PATENT COOPERATION TREATY
`
`PCT
`
`INTERNATIONAL PRELIMINARY REPORT ON PATENTABILITY
`
`(Chapter I of the Patent Cooperation Treaty)
`
`(PCT Rule 444is)
`
`Applicant’s or agent’s file reference
`44854-794601
`
`FOR FURTHER ACTION
`
`See item 4 below
`
`International application No.
`PCT/US2020/052291
`
`Internationalfiling date (day/month/vear)
`23 September 2020 (23.09.2020)
`
`Priority date (dav‘month/year)
`23 September 2019 (23.09.2019)
`
`International Patent Classification (8th edition unless older edition indicated)
`See relevant information in Form PCT/ISA/237
`
`Applicant
`TWIST BIOSCIENCE CORPORATION
`
`This international preliminary report on patentability (Chapter I) is issued by the International Bureauon behalf of the
`International Searching Authority under Rule 44 dis. 1(a).
`
`This REPORTconsists of a total of 15 sheets, including this cover sheet.
`
`In the attached sheets, any reference to the written opinion of the International Searching Authority should be read as a reference
`to the international preliminary report on patentability (Chapter I) instead.
`
`This report contains indications relating to the following items:
`
`Basis of the report
`
`Priority
`
`Non-establishment of opinion with regard to novelty, inventive step and industrial
`applicability
`
`Lack of unity of invention
`
`Reasoned statement under Article 35(2) with regard to novelty, inventive step or industrial
`applicability; citations and explanations supporting such statement
`
`Certain documents cited
`
`Certain defects in the international application
`
`Certain observations on the international application
`
`The International Bureau of WIPO
`34, chemin des Colombettes
`1211 Geneva 20, Switzerland
`
`Form PCT/IB/373 (revised January 2020)
`
`Date of issuance ofthis report
`15 March 2022 (15.03.2022)
`
`Authorized officer
`
`Athina Nickitas-Etienne c-mail pct.tcam4@wipo.int
`
`The International Bureau will communicate this report to designated Offices in accordance with Rules 444is.3(c) and 93dis.1 but
`nol, except where the applicant makes an express request under Article 23(2), before the expiration of 30 months fromthe priority
`date (Rule 44bis .2).
`
`Box No. I
`
`Box No. II
`
`Box No.
`
`
`
`

`

`PCT/US2020/052291 10.03.2021
`
`PATENT COOPERATION TREATY
`
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`
`To: Stephanie S. Dusaban Gonzales
`
`Wilson Sonsini Goodrich & Rosati
`650 Page Mill Road
`Palo Alto, CA 94304
`
`PCT
`
`WRITTEN OPINION OF THE
`
`(PCT Rule 43 dis.1)
`
` Psmonticty MAR 10 2021
`
`
`
`
`
`
`
`
`Applicant’s or agent’s file reference
`
`44854-794601
`
`International application No.
`Internationalfiling date (day/month/year)
`
`23 September 2020 (23.09.2020)
`PCT/US20/52291
`23 September 2019 (23.09.2019)
`
`
`International Patent Classification (IPC) or both national classification and IPC
`CO07K 16/28; C40B 40/08 (2020.01)
`
`
`
`IPC -
`
` cpec
`
`FOR FURTHER ACTION
`See paragraph 2 below
`
`Priority date (day/month/year)
`
`
`CO7K 16/2896; C40B 40/08
`
`
`Applicant Twist Bioscience Corporation
`
`
`This opinion containsindicationsrelating to the following items:
`Xx Box No.|
`Basis ofthe opinion
`Box No.
`Priority
`
`
`
`OOOXkXxO Box No. VIII Certain observations on the international application
`
`Box No.
`
`Box No.
`
`Box No.
`
`Non-establishmentof opinion with regard to novelty, inventive step and industrial applicability
`
`Lack of unity of invention
`
`Reasoned statementunder Rule 43 dis. 1(a)(i) with regard to novelty, inventive step and industrial applicability;
`citations and explanations supporting such statement
`
`Box No. VI
`
`Certain documents cited
`
`Box No. VII Certain defects in the international application
`
`FURTHER ACTION
`
`If a demandfor 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 wherethe applicant chooses an Authority
`otherthan this one to be the IPEA and the chosen IPEA hasnotified the International Bureau under Rule 66. 1dis(b) that written
`opinionsofthis 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 applicantis invited to submit to the IPEA
`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 from the priority date, whichever expires later.
`For further options, see Form PCT/ISA/220.
`
`Name and mailing address of the ISA/US| Date of completion of this opinion
`Mail Stop PCT,Attn: ISAVUS
`Commissionerfor Patents
`P.O. Box 1450, Alexandria, Virginia 22313-1450
`Facsimile No. 571-273-8300
`
`ry
`
`2021 (10.02.2021
`(
`
`10 February
`
`Authorized officer
`Shane Thomas
`PCT Help Desk
`Telephone No. 571-272-4300
`
`)
`
`Form PCT/ISA/237 (cover sheet) (revised January 2019)
`
`

`

`PCT/US2020/052291 10.03.2021
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`
`PCT/US20/52291
`
`Box No. I
`
`Basis of this opinion
`
`1. With regardto the language,this opinion has been established on the basis of:
`Xx]
`the international application in the language in which it wasfiled.
`C a translation ofthe international application into |
`furnished for the purposesof international search (Rules 12.3(a) and 23.1(b)).
`
`whichis the language ofa translation
`
`This opinion has been established taking into accountthe rectification of an obvious mistake authorized byornotified to
`this Authority under Rule 91 (Rule 43dis.1(b)).
`
`3. Xl] With regard to any nucleotide and/or amino acid sequencedisclosed in the international application, this opinion has been
`established on the basis of a sequencelisting:
`a, CL] forming part ofthe international application as filed:
`C] in the form of an Annex C/ST.25textfile.
`[] on paperorin the form of an imagefile.
`furnished together with the international application under PCT Rule 13¢er.1(a) for the purposes of international
`search only in the form of an Annex C/ST.25 textfile.
`
`$5. Additional comments:
`
`b.
`
`c,
`
`furnished subsequentto the internationalfiling date for the purposesof international search only:
`[X]
`in the form of an Annex C/ST.25textfile (Rule 13/er. 1(a)).
`[_]
`on paperorin the formof an imagefile (Rule 13¢er.1(b) and Administrative Instructions, Section 713).
`
`4. ><]
`
`In addition, in the case that more than one version or copy of a sequencelisting has beenfiled or furnished, the required
`statements that the information in the subsequentor additional copiesis identical to that forming part ofthe application as
`filed or does not go beyond the application as filed, as appropriate, were furnished.
`
`Form PCT/ISA/237 (Box No.I) (revised January 2019)
`
`

`

`PCT/US2020/052291 10.03.2021
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US20/52291
`
`Box No. HI
`
`Non-establishment ofopinion with regard to novelty, inventive step and industrial applicability
`
`The questions whetherthe claimed invention appears to be novel, to involve an inventive step (to be non obvious), or to be industrially
`applicable have not been examined in respectof:
`
`
`
`C] the said international application, or the said claims Nos. relate to the following
`
`[| the entire international application.
`x claims Nos. 77
`because:
`
`subject matter which does not require an international search (specify):
`
`[] See Supplemental Boxfor further details.
`
`x the description, claims or drawings (indicate particular elements below) or said claims Nos.
`are so unclear that no meaningful opinion could be formed (specify):
`
`_77
`
`Claim 77 is a dependent claim and is not drafted in accordance with the second andthird sentencesof Rule 6.4(a).
`
`(| the claims, or said claims Nos.
`by the description that no meaningful opinion could be formed (specify):
`
`are so inadequately supported
`
`TX]
`
`no international search report has been established for said claims Nos. 77
`
`[| a meaningful opinion could notbe formed without the sequencelisting; the applicant did not, within the prescribed timelimit:
`furnish a sequencelisting in the form of an Annex C/ST.25 textfile, and suchlisting was notavailable to the International
`Searching Authority in the form and manneracceptabletoit, or the sequencelisting furnished did not comply with the
`standard provided for in Annex C of the Administrative Instructions.
`furnish a sequencelisting on paperorin the formof an imagefile complying with the standard provided for in Annex
`C ofthe Administrative Instructions, and suchlisting was not available to the International Searching Authority in the
`form and manneracceptableto it, or the sequencelisting furnished did not comply with the standard provided for in
`Annex C of the Administrative Instructions.
`
`pay the required late furnishingfee for the furnishing ofa sequencelisting in responseto an invitation under Rule 13¢er.1(a)
`or (b).
`
`Form PCT/ISA/237 (Box No. III) (revised January 2019)
`
`

`

`PCT/US2020/052291 10.03.2021
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`PCT/US20/52291
`
`Box No. IV
`
`Lack of unity of invention
`
`1, x In response to the invitation (Form PCT/ISA/206) to pay additional fees the applicant has, within the applicable time limit:
`[| paid additionalfees.
`[| paid additional fees under protest and, where applicable, the protest fee.
`[] paid additional fees under protest but the applicable protest fee was not paid.
`
`International application No.
`
`
`
`
`
`
`
`
`
`
`not paid additional fees.
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`2. [] This Authority foundthat the requirement ofunity of invention is not complied with and chosenotto invite the applicantto
`pay additionalfees.
` 3. This Authority considers that the requirement of unity of invention in accordance with Rule 13.1, 13.2 and 13.3 is
`
` -***-Please See Supplemental Page-***-
`
`|
`I<]
`
`complied with.
`not complied with for the following reasons:
`
`
`
`
`
`4.
`
`Consequently, this opinion has been established in respect of the following parts of the international application:
`[] all parts.
`
`
`
`-***-Please See Supplemental Page-***-
`
`the parts relating to claims Nos.
`
`Form PCT/ISA/237 (Box No. IV) (revised January 2019)
`
`

`

`PCT/US2020/052291 10.03.2021
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US20/52291
`
`Box No. V
`
`Reasoned statement under Rule 43bdis.1(a)(i) with regard to novelty, inventive step and industrial applicability;
`citations and explanations supporting such statement
`
`Statement
`
`Novelty (N)
`
`Inventive step (1S)
`
`Industrial applicability (TA)
`
`Citations and explanations:
`2.
`-Continued from Box No. V. 1: Statement:
`
`Claims
`Claims
`
`1-14, 21-22, 46-50, 53-59, and 63-76
`None
`
`Claims
`Claims
`
`Claims
`Claims
`
`-***-Please See Below-***-
`-***-Please See Below-***-
`
`1-14, 21-22, 46-50, 53-59, and 63-76
`None
`
`-***-Continued in Supplemental Box-***-
`
`As per Claim 1, Twist discloses a nucleic acid library (a nucleic acid library; paragraph [0005]), comprising: a plurality of nucleic acids
`(comprising:a plurality of nucleic acids; paragraph [0005]), wherein each of the nucleic acids encodes for a sequence that whentranslated
`encodesfor a GPCR binding immunoglobulin (wherein each of the nucleic acids encodes for a sequence that whentranslated encodesfor
`a GPCRbinding immunoglobulin; paragraph (0005]) wherein the GPCR comprises, amonga plurality of GPCRs, CRTH2R(wherein the
`GPCR comprises, among a plurality of GPCRs, PTGDR (CRTH2R); Table 1, Table 2), wherein the CRTH2Rbinding immunoglobulin
`comprises a variant of a GPCR binding domain (wherein the CRTH2R binding immunoglobulin comprises a variant of a GPCR binding
`domain; paragraph (0005]). Twist further discloses wherein the library comprises at least 10°5 non-identical sequences encoding VH or VL
`domains (wherein thelibrary comprisesat least 10°5 non-identical sequences encoding VH or VL domains; Claims6, 9, 16).
`
`Inventive Step (IS): YES: Claims 7, 8, 21, 22, 46-50, 53-58, 71/7, 71/8, 72/71/7-74/7 V7, 72/7 1/8-74/7 1/8, 75/7, 75/8, 76/7 and 76/8
`
`Inventive Step (IS): NO: Claims 1-6, 9-14, 59, 63-70, 71/1-71/6, 71/9-71/14, 72/71/1-72/7 1/6, 72/7 1/9-72/71/14, 73/71/1-73/7116,
`73/7 149-7317 1114, 7417 111-74/7116, 74/7 1/9-7417 1/14, 75/1-75/6, 75/9-75/14, 76/1-76/6, and 76/9-76/14
`
`-Continued fram Box No. V. 2: Citations and Explanations:
`
`Claims 1-6, 9-14, 71/1-71/6, 74/9-71/14, 72/71/1-72/7 116, 72/7 1/9-72/71114, 73/71/1-73/7 1/6, 73/7 119-73/7 1/14, 74/71/1-74/7 116,
`T4I7T119-74/71114, 75/1-75/6, 75/9-75/14, 76/1-76/6, and 76/9-76/14 lack an inventive step under PCT Article 33(3) as being obvious over
`WO 2019/051501 A1 to Twist Bioscience Corporation (hereinafter ‘Twist'), in view of US 2016/0090422 A1 to Genentech, Inc. (hereinafter
`‘Genentech’').
`
`Twist does not disclose a specific embodiment wherein each of the nucleic acids encodes for a sequence that when translated encodes for
`a CRTH2Rbinding immunoglobulin, wherein the CRTH2R binding immunoglobulin comprises a variant of a CRTH2R binding domain (),
`wherein the CRTH2R binding domain is a tigand for the CRTH2R, and wherein the nucleic acid library comprises at least 10,000 variant
`immunoglobulin heavy chains and at least 10,000 variant immunoglobulin light chains.
`
`Genentechdiscloses antibodies that bind to human CRTH2R(antibodies that bind to human CRTH2R; paragraph [0006]), which are
`encoded by nucleic acids (which are encoded by nucleic acids; paragraph [0006]), wherein the antibodies are isolated by screening
`combinatoriallibraries for antibodies with desired activity (wherein the antibodies are isolated by screening combinatoriallibraries for
`antibodies with desired activity; paragraph (0149]).
`
`It would have been obvious to a personof ordinary skill in the art at the time the invention was made to have modified the disclosure of
`Twist to have specified a minimum numberof non-identical VH and VL domains encodedbythelibrary, such as 50,000 each, 25,000
`each, 20,000 each, or 10,000 eachin order to morefully describe the set of 10°5 non-identical nucleic acid sequences, and to have
`assembled the library using appropriate numbers of complementary sequencesto form a sufficiently large set of antibody variants
`comprising both VH and VL domains.It further would have been obvious to a person of ordinary skill in the art at the time the invention
`was made to have modified the disclosure of Twist to have specified the production andisolation of binding immunoglobulins to CRTH2R,
`as disclosed by Genentech, by screeningthelibrary disclosed by Twist, in orderto identify antibodies with desired activity andaffinity for
`the target, based on the disclosure of Genentech.
`
`As per claim 2, the combination of Twist and Genentech discloses the nucleic acidlibrary of claim 1. Twist further discloses wherein the
`library comprises at least 105 non-identical sequences encoding VH or VL domains (wherein thelibrary comprises at least 10*5
`non-identical sequences encoding VH or VL domains; Claims 6, 9, 16). Twist does not disclose wherein the nucleic acid library comprises
`at least 50,000 variant immunoglobulin heavy chains and at teast 50,000 variant immunoglobulin light chains. However, it would have been
`obviousto a person of ordinary skill in the art at the time the invention was made to have modified the disclosure of Twist to have specified
`a minimum numberof non-identical VH and VL domains encodedbythelibrary, such as 50,000 each, in order to more fully describe the
`set of 105 non-identical nucleic acid sequences, and to have assembled thelibrary using appropriate numbers of complementary
`
`Form PCT/ISA/237 (Box No. V) (revised January 2019)
`
`

`

`PCT/US2020/052291 10.03.2021
`
`INTERNATIONAL SEARCHING AUTHORITY
`
`WRITTEN OPINION OF THE
`
`International application No.
`PCT/US20/52291
`
`Supplemental Box
`
`
`
`In case the space in any ofthe preceding boxes is not sufficient.
`Continuationof.
`-***-Continued From Box IV (ii): Lack of unity of invention-***-
`
`
`This application contains the following inventions or groups of inventions which are not so finked as to form a single general inventive
`concept under PCT Rule 13.1. In orderfor all inventions to be examined, the appropriate additional examination fees mustbe paid.
`
`
`
` Claims 1-50, 53-58 (each in-part), 59-76, and an immunoglobulin comprising a heavy chain and a light chain (antibody type), comprising a
`heavy chain encompassing SEQ ID NO: 2338 (heavy chain sequence), andalight chain encompassing SEQ ID NO: 2361 (light chain
`sequence) are directed toward nucleic acid libraries, antibodies encodedbythelibraries, and methods associated therewith.
`
`
`
`The libraries, antibodies, and methodswill be searched to the extent they encompass an immunoglobulin comprising a heavy chain and a
`light chain (first exemplary antibody type), comprising a heavy chain encompassing SEQ ID NO: 2338(first exemplary heavy chain
`sequence), and a light chain encompassing SEQ ID NO: 2361 (first exemplary light chain sequence). Applicantis invited to elect additional
`antibody(ies) or antibody type(s), with specified chain(s), with specified SEQ ID NO: for each, or with specified substitution(s) at specified
`site(s) of a SEQ ID NO:, such that the sequence(s) of each elected speciesis fully specified (i.e. no optional or variable residues or
`substituents), to be searched. Additional antibody(ies) or antibody type(s) will be searched upon the paymentof additionalfees.It is
`believed that claims 1-6, 7-8 (each in-part), 9-14, 21-22 (eachin-part), 46 (in-part), 47-50, 53-58 (each in-part), 59, 63-70, and 71-76 (each
`in-part) encompassthis first named invention and thus these claimswill be searched withoutfee to the extent that they encompass an
`immunoglobulin comprising a heavy chain anda light chain (antibody type) comprising a heavy chain encompassing SEQ ID NO: 2338
`(heavy chain sequence), and a light chain encompassing SEQ ID NO: 2361 (light chain sequence). Applicants must specify the searchable
`claims that encompass any additionally elected antibody(ies), antibody type(s), and/or associated sequence(s). Applicants mustfurther
`indicate,if applicable, the claims which encompassthefirst named invention, if different than what was indicated abovefor this group.
`Failure to clearly identify how any paid additionalinvention fees are to be applied to the "+" group(s)will result in only thefirst claimed
`invention to be searched/examined. An exemplary election would be an immunoglobulin comprising a heavy chain and a light chain
`(antibody type), comprising a heavy chain encompassing SEQ ID NO: 2339 (heavy chain sequence), and a light chain encompassing SEQ
`
`ID NO: 2362 (light chain sequence).
`
` GroupsII+, Claims 51, 52, 53-58 (eachin-part), and SEQ ID NO: 2382 (CDR sequence)are directed toward antibodies, and methods
`associated therewith.
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`The antibodies and methods can be searchedto the extent they encompass SEQ ID NO: 2382(first exemplary CDR sequence). Applicant
`is invited to elect additional CDR(s), with specified SEQ ID NO: for each, or with specified substitution(s) at specified site(s) of a SEQ ID
`NO:, such that the sequenceof each elected speciesis fully specified (i.e. no optional or variable residues or substituents), to be searched.
`Additional CDR sequence(s) can be searched upon the paymentof additionalfees.It is believed that claims 51-58 (eachin-part)
`encompassthisfirst named invention of GroupsI+ and thus these claims can be searched with paymentof a fee for the search of Groups
`I+, to the extent that they encompass SEQ ID NO: 2382 (CDR sequence). Failure to clearly identify how any paid additional invention fees
`are to be applied to the "+" group(s) can result in only the first claimed invention of groups II+ to be searched/examined. An exemplary
`election would be SEQ ID NO: 2383 (CDR sequence).
`
`
`Theinventionslisted as Groups I+ and II+ do not relate to a single generalinventive concept under PCT Rule 13.1 because, under PCT
`Rule 13.2, they lack the sameor corresponding special technicalfeatures for the following reasons: the special technical features of
`
`
`GroupsI+ include: a nucleic acid library, not present in any of GroupsII+; the special technical features of Groups II+ include SEQ ID NO:
`
`2382, not present in any of GroupsI+.
`
`
`GroupsI+ and Il+ share the technical features including: antibodies or antibody fragment, wherein the antibody or antibody fragment
`
`comprises a COR; a methodoftreating a disease or disorderof the central nervous system, kidney,intestine, lung, hair, skin, bone, or
`
`
`cartilage, comprising administering the antibody or antibody fragment; a method oftreating a disease or disorder characterized by an
`inflammatory response, comprising administering the antibody or antibody fragment; a methodof treating an allergic reaction, comprising
`
`
`administering the antibody or antibody fragment; a method oftreating asthma, comprising administering the antibody or antibody fragment;
`and a methodof treating alopecia or baldness, comprising administering the antibody or antibody fragment.
`
`However, these shared technical features are previously disclosed by US 2009/0074771 A1 to Koeniget al. (hereinafter ‘Koenig’.
`
`
` Koenig discloses antibodies or antibody fragments, wherein the antibody or antibody fragment comprises a CDR(antibodies or antibody
`fragments, wherein the antibody or antibody fragment comprises a CDR; abstract, paragraphs [0146], [0147]); a methodoftreating a
`disease or disorder of the hair or skin, comprising administering the antibody or antibody fragment {a methodof treating alopecia (a
`
`
`disease ordisorder of the hair or skin), comprising administering the antibody or antibody fragment; paragraph [0507]); a method of
`treating a disease or disorder characterized by an inflammatory response (a methodoftreating a disease or disorder characterized by an
`inflammatory response; abstract, paragraph [0109]), comprising administering the antibody or antibody fragment (comprising administering
`
`
`the antibody or antibody fragment; paragraph [0109]); a method of treating an allergic reaction (a methodoftreating an allergic reaction,
`
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`abstract, paragraph (0111]), comprising administering the antibody or antibody fragment (comprising administering the antibody or antibody
`
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`fragment; paragraph [0111}); a methodoftreating asthma, comprising administering the antibody or antibody fragment (a method of
`
`
`treating asthma, comprising administering the antibody or antibody fragment; paragraph [0507]; Claims 41, 49); and a methodoftreating
`
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`alopecia or baldness, comprising administering the antibody or antibody fragment (a method oftreating alopecia or baldness, comprising
`
`administering the antibody or antibody fragment; paragraph [0507)).
`
` No technical features are shared between the antibodies or antibody sequences of Groups I+ and, accordingly, these groups lack unity a
`priori.
`
`
`-“"*-Continued Within the Next Supplemental Box-*"*-
`
`Form PCT/ISA/237 (Supplemental Box) (revised January 2019)
`
`

`

`PCT/US2020/052291 10.03.2021
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`Supplemental Box
`
`In case the space in any of the preceding boxesis not sufficient.
`Continuationof:
`-***-Continued from previous Supplemental Box-***-
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`Intemational application No.
`PCT/US20/52291
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`GroupsI+ further share the technical features including: a nucleic acid library, comprising: a plurality of nucleic acids, wherein each of the
`nucleic acids encodes for a sequence that whentranslated encodes for a CRTH2R binding immunoglobulin, antibody, or fragment thereof,
`
`
`wherein the CRTH2R binding immunoglobulin comprises a variant of a CRTH2R binding domain, wherein the CRTH2R binding domain is
`a ligand for the CRTH2R, and wherein the nucleic acid library comprises at feast 10,000 variant immunoglobulin heavy chains andat least
`10,000 variant immunoglobulin light chains; a nucleic acid library comprising a plurality of nucleic acids, wherein each nucleic acid of the
`plurality of nucleic acids encodes for a sequence that when translated encodesfor an antibody or antibody fragment thereof, wherein the
`antibody or antibody fragment thereof comprises a variable region of a heavy chain (VH) that comprises a CRTH2R binding domain,
`wherein each nucleic acid of the plurality of nucleic acids comprises a sequence encoding for a sequence variant of the CRTH2Rbinding
`domain, and wherein the antibody or antibody fragmentbinds to its antigen with a Kd of less than 100 nM; a nucleic acid library comprising:
`a plurality of nucleic acids, wherein eachofthe nucleic acids encodes for a sequence that when translated encodes for a CRTH2Rsingle
`domain antibody, wherein each sequenceofthe plurality of sequences comprises a variant sequence encoding for a CDR1, CDR2,or
`
`
`CDR3 ona variable region of a heavy chain (VH); wherein the Ilbrary comprises at least 30,000 variant sequences; and wherein the
`CRTH2R single domain antibody binds to its antigen with a Kd of less than 100 nM; a protein library encoded bythe nucleic acid library,
`wherein the protein library comprises peptides; a vectorlibrary comprising the nucleic acid library; a cell library comprising the nucleic acid
`
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`library; an antibody or antibody fragmentthat binds CRTH2R, comprising an immunoglobulin heavy chain and an immunoglobulin light
`chain: a. wherein the immunoglobulin heavy chain comprises an amino acid sequence; and b., wherein the immunoglobulin light chain ©
`comprises an amino acid sequence; and a method for generating a nucleic acid library encoding for a CRTH2Rantibody or antibody
`
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`fragment thereof comprising: (a) providing predetermined sequences encodingfor:i. a first plurality of polynucleotides, wherein each
`polynucleotideofthe first plurality of polynucleotides encodesfor at least 1000 variant sequence encoding for CDR1 on a heavy chain; ii. a
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`second plurality of polynucleotides, wherein each polynucleotide of the secondplurality of polynucleotides encodesfor at least 1000 variant
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`sequence encoding for CDR2 on a heavychain; iii. a third plurality of polynucleotides, wherein each polynucleotide of the third plurality of
`polynucleotides encodesforat least 1000 variant sequence encoding for CDR3 on a heavychain; and (b) mixing thefirst plurality of
`polynucleotides, the secondplurality of polynucleotides, and the third plurality of polynucleotides to form the nucleic acid library of variant
`nucleic acids encoding for the CRTH2R antibodyor antibody fragment thereof, and wherein at teast about 70% ofthe variant nucleic acids
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`encode for an antibody or antibody fragmentthat binds to its antigen with a KD of less than 100 nM.
` However, these shared technical features are previously disclosed by in view of WO 2005/093092 A2 to Bayer Healthcare AG (hereinafter
`‘Bayer’), in view of WO 2008/068280 A1 to Ablynx N.V. (hereinafter ‘Ablynx’), further in view of WO 2010/001251 A2 to Argen-X B.V.
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`(hereinafter 'Argen-X')
` Bayerdiscloses a nucleic acidlibrary (a library of amplified DNA sequencesthat encode chain-shuffled antibodies (a nucleic acid library);
`page 25, lines 20-31), comprising: a plurality of nucleic acids (comprising a library of amplified, randomly chain-shuffled
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`immunoglobulin-encoding sequences(a plurality of nucleic acids); page 25, lines 20-31), wherein each ofthe nucleic acids encodes for a
`sequence that when translated encodes for a CRTH2Rbinding antibody, or fragment thereof (wherein each of the nucleic acids encodes
`for a sequence that when translated encodes for a GPR44 receptor (CRTH2R) binding antibody, or fragment thereof; page 25,lines
`20-31), wherein the CRTH2Rbinding immunoglobulin comprises a variant of a CRTH2R binding domain (wherein the GPR44 (CRTH2R)
`binding immunoglobulin comprises a chain-shuffled random combinatorial immunoglobulin (variant) of a GPR44 (CRTH2R)binding
`domain; page 25,lines 20-31), wherein the CRTH2R binding domain is a tigand for the CRTH2R (wherein the antibodies bind to GPR44
`(CRTH2R binding domain is a ligand for the CRTH2R), page 25,lines 20-31); a nucleic acidlibrary (a library of amplified DNA sequences
`that encode chain-shuffled antibodies (a nucleic acid library); page 25,lines 20-31), comprising: a plurality of nucteic acids (comprising a
`library of amplified, randomly chain-shuffled immunoglobulin-encoding sequences(a plurality of nucleic acids); page 25, lines 20-31),
`wherein each of the nucleic acids encodes for a sequence that when translated encodes for a CRTH2Rbinding antibody, or fragment
`thereof (wherein eachof the nucleic acids encodes for a sequencethat whentranslated encodes for a GPR44 receptor (CRTH2R) binding
`antibody, or fragment thereof; page 25,lines 20-31), wherein each nucleic acid of the plurality of nucleic acids comprises a sequence
`encoding for a sequencevariant of the CRTH2R binding domain (wherein each nucleic acid of thelibrary (plurality of nucleic acids)
`comprises a sequence encoding for a chain-shuffled randomly combined immunoglobulin (sequence variant) of the GPR44 (CRTH2R)
`binding domain; page 25,lines 20-31); a nucleic acid library (a library of amplified DNA sequencesthat encode chain-shuffled antibodies {a
`nucleic acid library); page 25,lines 20-31), comprising: a plurality of nucteic acids (comprising a library of amplified, randomly
`chain-shuffled immunoglobulin-encoding sequences(a plurality of nucleic acids); page 25, lines 20-31), wherein eachof the nucleic acids
`encodes for a sequence that when translated encodes for a CRTH2Rbinding antibody, or fragment thereof (wherein each ofthe nucleic
`acids encodes for a sequencethat when translated encodes for a GPR44 receptor (CRTH2R)binding antibody, or fragment thereof, page
`25,lines 20-31); a protein library encoded by the nucleic acid library, wherein the protein library comprises peptides (an expressed
`immunoglobulin library produced by cloning an expression construct comprising the antibody-encoding sequences(aproteinlibrary
`encodedby the nucleic acid library, wherein the protein library comprises peptides); page 25, lines 20-31); a vector library comprising the
`nucleic acid library (a library of cloned expression constructs, comprising the antibody-encoding sequences(a vectorlibrary comprising the
`nucleic acid library); page 25,lines 20-31); a celllibrary comprising the nucleic acidlibrary (cells comprising the library of
`antibody-encoding sequences(cell library comprising the nucleic acid library); page 25,lines 20-31); Bayerfurther discloses wherein the
`antibodies are monoclonal antibodies (wherein the antibodies are monoclonal antibodies; page 25,lines 5-19); or single-chain antibodies
`(single-chain antibodies; page 25, lines 20-31)
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`Bayer does not disclose wherein the nucleic acid library comprises at least 10,000 variant immunoglobulin heavy chains and atleast
`10,000 variant immunoglobulin light chains; wherein the antibody or antibody fragmentthereof comprisesa variable region of a heavy
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`chain (VH) that comprises a CRTH2R binding domain; and wherein the antibody or antibody fragment binds to its antigen with a Kdofless
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`than 100 nM; a single domain antibody, wherein each sequenceofthe plurality of sequences comprises a variant sequence encodingfor a
`CDR1, CDR2, or CDR3 onavariable region of a heavy chain (VH); wherein thelibrary comprises at least 30,000 variant sequences; and
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`wherein the CRTH2R single domain antibody binds to its antigen with a Kd of less than 100 nM; an antibody or antibody fragmentthat
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`binds CRTH2R, comprising an immunoglobulin heavy chain and an immunoglobulin light chain: a. wherein the immunoglobulin heavy
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`chain comprises an amino acid sequence; and b. wherein the immunoglobulin light chain comprises an amino acid sequence; and a
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`method for
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`Form PCT/ISA/237 (Supplemental Box) (revised January 2019)
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`

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`PCT/US2020/052291 10.03.2021
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US20/52291
`
`Supplemental Box
`
`In case the spacein any of the preceding boxesis not sufficient.
`Continuation of:
`-***-Continued from previous Supplemental Box-***-
`
`generating a nucleic acidlibrary encoding for a CRTH2Rantibody or antibody fragment thereof comprising: (a) providing predetermined
`sequences encodingfor:i. a first plurality of polynucleotides, wherein each polynucleotide of thefirst plurality of polynucleotides encodes
`for at least 1000 variant sequence encoding for CDR1 on a heavy chain; ii. a second plurality of polynucleotides, wherein each
`polynucleotide of the secondplurality of polynucleotides encodesfor at