PCT/US2017/066847 04.05.2018
`
`PATENT COOPERATION TREATY
`
`From the INTERNATIONAL SEARCHING AUTHORITY
`To: DAVID HARBURGER
`WILSON SONSINI GOODRICH & ROSATI
`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
`
`How?
`
`(PCT Rule 44.1)
`
`
`Date of mailing
`davinonnyeors DA MAY 2018.
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`Applicant’s or agent’s file reference
`and 4 bel
`1
`hs
`§S
`FOR FURTHER ACTION’
`
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`
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`44854-73160 ee paragraphs|an elow
`
`
`Internationalfiling date
`International application No.
`15 December 2017
`(day/month/year)
`PCT/US2017/066847
`
`
`Applicant
`
`TWIST BIOSCIENCE CORPORATION
`
`
`
` L.
`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 amend the claimsof the international application (see Rute 46):
`
`
`When?=Thetime limit for filing such amendments is normally two months from the date of transmittal of the international
`search report.
`
`
`Directly to the International Bureau of WIPO preferably through ePCTor on paper to, 34 chemin des Colombettes
`1211 Geneva 20, Switzerland, Facsimile No.: +41 22 338 82 70
`
`
`
`For moredetailed instructions, see PCT Applicant’s Guide, International Phase, paragraphs 9.004 — 9.011.
`
`
`2. [J 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.
`
`
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`3. C] With regard to any protest 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 on the protest;
`the applicant will be notified as soon as a decision is made.
`CI
`4. Reminders
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`The applicant may submit commentson 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 been oris 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 completion of the technical preparations for
`international publication (Rules 90dis.1 and 90bis.3).
`Within 19 monthsfrom the priority date, but only in respect of some designated Offices, a demandfor international preliminary
`examination mustbefiled if the 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 (or later) will apply even if no demandis 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 months from thepriority date, the applicant mayrequest that a supplementaryinternational search be carried
`out by a different Intemational Searching Authority that offers this service (Rule 45d/s.1). The procedure for requesting
`supplementary international search is described in the PCT Applicani's Guide, International Phase, paragraphs 8.006-8.032.
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`4
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`Nameand mailing address of the ISA/US
`Mail Stop PCT, Attn: ISA/US
`Commissioner for Patents
`P.O. Box 1450, Alexandria, VA 22313-1450
`woe
`Facsimile No, 571-273-8300
`Form PCT/ISA/220 (July 2017)
`
`Authorized officer
`
`Blaine R. Copenheaver
`PCT Helpdesk: 571-272-4300
`Telephone No. ocy
`osp-
`
`

`

`PCT/US2017/066847 04.05.2018
`
`PATENT COOPERATION TREATY
`
`PCT
`
`INTERNATIONAL SEARCH REPORT
`
`(PCT Article 18 and Rules 43 and 44)
`
`Applicant’s or agent’s file reference
`44854-731601
`
`see Form PCT/ISA/220
`FOR FURTHER
`
`ACTION as well as, where applicable, item 5 below.
`
`International application No.
`PCT/US2017/066847
`
`(Earliest) Priority Date (day/month/vear)
`Internationalfiling date (day/nonth/year)
`16 December 2016
`15 December 2017
`
`
`Applicant
`TWIST BIOSCIENCE CORPORATION
`
`This intemational 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 ofatotal of £ sheets.
`[J It is also accompanied by a copy ofeach prior art documentcited in this report,
`
`Basis of the report
`a. With regard to the language, the international search was carried out onthebasis of:
`bx the international application in the language in whichit wasfiled.
`whichis the language of
`[] a translation ofthe international application into
`a translation furnished for the purposes of international search (Rules 12.3(a) and 23.1(b)).
`This international search report has been established taking into accountthe rectification of an obvious mistake
`authorized by or notified to this Authority under Rule 91 (Rule 43.6d/s(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. IT).
`
`Unityof invention is lacking (see Box No.IT).
`
`. With regardto thetitle,
`
`the text is approved as submitted by the applicant.
`] the text has been established by this Authority to read as follows:
`
`With regard to the abstract,
`[x] the text is approved as submitted by the applicant.
`C] the text has been established, according to Rule 38.2, by this Authority as it appears in Box No. IV. The applicant may,
`within one month fromthe date of mailing of this international search report, submit commentsto this Authority.
`
`b. C] none ofthe figures is to be published with the abstract.
`
`With regard to the drawings,
`a.
`the figure of the drawings to be published with the abstract is Figure No.
`CT] as suggested by the applicant.
`as selected by this Authority, because the applicant failed to suggest a figure.
`as selected by this Authority, because this figure better characterizes the invention.
`
`CT]
`
`_1A
`
`Form PCT/ISA/210 (first sheet) (January 2015)
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`

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`PCT/US2017/066847 04.05.2018
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US2017/066847
`
`Box No. I
`
`Nucleotide and/or amino acid sequence(s) (Continuation of item 1.c of the first sheet)
`
`With regard to any nucleotide and/or amino acid sequence disclosed in the international application, the international search was
`carried out on the basis of a sequencelisting:
`a.[] forming part of the international applicationas filed:
`[| in the form of an Annex C/ST.25textfile.
`[| on paperorin the form ofan imagefile.
`b. C] furnished together with the international application under PCT Rule 13¢ey.1(a) for the purposes of international search
`only in the form of an Annex C/ST.25 textfile.
`
`In addition, in the case that more than one version or copy of a sequencelisting has been filed or furnished, the required
`statements that the information in the subsequentor additional copiesis identical to that forming partof the application as
`filed or does not go beyondthe application as filed, as appropriate, were furnished.
`
`Additional comments:
`
`c.
`
`furnished subsequentto the intemationalfiling date for the purposes of inteational search only:
`
`XI
`
`in the form ofan Annex C/ST.25 textfile (Rule 13 ver. 1(a)).
`
`on paperorin the form of an imagefile (Rule 13er.1(b) and Administrative Instructions, Section 713).
`
`<I
`
`Form PCT/ISA/210 (continuation offirst sheet (1)) (January 2015)
`
`

`

`PCT/US2017/066847 04.05.2018
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US2017/066847
`
`Box No. II
`
`Observations where certain claims were found unsearchable (Continuation of item 2 offirst sheet)
`
`2. C] 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:
`
`3. Xx Claims Nos.: 33, 34
`because they are dependent claims andare not drafted in accordance with the second andthird sentences of Rule 6.4(a).
`
`Box No. TI
`
`Observations where unity of invention is lacking (Continuation of item 3 of first sheet)
`
`This International Searching Authority found multiple inventionsin this international application, as follows:
`
`This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
`1. ] Claims Nos.:
`because they relate to subject matter not required to be searched by this Authority, namely:
`
`No protest accompanied the payment of additional search fees.
`
`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 withouteffort justifying additional fees, this Authority did not invite payment of
`additional fees.
`
`Asonly someofthe 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;
`il is covered by claims Nos.:
`
`Remark on Protest
`
`The additional search fees were accompanied by the applicant’s protest and, where applicable, the
`paymentof a protest fee.
`Theadditional 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 PCTASA/210 (continuation offirst sheet (2)) January 2015)
`
`

`

`PCT/US2017/066847 04.05.2018
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US2017/066847
`
`A.
`CLASSIFICATION OF SUBJECT MATTER
`IPC(8) - AG1K 35/12; CO7K 14/705; CO7K 14/725; C12N 15/09; C12N 15/10; C12N 15/12 (2018.01)
`CPC- A61K 35/17; AG1K 38/00; CO7K 14/435; CO7K 2317/569; C12N 5/163; C12N 15/1037 (2018.02)
`
`According to International Patent Classification (IPC) or to both national classification and IPC
`FIELDS SEARCHED
`B.
`
`Minimumdocumentation searched (classification system followed by classification symbols)
`See Search History document
`
`Documentation searched other than minimum documentation to the extent that such documents are includedin the fields searched
`
`USPC - 435/5; 435/6; 506/9; 506/10; 506/18 (keyword delimited)
`
`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
`
`Relevant to claim No.
`
`US 2013/0040836 A1 (HIMMLERetal) 14 February 2013 (14.02.2013) entire document
`
`1-26, 28-32, 35-45
`
`~] HANet al. “Linking T-cell receptor sequence to functional phenotypeat the single-cell level,”
`Nature Biotechnology, 22 June 2014 (22.06.2014), Vol. 32, Iss. 7, Pgs. 684-692. entire
`document
`
`WO 2012/013913 A1 (IMMUNOCORELTDetal) 02 February 2012 (02.02.2012) entire
`document
`
`1-32, 35-45
`
`US 2003/0082719 A1 (SCHUMACHER etal) 01 May 2003 (01.05.2003) entire document
`
`1-32, 35-45
`
`WO 2010/089412 A1 (HELMHOLTZ ZENTRUM MUNCHEN DEUTSCHES
`FORSCHUNGSZENTRUM FUR GESUNDHEIT UND UMWELT (GMBR) et al) 12 August 2010
`(12.08.2010) entire document
`
`1-32, 35-45
`
`JAGERet al. "Simultaneous Humoral and Cellular immune Response against Cancer—Testis
`Antigen NY-ESO-1: Definition of Human Histocompatibility LeukocyteAntigen (HLA)-A2—binding
`Peptide Epitopes," J. Exp. Med. 19 January 1998 (19.01.1998), Vol. 187, No. 2, Pgs. 265-270.
`entire document
`
`1-32, 35-45
`
`WO 2017/158103 A1 (IMMATICS BIOTECHNOLOGIES GMBH) 21 September 2017
`(21.09.2017) entire document
`
`1-32, 35-45
`
`“T”
`
`
`
`[| See patent family annex.
`[| Further documents are listed in the continuation of Box C.
`later documentpublishedafter the international filing date or priority
`Special categories of cited documents:
`date and not in conflict with the application but cited to understand
`documentdefining the generalstate of the art which is not considered
`the principle or theory underlying the invention
`to be of particular relevance
`document ofparticular relevance; the claimed invention cannot be
`earlier application or patent but published onorafter 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
`documentofparticular relevance; the claimed invention cannot be
`sreeeaten qedtea date of another citation or other
`considered to involve an inventive step when the document
`is
`P
`P
`combined with one or more other such documents, such combination
`documentreferring to an oral disclosure, use, exhibition or other
`being obvious to a person skilled in the art
`means
`documentpublishedpriorto the internationalfiling date but laterthan «g document memberof the same patent family
`the priority date claimed
`Date of the actual completion of the international search
`
`29 March 2018
`
`Date of mailing of the international search report
`
`Q4 MAY. 2018 “
`
`Name and mailing address of the ISA/US
`Mail Stop PCT, Attn: ISA/US, Commissionerfor Patents
`P.O. Box 1450, Alexandria, VA 22313-1450
`Facsimile No. 571-273-8300
`Form PCT/ISA/210 (second sheet) (January 2015)
`
`Authorized officer
`
`Blaine R. Copenheaver
`PCT Helpdesk: 571-272-4300
`PCT OSP: 571-272-7774
`
`

`

`PCT/US2017/066847 04.05.2018
`
`PATENT COOPERATION TREATY
`
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`To: DAVID HARBURGER
`WILSON SONSINI GOODRICH & ROSATI
`650 PAGE MILL ROAD
`PALO ALTO, CA 94304
`
`PC T
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`(PCT Rule 43is.1)
`
`
`
`
`
` Date of mailing
`(day/month/vear)
`0 4 Mi AY 2018
`
`
`FOR FURTHER ACTION
`Applicant’s or agent’s file reference
`
`
`
`
`44854-731601
`
`See paragraph 2 below
`
`
`
`
`
`
`International application No.
`Internationalfiling date (day/month/vear)
`Priority date (day/month/year)
`
`
`PCT/US2017/066847
`15 December 2017
`
`
`
`16 December 2016
`
`
`International Patent Classification (IPC) or both national classification and IPC
`IPC(8) - A61K 35/12; CO7K 14/705; CO7K 14/725; C12N 15/09; C12N 15/10; C12N 15/12 (2018.01)
`CPC - 61K 35/17; A61K 38/00; CO7K 14/435; CO7K 2317/569; C12N 5/163; C12N 15/1037 (2018.02)
`
` Applicant TwiST BIOSCIENCE CORPORATION
`
`For further options, see Form PCT/ISA/220.
`HINOROBO
`
`{. This opinion contains indications relating to the following items:
`
`Box No. I
`
`Basis of the opinion
`
`Box No.IE
`
`Priority
`
`Box No. III Non-establishment of opinion with regard to novelty, inventive step and industrial applicability
`
`Box No. IV Lack of unity of invention
`
`Box No. V___Reasonedstatement under Rule 43dis. |(a)(i) with regard to novelty, inventive step andindustrial applicability;
`citations and explanations supporting such statement
`Box No. VI Certain documents cited
`
`Box No. VII Certain defects in the international application
`
`Box No. VIII Certain observations on the international application
`
`2. 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 IPEAhasnotified the International Bureau under Rule 66.1dis(b) that written
`opinions of this International Searching Authority will not be so considered.
`If this opinionis, 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 fromthe priority date, whichever expires later.
`
`PCT OSP: 571-272-7774
`
`Name and mailing address of the ISA/US] Date of completion ofthis opinion
`Mail Stop PCT,Attn: ISA/US
`Commissionerfor Patents
`P
`P.O. Box 1450, Alexandria, VA 22313-1450
`Facsimile No. 571-273-8300
`
`29 March 2018
`
`Authorized officer
`:
`Blaine R. Copenheaver
`PCT Helpdesk: 571-272-4300
`
`Form PCTASA/237 (cover sheet) (January 2015)
`
`

`

`PCT/US2017/066847 04.05.2018
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`Box No. I
`
`Basis of this opinion
`
`
`International application No.
`
`PCT/US2017/066847
`
`
`
`
`
`
`
`1. With regard to the language, this opinion has been established on the basis of:
`[Xx]
`the international application in the language in whichit was filed.
`a translation of the international application into
`
`which is the language ofa translation
`
`
`furnished for the purposes of international search (Rules 12.3(a) and 23.1(b)).
`this Authority under Rule 91 (Rule 43dis.1(a)).
` 2. | This opinion has been established taking into accountthe rectification of an obvious mistake authorizedby ornotified to
` 3. x] 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. C] forming part of the international application asfiled:
`CL]
`in the form of an Annex C/ST.25 textfile.
`
`
`C] on paperorin the form ofan image file.
`
`
`b. [_] furnished together with the international application under PCT Rule 1 3ver.1(a) for the purposes of international
`
`
`search only in the form of an Annex C/ST.25 text file.
`
`
`c. Xx] furnished subsequentto the internationalfiling date for the purposes ofinternational search only:
`x] in the form of an Annex C/ST.25 text file (Rule 13+e7.1(a)).
`
`
` CL] on paperor in the form of an imagefile (Rule 13ver.1(b) and Administrative Instructions, Section 713).
` 4. x In addition, in the case that more than one version or copy of a sequencelisting has been filed or furnished, the required
`
`
`statements that the information in the subsequentor 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:
`
`Form PCT/ISA/237 (Box No. D (January 2015)
`
`

`

`PCT/US2017/066847 04.05.2018
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US2017/066847
`
`Box No. IN
`
`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 examinedinrespect of:
`
`[] the entire international application.
`
`| claims Nos. 33, 34
`
`because:
`
`the said intemational application, or the said claims Nos.
`subject matter which does not require an international search (specify):
`
`relate to the following
`
`See Supplemental Box for further details.
`
`no international search report has been established for said claims Nos. 33. 34
`fx]
`[] a meaningful opinion could not be formed without the sequencelisting; 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 manneracceptable to it; or the sequence listing furnished did not
`comply with the standard provided for in Annex C of the Adininistrative Instructions.
`furnish a sequencelisting on paperor in the form of an image file complying with the standard provided for in Annex
`C of the Administrative Instructions, and suchlisting was not available to the Intemational 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.
`
`the description, claims or drawings (indicare particular elements below) or said claims Nos. 33. 34
`are so unclear that no meaningful opinion could be formed (specifi):
`
`Claims 33 and 34 are multiple dependentclaimsnot drafted in accordancewith the second and third sentences of 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
`
`pay the required late furnishing fee for the furnishing of a sequencelisting in response to an invitation under
`Rule 13ter.1(a) or (b).
`
`CJ
`
`Form PCT/ISA/237 (Box No. TID (January 2015)
`
`

`

`PCT/US2017/066847 04.05.2018
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US2017/066847
`
`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
`
`Statement
`
`Novelty (N)
`
`Inventive step (IS)
`
`Claims
`Claims
`
`Claims
`Claims
`
`
`
`27, 44, 45
`1-26, 28-32, 35-43
`
`None
`1-32, 35-45
`
`Industrial applicability (IA)
`
`Claims
`Claims
`
`1-32, 35-45
`None
`
`
`
`2.
`
`Citations and explanations:
`
`Claims 1-26, 28-32, and 35-43 lack novelty under PCT Article 33(2) as being anticipated by Himmleretal. (hereinafter Himmler).
`
`for example binding affinity to the T-cell receptor domain polypeptide's target, Para. [0098)).
`
`Regarding Claim 1, Himmler discloses a nucleic acid library (a polypeptide library or a nucleic acid library, Para. [0191]), wherein the
`nucleic acid library comprises at least 3000 variant nucleic acids (nucleic acid library preferably includes at least 10 different members
`(with at least one, more preferably at least two, even more preferably at least three, most preferably at least four potential amino acid
`modifications) and more preferably includes at least 100, more preferably 1000 or 10000 different members (e.g. designed by
`randomisation strategies or combinatory techniques). Even more diversified individual member numbers, such asat least 1000000orat
`least 10000000are also preferred, Para. [0191]), wherein each variant nucleic acid encodesfor a variant gene or gene fragmentfor a T
`cell receptor (TCR) protein (a polypeptide library or a nucleic acid library comprising a plurality of polypeptides comprising T-cell receptor
`domainsoratleast onestructural loop region contained in a minidomain, or nucleic acid molecules encoding the same, Para. [0191]), and
`wherein a region selected for variation spans up to 1000 basesin length (T-cell receptors with a modificationin at least onestructural loop
`region, alternatively with mutations of at least 3 amino acid positionsin at least one structural loop region. The T-cell
`receptor domain polypeptides can be V-alpha, V-beta, V-gamma, V-delta, C-alpha, C-beta, C-gammaor C- delta, Para. [0040]; See SEQ
`ID NOs 1-20, which are greater than 500 and less than 1000 basesin Jength, Pgs. 21-37; The library genes are assembled from specific
`synthetic oligonucleotides and cloned asfull length TCR alpha and beta chains displayed on filamentous phage, Para. [0220]).
`
`Regarding Claim 2, Himmler discloses the nucleic acid library of claim 1, wherein the variant gene or gene fragmentis from a variable
`domain (The inventive T-cell receptor domains can be selected from the variable or constant domains, Para. [0035]).
`
`Regarding Claim 3, Himmler discloses the nucleic acid library of claim 2, wherein the variable domain is a variable domain of TCR alpha,
`TCR beta, TCR gamma, or TCR delta (The inventive T-cell receptor domains can be selected from the variable or constant domains,
`preferably from V-alpha, V-beta, V-gamma, V-delta, C-alpha, C-beta, C-gamma, C-delta domains, Para. (0035)).
`
`Regarding Claim 4, Himmler discloses the nucleic acid library of claim 2, wherein the variable domain is specific to a cancer antigen (a
`method for engineering a T-cell receptor domain polypeptide binding specifically with its modified structural loops to an epitope of an
`antigen selected from the group consistingof... tumor associated antigens..., Para. [0056]; The inventive T-cell receptor domains can be
`selected from the variable or constant domains, preferably from V-alpha, V-beta, V-gamma, V-delta, C-alpha, C-beta, C-gamma, C-delta
`domains, Para. [0035]; the molecule binding to the modified structural loop region is selected from the group consisting of tumor
`associated antigens... Carcinoembryonic antigen (CEA), Para. (0160)).
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`Regarding Claim 5, Himmlerdiscloses the nucleic acidlibrary of claim 4, wherein the cancer antigen is MAGE A3, MAGE A12, MAGE A2,
`MAGE A6, NY-ESO-1, or CEA (the molecule binding to the modified structural loop region is selected from the group consisting of tumor
`associated antigens... Carcinoembryonic antigen (CEA), Para. [0160)).
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`Regarding Claim 6, Himmler discloses the nucleic acid library of claim 1, wherein the variant gene or gene fragmentis from a constant
`domain (The inventive T-cell receptor domains can be selected from the variable or constant domains, Para. [(0035]).
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`Regarding Claim 7, Himmler discloses the nucleic acid library of claim 1, wherein the variant gene or gene fragmentallows for generation
`of a TCR protein having increased specificity, avidity, affinity, stability, or expression (modified TCRs dueto binding to neonatal Fc
`receptors can be increasedif appropriate, Para. [0046); modified T-cell receptor domain polypeptides of the present invention shows
`increased serum halflife, Para. [0112]; As is knownin the art, some screening methods select for favourable membersof a library. The
`methodsare herein referred to as "selection methods", and these methods find use in the present invention for screening modified T-cell
`receptor domain polypeptides... in this way, selection orisolation of modified T-cell receptor domain polypeptides that meet somecriteria,
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`Form PCT/ISA/237 (Box No. V) (January 2015)
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`

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`PCT/US2017/066847 04.05.2018
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` International application No. WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`PCT/US2017/066847
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`Supplemental Box
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`In case the space in anyof the preceding boxesis not sufficient.
`Continuation of:
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`Regarding Claim 8, Himmler discloses a polynucleotidelibrary (a polypeptide library or a nucleic acid library, Para. [0191]), wherein the
`polynucleotide library comprises at least 3000 variant nucleic acids (nucleic acid library preferably includes at least 10 different members
`(with at least one, more preferably at least two, even more preferably at least three, most preferably at least four potential amino acid
`modifications) and more preferably includes at least 100, more preferably 1000 or 10000 different members(e.g. designed by
`randomisation strategies or combinatory techniques). Even more diversified individual member numbers, such as at least 1000000or at
`least 10000000are also preferred, Para. [0191]), wherein each polynucleotide is at least 15 basesin length (SEQ ID NO 1-20 areall
`greater than 15 basesin length, Pgs. 21-37; Thelibrary genes are assembled from specific synthetic oligonucleotides and cloned asfull
`length TCR alpha and beta chains displayed on filamentous phage, Para. [(0220]), wherein each polynucleotide encodesfor a variant
`within a variable domain of a T cell receptor (TCR)protein or fragment thereof (T-cell receptor according to the present invention
`comprises preferably at least one constant and/orat least one variable domain of a T-cell receptor or a part thereof, Para. (0150); The
`inventive T-cell receptor domains can be selected from the variable or constant domains, Para. [(0035]), wherein the variable domain
`comprises up to 1000 bases(T-cell receptors with a modification in at least one structural loop region, alternatively with mutations ofat
`least 3 amino acid positions in at least one structural loop region. The T-cell receptor domain polypeptides can be V-alpha, V-beta,
`V-gamma, V-delta, C-alpha, C-beta, C-gamma or C- delta, Para. [0040]; See SEQ ID NOs 1-20, which are greater than 500 andless
`than 1000 basesin length, Pgs. 21-37; Thelibrary genes are assembled from specific synthetic oligonucleotides and clonedasfull length
`TCR alpha and beta chains displayed onfilamentous phage, Para. [(0220)), and wherein each variant nucleic acid comprises atleast one
`variation at a preselected codon for an amino acid residue in an antigen contacting interface (The modification of amino acids may
`preferentially be biased in order to introduceinto structural loop regions amino acids which are knownto be frequently involved in
`protein-protein interactions, Para. [0087]; at least one nucleotide repeating unit within a structural loop coding region having the
`sequence 5'-NNS-3',5-NNN-3 or 5-NNK-3. In some embodiments the modified nucleic acid comprises nucleotide codons selected from
`the group of TMT, WMT, RMC, RMG, MRT, SRC, KMT, RST, YMT, MKC, RSA, RRC, NNK, NNN, NNS or any combination thereof (the
`coding is according to IUPAC), Para. [0082}; binding regions to antigens or antigen bindingsites to alt kinds of...tumor associated
`antigen... may be introducedinto a structural loop region of a given T-cell receptor domain structure, Para. (0060); Para. [0080); The
`structural loop regions of a T-cell receptor constant domain polypeptide are selected preferably from the structural loops that comprise
`amino acids 9 to 20, amino acids 27 to 36, amino acids 41 to 78, amino acids 82 to 85, amino acids 90 to 102 or amino acids 107 to 116,
`Para. [(0074)).
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`Regarding Claim 11, Himmler discloses the polynucleotidelibrary of claim 10, wherein the cancer antigen is MAGE A3, MAGE A12,
`MAGEA2, MAGE A6, NY-ESO-1, or CEA (the molecule binding to the modified structural loop region is selected from the group
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`consisting of tumor associated antigens... Carcinoembryonic antigen (CEA), Para. [0160}).
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`Regarding Claim 12, Himmler discloses the polynucleotide library of claim 8, wherein each variant nucleic acid comprisesa plurality of
`variations at preselected codons for amino acid residues in the antigen contacting interface (The modification of amino acids may
`preferentially be biased in order to introduce into structural loop regions amino acids which are knownto be frequently involved in
`protein-protein interactions, Para. [0087]; at least one amino acid of at least one structural loop region is modified by site-directed random
`mutation, wherein the randomly modified nucleic acid molecule can comprise at least one nucleotide repeating unit having the coding
`sequence NNS, NNN, NNK, TMT, WMT, RMC, RMG, MRT, SRC, KMT, RST, YMT, MKC, RSA, RRC, where the coding is according to
`IUPAC, Para. [0038]; binding regions to antigens or antigen binding sites to all kinds of...tumor associated antigen... may be introduced
`into a structural loop region of a given T-cell receptor domain structure, Para. [0060]; Para. [0080]: The structural loop regionsof a T-cell
`receptor constant domain polypeptide are selected preferably from the structural loops that comprise amino acids 9 to 20, amino acids 27
`to 36, amino acids 41 to 78, amino acids 82 to 85, amino acids 90 to 102 or amino acids 107 to 116, Para. [0074)).
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`Regarding Claim 9, Himmler discloses the polynucleotide library of claim 8, wherein the variable domain is a variable domain of TCR
`alpha, TCR beta, TCR gamma, or TCR delta (The inventive T-cell receptor domains can be selected from the variable or constant
`domains, preferably from V-alpha, V-beta, V-gamma, V-delta, C-alpha, C-beta, C-gamma, C-delta domains, Para. [0035)).
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`Regarding Claim 10, Himmierdiscloses the polynucleotidelibrary of claim 8, wherein the antigen is a cancer antigen (a method for
`engineering a T-cell receptor domain polypeptide binding specifically with its modified structural loops to an epitope of an antigen
`selected fro