PCT/U82018I050511 11 .01.2019
`
`PATENT COOPERATION TREATY
`
`PCT
`
`INTERNATIONAL SEARCH REPORT
`
`(PCT Article 18 and Rules 43 and 44)
`
`Applicant’s or agent’s file reference
`44854-741601
`
`FOR FURTHER
`ACTION
`
`see Form PCT/lSA/220
`as well as, where applicable, item 5 below.
`
`International application No.
`PCT/USZO18/O50511
`
`Applicant
`1W|ST BIOSCIENCE CORPORATION
`
`lntemational filing date (day/month/year)
`11 September 2018
`
`(Earliest) Priority Date (day/monIh/year)
`11 September 2017
`
`This international search report has been prepared by this lntemational Searching Authority and is transmitted to the applicant
`according to Article 18. A copy is being transmitted to the lntemational Bureau.
`
`This intemational search report consists ofa total of
`\ 2
`sheets.
`E] It is also accompanied by a copy ofeach prior an document cited in this report.
`
`1. Basis of the report
`a. With regard to the language, the international search was carried out on the basis of:
`
`XI the international application in the language in which it was filed.
`which is the language of
`[:1 a translation ofthe international application into
`a translation furnished for the purposes of intemational search (Rules 12.3(a) and 23.1(b)).
`
`b. E] 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 43.6bis(a)).
`c. E With regard to any nucleotide and/or amino acid sequence disclosed in the international application, see Box No. l.
`
`D Certain claims were found unsearchable (see Box No.11).
`
`CI Unity ofinvention is lacking (see Box No. Ill).
`
`4. With regard to the title,
`IX]
`the text is approved as submitted by the applicant.
`'3 the text has been established by this Authority to read as follows:
`
`b. D none ofthe figures is to be published with the abstract.
`
`5. With regard to the abstract,
`
`g] the text is approved as submitted by the applicant.
`'1 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 from the date of mailing ofthis international search report, submit comments to this Authority.
`
`6. With regard to the drawings,
`
`a.
`
`the figure ofthe drawings to be published with the abstract is Figure No.
`
`3
`
`[Z] as suggested by the applicant.
`D as selected by this Authority, because the applicant failed to suggest a figure.
`E] as selected hy this Authority, because this figure bcttcr Clldi'aulcliLcs the invention.
`
`Form PCT/lSA/ZIO (first sheet) (January 20l5)
`
`

`

`fitmished together with the international application under PCT Rule l3ter. l(a) for the purposes ofintemational search
`only in the form ofan Annex C/ST.25 text file.
`-
`
`fiu‘nished subsequent to the intemational filing date for the purposes of international search only:
`
`in the form ofan Annex C/ST.25 text file (Rule 13ter. 1(a)).
`
`D on paper or in the form of an image file (Rule l3ter. l(b) and Administrative Instructions, Section 7 l 3).
`
`2. K In addition, in the case that more than one version or copy ofa sequence listing has been filed or furnished, the required
`i
`statements that the information in the subsequent or additional copies is identical to that forming part ofthc application as
`filed or does not go beyond the application as filed, as appropriate, were furnished.
`
`3. Additional comments:
`
`PCT/USZO18IO50511 11 .01.2019
`
`INTERNATIONAL SEARCH REPORT
`
`lntemational application No.
`PCT/U32018/050511
`
`Box No.1
`
`Nucleotide and/or amino acid sequence(s) (Continuation ofitem Le of the first sheet)
`
`1. With regard to any nucleotide and/or amino acid sequence disclosed in the international application, the international search was
`carried out on the basis ofa sequence listing; '
`
`a. El forming part ofthe international application as filed:
`D in the form ofan Annex C/ST,25 text file.
`I: on paper or in the form ofan image file.
`
`SEQ ID NOs: 2420-2436 were searched.
`
`Form PCT/lSA/ZIO (continuation offirst sheet (1)) (January 2015)
`
`

`

`PCT/US2018I050511 11.01.2019
`
`INTERNATIONAL SEARCH REPORT
`
`International application No,
`PCT/USZO18/050511
`
`A.
`
`CLASSIFICATION OF SUBJECT MATTER
`
`|PC(8) - CO7K 16/00; CO7K 16/28; C07K 16/46; C07K 19/00; C12N 15/13; C4OB 30/04 (2018.01)
`CPC ' A61K 38/00; A61 K 2039/505; CO7K 2317/24; CO7K 2317/565; CO7K 2317/567; CO7K 2319/00;
`C12N 15/1037; C40B 40/02; G01 N 2333/726 (2018.08)
`
`According to International Patent Classification (ll’C) or to both national classification and [PC
`B.
`FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`See Search History document
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`USPC - 435/7.1; 506/9; 506/14; 530/3873; 536/2353; SSS/23.5 (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
`
`
`
`with a long VH CDR3 targeting the Class A GPCR formyl-peptide receptor 1," mAbs, 01 January 25-28
`2015 (01.01.2015), Vol. 7, Iss. 1, P95. 152-166. entire document
`
`6,10,11,16,18,19.23,
`24, 34, 35
`
`US 2017/0253644 A1 (VIB VZW et al) 07 September 2017 (07.09.2017) entire document
`
`29-33, 36
`
`US 2017/0066844 A1 (DISTRIBUTED BIO, INC.) 09 March 2017 (09.03.2017) entire document
`
`6. 16. 18. 19. 34. 35
`
`US 2013/0164308 A1 (RINAT NEUROSCIENCE CORP. et al) 27 June 2013 (27.06.2013) entire 10, 11, 23, 24
`document
`
`WO 2016/173719 A1 (ABCHECK S.R.O. et al) 03 November 2016 (03.11.2016) entire
`document
`
`Jo at al. “Engineering therapeutic antibodies targeting G-protein-coupled receptors," Exp Mol
`Med, 05 February 2016 (05.02.2016), Vol. 48, e207, Pgs. 1—9. entire document
`
`WO 2016/161244 A2 (THE SCRIPPS RESEARCH INSTITUTE) 06 October 2016 (06.10.2016)
`entire document
`
`C] Further documents are listed in the continuation of Box C.
`Special categories M and documents:
`document defining the general state of the art which is not considered
`to be of particular relevance
`earlier application 0" patent b”! published on or afierthe international
`films date
`document which may throw doubts on priority claim(s) or which is
`g'teegglorgsggglzsa: éfigggfwon date 0f another Citation or other
`p
`p
`document referring to an oral disclosure, use, exhibition or other
`means
`document publishedlprior to the international filing date but laterthan
`the priority date claimed
`Date ofthe actual completion of the international search
`
`“T”
`
`I: See patent family annex.
`riority
`later document published after the international filing date or
`date and ‘not in conflict with the application but cited to un erstand
`the pnncrple or theory underlying t e invention
`“X" document of particular relevance; the claimed invention cannot'be
`considered novel or cannot be considered to involve an inventive
`step when the document I5 taken alone
`“Y” document of panicular relevanceythe claimed invention cannot be
`consrdcred to involve an inventive step when the document
`IS
`combined with one or more other such documents, such combination
`being obvious to a person skilled in the art
`document member ofthe same patent famin
`
`Date of mailing ofthe international search report
`
`20November2018
`Name and mailing address ofthe ISA/US
`Mail Stop PCT, Attn: ISA/US, Commissioner for Patents
`Po. Box 1450, Alexandria, VA 22313-1450
`Facsimile N0. 571-273-8300
`Form PCT/lSA/210 (second sheet) (January 2015)
`
`1 1 JAN 20I9
`Authorized officer
`
`Blaine R. Copenheaver
`PCT Helpdesk: 571-272-4300
`PCT 05?: 571-272-7774
`
`

`

`PCT/U82018/050511 11.01.2019
`
`PATENT COOPERATION TREATY
`
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`
`T01 DAVID s. HARBURGER
`WILSON SONSINI GOODRICH & ROSATI
`650 PAGE MILL ROAD
`PALO ALTO, CA 94304-1050
`
`
`
`Applicant’s or agent’s file reference
`44854-741601
`
`PCT
`
`-
`1
`WRITTEN OP‘N’ON 0* THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`(PCT Rule 431m. 1)
`
`Date ofmailing
`d /
`th/
`( ay man year)
`FOR FU R'I'H ER ACTION
`See paragraph 2 below
`
`.
`
`A h 2019
`
`lntemational application No.
`
`International filing date (day/monrh/year)
`
`Priority date (day/mamh/year)
`
`PCT/U82018/050511
`
`11 September 2018
`
`11 September 2017
`
`lntemational Patent Classification (lPC) or both national classification and IPC
`[PC(8) - CO7K 16/00; CO7K 16/28; C07K 16/46; CO7K 19/00; C12N 15/13; C4OB 30/04 (2018.01)
`CPC '
`A61 K 38/00; A61 K 2039/505; CO7K 2317/24; CO7K 2317/565; CO7K 2317/567; CO7K 2319/00;
`C12N 15/1037; C408 40/02; G01 N 2333/726 (2018.08)
`
`Applican‘ TWIST BIOSCIENCE CORPORATION
`
`
`I. This Opinion contains indications relating to the following items:
`
`Box No.
`
`I
`
`Basis ofthe opinion
`
`Box No. II
`
`Priority
`
`Box No. 111
`
`Non—establishment of opinion with regard to novelty, inventive step and industrial applicability
`
`Box No. IV
`
`Lack of unity ofinvention
`
`DEIEIHEDGE Box No. VIII Certain observations on the intemational application
`
`
`
`Box No. V
`
`Box No. Vl
`
`Reasoned statement under Rule 43bis. I (a)(i) with regard to novelty, inventive step and industrial applicability;
`citations and explanations supporting such statement
`Certain documents cited
`
`Box No. Vll Certain defects in the international application
`
`2. FURTHER ACTION
`
`lt'a demand for international preliminary examination is made, this opinion will be considered to be a written opinion ofthe
`lntemational Preliminary Examining Authority (“IPEA”) except that this does not apply where the applicant chooses an Authority
`other than this one to be the IPEA and the chosen IPEA has notified the lntemational Bureau under Rule 66.1bis(b) that written
`opinions ofthis lntemational Searching Authority will not be so considered.
`It this opinion is, as provided above, considered to be a written opinion ofthe IPEA, the applicant is invited to submit to the IPEA
`a written reply together, where appropriate, with amendments, before the expiration of3 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/lSA/220.
`
`PCT He'pdesk: 5714724300 Facsimile No. 571-273-8300
`
`Name and mailing address ofthe ISA/US Date of completion ofthis opinion
`Commissioner for Patents
`Mail Stop PCT. Attn: ISA/US
`PO. Box 1450, Alexandria, VA 22313-1450
`
`20 November 2018
`
`Form PCT/ISA/237 (cover sheet) (January 2015)
`
`Authorized officer
`.
`Blaine R Copenhe
`
`aver
`
`PCT OSP: 571-272-7774
`
`

`

`a. I: forming part ofthe international application as filed:
`D in the form of an Annex C/ST.25 text file.
`D on paper or in the form ofan image file.
`
`b. [j furnished together with the international application under PCT Rule 13ter.l(a) for the purposes ofinternational
`search only in the form of an Annex C/ST.25 text file.
`
`c.
`
`furnished subsequent to the international filing date for the purposes ofintemational search only:
`
`in the form ofan Annex C/ST.25 text file (Rule lSter.l(a)).
`[2]
`[:1 on paper or in the form ofan image file (Rule 13ter.1(b) and Administrative instructions, Section 713).
`
`m In addition, in the case that more than one version or copy ofa sequence listing has been filed or furnished, the required
`statements that the information in the subsequent or additional copies is identical to that forming part ofthe application as
`filed or does not go beyond the application as filed, as appropriate, were furnished,
`
`5. Additional comments:
`
`PCT/USZO18IO50511 11 .01.2019
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`lntemational application No.
`PCT/USZO18/050511
`
`Box No. l
`
`Basis of this opinion
`
`1. With regard to the language, this opinion has been established on the basis of:
`
`X the international application in the language in which it was filed.
`:1 a translation ofthe international application into
`fumished for the purposes of international search (Rules 12.3(a) and 23.1(b)).
`
`which is the language ofa translation
`
`This opinion has been established taking into account the rectification of an obvious mistake authorized by or notified to
`this Authority under Rule 91 (Rule 43bis. 1(a)).
`
`With regard to any nucleotide and/or amino acid sequence disclosed in the intemational application, this opinion has
`been established on the basis ofa sequence listing:
`
`SEQ ID NOs: 2420-2436 were searched.
`
`Form PCT/lSA/237 (Box No. l) (January 2015)
`
`

`

`PCT/USZO18IO50511 11.01.2019
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`lntemational application No.
`PCT/U52018/05051 1
`
`Box No. V
`
`Reasoned statement under Rule 43bis.1(a)(i) with regard to novelty, inventive step and industrial applicability;
`citations and explanations supporting such statement
`
`Statement
`
`Novelty (N)
`
`inventive step 08)
`
`Claims
`Claims
`
`Claims
`Claims
`
`1-5, 8, 10-16, 13, 19, 23-26, 29-36
`6. 7, 9, 17, 70-77, 27, 28
`
`1‘5
`6'36
`
`
`
`industrial applicability (IA)
`
`Claims
`Claims
`
`1'35
`None
`
`Citations and explanations:
`2.
`Claims 6, 7, 9, 17, 20-22, 27, and 28 lack novelty under PCT Article 33(2) as being anticipated by Douthwaite et al. (hereinafter
`Douthwaite).
`
`Regarding claim 6, Douthwaite discloses a nucleic acid library (Pg. 155, Figure 1 (B) includes 7 targeted mutagenesis libraries of VH
`CDR3 of Hy3B-1; Pg. 162, left-hand column, last paragraph, Generation and selection of targeted mutagenesis libraries: For targeted
`mutagenesis of Hy38-1, the VH and VL coding regions were used to prepare a scFv construct for optimization in phage display format
`Nineteen individual Hy38-1 scFv phage display libraries targeting all 6 CDRs were constructed (Fig. 18) [Fig. 18 includes 7 targeted
`mutagenesis libraries of VH CDR3]) comprising a plurality of nucleic acids, wherein each nucleic acid encodes for a sequence that when
`translated encodes for an immunoglobulin scaffold, wherein the immunoglobulin scaffold comprises a CDR-H3 loop that comprises a
`GPCR binding domain, and wherein each nucleic acid comprises a sequence encoding for a sequence variant of the GPCR binding
`domain (Pg. 152, left-hand column, 1st paragraph, The formyl peptide receptor (FPR) family is a group of Class A G—protein coupled
`receptors (GPCRs); Pg. 153, right-hand column, 2nd paragraph, Hy38-1 is a human monoclonal antibody specific for human FPR1 that
`was derived by immunization of transgenic mice expressing human variable region genes; Pg. 162, left-hand column, last
`paragraph-right-hand column, 1st paragraph, Generation and selection of targeted mutagenesis libraries: For targeted mutagenesis of
`Hy38-1, the VH and VL coding regions were used to prepare a scFv construct for optimization in phage display format. Large,
`CDR-targeted scFv phage libraries (greater than approximately 10‘9 variant scFvs) were created by oligonucleotide-directed mutagenesis
`in which degenerate codons (NNS) were used to fully randomize regions of 6 consecutive amino acid residue using Kunkel mutagenesis
`In total, 19 individual scFv phage libraries were prepared and pooled for selection to a maximum of 3 libraries per pool resulting in 8
`library pools ; Pg. 154, left—hand column, Potency optimization of Hy38-1 CDR-targeted mutagenesis: An overview of the selection and
`screening cascade to improve the potency of Hy38—1 against both human and cynomolgus FPR1 is illustrated in Figure 1A. The CDRs of
`Hy38-1 (defined by Kabat and numbered accordingly throughout) are shown in Figure 18. At 24 residues, the VH CDR3 of Hy38-1 is
`longer than average for a human antibody, in which the VH CDR3 regions are more typically in the region of 8 to 18 amino acids. Longer
`VH CDR3 regions have been suggested to be important for binding to certain target classes, such as GPCRs, where antigen binding might
`be facilitated by a longer projecting structure. Interestingly, the aforementioned human FPR1-specific antibody isolated by immunization
`also had long VH CDR3 region (22 amino acids). We therefore considered that the VH CDR3 of Hy38-1 could be particularly critical for
`FPR1 binding, and so, in the design of the targeted mutagenesis approach, we allowed the VH CDR3 to be very thoroughly explored in a
`range of libraries
`Nineteen individual Hy38-1 scFv phage display libraries targeting all 6 CDRs were constructed (Fig. 1B). In each
`library, 4 to 6 consecutive codons were replaced by NNS codons to allow for the inclusion of any amino acid at these targeted positions;
`Pg. 155, Figure 1. Antibody engineering strategy (A) and selection and screening cascade (B) used for the optimization of Hy38-1. Amino
`acid residues of Hy38-1 are shown in uppercase
`X denotes replacement of a codon with the degenerate codon NNS. The individual
`libraries within each CDR were pooled for selection as shown by the boxes. CDR residues are numbered according to Kabat [Figure 1 (B)
`includes 7 targeted mutagenesis libraries of VH CDR31).
`
`Regarding claim 7, Douthwaite discloses the nucleic acid library of claim 6, wherein a length of the CDR-H3 loop is about 20 to about 80
`amino acids (Pg. 154, left-hand column, 2nd paragraph, At 24 residues, the VH CDR3 of Hy38-1 is longer than average for a human
`antibody, in which the VH CDR3 regions are more typically in the region of 8 to 18 amino acids; see Figure 1 (8)).
`
`Regarding claim 9, Douthwaite discloses the nucleic acid library of claim 6, wherein the immunoglobulin scaffold further comprises one or
`more domains selected from variable domain, light chain (VL), variable domain, heavy chain (VH), constant domain, light chain (CL). and
`constant domain, heavy chain (CH) (Pg. 162, left-hand column, last paragraph-right-hand column, 1st paragraph, Generation and
`selection of targeted mutagenesis libraries: For targeted mutagenesis of Hy38-1, the VH and VL coding regions were used to prepare a
`scFv construct for optimization in phage display format. Large, CDR-targeted scFv phage libraries (greater than approximately 10‘9
`variant scFvs) were created by oligonucleotide-directed mutagenesis in which degenerate codons (NNS) were used to fully randomize
`regions of 6 consecutive amino acid residue using Kunkel mutagenesis
`In total, 19 individual scFv phage libraries were prepared and
`pooled for selection to a maximum of 3 libraries per pool resulting in 8 library pools).
`
`Regarding claim 17, Douthwaite discloses the nucleic acid library of claim 6, wherein the immunoglobulin scaffold comprises a single
`immunoglobulin domain (Pg. 162, left-hand column, last paragraph-right-hand column, 1st paragraph, Generation and selection of
`targeted mutagenesis libraries: For targeted mutagenesis of Hy38-1, the VH and VL coding regions were used to prepare a scFv
`construct for optimization in phage display format. Large, CDR-targeted scFv phage libraries (greater than approximately 10‘9 variant
`scFvs) were created by oligonucleotide-directed mutagenesis in which degenerate codons (NNS) were used to fully randomize regions of
`6 consecutive amino acid residue using Kunkel mutagenesis).
`
`Form PCT/ISA/237 (Box No. V) (January 2015)
`
`

`

`PCT/USZO1 8/050511 11.01.2019
`
`WRITTEN OPINION OF THE
`
`INTERNATIONAL SEARCHING AUTHORITY
`
`Supplemental Box
`
` International application No.
`
`
`
`PCT/U32018/050511
`
`in case the space in any of the preceding boxes is not sufficient.
`Continuation of:
`
`
`
`
`
`Regarding claim 20, Douthwaite discloses a protein library (Pg. 155. Figure 1 (B) includes 7 targeted mutagenesis libraries of VH CDR3
`of Hy38-1; Pg. 162, left-hand column. last paragraph, Generation and selection of targeted mutagenesis libraries: For targeted
`mutagenesis of Hy38-1, the VH and VL coding regions were used to prepare a scFv construct for optimization in phage display format
`
`
`Nineteen individual Hy38—‘l scFv phage display libraries targeting all 6 CDRs were constructed (Fig. 18) [Fig. 18 includes 7 targeted
`
`
`mutagenesis libraries of VH CDR3]) comprising a plurality of proteins, wherein each of the proteins of the plurality of proteins comprise
`
`
`an immunoglobulin scaffold. wherein the immunoglobulin scaffold comprises a CDR-H3 loop that comprises a sequence variant of a
`
`
`GPCR binding domain (Pg. 152. left-hand column, 1st paragraph, The formyl peptide receptor (FPR) family is a group of Class A
`
`
`G-protein coupled receptors (GPCRs); Pg. 153, right-hand column, 2nd paragraph, Hy38-1 is a human monoclonal antibody specific for
`
`
`human FPR1 that was derived by immunization of transgenic mice expressing human variable region genes; Pg. 162, left-hand column,
`
`
`last paragraph-right—hand column. 1st paragraph. Generation and selection of targeted mutagenesis libraries: For targeted mutagenesis
`
`
`of Hy38-1, the VH and VL coding regions were used to prepare a scFv construct for optimization in phage display format. Large,
`
`
`CDR-targeted scFv phage libraries (greater than approximately 10"9 variant scFvs) were created by oligonucleotide—directed
`
`
`mutagenesis in which degenerate codons (NNS) were used to fully randomize regions of 6 consecutive amino acid residue using Kunkel
`
`
`mutagenesis
`In total, 19 individual scFv phage libraries were prepared and pooled for selection to a maximum of 3 libraries per pool
`
`
`resulting in 8 library pools ; Pg. 154, left-hand column, Potency optimization of Hy38-1 COR-targeted mutagenesis: An overview of the
`
`
`selection and screening cascade to improve the potency of Hy38-1 against both human and cynomolgus FPR1 is illustrated in Figure 1A.
`
`
`The CDRs of Hy38-1 (defined by Kabat and numbered accordingly throughout) are shown in Figure 15. At 24 residues, the VH CDR3 of
`
`
`Hy38-1 is longer than average for a human antibody, in which the VH CDR3 regions are more typically in the region of 8 to 18 amino
`
`
`acids. Longer VH CDR3 regions have been suggested to be important for binding to certain target classes, such as GPCRs, where
`
`
`antigen binding might be facilitated by a longer projecting structure. Interestingly, the aforementioned human FPR1-specific antibody
`
`
`isolated by immunization also had long VH CDR3 region (22 amino acids). We therefore considered that the VH CDR3 of Hy38~1 could
`
`
`be particularly critical for FPR1 binding, and so, in the design of the targeted mutagenesis approach. we allowed the VH CDR3 to be very
`
`
`thoroughly explored in a range of libraries
`Nineteen individual Hy38-1 scFv phage display libraries targeting all 6 CDRs were
`
`
`constructed (Fig. 1B). In each library, 4 to 6 consecutive codons were replaced by NNS codons to allow for the inclusion of any amino
`
`
`acid at these targeted positions: Pg. 155, Figure 1. Antibody engineering strategy (A) and selection and screening cascade (8) used for
`
`
`the optimization of Hy38-1. Amino acid residues of Hy38-1 are shown in uppercase
`X denotes replacement of a codon with the
`
`
`degenerate codon NNS. The individual libraries within each CDR were pooled for selection as shown by the boxes. CDR residues are
`
`
`numbered according to Kabat [Figure 1 (B) includes 7 targeted mutagenesis libraries of VH CDR3]).
`
`Regarding claim 21, Douthwaite discloses the protein library of claim 20, wherein a length of the CDR-H3 loop is about 20 to about 80
`amino acids (Pg. 154, left-hand column, 2nd paragraph, At 24 residues, the VH CDR3 of Hy38-1 is longer than average for a human
`
`antibody, in which the VH CDR3 regions are more typically in the region of 8 to 18 amino acids; see Figure 1 (8)).
`
`Regarding claim 22, Douthwaite discloses the protein library of claim 20, wherein the immunoglobulin scaffold further comprises one or
`
`
`more domains selected from variable domain, light chain (VL), variable domain, heavy chain (VH), constant domain, light chain (CL), and
`constant domain, heavy chain (CH) (Pg. 162, left-hand column, last paragraph-right-hand column, 1st paragraph, Generation and
`
`selection of targeted mutagenesis libraries: For targeted mutagenesis of Hy38-1, the VH and VL coding regions were used to prepare a
`
`scFv construct for optimization in phage display format. Large, COR-targeted scFv phage libraries (greater than approximately 10"9
`variant scFvs) were created by oligonucleotide—directed mutagenesis in which degenerate codons (NNS) were used to fully randomize
`
`
`regions of 6 consecutive amino acid residue using Kunkel mutagenesis
`In total, 19 individual scFv phage libraries were prepared and
`
`pooled for selection to a maximum of 3 libraries per pool resulting in 8 library pools),
`
` Regarding claim 27. Douthwaite discloses the protein library of claim 20. Further, in regards to the limitation relating to "the plurality of
`proteins are used to generate a peptidomimetic library," a recitation of the intended use of the claimed invention must result in a
`
`structural difference between the claimed invention and the prior art in order to distinguish the claimed invention from the prior art.
`If the
`
`prior art is capable of performing the intended use, it meets the limitation for being used to generate a peptidomimetic library.
`Regarding claim 28, Douthwaite discloses the protein library of claim 20, wherein the protein library comprises antibodies (Pg. 162.
`
`
`left-hand column, last paragraph-right-hand column, 1st paragraph, Generation and selection of targeted mutagenesis libraries: For
`
`
`targeted mutagenesis of Hy38-1, the VH and VL coding regions were used to prepare a scFv construct for optimization in phage display
`format. Large. COR-targeted scFv phage libraries (greater than approximately 10‘9 variant scFvs) were created by
`oligonucleotide—directed mutagenesis in which degenerate codons (NNS) were used to fully randomize regions of 6 consecutive amino
`acid residue using Kunkel mutagenesis
`In total, 19 individual scFv phage libraries were prepared and pooled for selection to a
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`maximum of 3 libraries per pool resulting in 8 library pools).
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` Claims 8. 12-15, 25, and 26 lack an inventive step under PCT Article 33(3) as being obvious over Douthwaite et al. (hereinafter
`Douthwaite).
` Regarding claim 8, Douthwaite discloses the nucleic acid library of claim 6, but Douthwaite fails to explicitly disclose wherein a length of
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`the CDR—H3 loop is about 80 to about 230 base pairs.
`However, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Douthwaite to include
`
`wherein a length of the CDR-H3 loop is about 80 to about 230 base pairs, since where the general conditions of the claim are disclosed
`in the prior art (Pg. 154, left-hand column, 2nd paragraph, At 24 residues, the VH CDR3 of Hy38-1 is longer than average for a human
`
`antibody, in which the VH CDR3 regions are more typically in the region of 8 to 18 amino acids; see Figure 1 (8)): 24 amino acids x3
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`nucleotides/amino acids = 72 amino acids), discovering the optimal length of the CDR-H3 loop involves only routine skill in the art. The
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`motivation of doing so would be to develop various nucleic acid libraries using various CDR-HS loops.
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`Form PCT/lSA/237 (Supplemental Box) (January 2015)
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`

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`PCT/U82018I050511 11.01.2019
`
`WRITTEN OPINION OF THE
`
`INTERNATIONAL SEARCHING AUTHORITY
`
`Penuszmsmsosfl
`
`
` lntemational application No.
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`
`Supplemental Box
`
`in case the Space in any of the preceding boxes is not sufficient.
`Continuation of:
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`Regarding claim 12, Douthwaite discloses the nucleic acid library of claim 9, but Douthwaite fails to explicitly disclose wherein a length of
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`the VH domain is about 90 to about 100 amino acids.
`However, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Douthwaite to include
`
`
`wherein a length of the VH domain is about 90 to about 100 amino acids. since where the general conditions of the claim are disclosed in
`the prior art (Pg. 155, Figure 1 (B) Amino acid residues of Hy38-1 are shown in uppercase
`CDR residues are numbered according to
`
`
`Kabat [VH CDR3 ends at amino acid 102 according to Kabat]), discovering the optimal length of the VH domain involves only routine skill
`in the art. The motivation of doing so would be to develop various nucleic acid libraries using various VH domains.
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` Regarding claim 13, Douthwaite discloses the nucleic acid library of claim 9, but Douthwaite fails to explicitly disclose wherein a length of
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`the VL domain is about 90 to about 120 amino acids
`However, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Douthwaite to include
`
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`wherein a length of the VL domain is about 90 to about 120 amino, since where the general conditions of the claim are disclosed in the
`prior art (Pg. 155, Figure 1 (B) Amino acid residues of Hy38-1 are shown in uppercase
`CDR residues are numbered according to
`Kabat [VL CDR3 ends at amino acid 97 according to Kabat]), discovering the optimal length of the VH domain involves only routine skill
`in the art. The motivation of doing so would be to develop various nucleic acid libraries using various VL domains.
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` Regarding claim 14, Douthwaite discloses the nucleic acid library of claim 9, but Douthwaite fails to explicitly disclose wherein a length of
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` Regarding claim 15, Douthwaite discloses the nucleic acid library of claim 9, but Douthwaite fails to explicitly disclose wherein a length of
`the VL domain is about 300 to about 350 base pairs.
`
`However, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Douthwaite to include
`wherein a length of the VL domain is about 300 to about 350 base pairs, since where the general conditions of the claim are disclosed in
`
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`the prior art (Pg. 155, Figure 1 (B) Amino acid residues of Hy38-1 are shown in uppercase
`CDR residues are numbered according to
`Kabat [VL CDR3 ends at amino acid 97 according to Kabat]), discovering the optimal length of the VH domain involves only routine skill
`
`in the art. The motivation of doing so would be to develop various nucleic acid libraries using various VL domains.
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` Regarding claim 25, Douthwaite discloses the protein library of claim 20, but Douthwaite fails to explicitly disclose wherein a length of the
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`VH domain is about 90 to about 100 amino acids.
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`However, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Douthwaite to include
`
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`wherein a length of the VH domain is about 90 to about 100 amino acids, since where the general conditions of the claim are disclosed in
`the prior art (Pg. 155, Figure 1 (B) Amino acid residues of Hy38-1 are shown in uppercase
`CDR residues are numbered according to
`Kabat [VH CDR3 ends at amino acid 102 according to Kabat]), discovering the optimal length of the VH domain involves only routine skill
`
`in the art. The motivation of doing so would be to develop various protein libraries using various VH domains.
`Regarding claim 26, Douthwaite discloses the protein library of claim 20. but Douthwaite fails to explicitly disclose wherein a length of the
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`VL domain is about 90 to about 120 amino acids.
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`However, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Douthwaite to include
`
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`wherein a length of the VL domain is about 90 to about 120 amino, since where the general conditions of the claim are disclosed in the
`prior art (Pg. 155, Figure 1 (8) Amino acid residues of Hy38-1 are shown in uppercase
`CDR residues are numbered according to
`Kabat [VL CDR3 ends at amino acid 97 according to Kabat]), discovering the optimal length of the VH domain involves only routine skill
`in the art. The motivation of doing so would be to develop various protein libraries using various VL domains.
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`the VH domain is about 280 to about 300 base pairs.
`However, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Douthwaite to include
`wherein a length of the VH domain is about 280 to about 300 base pairs, since where the general conditions of the claim are disclosed in
`the prior art (Pg. 155. Figure 1 (B) Amino acid residues of Hy38-1 are shown in uppercase
`CDR residues are numbered according to
`Kabat [VH CDR3 ends at amino acid 102 according to Kabat]), discovering the optimal length of the VH domain involves only routine skill
`in the art. The motivation of doing so would be to develop various nucleic acid libraries using various VH domains.
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`Form PCT/ISA/237 (Supplemental Box) (January 2015)
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`

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`PCT/USZO18IO50511 11.01.2019
`
`WRITTEN OPINION OF THE
`
`INTERNATIONAL SEARCHING AUTHORITY
`
` International application No.
`
`PCTmszommsosfi
`
`Supplemental Box
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`Claims 29-33 and 36 lack an inventive step under PCT Article 33(3) as being obvious over VIB VZW et al. (hereinafter VIB VZW).
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`In case the space in any of the preceding boxes is not sufficient.
`Continuation of:
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