PCT/USZO18I057857 18.03.201 9
`
`PATENT COOPERATION TREATY
`
`PCT
`
`INTERNATIONAL SEARCH REPORT
`
`(PCT Article 18 and Rules 43 and 44)
`
`App'icam's °r 3156’“ file ”meme
`44854-740601
`
`FOR FURTHER
`ACTION
`
`see Form PCT/ISA/220
`as well as, where applicable, item 5 below.
`
`TWIST BIOSCIENCE CORPORATION This international search report has been prepared by this lntemational Searching Authority and is transmitted to the applicant
`
`lntemational application No.
`PCT/US 18/57857
`Applicant
`
`lntemational filing date (day/month/year)
`26 October 2018 (26.10.2018)
`
`(Earliest) Priority Date (day/month/year)
`27 October 2017 (27.10.2017)
`
`according to Article 18. A copy is being transmitted to the International Bureau.
`
`
`
` This international search report consists ofa total of sheets.
`D It is also accompanied by a copy of each rior art 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:
`
`
`[X]
`the international application in the language in which it was filed.
`
`
`
`which is the language of
`I: a translation ofthe international application into
`
`
`a translation furnished for the purposes ofintemational search (Rules 12.3(a) and 23.1(b)).
`
`
`b. D 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)).
`
`
`
` With regard to any nucleotide and/or amino acid sequence disclosed in the international application, see Box No. l.
`
`
`Certain claims were found unsearchable (see Box No.11).
`Unity of invention is lacking (see Box No. Ill).
`
`
` 4. With regard to the title,
`E the text is approved as submitted by the applicant.
`
`
`i: the text has been established by this Authority to read as follows:
`
`
`
`
`
`
`5. With regard to the abstract,
`
`7
`
`the text is approved as submitted by the applicant.
`
`
`Ci 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.
`1
`
`
`
`A as suggested by the applicant.
`E] as selected by this Authority, because the applicant failed to suggest a figure.
`
`
`[:1 as selected by this Authority, because this figure better characterizes the invention.
`
`b. D none ofthe figures is to be published with the abstract.
`
`Form PCT/lSA/ZIO (first sheet) (January 2015)
`
`

`

`fonning pan ofthe international application as filed:
`
`fi in the form ofan Annex C/ST.25 text file.
`‘1 on paper or in the form ofan image file.
`
`fiJmished together with the international application under PCT Rule l3ter. 1(a) for the purposes ofintemational search
`only in the form ofan Annex C/ST.25 text file.
`
`fumished subsequent to the international filing date for the purposes ofintemational search only:
`C] in the form ofan Annex C/ST.25 text file (Rule 13m. 1(a)).
`D on paper or in the form ofan image file (Rule lBter. l (b) and Administrative Instructions. Section 713).
`
`In addition, in the case that more than one version or copy ofa sequence listing has been filed or fumished, 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.
`
`PCTIUSZO18I057857 1 8.03.201 9
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US 18/57857
`
`Box No. 1
`
`Nucleotide and/or amino acid sequence(s) (Continuation ofitem LC of the first sheet)
`
`1. With regard to any nucleotide and/or amino acid sequence disclosed in the intemational application, the intemational search was
`carried out on the basis ofa sequence listing:
`
`3. Additional comments:
`
`Form PCT/ISA/ZIO (continuation of first sheet (1)) (January 2015)
`
`

`

`PCTIUSZO18I057857 1 8.03.201 9
`
`INTERNATIONAL SEARCH REPORT
`
`[ntemational application No,
`
`PCT/US 18/57857
`
`
`Box No. 1]
`
`Observations where certain claims were found unsearchable (Continuation ofitem 2 of first sheet)
`
`This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
`
`1. I: ClaimsNos.:
`because they relate to subject matter not required to be searched by this Authority, namely:
`
`
`
`
`
`
` 2. D ClaimsNos.:
`
`
`
`
`
`because they relate to parts ofthe international application that do not comply with the prescribed requirements to such an
`
`extent that no meaningful international search can be carried out, specifically:
`
`"Claims 4-6, 8, 10, 12. 14-15. 17, 19, 21, 25, 27, 29. 31, 33-34, 36, 38. 43, 45, 47-52, 58, 60 and 62-67
`
`V“
`
`3.
`
`Claims Nos.: Please see above'
`because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
`
`Box No. 111
`
`Observations where unity ofinvention is lacking (Continuation ofitem 3 of first sheet)
`
`This lntemational Searching Authority found multiple inventions in this international application, as follows:
`----P|ease see continuation In first extra sheet --—---------—---
`
`
`
`As all required additional search fees were timely paid by the applicant, this international search report covers all searchable
`claims.
`
`
` As all searchable claims could be searched without effortjustifying additional fees, this Authority did not invite payment of
`additional fees.
`
` As only some of the required additional search fees were timely paid by the applicant, this international search report covers
`
`only those claims for which fees were paid, specifically claims Nos.;
`
`
`
`
`4.
`
`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;
`it is covered by claims Nos.;
`1-3, 7, 9, 11, 13, 16, 18, 20, 22-24. 26, 28, 30.32.35 and 37
`
`
`
`Remark on Protest
`
`
`The additional search fees were accompanied by the applicant’s protest and, where applicable, the
`payment of a protest fee.
`
`
`E] The additional search fees were accompanied by the applicant’s protest but the applicable protest
`
`
`fee was not paid within the time limit specified in the invitation.
` No protest accompanied the payment of additional search fees:
`Form PCT/ISA/ZIO (continuation of first sheet (2)) (January 2015)
`
`

`

`PCT/U8201 8/057857 1 8.03.201 9
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US 18/57857
`
`A.
`
`CLASSIFICATION OF SUBJECT MATTER
`
`IPC(8)- C12N 15/00, C12N 15/10, C12N 15/09 (2018.01)
`CPC - C12N 15/1031, C12P 19/34, G06F 19/22, BO1J 2219/00695, BO1J 2219/00689
`
`According to lntemational Patent Classification (IPC) 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
`See Search History Document
`
`Electronic data base consulted during the international Search (name of data base and, where practicable, search terms used)
`See Search History Document
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`- Citation ofdocument, with indication, where appropriate, ofthe relevant passages
`Relevant to Claim NO.
`
`X
`US 2016/0264958 A1 (TWIST BIOSCIENCE CORPORATION) 15 September 2016
`1-3, 7, 9, 11, 13, 16. 18,
`(15.09.2016) Abstract; Claim 36; para [0015]; para [0031]; para [0047-0048]; para [0061]; para
`20, 22-24, 26, 28, 30. 32.
`[0089]; para [0127]; para [0132-0133]; para [0135]; para [0137—0138], Figs. 7, 8
`35, 37
`
`A
`
`us 2013/0196864 A1 (GOVINDARAJAN et al.) 01 August 2013 (01.08.2013) para [0100],
`[0173]
`
`1-3,7,9,11,13,16,18,
`20, 22-24. 26,28, 30, 32,
`35. 37
`
`
`
`E] Further documents are listed in the continuation of Box C. D See patent family annex.
`riority
`Special categories 0f cited documents:
`“T"
`later document published afier the international filing date or
`document defining the general state ofthe art which is not considered
`date and not in conflict with the ap lication but cited to un erstand
`to be of particular relevance
`the prmctple or theory underlying t e Invention
`“Effie" applicationor patentbut PUbllShed on 01' afierthe intemationai
`“X" document of particular relevance; the claimed invention cannot be
`filing date
`considered novel or cannot be considered to involve an inventive
`document which may throw doubts on priority claim(s) or which is
`step when the document is taken alone
`:Iteegiatlorg:;ggll(szll; :hgcpgg‘ljlfatlon date 0f another Citation or other “Y" document of particular relevanccithe claimed invention cannot be
`p
`p
`cons1dered to Involve an Inventive step when the document 15
`document referring to an oral disclosure, use, exhibition 01' other
`combined with one or more other such documents, such combination
`means
`being obvious to a person skilled in the art
`
`document published prior to the international filing date but later than u&n document member of the same patent family
`the priority date claimed
`
`Date ofthe actual completion ofthe international search
`29 December2018
`Name and mailing address ofthe ISA/US
`Mail Stop PCT, Attn: ISA/US. Commissioner for Patents
`PO. Box 1450, Alexandria, Virginia 22313—1450
`Facsimile No.
`571-273-8300
`Form PCT/iSA/ZIO (second sheet) (January 2015)
`
`Date of mailing ofthe international search report
`1 8 MAR ZOlg
`Authorized officer:
`
`Lee W. Young
`
`PCT Helpdesk: 571-272-4300
`PCT osp; 571-272-7774
`
`

`

`PCT/USZO18I057857 18.03.2019
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US 18/57857
`
`Continuation of Box No. III. Observations where unity of invention is lacking.
`
`This application contains the following inventions or groups of inventions which are not so linked as to form a single general inventive
`concept under PCT Rule 13.1. In order for all inventions to be searched, the appropriate additional search fees must be paid.
`
`Group I: Claims 1-3, 7, 9. 11. 13, 16, 18. 20. 22-24, 26, 28, 30. 32. 35 and 37 directed to a system and method for assembling and
`synthesizing a full length polynucleotide by designing overlapping sub-fragments having optimal Tm in overlaps and synthesizing the full
`—tength sequence from optimized overlapping polynucleotides.
`
`Group II: Claims 39-42. 44. 46, 53-57, 59. 61. directed to a system and method for assembling and synthesizing a full-length
`polynucleotide by designing sets of sub-sequences and generating a pass score for each sequence based on GC content and presence
`of direct repeats. and synthesizing a set of sequences having a pass score above a threshold value to produce the full-length sequence.
`
`—-———-—-—- see next extra sheet --------------
`
`The inventions listed as Groups I and N do not relate to a single general inventive concept under PCT Rule 13.1 because. under PCT
`Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
`Special Technical Features
`
`Groups II does not require designing overlapping fragments of a full-length sequence with optimal TMs in overlapping regions, as
`required by group I.
`
`Group I does not require generating sets of sub-sequences, assigning a pass score to each sub-sequence, and generating a score for
`each set of sub-sequence scores to determine sets that meet a threshold score, as required by group II.
`Common Technical Features
`
`The common technical feature shared by Groups I and II. is a computerized system for polynucleotide assembly, comprising a general
`purpose computer; and a computer readable medium comprising functional modules including instructions for the general purpose
`computer. wherein said computerized system is configured for operating in a method ofreceiving a full length polynucleotide sequence.
`automatically generating a plurality of designs each comprising a plurality of polynucleotide sequences, and automatically selecting a
`design from the plurality of designs. However, this shared technical feature does not represent a contribution over prior art, because the
`shared technical feature is anticipated by US 2016/0264958 A1 to Twist Bioscience Corporation (hereinafter 'Twist'). Twist teaches a
`computerized system for polynucleotide assembly (Abstract - 'Methods and compositions are provided for assembly of large nucleic
`acids'; para [0132] - 'The methods and systems described herein may comprise and/or are performed using a software program on a
`computer system.') comprising: a generalpurpose computer (para [0015] - 'FIG. 7 illustrates an example of a computer system.'); and a
`computer readable medium comprising functional modules including instructions for the general purpose computer (para [0137] - 'The
`computer system 700 illustrated in FIG. 7 depicts a logical apparatus that reads instructions from media 711 and/or a network port 705.
`which is optionally be connected to server 709 having fixed media 712. In some cases, a computer system, such as shown in FIG. 7,
`includes a CPU 701, disk drive 703, optional input devices such as keyboard 715 and/or mouse 716 and optional monitor 707.'), wherein
`said computerized system is configured for operating in a method of: receiving operating instructions, wherein the operating instructions
`comprise a full length polynucleotide sequence and automatically generates a plurality of designs each comprising a plurality of
`polynucleotide sequences [fragments]. (para [0132] - 'Accordingly. computerized control for the optimization of design algorithms
`described herein and the synthesis and assembly of nucleic acids are within the bounds of this disclosure.
`a computer system
`described herein accepts as an input one or more orders for one or more nucleic acids of predetermined sequence, devises an
`algorithm(s) for the synthesis and/or assembly of the one or more nucleic acid fragments. provides an output in the form of instructions
`to a peripheral device(s) for the synthesis and/or assembly of the one or more nucleic acid fragments, and/or instructs for the production
`of the one or more nucleic acid fragments by the peripheral devices to form the desired nucleic acid of predetermined sequence.
`a
`computer system operates without human intervention during one or more of steps for the production of a target nucleic acid of
`predetermined sequence or nucleic acid fragment thereof.’. para [0135] - 'breakpoint selection [ends of fragments] is continued for sites
`up to
`including each breakpoint or near each breakpoint. Site candidates are evaluated so as to reduce the presence of at least one of
`palindromic sequences, homopolymers, extreme GC content, and extreme AT content.'). Twist does not expressly recite automatically
`selecting a design from the plurality of designs, however, it would have been obvious to one of ordinary skill in the art that Twists
`computer algorithms operates without human intervention, and would by necessity generate multiple designs for a set of fragments by
`reviewing breakpoint site candidates. thus, a computerized system of Twist would include selecting a design from the plurality of
`designs.
`
`Form PCT/lSA/ZIO (extra sheet) (January 2015)
`
`

`

`PCT/USZO1 8/057857 1 8.03.201 9
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US 18/57857
`
`Continuation of Box No. I”. Observations where unity of invention is lacking.
`
`continuation of previous extra sheet:
`
`Another common technical feature shared by Groups I and II, is a method for polynucleotide synthesis of the full-length sequence
`inputted by the computer system discussed above, wherein the selected design(s) generated by the computerized system is
`synthesized. However, this shared technical feature does not represent a contribution over prior art, because the shared technical
`feature is anticipated by Twist (para [0132] — 'Accordingly, computerized control for the optimization of design algorithms described
`herein and the synthesis and assembly of nucleic acids are within the bounds of this disclosure.
`a computer system described herein
`accepts as an input one or more orders for one or more nucleic acids of predetermined sequence, devises an algorithm(s) for the
`synthesis and/or assembly of the one or more nucleic acid fragments, provides an output in the form of instructions to a peripheral
`device(s) for the synthesis and/or assembiy of the one or more nucleic acid fragments, and/or instructs for the production of the one or
`more nucleic acid fragments by the peripheral devices to form the desired nucleic acid of predetermined sequence.
`a computer
`system operates without human intervention during one or more of steps for the production of a target nucleic acid of predetermined
`sequence or nucleic acid fragment thereof.').
`
`As the technical feature was known in the art at the time of the invention, this cannot be considered a special technical feature that
`would otherwise unify the groups.
`
`Groups 1 and ll therefore lack unity under PCT Rule 13 because they do not share a same or corresponding special technical feature.
`
`dependent claims.
`
`Item 4, continued: claims 4-6, 8, 10, 12, 14—15, 17, 19, 21, 25, 27, 29, 31, 33-34, 36. 38, 43, 45, 47-52, 58, 60 and 62-67 are held
`unsearchable because they are not drafted in accordance with the second and third sentences of Rule 6.4(a) regarding multiply
`
`Form PCT/ISA/ZIO (extra sheet) (January 2015)
`
`

`

`PCT/U82018I057857 1 8.03.201 9
`
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`
`PATENT COOPERATION TREATY
`
`To; SEAN A. REED
`WILSON SONSINI GOODRICH & ROSATI
`650 PAGE MILL ROAD
`PALO ALTO, CA 94304-1050
`
`PC T
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`(PCT Rule 43bis.1)
`
`
`
`Applicant‘s or agent‘s file reference
`FOR FURTHER ACTION
`
`44854-740601
`See paragraph 2 below
`
`
`International application No.
`International filing date {day/month/year)
`
`
`26 October 2018 (26.10.2018)
`PCT/US 18/5785?
`
`
`International Patent Classification (IPC) or both national classification and IPC
`
`
`|PC(8) - C12N 15/00, C12N 15/10, C12N 15/09 (2018.01)
`CpC _
`C12N 15/1031, C12P 19/34, G06F 19/22, BO1J 2219/00695. BO1J 2219/00689
`
`
`
`
`Priority date (day/monrh/year)
`
`27 October 2017 (27.10.2017)
`
`
`
` iii/22%;?» 1 8 M A R 2019
`
`
`
`
`Applicant TWIST BIOSCIENCE CORPORATION
`
`
`
`
`
`I. This opinion contains indications relating to the following items:
`
`
`
`DEIEIREESE
`
`Box No. I
`
`Basis ofthe opinion
`
`Box No. II
`
`Priority
`
`Box No. III Non-establishment of opinion with regard to novelty, inventive step and industrial applicability
`
`Box No. IV Lack of unity ofinvention
`
`Box No. V
`
`Reasoned statement under Rule 43bis. l (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
`
`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 ofthe
`International Preliminary Examining Authority (“IPEA”) except that this does not apply where the applicant chooses an Authority
`other than this one to be the IPEA and the chosen IPEA has notified the International Bureau under Rule 66.1bis(b) that written
`opinions ofthis International Searching Authority will not be so considered.
`lfthis 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/ZZO or before the expiration of 22 months from the priority date, whichever expires later.
`For further options, see Form PCT/ISA/ZZO.
`
`Name and mailing address ofthe ISA/US Date of completion of this opinion
`Mail Sto PCT. Attn: ISA/US
`Commissioner for Patents
`D
`PO. Box 1450, Alexandria, Virginia 22313-1450
`Facsimile No.
`571—273—8300
`
`29 December 2018
`
`PCT 05?: 571-272-7774
`
`Authorized officer
`
`Lee W. Young
`pCT Helpdesk: 5714724300
`
`Form PCT/lSA/237 (cover sheet) (January 2015)
`
`

`

`PCT/USZO18I057857 1 8.03.201 9
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`lnternational application No.
`PCT/US 18/57857
`
`Box No. I
`
`Basis of this opinion
`
`1. With regard to the language, this opinion has been established on the basis of:
`
`the international application in the language in which it was filed.
`LXI
`E] a translation of the international application into
`furnished for the purposes ofintemational search (Rules 12.3(a) and 23.](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 9| (Rule 43bis. 1(a)).
`
`With regard to any nucleotide and/or amino acid sequence disclosed in the international application, this opinion has
`been established on the basis ofa sequence listing:
`
`a.
`
`forming part ofthe international application as filed:
`
`m in the form of an Annex C/ST.25 text file.
`[:1 on paper or in the form of an image file.
`b. D furnished together with the international application under PCT Rule lSter.l(a) for the purposes ofinternational
`search only in the form of an Annex C/ST.25 text file.
`
`c. D furnished subsequent to the international filing date for the purposes ofintemational search only:
`C] in the form of an Annex C/ST.25 text file (Rule 13ter. 1(a)).
`D on paper or in the form of an image file (Rule 131er.1(b) and Administrative Instructions, Section 713).
`
`4. D 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:
`
`Form PCT/ISA/237 (Box No. 1) (January 20l5)
`
`

`

`PCT/USZO18I057857 1 8.03.201 9
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`lntemational application No.
`
`PCT/US 18157857
`
`Box No. II]
`
`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 examined in respect of:
`
`I: the entire international application.
`
`m claims Nos. 4—6. 3. 1o. 12. 14-15. 17. 19. 21. 25, 27. 29, 31, 33-34. 36. 38. 43-45. 47-52. 58. 60. 62-67
`
`because:
`
`the said international application, or the said claims Nos.
`subject matter which does not require an international search (spect‘fiz):
`
`relate to the following
`
`the description, claims or drawings (indicate particular elements below) or said claims Nos. see below
`are so unclear that no meaningful opinion could be formed (specijjz):
`Claims 4-6. 8. 10. 12. 14-15. 17, 19, 21. 25. 27. 29. 31. 33-34. 36, 38. 4345. 47-52. 58, 60, 62-67 are dependent claims and are not
`drafted in accordance with the second and third sentences of Rule 6.4(a).
`
`D the claims, or said claims Nost
`by the description that no meaningful opinion could be formed (specifil):
`
`are so inadequately supported
`
`See Supplemental Box for further details.
`
`'Claims 4-6, 8, 10. 12, 14-15, 17. 19. 21, 25, 27, 29, 31, 33-34, 36, 38, 43-45, 47-52, 58, 60, 62-67
`
`}‘
`
`no intemational search report has been established for said claims Nos. see above'
`
`a meaningful opinion could not be formed without the sequence listing; the applicant did not, within the prescribed time limit:
`furnish a sequence listing in the form of an Annex C/ST.25 text file, and such listing was not available to the
`lntemational Searching Authority in the form and manner acceptable to it; or the sequence listing furnished did not
`comply with the standard provided for in Annex C ofthe Administrative Instructions.
`furnish a sequence listing on paper or in the form of an image file complying with the standard provided for in Annex
`C ofthe Administrative Instructions, and such listing was not available to the lntemational Searching Authority in the
`form and manner acceptable to it; or the sequence listing furnished did not comply with the standard provided for in
`Annex C ofthe Administrative Instructions.
`
`pay the required late furnishing fee for the furnishing of a sequence listing in response to an invitation under
`Rule l3ter.l(a) or (b).
`
`El
`
`E]
`
`Form PCT/ISA/237 (Box No. III) (January 2015)
`
`

`

`PCT/USZO18I057857 18.03.2019
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`lntemational application No.
`PCT/US 18/5785?
`
`Box No. IV
`
`Lack of unity ofinvention
`
`l. m In response to the invitation (Form PCT/lSA/206) to pay additional fees the applicant has, within the applicable time limit:
`
`paid additional fees.
`
`paid additional fees under protest and, where applicable, the protest fee.
`
`paid additional fees under protest but the applicable protest fee was not paid.
`
`not paid additional fees.
`
`
`
`2. D This Authority found that the requirement of unity of‘invention is not complied with and chose not to invite the applicant to
`pay additional fees.
`
`3. This Authority considers that the requirement of unity ofinvention in accordance with Rule 13.], 13.2 and 13.3 is
`
`D complied with.
`
`El not complied with for the following reasons:
`This application contains the following inventions or groups of inventions which are not so linked as to form a single general inventive
`concept under PCT Rule 13.1. in order for all inventions to be searched, the appropriate additional search fees must be paid.
`
`Group I: Claims 1-3, 7, 9, 11, 13, 16, 18, 20, 22-24, 26, 28, 30, 32, 35 and 37 directed to a system and method for assembling and
`synthesizing a full length polynucleotide by designing overlapping sub-fragments having optimal Trn in overlaps and synthesizing the full-
`Iength sequence from optimized overlapping polynucleotides.
`
`Group II: Claims 39—42, 44, 46, 53—57, 59, 61, directed to a system and method for assembling and synthesizing a full-length
`polynucleotide by designing sets of sub—sequences and generating a pass score for each sequence based on GC content and presence
`of direct repeats, and synthesizing a set of sequences having a pass score above a threshold value to produce the full-length sequence.
`
`The inventions listed as Groups I and N do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT
`Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
`
`Special Technical Features
`
`Groups II does not require designing overlapping fragments of a full-length sequence with optimal TMs in overlapping regions, as
`required by group I.
`
`Group | does not require generating sets of sub-sequences, assigning a pass score to each sub-sequence, and generating a score for
`each set of sub»sequence scores to determine sets that meet a threshold score, as required by group II.
`
`----Please see continuation in first supplemental box---------------
`
`Consequently, this opinion has been established in respect ofthe following parts ofthe international application:
`
`|:| all parts.
`
`IX the parts relating to claims Nos. 1-3, 7. 9. 11, 13, 16 18, 20, 22-24, 26, 28, 30, 32, 35 and 37
`
`Form PCT/lSA/237 (Box No. IV) (January 2015)
`
`

`

`PCT/USZO1 8/057857 18.03.2019
`
`WRITTEN OPINION OF THE
`
`International application No.
`
`INTERNATIONAL SEARCHING AUTHORITY
`
`PCT/US 18/57857
`
`Box No. V
`
`Reasoned statement under Rule 43bis.l(a)(i) with regard to novelty, inventive step or industrial applicability;
`citations and explanations supporting such statement
`
`Statement
`
`Novelty (N)
`
`Claims
`Claims
`
`1—3, 7, 9, 11, 13, 16, 18. 20, 22-24, 26, 28, 30, 32, 35, 37
`None
`
`----Please see continuation in second supplemental box................
`
`Inventive step (IS)
`
`Claims
`Claims
`
`None
`1-3, 7, 9, 11, 13. 16, 18, 20, 22-24, 26, 28, 30, 32, 35, 37
`
`Industrial applicability (IA)
`
`Claims
`Claims
`
`1-3, 7, 9. 11, 13, 16, 18, 20, 22-24, 26, 28, 30, 32, 35, 37
`None
`
`Citations and explanations:
`2.
`Claims 1-3, 7, 9. 11. 13. 16. 18. 20, 22-24, 26, 28. 30, 32, 35 and 37 lack an inventive step under PCT Article 33(3) as being obvious over
`US 2016/0264958 A1 to Twist Bioscience Corporation (hereinafter 'Twist').
`
`Regarding claim 1, Twist teaches a computerized system for polynucleotide assembly (Abstract - "Methods and compositions are provided
`for assembly of large nucleic acids"; para [0132] - "The methods and systems described herein may comprise and/or are performed using
`a software program on a computer system") comprising:
`a general purpose computer (para [0015] - "FIG. 7 illustrates an example of a computer system"); and a computer readable medium
`comprising functional modules including instructions for the general purpose computer (para [0137] - "The computer system 700 illustrated
`in FIG. 7 depicts a logical apparatus that reads instructions from media 711 and/or a network port 705, which is optionally be connected to
`sewer 709 having fixed media 712. In some cases, a computer system, such as shown in FIG. 7, includes a CPU 701, disk drive 703,
`optional input devices such as keyboard 715 and/or mouse 716 and optional monitor 707."), wherein said computerized system is
`configured for operating in a method of:
`i) receiving operating instructions, wherein the operating instructions comprise a full length polynucleotide sequence; ii) automatically
`generating a plurality of designs each comprising a plurality of polynucleotide sequences (para [0132] - "Accordingly, computerized control
`for the optimization of design algorithms described herein and the synthesis and assembly of nucleic acids are within the bounds of this
`disclosure... In some instances, a computer system described herein accepts as an input one or more orders for one or more nucleic
`acids of predetermined sequence, devises an algorithm(s) for the synthesis and/or assembly of the one or more nucleic acid fragments,
`provides an output in the form of instructions to a peripheral device(s) for the synthesis and/or assembly of the one or more nucleic acid
`fragments, and/or instructs for the production of the one or more nucleic acid fragments by the peripheral devices to form the desired
`nucleic acid of predetermined sequence"; para [0138] - "The example computer system of FIG. 8 includes a processor 802 for processing
`instructions"); wherein the plurality of polynucleotide sequences each comprises at least one overlap region of 1 to 10 or more bases in
`length (para [0061] - "An overhang is capable of annealing to a complementary overhang under suitable reaction conditions. In some
`cases, "sticky end" and "overhang" are used interchangeably. Non-limiting examples of overhang lengths include 1, 2, 3, 4, 5, 6, 7, 8, 9,
`10 or more bases"),
`wherein each overlap region is complementary to another overlap region (para [0132] - "In some instances, a computer system is
`programmed to search for sticky end motifs in a user specified predetermined nucleic acid sequence, interface these motifs with a list of
`suitable nicking enzymes, and/or determine one or more assembly algorithms to assemble fragments defined by the sticky end motifs"),
`and wherein each of the at least one overlap regions does not comprise a homopolymeric sequence (para [0135] - "Site candidates are
`evaluated so as to reduce the presence of at least one of palindromic sequences, homopolymers").
`Twist does not expressly teach overlap region of 30 to 50 bases in length, or iii) automatically selecting a design from the plurality of
`designs that comprises polynucleotide sequences having the lowest variance in Tm between the at least one overlap regions. However,
`since Twist teaches sticky and overhangs comprising overlap regions can be of variable length, from 1-10 or more bases (para [0061] -
`"Non-limiting examples of overhang lengths include 1, 2, 3, 4, 5, 6, 7, 8. 9, 10 or more bases"), it would have been obvious to one of
`ordinary skill in the an that the overlap region can be of variable length, and could be easily optimized by routine experimentation. Further,
`since Twist teaches consideration of melting temperature for annealing of complementary sticky ends under stringent hybridization
`conditions (para [00311- "The annealing and ligation reactions 150 can include rounds of annealing, ligating and melting under conditions
`such that only desired sticky ends 140 a—140 d are able to anneal and ligate, while cleaved end fragments remain unligated."; para [0047] -
`"