:
`a. [J forming part of the international applicationasfiled:
`L_]
`in the fori of au Aunex C/ST.25 text file.
`LJ on paperor in the form of an imagefile.
`
`
`furnished together with the international application under PCT Rule 13zer.1(a) for the purposes of international
`search only in the form of an Annex C/ST.2S text file.
`
`
`c. LJ furnished subsequentto the international filing date for the purposes of international search only:
`[__]
`inthe formofan Annex C/ST.25 text file (Rule 13ser.1(a)).
`
`L_] on paperorin the form of an image file (Rule 13¢er. 1(b) and Administrative Instructions, Section 713).
`
`statements that the information in the subsequent or additional copiesis identical to that formingpartofthe application as
`
`filed or does not go beyond the applicationas filed, as appropriate, were furnished.
`5. Additional comments:
`
` 4. CL] In addition, in the case that more than one version or copy of a sequencelisting has been filed or furnished, the required
`
`1, With regard to the language, this opinion has been established on the basis of:
`x the international application in the language in whichit wasfiled.
`|
`|
`a translation ofthe international application into
`furnished for the purposes of international search (Rules 12.3(a) and 23.1(b)).
`
`whichis the languageofa translation
`
`
`
`
`
`
`
`
`
`Form PCT/ISA/237 (Box No. I) (revised January 2019)
`
`

`

`PCT/US2020/065149 22.03.2021
`
`WRITTENOPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US 20/65149
`
`Box No. HI
`
`Non-establishment of opinion with regard to novelty, inventive step and industrial applicability
`
`The questions whetherthe claimed invention appearsto be novel, to involve an inventive step (to be non obvious), or to be industrially
`applicable have not been examined in respectof.
`
`[] ihe entire international application.
`claims Nos. 4-6, 10-18, 33-42, 53-64, 82-100, 102
`
`because:
`
`the said international application, or the said claims Nos.
`subject matter which does not require an international search (specify):
`
`relate to the following
`
`the description, claims or drawings (indicate particular elements below) orsaid claims Nos._4-6, 10-18, 33-42, 53-64, 82-10
`are so unclear that no meaningful opinion could be formed (specify):
`
`because they are dependentclaims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
`
`[| See Supplemental Box for further details.
`
`a meaningful opinion could notbe formed without the sequencelisting; the applicant did not, within the prescribed time limit:
`furnish a sequencelisting in the form ofan Annex C/ST.25 text file, and such listing was not available to the International
`Searching Authority in the form and manneracceptable to it; or the sequencelisting furnished did not comply with the
`standard provided for in Annex C of the Administrative Instructions.
`furnish a sequence listing on paperorin the form of an imagefile complying with the standard provided for in Annex
`C of the Administrative Instructions. and suchlisting was not available to the International Searching Authority in the
`form and manner acceptable to it; or the sequencelisting furnished did not comply with the standard provided for in
`Annex C ofthe Administrative Instructions.
`
`[_]
`
`the claims, or said claims Nos.
`by the description that no meaningful opinion could be formed (specify):
`
`are so inadequately supported
`
`no international search report has been established for said claims Nos. 4-6, 10-18, 33-42, 53-64, 82-100, 102
`
`pay the required late furnishing fee for the furnishing ofa sequencelisting in responseto an invitation underRule 13zer.1(a)
`or (b).
`
`Form PCT/ISA/237 (Box No. Hl) (revised January 2019)
`
`

`

`PCT/US2020/065149 22.03.2021
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No,
`PCT/US 20/65149
`
`Box No. V
`
`Reasoned statement under Rule 43dis.1(a)(i) with regard to novelty, inventive step and industrial applicability;
`citations and explanations supporting such statement
`
`eee
`
`Regarding claim 19, Sydnexis teaches the ophthalmic composition of claim 1, wherein the ophthalmic composition comprises less than
`about 10% of a degradant of the muscarinic antagonist formed from degradation of the muscarinic antagonist (para [0013], "In some
`embodiments, the composition comprises less than 10% of major degradant based on the concentration of the ophthalmic agentafter
`extended period of time under storage condition. In some embodiments, the composition comprises less than 5%of major degradant
`based on the concentration of the ophthalmic agent after extended period of time under storage condition"; para [0187], “Accordingly,
`provided herein are methodsfor sterilization of ophthalmic formulations that prevent degradation of polymeric components(e.g.,
`thermosetting and/or other viscosity enhancing agents) and/or the ophthalmic agent during the processofsterilization. In some
`embodiments, degradation of the ophthalmic agent (e.g., a muscarinic antagonist such asatropine or atropine sulfate) is reduced or
`eliminated...").
`****See Supplemental Box
`
`Statement
`
`Novelty (iN)
`
`Inventive step (IS)
`
`Claims
`Claims
`
`Claims
`Claims
`
`20 32, 43-52, 65-81, 101
`1-3, 7-9, 19
`
`None
`
`1-3, 7-9, 19-32, 43-52, 65-81, 101
`
`Industrial applicability (IA)
`
`Claims
`Claims
`
`1-3, 7-9, 19-32, 43-52, 65-81, 101
`None
`
`Citations and explanations:
`2.
`Claims 1-3, 7-9, and 19 lack novelty under PCT Article 33(2) as being anticipated by US 2018/0193326 A1 to Sydnexis, Inc. (hereinafter
`“Sydnexis").
`
`Regarding claim 1, Sydnexis teaches an ophthalmic composition comprising from about 0.001 wt% to about 0.5 wt% of a muscarinic
`antagonist and deuterated water, at a pH of from about 4.2 to about 7.9, wherein the ophthalmic composition is substantially free of a
`benzalkonium chloride preservative (abstract, "Provided herein is an ophthalmic composition"; pg 34 TABLE 7, “Thermosetting Gel
`Formulation (Atropine Sulfate)... Atropine sulfate... 0.001 - 0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Waterq.s. to 100 wt %", para [0003],
`"muscarinic antagonist comprises atropine..."; TABLE 7 example does not teach inclusion of benzalkonium chloride preservative, whereas
`other examples teach optional inclusion of benzalkonium chloride preservative; see pg 33 TABLE 1-5).
`
`Regarding claim 2, Sydnexis teaches the ophthaimic composition of claim 1, wherein the ophthalmic composition is substantially free of a
`preservative selected from cetrimonium, sodium perborate, stabilized oxychloro complex, SofZia, polyquaternium-1, chlorobutanol,
`edetate disodium, polyhexamethylene biguanide, or combinations thereof (pg 34 TABLE 7, "Thermosetting Gel Formulation (Atropine
`Sulfate)... Atropine sulfate... 0.001 - 0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Water q.s. to 100 wt %"; para [0003], "muscarinic
`antagonist comprisesatropine..."; TABLE 7 example does not teach inclusion of preservative selected from cetrimonium, sodium
`perborate, stabilized oxychloro complex, SofZia, polyquaternium-1, chlorobutanol, edetate disodium, polynhexamethylene biguanide, or
`combinations thereof, whereas other examples teach optional inclusion of said preservatives; see pg 33 TABLE 1-5).
`
`Regarding claim 3, Sydnexis teaches the ophthalmic composition of any of claims 1 or 2, wherein the ophthalmic composition has no
`detectable amount of a benzalkonium chloride preservative (pg 34 TABLE 7, "Thermosetting Gel Formulation (Atropine Sulfate)...
`Atropine sulfate... 0.001 - 0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Water q.s. to 100 wt %"; para [0003], “muscarinic antagonist
`comprisesatropine..."; TABLE 7 example does not teach inclusion of benzalkonium chloride preservative, whereas other examples teach
`optional inclusion of benzalkonium chloride preservative; see pg 33 TABLE 1-5).
`
`Regarding claim 7, Sydnexis teaches the ophthalmic composition of claim 1, wherein the muscarinic antagonist is atropine or a
`pharmaceutically acceptable salt of atropine (pg 34 TABLE 7, "Thermosetting Gel Formulation (Atropine Sulfate)... Atropine sulfate...
`0.001 - 0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Waterq.s. to 100 wt %"; para [0045], "The present disclosure recognizes that muscarinic
`antagonist (e.g. atropine or its pharmaceutically acceptable salts)...").
`
`Regarding claim 8, Sydnexis teaches the ophthalmic composition of claim 1, wherein the muscarinic antagonist is presentin the
`ophthalmic composition at a concentration of one of: from about 0.001 wt% to about 0.40 wt%, from about 0.001 wt% to about 0.30 wt%,
`from about 0.001 wt%to about 0.20 wt%, from about 0.001 wt%to about 0.10 wt%, from about 0.001 wt%to about 0.09 wt%, from about
`0.001 wt% to about 0.08 wt%, from about 0.001 wt% to about 0.07 wt%, from about 0.001 wt%to about 0.06 wt%, from about 0.001 wt%
`to about 0.05 wt%, from about 0.001 wt% to about 0.04 wt%, from about 0.001 wt% to about 0.03 wt%, from about 0.001 wt% to about
`0.025 wt%, from about 0.001 wt% to about 0.02 wt%, from about 0.001 wt%to about 0.01 wt%, from about 0.001 wt% to about 0.008 wt%,
`or from about 0.001 wt% to about 0.005 wt% (pg 34 TABLE 7, "Thermosetting Gel Formulation (Atropine Sulfate)... Atropine sulfate...
`0.001 - 0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Water q.s. to 100 wt %"; para [0003], "muscarinic antagonist comprises atropine...").
`
`Regarding claim 9, Sydnexis teaches the ophthalmic composition of claim 1, wherein the muscarinic antagonist is present in the
`ophthalmic composition at a concentration from about 0.001 wt% to about 0.10 wt% (pg 34 TABLE 7, "Thermosetting Gel Formulation
`(Atropine Sulfate)... Atropine sulfate... 0.001 - 0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Water q.s. to 100 wt %"; para [0003), "muscarinic
`antagonist comprises atropine...”).
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`Form PCT/ISA/237 (Box No. V) (revised January 2019)
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`

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`PCT/US2020/065149 22.03.2021
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`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
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`International application No.
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`PCT/US 20/65149
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`Supplemental Box
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`In case the space in any of the preceding boxesis not sufficient.
`Continuation of:
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`Box V Citations and Explanations
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` Claims 20-22, 27-29, 30/(20-22, 27-29), 31/(30/(20-22, 27-29)), 32/(31/(30/(20-22, 27-29))), 43-46, 49-52, 65-81, and 101 lack an inventive
`step under PCTArticle 33(3) as being obvious over Sydnexis.
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` Regarding claim 20, Sydnexis teaches an ophthalmic composition comprising from about 0.001 wt% to about 0.5 wt% of a muscarinic
`antagonist, deuterated water, at a pH of from about4.2 to about 7.9 (abstract, "Provided herein is an ophthalmic composition”; pg 34
`TABLE 7, "Thermosetting Gel Formulation (Atropine Sulfate)... Atropine sulfate... 0.001 - 0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Water
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`q.s. to 100 wt %"; para [0003], "muscarinic antagonist comprises atropine...”), and one or more sodium phosphate buffers (para (0097), “In
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`some embodiments, phosphate buffering agents include phosphoric acid; alkali metal phosphates such as disodium hydrogen phosphate,
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`sodium dihydrogen phosphate, trisodium phosphate "), but does not explicitly teach wherein at least one sodium phosphate buffer of the
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`one or more sodium phosphatebuffers is present in the ophthalmic composition at a concentration of about 0.004 wt% to about 0.20 wth.
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`However,it would have been obvious to one of ordinary skill in the art to to provide the one or more sodium phosphate buffers is present in
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`the ophthalmic composition at a concentration of about 0.004 wt% to about 0.20 wt% by routine experimentation to optimize the buffering.
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` Regarding claim 21, Sydnexis teaches the ophthalmic composition of claim 20, wherein the muscarinic antagonist comprises atropine,
`atropine sulfate, noratropine, atropine-N-oxide,tropine, tropic acid, hyoscine, scopolamine, tropicamide, cyclopentolate, pirenzepine,
`homatropine, or a combination thereof (pg 34 TABLE 7, "Thermosetting Gel Formulation (Atropine Sulfate)... Atropine sulfate... 0.004 -
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`0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Water q.s. to 100 wt %”"; para [0003], "muscarinic antagonist comprises atropine...").
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`Regarding claim 22, Sydnexis teaches the ophthalmic composition of claim 20, wherein the muscarinic antagonistis atropine or a
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`pharmaceutically acceptable salt of atropine (pg 34 TABLE 7, "Thermosetting Gel Formulation (Atropine Sulfate)... Atropine sulfate...
`0.001 - 0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Water q.s. to 100 wt %"; para [0045], "The present disclosure recognizes that muscarinic
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`antagonist (e.g. atropine orits pharmaceutically acceptable salts)...").
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`Regarding claim 27, Sydnexis teaches the ophthalmic composition of claim 20, wherein the muscarinic antagonistis presentin the
`ophthalmic composition at a concentration of oneof: from about 0.001 wt%to about 0.40 wt%, from about 0.001 wt% to about 0.30 wt%,
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`from about 0.001 wt% to about 0.20 wt%, from about 0.001 wt%to about 0.10 wt%, from about 0.001 wt%to about 0.09 wt%, from about
`0.001 wt% to about 0.08 wt%, from about 0.001 wt% to about 0.07 wt%, from about 0.001 wt% to about 0.06 wt%, from about 0.001 wt%
`to about 0.05 wt%, from about 0.001 wt% to about 0.04 wt%, from about 0.001 wt% to about 0.03 wt%, from about 0.001 wt%to about
`0.025 wt%, from about 0.001 wt% to about 0.02 wt%, from about 0.001 wt% to about 0.01 wt%, from about 0.001 wt% to about 0.008 wt%,
`or from about 0.001 wt% to about 0.005 wt% (pg 34 TABLE 7, "Thermosetting Gel Formulation (Atropine Sulfate)... Atropine sulfate...
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`0.001 - 0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Water q.s. to 100 wt %"; para [0003], "muscarinic antagonist comprisesatropine...").
`Regarding claim 28, Sydnexis teaches the ophthalmic composition of claim 20, wherein the muscarinic antagonist is presentin the
`ophthalmic composition at a concentration from about 0.001 wt% to about 0.10 wt% (pg 34 TABLE 7, “Thermosetting Gel Formulation
`(Atropine Sulfate)... Atropine sulfate... 0.001 - 0.05 (wt %)... pH = 4.2 - 7.9... Deuterated Water q.s. to 100 wt %"; para [0003], “muscarinic
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`antagonist comprises atropine...").
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`Regarding claim 29, Sydnexis teaches the ophthalmic composition of claim 20, wherein the ophthalmic composition is essentially free of
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`citrate and acetate buffering agents (pg 34 TABLE 7, “Thermosetting Gel Formulation (Atropine Sulfate)... Atropine sulfate... 0.001 - 0.05
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`(wt %)... pH = 4.2 - 7.9... Deuterated Waterq.s. to 100 wt %"; TABLE 7 example teachesacetate is optional; pg 34 TABLE 7, "Buffer agent
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`and/or pD adjusting agent (e.g., sodium acetate and/or OCI )"; para [0094], "In some embodiments, a buffer is selected from borates,
`borate-polyol complexes, phosphate buffering agents, citrate buffering agents, acetate buffering agents, carbonate buffering agents,
`organic buffering agents, amino acid buffering agents, or combinations thereof").
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` Regarding claim 30/(20-22, 27-29), Sydnexis teaches the ophthalmic composition of any of claims 20-22, 27-29, wherein the ophthalmic
`composition further comprises an osmolarity adjusting agent (pg 34 TABLE 7, “Osmolarity modifier (e.g. NaCl)").
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` Regarding claim 31/(30/(20-22, 27-29)), Sydnexis teaches the ophthalmic composition of claim 30/(20-22, 27-29), wherein the osmolarity
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`Regarding claim 32/(31/(30/(20-22, 27-29))), Sydnexis teaches the ophthalmic composition of claim 31/(30/(20-22, 27-29)), but does not
`explicitly teach wherein the sodium chloride is present in the ophthalmic composition at a concentration of oneof: from about 0.01 wt% to
`about 1.0 wt%, from about 0.05 wt% to about 1.5 wt%, from about 0.075 wt% to about 2.0 wt%, or from about 0.1 wt% to about 3.0 wt%.
`However, it would have been obviousto oneof ordinary skill in the art to provide the sodium chloride is presentin the ophthalmic
`composition at a concentration of one of: from about 0.01 wt%to about 1.0 wt%, from about 0.05 wt% to about 1.5 wt%, from about 0.075
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`wt% to about 2.0 wt%, or from about 0.1 wt% to about 3.0 wt% by routine experimentation to optimize the osmolarity.
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`Regarding claim 43, Sydnexis teaches an ophthalmic composition comprising from about 0.001 wt% to about 0.5 wt% ofa muscarinic
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`antagonist, deuterated water, at a pH offrom about4.2 to about 7.9, and EDTA(abstract, "Provided herein is an ophthalmic co