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`
`PATENT COOPERATION TREATY
`
`‘PCT
`
`eye Oe
`From the INTERNATIONAL:SEARCHING AUTHORITY
`
`To: Frank Yang
`
`
`Wilson Sonsini Goodrich & Rosati
`
`
`650 Page Mill Road
`NOTIFICATION OF TRANSMITTALOF
`Palo Alto, California 94304
`
`THE INTERNATIONAL SEARCH REPORT AND
`United States of America
`THE WRITTEN OPINION OF THE INTERNATIONAL
`
`SEARCHING AUTHORITY, OR THE DECLARATION
`
`
`(PCT Rule 44.1)
`
`
`Date of mailing
`(dayrmonthiyear) D3 AUG 2016
`
` Applicant’s or agent’s file reference
`
`
`
`
`
`I. Xx 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 applicant is entitled, if he so wishes, to amend the claims of the international application (see Rule 46):
`
`
`When?=The time limit forfiling such amendments is normally two monthsfromthe date oftransmittal of the international
`search report.
`
`
`Directly to the Intemational Bureau of WIPO preferably through ePCTor on paper to, 34 chemin des Colombettes
`121} Geneva 20, Switzerland, Facsimile No.: +41 22 338 82 70
`For more detailed instructions, see PCT Applicant's Guide, Internationa! Phase, paragraphs 9.004 - 9.011.
`
`
`
`2. Cl 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. CJ With regard to any protest against paymentof (an) additional fee(s) under Rule 40.2, the applicant is 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 on the protest,
`the applicant will be notified as soon as a decision is made.
`C]
`4. Reminders
`
`
`
`
`The applicant may submit com ments on an informal basis-on the written opinion of the International Searching Authority
`to the International Bureau. These comments will be made available 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 beenoris to be established.
`Shortly after the expiration of 18 months from the priority date, the international application will be published by the
`International Bureau.
`If the applicant wishes to avoid or postpone publication, a notice of withdrawal of the international
`application, or of the priority claim, must reach the International Bureau before the completionof the technical preparations for
`intemational publication (Rules 90dis.1 and 90is.3).
`Within 19 months from the priority date, but only in respect of some designated Offices, a demandforinternational preliminary
`examination mustbe filed ifthe applicant wishes to postponethe entry into the national phase until 30 months from the priority
`date (in some Offices even later); 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 demandis filed within 19 months. For details about the applicable time
`limits, Office by Office, see www.wipo.int/pevVen/texts/time_limits.htm! and the PCT Applicant's Guide, National Chapters.
`Within 19 months from the priority date, the applicant may request that a supplementary international search be carried
`out by a different International Searching Authority that offers this service (Rule 45bis.1). The procedure for requesting
`supplementary international search is described in the PCT Applicant's Guide, Intemational Phase, paragraphs 8.006-8.032.
`
`46682-702.601
`
`FOR FURTHER ACTION See paragraphs 1 and 4 below
`
`
`
`Intemational application No.
`Internationalfiling date
`(day/month/year)
`27 May 2016 (27.05.2016)
`
`PCT/US16/34823
` SYDNEXIS, INC.
`Applicant
`
`How?
`
`
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`
`
`
`
`
`
`
`
`
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`
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`
`
`
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`
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`
`
`Nameand mailing address of the ISA/
`Authorized officer
`Mail Stop PCT, Attn: ISA/US
`
` Shane Thomas
`Commissionerfor Patents
`
`P.O. Box 1450, Alexandria, Virginia 22313-1450
`
`.
`PCT Helpdesk: §71-;
`Facsimile No. 571-273-8300
`Telephone No. pet osp: 571.272.
`
`Form PCT/ASA/220 (July 2014)
`
` U.S._____FOREIGN:
`DOCKETED:8/34/i6By:
`_«
`ACTION: Coand sopnk
`fri)
`DUE DATESte Doin
`34 ¢
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`Asatia——lh$QedAl
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`ATTY__C/M #
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`

`

`PATENT COOPERATION TREATY
`
`PCT
`
`INTERNATIONAL SEARCH REPORT
`
`(PCT Article 18 and Rules 43 and 44)
`
`Applicant’s or agent's file reference
`46682-702.601
`
`FOR FURTHER
`ACTION
`
`see Form PCT/ISA/220
`as well as, where applicable, item 5 below.
`
`Intemational application No.
`PCT/US16/34823
`
`International filing date (day/month/year)
`27 May 2016 (27.05.2016)
`
`(Earliest) Priority Date (day/month/year)
`29 May 2015 (29.05.2015)
`
`Applicant
`SYDNEXIS, INC.
`
`This international search report has been prepared by this 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 ofa total of 2 sheets.
`CJ It is also accompanied by a copy of each prior art documentcited in this report.
`
`Basis of the report
`a. With regard to the language, the international search was carried out onthe basis of:
`[Xx]
`the international application in the language in which it wasfiled.
`whichis the language of
`[] a translation of the international application into
`a translation furnished for the purposes of international search (Rules 12.3(a) and 23.1(b)).
`b. CC) This international search report has been established taking into account the rectification of an obvious mistake
`authorized by or notified to this Authority under Rule 91 (Rule 43.65is(a)).
`c. L) With regard to any nucleotide and/or amino acid sequence disclosed in the international application, see Box No. |.
`
`db. [_] noneofthe figures is to be published with the abstract.
`
`Xx] Certain claims were found unsearchable (see Box No.II).
`
`C) Unity of invention is lacking (see Box No.If).
`
`4. With regard to the title,
`the text is approved as submitted by the applicant.
`LJ the text has been established by this Authority to read as follows:
`
`5. With regard to the abstract,
`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 ofthis international search report, submit commentsto this Authority.
`
`6. 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 applicant failed (o suggest a figure.
`L} as selected by this Authority, because this figure better characterizes the invention.
`
`1
`
`Form PCT/ISA/210 (first sheet) (ianuary 2015)
`
`

`

`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:
`
`
`
`
`
`
`
`
`
`
`Box No.1]
`
`Observations where unity of invention is lacking (Continuation of item 3 offirst sheet)
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US 16/34823
`
`Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)
`
`
`
`
`
`This intemational search report has not beenestablished in respect of certain claims under Article 17(2)(a) for the following reasons:
`1. [J Claims Nos.:
`because they relate to subject matter not required to be searched by this Authority, namely:
`
`Box No. II
`
`
`
`
`
`3. x] Claims Nos.: 4-8 and 14-30
`
`because they are dependentclaims and are notdrafted in accordance with the second andthird sentences of Rule 6.4(a).
`
`
`
`This International Searching Authority found multiple inventions in this international application, as follows:
`
`
`
`additional fees.
`
`
`it is covered by claims Nos.:
`
`Asall required additional search fees were timely paid by the applicant, this international search report coversall searchable
`claims.
`
`As all searchable claims could be searched without effort justifying additional fees, this Authority did not invite payment of
`
`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.:
`
`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,
`
`
`
`Remark on Protest
`[] Theadditional search fees were accompaniedby the applicant’s protest and, where applicable,the
`paymentof a protest fee.
`- The additional search fees were accompaniedby the applicant’s protest but the applicable protest
`
`
`fee was not paid within the time limit specified in the invitation.
`
`No protest accompanied the paymentof additional search fees.
`Form PCT/ISA/210 (continuation of first sheet (2)) (January 2015)
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`Jntemational application No.
`PCT/US16/34823
`
`CLASSIFICATION OF SUBJECT MATTER
`A.
`IPC(8) - A6G1K 9/00, 31/00, 47/02, 47/30, A61P 27/02 (2016.01)
`CPC - A61K 9/00, 31/00, 47/02, 47/30
`According to International Patent Classification (IPC) or to both nationalclassification and LPC
`B.
`FIELDS SEARCHED
`
`Minimum documentation searched(classification system followed byclassification symbols)
`IPC (8) - AG1F 9/00; A61K 9/00, 9/08, 31/00, 47/02, 47/30; A61P 27/02 (2016.01);
`CPC - A61K 9/00, 9/08, 9/0048, 31/00, 47/02, 47/30
`
`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 practicable, search terms used)
`PatSeer (US, EP, WO, JP, DE, GB, CN, FR, KR, ES, AU, IN, CA, Other Countries (INPADOC), RU, AT, CH, TH, BR, PH); EBSCO;
`Google/Google Scholar; PubMed; ophthalmic composition, ophthalmic agent, deuterated water, singlet oxygen, aflibercept, ranibizumab,
`cyclpentolate, tropicamide, tatracaine, azelastine, oxymetazoline, phenylephrine, tetrahydrozoline, osmolarity adjusting agent, pD,tonicity
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category*
`
`Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevantto claim No.
`
`US 7,691,099 B2 (BERRY, MJ) 6 April 2010; column2,tines 23-36
`
`US 8,980,839 B2 (MITRA,AKetal.) 17 March 2015; column 10,lines 57-67; column 11, lines
`1-11; column 12,lines 19-33
`
`4-2, 3/1-2, 9-13
`
`1-2, 3/1-2, 9-13
`
`(U.S, DEPARTMENT OF HEALTH AND HUMANSERVICES FOOD AND DRUG
`ADMINISTRATION) Guidance for Industry Q1A (R2) Stability Testing of New Drug Substances
`and Products. November 2003 [retrieved on 27 July 2016]. Retrieved from the internet; URL:
`<http://iwww.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
`073369.pdf>; page 1, third paragraph; page 2, fourth-fifth paragraphs; page 4, sixth-seventh
`paragraphs; page 11, first-fourth paragraphs
`
`3/1-2
`
`PCT OSP: 571-272-7774
`
`[J See patent family annex.
`[| Further documentsarelisted in the continuation of Box C.
`Special categories of cited documents:
`later documentpublishedafter the internationalfiling date or priority
`date and not in conflict with the application but cited to understand
`documentdefining the generalstate ofthe art which is not considered
`e invention
`the principle or theory underlying t
`to be of particular relevance
`documentofparticular relevance, the claimed invention cannot be
`earlier application or patent but published on orafter the international
`considered novel or cannot be considered to involve an inventive
`filing date
`step when the documentis taken alone
`document which may throw doubts on priority claim(s) or which is
`Specialreasonxe theewe date of anothercitation or other wy~ documentof particular relevance;the claimed invention cannot be
`pec
`S
`Spe
`.
`.
`wo
`considered to involve an inventive step when the documentis
`* documentreferring to an oral disclosure, use, exhibition or other
`combined with one or more other such documents, such combination
`means
`being obvious to a person skilled in the art
`documentpublishedprior to the internationalfiling date but later than «g- document member of the samepatent family
`the priority date claimed
`
`“tT
`
`“Xx”
`
`Date of the actual completion of the international search
`
`Date of mailing of the international search report
`
`27 Juty 2016 (27.07.2016)
`
`Nameand mailing address of the ISA/
`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) (January 2015)
`
`2 3 A U G 2016
`
`Authorized officer
`
`PCT Helpdesk: 571-272-4300
`
`Shane Thomas
`
`

`

`:
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`
`PATENT COOPERATION TREATY
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`(PCT Rule 43is.1)
`
` PCT
`To: Frank Yang
`
`
`Wilson Sonsini Goodrich & Rosati
`
`
`650 Page Mill Road
`Palo Alto, California 94304
`
`United States of America
`
`
`
`Date ofmailing
`(day/month/year)
`2 3 AU G 2016
`
`Applicant's or agent’s file reference
`46682-702.601
`
`See paragraph 2 below
`
`International application No.
`
`International filing date (day/month/year)
`
`Priority date (day/month/year)
`
`
`
`
`
`
`PCT/US16/34823
`
`International Patent Classification (IPC) or both national classification and IPC
`IPC(8) - A61K 9/00, 31/00, 47/02, 47/30; A61P 27/02 (2016.01)
`
`
`CPC -
` A61K 9/00, 31/00, 47/02, 47/30
`
`
`
`Applicant -VONEXIS, INC.
`
`
`29 May 2015 (29.05.2015)
`
`1. This opinion contains indicationsrelating to the following items:
`
`Box No.
`
`Box No.
`
`Box No.
`
`Box No.
`
`Box No.
`
`Box No. V]_—
`
`Basis of the opinion
`
`Priority
`
`Non-establishment of opinion with regard to novelty, inventive step and industrial applicability
`
`Lack of unity of invention
`
`Reasoned statement under Rule 43 b/s. 1(a){i) with regard to novelty, inventive step and industrial applicability;
`citations and explanations supporting such statement
`Certain documents cited
`
`OOOKOKOX Box No. VIII Certain observations on the international application
`
`Shane Thomas
`
`Box No. VI] Certain defects in 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”) exceptthat this does not apply where the applicant chooses an Authority
`other than this one to be the IPEA and the chosen IPEA hasnotified the Intemational Bureau under Rule 66.1 is(b) that written
`opinionsof this International Searching Authority will not 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 to the PEA
`a written reply together, where appropriate, with amendments, before the expiration of 3 months from the date of mailing of Form
`PCT/ISA/220 or before the expiration of 22 months fromthe priority date, whichever expireslater.
`For further options, see Form PCT/ISA/220.
`
`Nameand mailing address ofthe ISA/
`Mail Stop PCT, Attn: ISA/US
`Commissionerfor Patents
`P.O. Box 1450, Alexandria, Virginia 22313-1450
`Facsimile No. 571-273-8300
`
`Date of completion ofthis opinion
`
`Authorized officer
`
`27 July 2016 (27.07.201 8)
`
`PCT Helpdesk: 571-272-4300
`PCT OSP: 571-272-7774
`
`Form PCT/ISA/237 (cover sheet) (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`PCT/US16/34823
`
`Box No. I
`
`Basis ofthis opinion
`
` International application No.
`
`
`
`
`
`
`furnished for the purposes of international search (Rules 12.3(a) and 23. 1(b)). 2. C] This opinion has been establishedtaking into accountthe rectification of an obvious mistake authorized by ornotified to
` 3. C] With regard to any nucleotide and/or amino acid sequence disclosed in the international application, this opinion has
`been established on the basis of a sequencelisting:
`
`
`
`a CJ forming part of the international application asfiled:
`CJ in the form of an Annex C/ST.25 textfile.
`
`
`C] on paperor in the form of an imagefile.
`
`
`b. ["] furnished together with the intemational application under PCT Rule 13¢er.1(a) for the purposes of international
`
`
`
`search only in the form of an Annex C/ST.25 text file.
`
`
`c. C] furnished subsequentto the intemational filing date for the purposes of intemational search only:
`[_] intheform of an Annex C/ST.25 text file (Rule 13¢er. 1(2)).
`
`
` [] on paperor in the form of an imagefile (Rule |3ser.1(b) and Administrative Instructions, Section 713).
` 4. C] In addition, in the case that more than one version or copy of a sequencelisting has been filed or furnished, the required
`statementsthatthe information in the subsequent or additional copies is identical to that forming part of the application as
`
`
`filed or does not go beyond the application as filed, as appropriate, were furnished.
`
`
` 5. Additional comments:
`
`1, With regard to the language, this opinion has been established onthe basisof:
`x] the international application in the language in which it was filed.
`a translation of the international application into
`
`
`
`whichis the languageofa translation
`
`this Authority under Rule 91 (Rule 43 bis. }(a)).
`
`Form PCT/ISA/237 (Box No. }) (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US16/34823
`
`Box No. If]
`
`Non-establishment of opinion with regard to novelty, inventive step and industrial applicability
`
`The questions whether the claimed invention appears to be novel, to involve an inventive step (to be non obvious), or to be industrially
`applicable have not been examinedin respectof:
`
`| the entire international application.
`P<]
`claims Nos. 4-8, 14-30
`
`because:
`
`the said intemational application, or the said claims Nos.
`subject matter which does not require an intemational search (specify):
`
`relate to the following
`
`x the description, claims or drawings(indicate particular elements below) or said claims Nos. 4-8, 14-30
`are so unclear that no meaningful opinion could be formed (specify):
`
`Claims 4-8 and 14-30 are all dependent claims and are not drafted in accordance with the second andthird sentences of Rule 6.4(a)
`
`[| See Supplemental Box for further details.
`
`[] a meaningful opinion could not be formed without the sequence listing; the applicantdid not, within the prescribed timelimit:
`furnish a sequence listing in the form of an Annex C/ST.25 text file, and such listing was not available to the
`International Searching Authority in the form and manner acceptable to it, or the sequence listing furnished did not
`comply with the standard provided for in Annex C of the Administrative Instructions.
`furnish a sequencelisting on paperorin the form of an imagefile complying with the standard providedfor 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 sequence listing furnished did not comply with the standard provided for in
`Annex C of the Administrative Instructions.
`
`| the claims, or said claims Nos.
`by the description that no meaningful opinion could be formed (specify):
`
`are so inadequately supported
`
`DX no international search report has been established for said claims Nos. 4-8, 14-30
`
`pay the required late furnishing fee for the furnishing of a sequence listing in response to an invitation under
`Rule 13¢er.1(a) or (b).
`
`Form PCT/ISA/237 (Box No.III) (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US16/34823
`
`Box No. V
`
`Reasoned statement under Rule 43dis.1(a)(i) with regard to novelty, inventive step and industrial applicabitity;
`citations and explanations supporting such statement
`
`Statement
`
`Novelty (N)
`
`Inventive step (IS)
`
`Claims
`Claims
`
`Claims
`Claims
`
`1-2, 3/1-2, 9-13
`NONE
`
`NONE
`1-2, 3/1-2, 9-13
`
`Industrial applicability (IA)
`
`Claims
`Claims
`
`1-2, 3/1-2, 9-13
`NONE
`
`-"**.Continued Within the Next Supplemental Box-***-
`
`As per claim 2, Berry and Mitra, in combination,disclose the ophthalmic composition of claim 1, and Berry further discloses wherein the
`ophthalmic agent comprisesaflibercept, ranibizumab, pegaptanib, cyclopentoiate, phenylephrine, homatropine, scopolamine,
`cyclopentolate/phenylephrine, phenylephrine/scopolamine, tropicamide, ketorolac/phenylephrine, hydroxyamphetamine/tropicamide,
`cysteamine, ocriplasmin, mitomycin, dapiprazole,lidocaine, proparacaine (proparacaine; column 2,lines 35-36), tetracaine, benoxinate,
`azithromycin,bacitracin, besifloxacin, boric acid, chloramphenicol, ciprofloxacin, erythromycin, ganciclovir, gatifloxacin, gentamicin,
`idoxuridine, !evofioxacin, moxifloxacin, natamycin, norfloxacin, ofloxacin, bacitracin/polymyxin b, tobramycin, polymyxin b/trimethoprim,
`povidoneiodine,trifluridine, gramicidin/neomycin/polymyxin b, sulfacetamida sodium, sulfisoxazole, bacitracinineomycin/polymyxin b,
`oxytetracycline/polymyxin b, phenylephrine/sulfacetamide sodium, vidarabine, bromfenac, nepafenac, ketorolac, cyclosporine, flurbiprofen,
`suprofen, diclofenac, alcaftadine, azelastine, bepotastine, cromolyn, emedastine, epinastine, ketotifen, levocabastine, lodoxamide,
`nedocromil, naphazoline, naphazoline/pheniramine, naphazoline/zinc sulfate, olopatadine, oxymetazoline, pemirolast, phenylephrine,
`phenylephrine/zinc sulfate, tetrahydrozoline, tetrahydrozoline/zinc sulfate, fluorescein, fluorescein/proparacaine, benoxinate/luorescein,
`indocyanine green, trypan blue, acetylcholine, apracionidine, betaxolol, bimatoprost,brimonidine, brinzolamide, brimonidine/brinzolamide,
`carbachol, carteolol, demecarium bromide,dipivefrin, dorzolamide, dorzolamide/timolol, echothiophate iodide, epinephrine,
`epinephrine/pilocarpine, latanoprost, tevobunolol, levobetaxolol, metipranolol, physostigmine, pilocarpine, tafluprost, timolol, travoprost,
`unoprostone, artifical tear, dexamethasone,difluprednate,fluocinolone, ftucrometholone, foteprednol, medrysone, prednisolone,
`timexolone, triamcinolone, fluorometholone/sulfacetamide snriiim, dexamethasone/neomycin, dexamethasone/tobramycin,
`dexamethasone/neomycin/polymyxin b, loteprednol/tobramycin, prednisolone/sulfacetamide sodium,
`bacitracin/hydrocortisone/neomycin/polymyxin b, hydrocortisone/neomycin/polymyxin b, chloramphenicol/hydrocortisone/polymyxin b,
`neomycin/polymyxin b/prednisolone, gentamicin/prednisolone, ketorolac/phenylephrine, diphenhydramine, dimenhydrinate, dicyciomine,
`flavoxate, oxybutynin, tiotropium, hyoscine, scopolamine(L-hyoscine), hydroxyzine, ipratropium, pirenzapine,solifenacin, darifenacin,
`benzatropine, mebeverine, procyclidine, aclidinium bromide,trinexyphenidyl/oenzhexol, tolterodina, or any combinations thereof.
`
`Citations and explanations:
`2.
`Claims 1-2 and 9-13 lack an inventive step under PCT Article 33(3) as being obvious over US 7,691,099 B2 (‘BERRY’)in view of US
`8,980,839 B2 to Mitra, et al. (hereinafter ‘Mitra’).
`
`As perclaim 1, Berry discloses an ophthalmic composition (ocular solutions; column 2, lines 23-28) comprising an ophthalmic agent
`(ocular drug; column 2,lines 26-28) and deuterated water (deuterated water; column2, lines 26-28), wherein the ophthalmic agentis not a
`muscarinic antagonist (ocular agent is proparacaine whichis not a muscarinic antagonist; column 2, lines 35-36), and wherein the
`ophthalmic agent does not extend singlet oxygenlifetime (ocular agent is proparacaine which is not a photosensitizer and therefore does
`not extend singlet oxygenlifetime; column 2, lines 35-36), but Berry does not disclose comprising at a pD of from about 4 to about 8.
`However, Mitra discloses comprising a pD of from about 4 to about 8 (pH, pD measuredin deuterated water,of liquid ophthalmic drug
`compositions range from 5 to 8; column 10, lines 60-64).
`{t would have been obviausto oneskilled in the art at the time of the invention to
`have modified the ophthalmic composition, as disclosed by Berry, to provide the ophthalmic composition comprising at a pD of from about
`4 to about 8, as disclosed by Mitra, as pH values (pD values) inside the rangeof 5 -8 are preferable for formulating ophthalmic
`preparationsfor topical applications to the eye (Mitra; column 10,lines 60-64).
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`Asper claim 9, Berry and Mitra, in combination, disclose the ophthalmic composition of claim 1, but Berry doesnot disclose whereinthe
`ophthalmic composition further comprises an osmolarity adjusting agent, a preservative, a buffer agent, a tonicity adjusting agent, a pD
`adjusting agent, or a combination thereof. However, Mitra discloses wherein the ophthalmic composition further comprises an osmolarity
`adjusting agent (osmolarity adjusting agents; column 11, lines 2-3), a preservative (a preservative; column 10,lines 57-60), a buffer agent
`(a buffer agent: column 10, lines 57-60), a tonicity adjusting agent(a tonicity adjusting agent; column 10,lines 57-60), a pD adjusting
`agent(a pH, pD in deuterated water, adjusting buffer; column 10, lines 57-60, column 11, lines 2-3), or a combination thereof
`(combinationsthereof; column 10, lines 57-60).
`It would have been obviousto oneskilled in the art at the time of the invention to have
`modified the ophthalmic composition, as disclosed by Berry, to provide the ophthalmic composition wherein the ophthalmic composition
`further comprises an osmolarity adjusting agent, a preservative, a buffer agent, a tonicity adjusting agent, a pD adjusting agent, or a
`combination thereof, as disclosed by Mitra, as ophthalmic compositions for topical application to the eye are formulated with a variety of
`additives to adjust the pH, osmolarity, etc. for the particular treatment need (Mitra; column 10,lines 57-67; column 11; lines 1-3).
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`Form PCT/ISA/237 (Box No. V) (January 2015)
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`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`Supplemental Box
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`International application No.
`PCTIUS16/34823
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`In case the space in any of the preceding boxesis notsufficient.
`Continuation of:
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`-***.Continued from Box V: Citations and Explanations-***-
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`As per claim 10, Berry and Mitra, in combination, disclose the ophthalmic composition of claim 9, but Berry does not disclose wherein the
`osmolarity adjusting agent is sodium chloride. However, Mitra discloses wherein the osmolarity adjusting agent is sodium chloride
`(osmolarity adjusting agent is sodium chloride; column 11, lines 9-11).
`It would have been obvious to oneskilled in the art at the time of
`the invention to have modified the ophthalmic composition, as disclosed by Berry, to provide the ophthalmic composition wherein the
`osmolarity adjusting agent is sodium chloride, as disclosed by Mitra, as sodium chloride is a tonicity agentthat is used to adjust the
`osmolality of ophthalmic compositions to a preferred range (Mitra; column 11, tines 9-15) and sodium chloride is an aprotic agent that
`would not exchange with deuterium of deuterated water.
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`As per claim 11, Berry and Mitra, in combination, disclose the ophthalmic composition of claim 9, but Berry does not disclose wherein the
`preservative is selected from benzalkonium chlorida, cetrimonium, sodium perborate, stabilized oxychloro complex, SofZia,
`polyquaternium-1, chlorobutanol, edetate disodium, polyhexamethylene biguanide, or combinations thereof. However, Mitra discloses
`wherein the preservative is selected from benzalkonium chloride (benzalkonium chloride; column 12, lines 19-23), and edetate disodium
`(EDTA; column 12, lines 19-23).
`It would have been obviousto oneskilled in the art at the time of the invention to have modified the
`ophthalmic composition, as disclosed by Berry, to provide the ophthalmic composition wherein the preservative is selected from
`benzalkonium chloride and edetate disodium, as disclosed by Mitra, as ophthalmic composition may be preserved by addition of a
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`preservative that is suitable for topical administration to the eye (Mitra; column 12,lines 19-33) and provides addedshelf-life stability to the
`formulation.
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`As per claim 12, Berry and Mitra, in combination, disclose the ophthalmic composition of claim 9, but Berry does not disclose wherein the
`buffer agent is selected from borates, borate-polyal complexes, phosphate buffering agents, citrate buffering agents, acetate buffering
`agents, carbonate buffering agents, organic buffering agents, amino acid buffering agents, or combinations thereof. However, Mitra
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`discloses wherein the buffer agent is selected from borates (borates; column 10; lines 66-67; column 11, tine 1), borate-polyol complexes
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`(borate-polyol complexes; column 11, line 2), phosphate buffering agents (phosphate buffer; column 11, line 1), citrate buffering agents
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`(citrate buffer; colurnmn 11, line 1), acetate buffering agents (acetate buffer; column 11, line 1), or carbonate buffering agents (carbonate
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`buffer; column 11, line 1).
`It would have been obvious to one skilled in the art at the time of the invention to have modified the ophthalmic
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`composition, as disclosed by Berry, to provide the ophthalmic composition wherein the buffer agent is selected from borates, borate-palyol
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`complexes, phosphate buffering agents,citrate buffering agents, acetate buffering agents, or carbonate buffering agents, as disclosed by
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`Mitra, as borate, borate-polyol complexes, phosphates,citrate, acetate, and carbonate buffers are commonly used to adjust the pH, pDin
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`the case of deuterated water, of ophthalmic formulation for topical administration to the eye (Mitra; column 10,lines 60-67; column 11, lineg
`1-4).
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`As per claim 13, Berry and Mitra, in combination, disclose the ophthalmic composition of claim 9, but Berry does not disclose wherein the
`tonicity adjusting agent is selected from sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium
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`chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium
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`thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose
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`mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or a combination thereof. However, Mitra discloses wherein the
`tonicity adjusting agent is sodium chloride (sodium chloride; column 11, lines 9-11).
`it would have been obviousto one skilled in the art at
`the time of the invention to have modified the ophthalmic composition, as disclosed by Berry, to provide the ophthalmic composition
`wherein the tonicity adjusting agent is sodium chloride, as disclosed by Mitra, as sodium chloride is a tonicity agent that is use to adjust
`ophthalmic compositions to a preferred range (Mitra; column 11, lines 9-15) and sodium chloride is an aprotic agent that would not
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`exchangewith deuterium of deuterated water.
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` Claims 3/1-2 lack an inventive step under PCT Article 33(3) as being obvious Berry in view of Mitra and in further view of the publication
`“Guidancefor Industry Q1A (R2) Stability Testing of New Drug Substances and Products” by U.S. Department of Health and Human
`Services Food and Drug Administration (hereinafter 'FDA’).
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`As per claims 3/1-2, Berry and Mitra, in combination, disclose the ophthalmic composition of claim 1 or 2, but Berry does not disclose
`wherein the ophthalmic composition comprisesat least one of: about 80 percent, about 85 percent, about 90 percent, about 95 percent,
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`about 97 percent, about 98 percent, or about 99 percent of the ophthalmic agent based oninitial concentration after extended period of
`time under storage condition. However, FDA discloses wherein the ophthalmic composition comprises at least one of: about 95 percent,
`about 97 percent, about 98 percent, or about 99 percentof the ophthalmic agent based oninitial concentration after extended period of
`time under storage condition (extended storage conditions and times must meet standards including having 95 percent of original value of
`ophthalmic agent and may haveother requirements for stability purity; page 1, third paragraph; page 2, fourth paragraph; page 11,
`first-fourth paragraphs).
`It would have been obvious to oneskilled in the art at the time of the invention to have modified the ophthalmic
`compo