PCT/USZO19IO32992 28.10.2019
`
`PATENT COOPERATION TREATY
`
`PCT
`
`INTERNATIONAL SEARCH REPORT
`
`(PCT Article 18 and Rules 43 and 44)
`
`Applicant’s or agent’s file reference
`44854-776601
`
`FOR FURTHER
`ACTION
`
`see Form PCT/ISA/220
`as well as, where applicable, item 5 below.
`
`lntemational application No.
`PCT/US 19/32992
`
`lntemational filing date (day/month/year)
`17 May 2019 (17.05.2019)
`
`(Earliest) Priority Date (day/manth/year)
`18 May 2018 (18.05.2018)
`
`TWIST BIOSCIENCE CORPORATION
`
`Applicant
`
`
`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 international search report consists ofa total of Q sheets.
`
`
`El It is also accompanied by a copy ofeach prior 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:
`
`
`the international application in the language in which it was filed.
`
`
`which is the language of
`E] a translation ofthe international application into
`a translation furnished for the purposes ofintemational search (Rules 12.3(a) and 23.1(b)).
`
`b. [:1 This intemational search report has been established taking into account the rectification of an obvious mistake
`authorized by or notified to this Authority under Rule 9] (Rule 43.6bis(a)).
`
`With regard to any nucleotide and/or amino acid sequence disclosed in the international application, see Box No. 1.
`
`Certain claims were found unsearchable (see Box No. ll).
`
`Unity of invention is lacking (see Box No. Ill).
`
`the text is approved as submitted by the applicant.
`E] the text has been established by this Authority to read as follows;
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`
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`5. With regard to the abstract,
`
`
`
`
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`the text is approved as submitted by the applicant.
`E! the text has been established, according to Rule 38.2, by this Authority as it appears in Box No. [V. The applicant
`
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`may, within one month from the date ofmailing 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. 1A
`E as suggested by the applicant.
`
`[:1 as selected by this Authority, because the applicant failed to suggest a figure.
`D as selected by this Authority, because this figure better characterizes the invention.
`
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`b. E] none ofthe figures is to be published with the abstract.
`
`Form PCT/lSA/210 (first sheet) (January 2015)
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`4. With regard to the title,
`
`
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`
`

`

`furnished together with the intemational application under PCT Rule 131er. 1(a) for the purposes ofinternational search
`only in the form of an Annex C/ST.25 text file
`
`fumished subsequent to the international filing date for the purposes ofintemational search only:
`in the form ofan Annex C/ST.25 text file (Rule IBIert 1(a)).
`
`D on paper or in the form ofan image file (Rule l3rer.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 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 fumished.
`
`PCT/USZO19IO32992 28. 1 0.2019
`
`INTERNATIONAL SEARCH REPORT
`
`lntemational application No.
`PCT/US 19132992
`
`Box No.1
`
`Nucleotide and/or amino acid sequence(s) (Continuation ofitem l.c ofthe 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 fonning part ofthe international application as filed:
`E] in the form of an Annex C/ST.25 text file.
`I: on paper or in the form ofan image file.
`
`3, Additional comments:
`
`Form PCT/lSA/ZlO (continuation of first sheet (1)) (January 2015)
`
`

`

`PCT/USZO19IO32992 28. 1 0.2019
`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/US 19/32992
`
`
`
`Observations where certain claims were found unsearchable (Continuation ofitem 2 of first sheet)
`
`
`
`Box No. II
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`
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`This international search report has not been established in respect of certain claims under Article l7(2)(a) for the following reasons:
`
`1. E] ClaimsNos.:
`because they relate to subject matter not required to be searched by this Authority, namely:
`
`
`2. El ClaimsNos.:
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`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:
`
`3.
`
`
`
`
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`Claims N05,: 5-23. 27-37. 41-58, 63. 65-75, 61-93, 97-107
`
`because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
`Box No.1"
`
` Observations where unity ofinvention is lacking (Continuation ofitem 3 of first sheet)
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`This lntemational Searching Authority found multiple inventions in this international application, as follows:
`
`- see extra sheet for Box No. Ill Observations where unity of invention is lacking —
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`
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`
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`claims.
`As all required additional search fees were timely paid by the applicant, this international search report covers all searchable
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`
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`As all searchable claims could be searched without effortjustifying additional fees, this Authority did not invite payment of
`additional fees.
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`As only some ofthe 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.:
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`
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`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.:
`1-4
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`Remark on Protest
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`Form PCT/ISA/ZlO (continuation of first sheet (2)) (January 2015)
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`The additional search fees were accompanied by the applicant’s protest and, where applicable, the
`payment of a protest fee.
`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.
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`EDD No protest accompanied the payment of additional search fees.
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`

`

`PCT/U82019I032992 28. 1 0.2019
`
`
`INTERNATIONAL SEARCH REPORT
`lntemational application No.
`PCT/US 19/132992
`
`A.
`CLASSIFICATION OF SUBJECT MATTER
`
`
`|PC(8) - C12N 15/10, C12Q 1/68 (2019.01)
`
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`CPC — C12N 15/1093, C12Q 1/6874, C408 40/06
`
` Accordin
`
` g to lntemational Patent Classification (lPC) or to both national classification and lPC
`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
`
`
`
`Category‘
`Y
`
`
`
`Citation of document, with indication, where appropriate, ofthe relevant passages
`
`Relevant to claim No.
`
`
`
`
`
`1-4
`US 2017/0355984 A1 (COUNSYL, INC.) 14 December 2017 (14.12.2017) para [0117]. [0187],
`
`[0190], [0231]. [0232]. [0235], [0236]
`
`
`Y
`US 2016/0019341 A1 (PERSONALIS, INC.) 21 January 2016 (21.01.2016) Claim 1, para
`
`
`
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`[0025]. Fig. 3
`
`
`
`D Further documents are listed in the continuation of Box C.
`El See patent family annex.
`‘
`Special categories 0f and documents:
`riority
`later document published after the international filing date or
`“A“ document defining the general state ofthe art which is not considered
`date and not in conflict With the application but cited to un erstand
`to be of particular relevance
`the principle or theory underlying t e invention
`“E"
`earlier application or patent bl" PUbliShed 0" 0" afterthe international
`“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 '5 taken alone
`Cited to establish the publication date of another citation or other
`“Y“ document of particular relevance; the claimed invention cannot be
`
`
`
`
`specral reason (as specrfied)
`.
`. ..
`considered to involve an inventive step when the document. is
`“0” document referring to an oral disclosure, use, exhibition or other
`combined _with one or more other such documents, such combination
`means
`being obvrous to a person skilled in the art
`
`
`document member ofthe same patent family
`document published prior to the international filing date but later than
`“P“
`«&n
`
`the priority date claimed
`
`
`Date ofthe actual completion ofthe international search
`Date of mailing ofthe international search report
`14 October 2019
`28 OCT 2019
`
`
`
`
`Authorized officer:
`Name and mailing address ofthc ISA/US
`
`
`Lee W. Young
`Mail Stop PCT, Attn: ISA/US. Commissioner for Patents
`
`PO. Box 1450, Alexandria. Virginia 22313-1450
`
`Facsimile No.
`571-273-8300
`
`Form PCT/lSA/ZIO (second sheet) (January 2015)
`
`
`
`“L"
`
`“T”
`
`
`
`
`
`
`PCT Helpdesk: 571-272-4300
`PCT OSP: 571-272-7774
`
`

`

`PCT/USZO19IO32992 28.10.2019
`
`INTERNATIONAL SEARCH REPORT
`
`lntemational applicafion NO.
`PCT/US 19/32992
`
`Continuation of:
`Box No. lll. 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.
`
`Groups I: Claims 1-4, drawn to a method for sequencing genomic DNA comprising a polynucleotide library which provides a specific
`ratio of the read depth of the bases of the genomic fragments.
`
`Groups II: Claims 24-26, 38-40, drawn to a composition comprising a polynucleotide library.
`
`Groups l||: Claims 59-62, 64, 76—80, 94-96, drawn to a composition for nucleic acid hybridization, and a method of use for nucleic acid
`hybridization or genomic sequencing.
`
`The inventions listed as Groups I through lll 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
`
`----continued on next sheet—---
`
`Group | includes the special technical feature of adding a second polynucleotide library comprising at least one polynucleotide that binds
`to genomic fragments comprising the one or more positions having less than average read depth. not required by Groups II and III.
`
`Group II includes the special technical feature of a composition comprising a polynucleotide library, wherein less than all polynucleotides
`comprises a molecular tag, an index sequence, an adapter or a blocker, not required by Groups I and III.
`
`Group III includes the special technical feature of a composition for nucleic acid hybridization or genomic sequencing comprising an
`additive, wherein the additive reduces off-target hybridization of the at least one polynucleotide or reduce the local concentration of
`nucleic acid at the air-liquid interface. not required by Groups | and II.
`
`Common Technical Features
`
`The inventions of Groups l—lll share the technical feature of a polynucleotide library, nucleic acid hybridization and genomic sequencing.
`
`The inventions of Groups I and ll share the technical feature of a polynucleotide library that provides
`a read depth of at least 80 percent of the bases of the genomic fragments corresponding to the polynucleotides; and a total number of
`sequencing reads. wherein the total number of sequencing reads are capable of covering 100 percent of each of the bases of the
`genomic fragments corresponding to the polynucleotides at a theoretical read depth, wherein the ratio of the read depth of at least 80
`percent of the bases of the genomic fragments corresponding to the polynucleotides to the theoretical read depth is at least 0.5 with a
`plurality of genomic fragments.
`
`However, these shared technical features do not represent a contribution over prior art in view of US 2017/0355984 A1 to Counsyl, Inc.
`(hereinafter "Counsyl") and US 2016/0019341 A1 to Personalis, Inc. (hereinafter "Personalis")
`
`Counsyl teaches (instant claim 1) a method for sequencing genomic DNA (para [0117], methods of sequencing a nucleic acid molecule,
`methods of sequencing a nucleic acid |ibrary.), comprising:
`(a) contacting a composition comprising a first polynucleotide library comprising at least 30.000 polynucleotides, wherein each of the at
`least 30,000 polynucleotides (para [0187], A set of capture probes (also referred to as a capture probe library) can be used to enrich a
`plurality of nucleic acid molecules (for example. in a sequencing library which may or may not be amplified, for example using PCR). The
`capture probes comprise a nucleic acid sequence complementary to various portions within the region of interest. In some
`embodiments, a set of capture probes includes, for example, between about 2 and about 20,000 capture probe... A sequencing library
`can include nucleic acid molecules comprising a portion of the region of interest (for example, genomic DNA containing the region of
`interest can be fragmented into a plurality of nucleic acid molecules, with each nucleic acid molecule originating from the region of
`interest comprising a portion of the region of interest) is present in an amount such that, following hybridization with genomic fragments
`and sequencing of the hybridized genomic fragments (para [0190], An equal number of each capture probe in the set of capture probes
`can result in sequencing depth variation because some capture probes may more efficiently bind a particular fragment of a sequence of
`interest than another capture probe. This may be due, for example, to a variance in the concentration of the capture probe,....Large
`variance in sequencing depth can decrease overall sequence quality by limiting sensitivity and specificity in low sequencing depth sub-
`regions of a region of interest), the polynucleotide library provides:
`a read depth of of the genomic fragments corresponding to the polynucleotides (para [0235], Sequencing depth variation (for example,
`after sequencing a nucleic acid sequencing library described herein) can be improve by balancing the different capture probes in the set
`of capture probes. Balanced capture probes are a set of capture probes for a sequence of interest, wherein the amount of each capture
`probe in the set is predetermined to account for varying efficiency of capture for each probe.)
`
`Form PCT/lSA/2l0 (extra sheet) (January 2015)
`
`

`

`PCT/USZO1 9/032992 28.10.2019
`
`INTERNATIONAL SEARCH REPORT
`
`lntemational application No.
`PCT/US 19/32992
`
`Continuation of:
`Box No. lll. Observations where unity of invention is lacking
`
`Counsyl does not specifically teach wherein said read depth covers at least 80 percent of the bases of the genomic fragment and a total
`number of sequencing reads. wherein the total number of sequencing reads are capable of covering 100 percent of each of the bases of
`the genomic fragments corresponding to the polynucleotides at a theoretical read depth. wherein the ratio of the read depth of at least
`80 percent of the bases of the genomic fragments corresponding to the polynucleotides to the theoretical read depth is at least 0.5 with a
`plurality of genomic fragments. However. Counsyl teaches that a balanced capture probes provides improved sequencing efficiency by
`providing the ratio of a predicted sequencing depth profile and a desired sequencing depth profile as an objective function of the
`balanced capture probes (para [0236]. a balanced set of capture probes is constructed to enrich a nucleic acid library (or nucleic acid
`sequencing library) to minimize the difference between a predicted sequencing depth profile and a desired sequencing depth profile. The
`desired sequencing depth profile can be uniform or non-uniform. and the desired sequencing depth profile can be implied by an
`objective function used to minimize the difference between the predicted and desired sequencing depth profiles. In some embodiments.
`construction of the balanced set of capture probes is constrained by a minimum amount or a maximum amount of the capture probes in
`the balanced set of capture probes. The desired sequencing depth profile is made in reference to a reference sequencing library, which
`is a nucleic acid library used to prepare the balanced set of capture probes. Thus. when a set of capture probes is balanced using a
`reference sequencing library. the sequencing depth profile obtained after sequencing a test sequencing library may be different from the
`desired sequencing depth profile due to differences between the reference sequencing library and the test sequencing library). Thus. it
`would have been obvious to one of ordinary skill in the art to have provided a balanced capture probes to achieve the claimed
`limitations: "wherein the ratio of the read depth of at least 80 percent of the bases of the genomic fragments corresponding to the
`polynucleotides to the theoretical read depth is at least 0.5 with a plurality of genomic fragments".
`
`Counsyl further teaches:
`(b) enriching at least one genomic fragment that binds to the first polynucleotide library to generate at least one enn‘ched target
`polynucleotide (para [0232], hybrid capture methods are used to enrich the region of interest by combining capture probes that are
`substantially complementary to a portion of the region of interest with the nucleic acid library (or nucleic acid sequencing library), thereby
`hybridizing the capture probes to nucleic acid molecules comprising the portion of the region of interest);
`(0) sequencing the at least one enriched target polynucleotide (para [0232]. the enriched nucleic acid molecules from the nucleic acid
`library (or nucleic acid sequencing library) can be sequenced);
`(e) repeating steps a»c. wherein a second polynucleotide library comprising capture probes is added to the composition. wherein the
`second polynucleotide library comprises at least one polynucleotide that binds to genomic fragments (para [0231], the enriched nucleic
`acid molecules are re-enriched in a second (or more) round of hybridization to the capture probes).
`
`feature.
`
`Counsyl does not specifically teach (d) identifying one or more positions of the at least one enriched polynucleotide having less than
`average read depth; adding at least 1500 polynucleotides to the composition; wherein the presence of the second polynucleotide library
`increases the read depth at the one or more positions having less than average read depth. Personalis teaches (b) enriching at least
`one genomic fragment that binds to the first polynucleotide library to generate at least one enriched target polynucleotide (Claim 1, A
`method for genetic analysis of a subject, comprising: b. subjecting a second nucleic acid sample of said subject to target-specific
`sequencing to generate target—specific sequencing data;), and (d) identifying one or more positions of the at least one enriched
`polynucleotide having less than average read depth (para [0025], FIG. 3 illustrates a statistical model on sensitivity vs. coverage of
`genomic regions with single run whole genome sequencing data). It would have been obvious to one of ordinary skill in the art to have
`adding a second balanced capture probes. such as at least 1500 polynucleotides, to the genomic region having less than average read,
`to improve the read depth of said region.
`
`As said technical features were known in the art at the time of the invention. these cannot be considered special technical features that
`would otherwise unify the groups.
`
`Groups I through ”I therefore lack unity under PCT Rule 13 because they do not share a same or corresponding special technical
`
`Form PCT/ISA/2l0 (extra sheet) (January 2015)
`
`

`

`PCT/U82019/032992 28.10.2019
`
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`
`PATENT COOPERATION TREATY
`
`PCT
`
`
`To: SEAN A. REED
`WILSON SONSINI GOODRICH & ROSATI
`
`
`650 PAGE MILL ROAD
`
`
`PALO ALTO, CA 94304
`
`
`
`
`i; gags/3221222250
`
`‘ FOR FURTHER ACTION
`
`
`Applicant’s or agent’s file reference
`Sec paragraph 2 below
`44854—776601
`
`
` Priority date (day/monrh’year)
`
`
`lntemational application No.
`International filing date (day/mom/zryear)
`
`18 May 2018 (18.05.2018)
`PCT/US 19/32992
`17 May 2019 (17.05.2019)
`
`
`
`lntemational Patent Classification (lPC) or both national classification and lPC
`
`
`IPC(8) - C12N 15/10. C120 1/68 (2019.01)
`
`CPC _
`C12N 15/1093. C1ZQ1/6874, 0408 40/06
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`(PCT Rule 43 bis. I )
`
`2 8 0. CT 2019
`
`
`
`Applicant TWIST BIOSCIENCE CORPORATION
`
`
`
`
` E
`
`1. This opinion contains indications relating to the following items:
`Box No.
`I
`Basis of the opinion
`
`Box No. II
`
`Priority
`
`Box No. Ill Non-establishment ofopinion with regard to novelty, inventive step and industrial applicability
`
`Box No. IV
`
`Lack of unity ofinvention
`
`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
`
`DEEDREESE Box No. Vlll Certain observations on the international application
`
`
`
`Box No. Vl
`
`Certain documents cited
`
`Box No. Vll Certain defects in the international application
`
`2. FURTHER ACTION
`
`i
`*
`-
`
`If a demand for inteniational preliminary examination is made, this opinion will be considered to be a written opinion of the
`International Preliminary Examining Authority (“IPEA") except that this does not apply 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.
`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 Fomi
`PCT/lSA/220 or before the expiration of22 months from the priority date, whichever expires later.
`For further options, see Fomi PCT/ISA/220.
`
`
`
`Name and mailing address ofthe ISA/US Date of completion ofthis opinion
`Authorized officer
`Mail Stop PCT, Attn: ISA/US
`
`Lee W. Young
`
`Commissioner for Patents
`
`14 October 2019
`
`PCT Helpdesk: 571-272-4300
`
`
`P.O. Box 1450, Alexandria, Virginia 22313-1450
`
`PCT OSP: 571-272-7774
`
`Facsimile No. 571-273-8300
`
`
`Form PCT/ISA/237 (cover sheet) (January 2015)
`
`

`

`PCT/USZO19IO32992 28.10.2019
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`lntemational application No.
`PCT/US 19/32992
`
`Box No. l
`
`Basis of this opinion
`
`I. With regard to the language, this opinion has been established on the basis of:
`
`E the international application in the language in which it was filed.
`D a translation ofthe 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 91 (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. [:1 forming part ofthe international application as filed:
`CI in the form of an Annex C/ST.25 text file.
`1:] on paper or in the form of an image file.
`b. E] fumished together with the international application under PCT Rule 13ter.1(a) for the purposes ofintemational
`search only in the form of an Annex C/ST.25 text file.
`
`
`
`
`
`
`
`
`
`
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`(3. K furnished subsequent to the intemational filing date for the purposes ofintemational search only:
`
`
`E in the form of an Annex C/ST.25 text file (Rule 13ter. 1(a)).
`
`
`[j on paper or in the form ofan image file (Rule l3ter. 1(b) and Administrative Instructions, Section 713).
`
`
`
`4.12 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 fomiing part ofthe application as
`
`
`filed or does not go beyond the application as filed, as appropriate, were fumished.
`
`Additional comments:
`
`
`
`Form PCT/lSA/237 (Box No. l) (January 2015)
`
`

`

`PCT/USZO19IO32992 28. 1 0.2019
`
`
`WRITTEN OPINION OF THE
`International application No.
`INTERNATIONAL SEARCHING AUTHORITY
`PCT/US 19/32992
`
`
`
`Box No.1"
`Non-establishment ofopinion 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:
`
`
`D the entire international application.
`
`m claims Nos. 5-23, 27-37,41-5a, 63, 65-75. 81-93. 97.107
`
`because:
`relate to the following
`the said intemational application, or the said claims Nos.
`
`
`subject matter which does not require an intemational search (specifiz):
`
`
`
`
`the description, claims or drawings (indicate particular elements below) or said claims Nos. 5'23: 27'37- 41-58- 63. 65-75. 8
`are so unclear that no meaningful opinion could be fomied (specify):
`
`
`
`
`Claims 5-23. 27-37, 41-58, 63. 65-75. 81-93, 97-107 are held unsearchable because they are dependent claims and are not drafted in
`accordance with the second and third sentences of Rule 6.4(a).
`
`
`
`are so inadequately supported
`
`
`
`C]
`
`the claims, or said claims Nose
`by the description that no meaningful opinion could be formed (Specify):
`
`
`
`
`
`
`
`K no international search report has been established for said claims Nos. 5‘23. 27-37. 41'58- 63. 65'75: 81'93' 97'107
`
`
`[j a meaningful opinion could not be formed without the sequence listing; the applicant did not, within the prescribed time limit:
`[:l 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 fumished did not
`comply with the standard provided for in Annex C ofthe Administrative Instructions.
`
`
`E] fumish 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
`
`E] pay the required late furnishing fee for the furnishing of a sequence listing in response to an invitation under
`Rule l3!er. 1(3) or (b).
`
`
`[:1 See Supplemental Box for further details.
`
`
`Form PCT/lSA/237 (Box No. Ill) (January 2015)
`
`

`

`PCT/USZO19IO32992 28.10.2019
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`
`
`lntemational application No.
`PCT/US19/32992
`
`Box No. IV
`
`Lack of unity ofinvention
`
`I.
`
`'2'
`
`In response to the invitation (Form PCT/lSA/206) to pay additional fees the applicant has, within the applicable time limit:
`
`
`
`3. This Authority considers that the requirement of unity ofinvention in accordance with Rule 13.1, 13.2 and 13.3 is
`
`D complied with.
`
`not complied with for the following reasons:
`IX]
`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.
`
`Groups I: Claims 1—4, drawn to a method for sequencing genomic DNA comprising a polynucleotide library which provides a specific ratio
`of the read depth of the bases of the genomic fragments.
`
`Groups II: Claims 24-26, 38-40, drawn to a composition comprising a polynucleotide library.
`
`Groups lll: Claims 59-62, 64, 76-80, 94-96, drawn to a composition for nucleic acid hybridization, and a method of use for nucleic acid
`hybridization or genomic sequencing.
`
`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 ofinvention is not complied with and chose not to invite the applicant to
`pay additional fees.
`
`
`
`
`
`
`
`
`
`
`
`
`
`The inventions listed as Groups I through Ill 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Consequently, this opinion has been established in reSpect of the following parts ofthe international application:
`
`
`El all parts.
`
`
`Group I includes the special technical feature of adding a second polynucleotide library comprising at least one polynucleotide that binds
`to genomic fragments comprising the one or more positions having less than average read depth, not required by Groups II and III.
`
`Group ll includes the special technical feature of a composition comprising a polynucleotide library, wherein less than all polynucleotides
`comprises a molecular tag, an index sequence. an adapter or a blocker, not required by Groups I and III.
`
`Group III includes the special technical feature of a composition for nucleic acid hybridization or genomic sequencing comprising an
`additive, wherein the additive reduces off-target hybridization of the at least one polynucleotide or reduce the local concentration of
`nucleic acid at the air-liquid interface, not required by Groups | and II.
`
`Common Technical Features
`
`The inventions of Groups |-|ll share the technical feature of a polynucleotide library, nucleic acid hybridization and genomic sequencing.
`
`The inventions of Groups I and II share the technical feature of a polynucleotide library that provides
`a read depth of at least 80 percent of the bases of the genomic fragments corresponding to the polynucleotides; and a total number of
`sequencing reads, wherein the total number of sequencing reads are capable of covering 100 percent of each of the bases of the
`genomic fragments correSponding to the polynucleotides at a theoretical read depth, wherein the ratio of the read depth of at least 80
`percent of the bases of the genomic fragments corresponding to the polynucleotides to the theoretical read depth is at least 0.5 with a
`plurality of genomic fragments.
`
`However, these shared technical features do not represent a contribution over prior art in view of US 2017/0355984 A1 to Counsyl, Inc.
`(hereinafter "Counsy|") and US 2016/0019341 A1 to Personalis, Inc. (hereinafter "Personalis")
`————————continued in Supplemental Box--------
`
`[Z the parts relating to claims Nos. 1-4
`
`Form PCT/lSA/237 (Box No. IV) (January 2015)
`
`

`

`PCT/U8201 9/032992 28.10.2019
`
`
`WRITTEN OPINION OF THE
`lntemational application No.
`T
`t
`PCT/US 19/32992
`[N ERNATIONAL SEARCHING AUTHORITY
`
`
`
`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
`1-4
`YES
`
`
`Claims
`
`
`Claims
`Inventive step (IS)
`
`
`
`Claims
`1'4
`NO
`
`
`Industrial applicability (IA)
`Claims
`1'4
`YES
`Claims
`
`
`
`Citations and explanations:
`2.
`Claims 1-4 lack an inventive step under PCT Article 33(3) as being obvious over US 2017/0355984 A1 to Counsyl, Inc. (hereinafter
`"Counsyl") and US 2016/0019341 A1 to Personalis, lnc. (hereinafter "Personalis").
`
`Regarding claim 1, Counsyl teaches a method for sequencing genomic DNA (para [0117], methods of sequencing a nucleic acid molecule,
`methods of sequencing a nucleic acid library.), comprising:
`(a) contacting a composition comprising a first polynucleotide library comprising at least 30,000 polynucleotides, (para [0187], "A set of
`capture probes (also referred to as a capture probe library) can be used to enrich a plurality of nucleic acid molecules (for example, in a
`sequencing libr