From the INTERNATIONAL SEARCHING AUTHORITY
`
`
`
`PATENT COOPERATION TREATY
`
`TozDanielJ. Kennedy
`Wilson Sonsini Goodrich & Rosati
`
`650 Page Mill Road
`Palo Alto, California 94304
`United States of America
`
`PCT
`
`FEE: 2:3: 2&3
`
`,
`...
`..
`1
`‘
`,.
` If SUN‘SINL
`NUUHCAUUN Ol‘ IRANS
`THE INTERNATIONAL SEARC ’
`_
`AFNIIS ROSATE
`TIIE WRITTEN OPINION OF THE INTERNATIONAL
`SEARCHING A U'I‘HORI'I‘Y, OR THE DECLARATION
`
`
`
`(PCT Rule 44.1)
`
`Datc ofmailing
`
`
`2 1 FEB 2018
`
`
`Applicant’s or agent‘s tile reference
`
`
`FOR FURTHER ACTION See paragraphs 1 and 4 below
`
`
`
`53242-701601
`
`
`International filing date
`International application No.
`
`
`(day/m0’7’h0’earl
`05 December 2017 (05.12.2017)
`PCT/U817/64745
`
`
`
`Applicant
`
`
`DARMIYAN, INC.
`
`1. X] The applicant is hereby notified that the international search report and the written opinion of the International Searching
`Authority have been established and are transmitted herewith.
`Filing of amendments and statement under Article 19:
`The applicant is entitled, if he so wishes, to amend the claims of the international application (see Rule 46):
`When? The time limit for filing such amendments is normally two months from the date oftransmittal ofthe international
`search report.
`Directly to the International Bureau of WIPO preferably through ePCT or on paper to? 34 chemin des Colombenes
`1211 Geneva 20, Switzerland, Facsimile No.2 +41 22 338 82 70
`For more detailed instructions, sec PCT Applicant 's Guide, International Phase, paragraphs 9.004 79.011.
`
`
`
`How?
`
`2. D The applicant is hereby notified that no international search report will be established and that the declaration under
`Article l7(2)(a) to that effect and the written opinion of the International Searching Authority are transmitted herewith
`
`3. [3 With regard to any protest against payment of(an) additional fee(s) under Rule 40.2, the applicant is notified that:
`C]
`the protest together with the decision thereon has been transmitted to the International Bureau together with any
`request to forward the texts ofboth the protest and the decision thereon to the designated Offices
`[3 no decision has been made yet on the protest;
`the applicant will be notified as soon as a decision is made.
`4. Reminders
`
`The applicant may submit comments on an informal basis on the written opinion ofthe International Searching Authority
`to the International Bureau. These comments will be made available to the public after international publication. The
`lntemational Bureau will send a copy of such comments to all designated Offices unless an international preliminary
`examination report has been or is to be established.
`Shortly alter the expiration 01‘ I8 months from the priority date, the international application will be published by the
`International Bureau.
`Ifthc applicant wishes to avoid or postpone publication, 3 notice of withdrawal of the international
`applications, or ofthe priority Claim, must reach the International Bureau before the completion ot‘tht= technical preparations for
`international publication (Rules 90bis.l and 90bisi3).
`Within 1‘) months from the priority date. but only in respect ofsome designated Offices. a demand for international preliminary
`examination must he filed it‘the applicant wishes to postpone the entry into the national phase until 30 months trom the pi iorit)’
`date (in some (‘lt‘iices even later); otherwise. the applicant must. within 20 months from the priority date. perform the
`prescribed acts for entry into the national phase before those destgnated Offices
`In respect ot‘other designated ()fliccs, the
`
`time limit oldtl months (or later} will apply even if no demand is filed within 19 months For details 2
`iii c applgt‘able time
`limits; ()tlice by ('lt‘lice, see www.mpo.iiiUpct/en/texts/tirnejnnits.htrnl and the Pt)! .v’lppllcant '5 (juideg National Chapters
`Within 22 months from the priority date, the applicant may request that a supplementary international search he carried
`out by a different Intcmational Searching Authority that offers this service (Rule 45/713 It The procedure for requesting
`supplementary international search is described in the Pt‘TApp/zcam ’5 Guide, International Phase. paragraphs X Otto-8.032
`1—...
`L
`
`
`
`
`
`
`Name and mailing address ofthc ISA/US
`Mail Stop PCT. Attn: ISA/US
`Commissioner for Patents
`PO. Box 1450. Alexandria, Virgsnia 22313-1450
`Facsimile Nor 571-273-8300
`
`Form PCT/lSA/270 (July 2017)
`
`
`Authorized officer
`Shane Thomas
`
`
`PCT Helpdchk. 571-272-4300
`
`
`Telephone No PCT 08?; 57l-272-77’74
`
`
`
`

`

`PATENT COOPERATION TREATY
`
`PCT
`
`INTERNATIONAL SEARCH REPORT
`
`(PCT Article 18 and Rules 43 and 44)
`
`see Form PCT/lSA/ZZO
`FOR FURTHER
`Applicant’s or agent’s file reference
`
`53242.701601 as well as, where applicable, item 5 below. ; ACTION
`
`
`
`
`(Earliest) Priority Date (day/manth/year)
`International filing date (day/monthbvear)
`lntemational application No.
`
`
`05 December 2017 (05.12.2017)PCT/U517/64745 06 December 2016 (06122016)
`Applicant
`DARMIYAN, NC.
`
`This international search report has been prepared by this International Searching Authority and is transmitted to the applicant
`according to Article 18‘ A copy is being transmitted to the lntemational Bureau.
`
`This international search report consists of a total of&_ sheets
`[:1 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 of the international application into
`a translation furnished for the purposes of international search (Rules 12i3(a) and 23,1(b)).
`h 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)).
`l::l With regard to any nucleotide and/0r amino acid sequence disclosed in the international application, see Box No. I.
`
`ct
`
`D Certain claims were found unsearchable (see Box No. 11).
`
`El Unity ofiuvention is lacking (see Box No, Ill),
`
`4‘ With regard to the title,
`lZl the text is approved as submitted by the applicant
`l: the text has been established by this Authority to read as follows:
`
`b. E] none of the figures is to be published with the abstract.
`
`With regard to the abstract,
`
`the text is approved as submitted by the applicant.
`
`D the text has been established, according to Rule 38.21 by this Authority as it appears in Box No W. The applicant may,
`within one month from the date ofmailing of this international search report, submit comments to this Authority,
`
`With regard to the drawings,
`
`a,
`
`the figure ofthc drawings to be published with the abstract is Figure No.
`
`1
`
`[X] as suggested by the applicant.
`C] 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.
`
`Form PCT/ISA/210 (first sheet) (January Ni 5)
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`International application No,
`PCT/US17/64745
`
`A.
`
`CLASSIFICATION OF SUBJECT MATTER
`
`33% - A61B 5/00, 5/055; (301 R 33/20. 33/48; 606K 9/20; GOST 7/00 (2018.01)
`A61B 5/0013, 5/055; GO1R 33/20, 33/483, 33/50, 33/56; G06T 7/00, 7/277, 17/00; 606K 9/46
`
`According to International Patent Classification (lPC) or to both national classification and IPC
`
`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*
`
`Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`US 2015/0073258 A1 (MAZER. A et a1.) Match 12. 2015; figures 8. 11—13. 19; paragraphs
`[0008140010]. [00291—[0034], [0037], [0049]. [0059]. [0105]. [0108}[0111], [0118]. [01581—[0161],
`[0167]. [0180). [0194]. [0217]-[0219]. [0224]
`
`1—14, 40-41
`
`17/6-9, 18/6—9
`
`
`
`
`
`
`a... “Diagnostic neuroimaging across diseases: (KLOPPEL, S et al.) Neurolmage. November 7.
`2011. Volume 61. DO|210.1016/j.neuroimage,2011.11.002. Last accessed January 30, 2018.
`page 458, column 1, paragraph 5; page 460, column 1, paragraph 1
`
`15/6—9, 16/ 1 5/69
`--—-—--——- mm... m.-.
`17/6-9, 18l6~9
`
`“inferring causality in brain images: a perturbation approach" (PAUS, T) Philosophical
`Transactions of the Royal Society B. May 29, 2005. Volume 360. pages 11094114.
`DOI:10.1098lrstb.2005.1652. Last accessed January 30, 2018
`
`”Detecting microstructurai properties 01 white matter based on compartmentalization ot
`magnetic susceptibility.” (CHEN, WC et at.) Neuroimage. December 23, 2012. Volume 70,
`pages 1-9. DOI:10.1016/}.neuroimage.2012.12.032. Last accessed January 30. 2018.
`
`i 17/6—9, 18/6-9
`-
`
`17/6—9. 18/69
`
`
`
`[:1 Further documents are listed in the continuation of Box C. E] See patent family annex.
`Special categories 0f cited documents:
`“T"
`later document published alter the international filing date or
`riority
`document defining the general state of the art which is not considered
`date and not in conflict with the application but cited to on erstand
`to be of particular relevance
`the principle or theory underlying the invention
`will” application or patent bl” PUbl‘Shed 0“ 0‘ after the international
`” document of particular relevance, the claimed invention cannot be
`filing date
`consrdered novel or cannot be considered to involve an inventive
`document which may throw doubts on priority claimts) or which 18
`step when the document '5 taken alone
`cited to establish the publication date of another citation or other
`. document ol particular relevance the claimed invention cannot be
`specral rcason(asspcc1ficd)
`.
`_
`_
`.
`constdered to involve an inventive step when the document is
`document referring to an oral disclosure, use, exhibition or other
`combined with one or more other such documents such combination
`means
`being obvious to a person skil ledin the art
`document published prior to the international filing date but later than
`d
`n
`:m ‘r of the same at m fam'l
`the priority date claimed
`ocumc ‘ mc b”
`<
`P 5
`1 Ft
`Date 01 the actual completion ot‘thc international search
`Date of mailing oi the international search report
`
`“
`
`,.
`
`’
`
`30 January 2018(30.01.2018) 2 1 FEB 2018
`
`Name and mailing address of the ISA/
`Authorized officer
`Mail Stop PCT. Attn: ISA/US, Commissioner for Patents
`PO. Box 1450, Alexandria, Virginia 22313-1450
`Facsimile N0. 571-273-8300
`Form PCT/ISA/ZIO (second sheet) (January 2015)
`
`,
`PCT Heipdesk: 571272-4300
`PCT 0st 57147277774
`
`Shane Thomas
`
`

`

`From the
`INTERNATIONAL SEARCHING AUTHORITY
`
`PATENT COOPERATION TREATY
`
`TO: Daniel J. Kennedy
`Wilson Sonsini Goodrich & Rosati
`650 Page Mill Road
`Palo Alto, California 94304
`United States of America
`
`PCT
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`(PCT Rule 43 bis.l)
`
`
`
`2 1 FEB 2018
`mania)
`FOR FURTHER ACTION
`Applicant’s or agent’s file reference
`
` 53242-701601 See paragraph 2 below
`
`3--.“.
`
`WW7,
`
`
`
`3
`Priority date {day/month/year)
`International filing date (daybionth/year)
`International application No.
` PCT/US17/64745 i r 05 December 2017 (05.12.2017) 06 December 2016 (06.12.2016)
`
`
`International Patent Classification (lPC) or both national classification and lPC
`lPC - A61B 5/00, 5/055; G01R 33/20, 33/48; G06K 9/20; 606T 7/00 (2018.01)
`CPC -
`
`A818 5/0013, 5/055; 601R 33/20, 33/483, 33/50, 33/56; GOBT 7/00, 7/277, 17/00; GOBK 9/46
`
`
`
`”Want DARMIYAN, iNC.
`
`1. This opinion contains indications relating to the following items:
`
`Box No, I
`
`Basis of the opinion
`
`
`
`
`
`i
`
`I
`
`l li
`
`i
`i
`
`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 of invention
`
`DEE]HEDGE Box No. Vii Certain defects in the international application
`
`
`
`Box No. V
`
`Box No, Vi
`
`Reasoned statement under Rule 43br‘s. l(a)(i) with regard to novelty, inventive step and industrial applicability;
`citations and explanations supporting such statement
`Certain documents cited
`
`Box No: Viil Certain observations on the intemationai application
`
`2. FURTHER ACTION
`
`if a demand for international preliminary examination is made. this opinion will be considered to be a written opinion ofthe 5
`international Preliminary Examining Authority (“IPEA”) except that this does not apply where the applicant chooses an Authority 3
`other than this one to be the IPEA and the chosen {PEA has notified the international Bureau under Rule 66.1bis(b) that written
`3
`opinions ofthis International Searching Authority will not be so considered.
`3l
`ifthis opinion is, as provided above, considered to be a written opinion ofthc lPEA, the applicant is invited to submit to the il’EA
`l
`a written reply together, where appropriate, with amendments. before the expiration oi‘3 months from the date of mailing ofi‘orm
`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
`
`;
`
`._
`
`PCT OSP: 571-272-7774
`
`Authorized officer
`Shane Thomas
`
`PCT Helpdesk: 571.272.4300
`
`Name and mailing address of the iSA/US Date ofcompletion oi‘this opinion
`Mail Stop PCT, Attn: iSA/US
`Commissioner for Patents
`PO. Box 1450, Alexandria, Virginia 22313-1450
`Facsimile Nor 57i~273v8300
`
`30 January 2018 (30.01 .2018)
`
`Form PCT/ISA/237 (cover sheet) (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/USl7/64745
`
`
`
`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.
`[X]
`D a translation of the intemational application into
`furnished for the purposes of international search (Rules 12.3(a) and 23il(b)).
`
`which is the language of a 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 431»; 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 of a sequence listing:
`
`a. [:1 forming part ofthe international application as filed:
`[3 in the form ofan Annex C/STi25 text file.
`[:1 on paper or in the fomi of an image file
`b. D furnished together with the international application under PCT Rule l3ter.1(a) for the purposes of international
`search only in the form ofan Annex C/ST.25 text file
`
`c. D furnished subsequent to the international filing date for the purposes of international search only:
`D in the form ofan Annex C/ST.25 text file (Rule 13ter.l(a)).
`D on paper or in the form of an image file (Rule 13Ierr 1(b) and Administrative Instructions, Section 713)
`
`5, Additional comments:
`
`4, E] In addition, in the case that more than one version or copy of a 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 of the application as
`filed or does not go beyond the application as filed, as appropriate, were fumished.
`
`Form I’CT/ISA/237 (Box No. I) (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/USlT/64745
`
`Reasoned statement under Rule 43bis.1(a)(i) with regard to novelty, inventive step and industrial applicability;
`Box No. V
`citations and explanations supporting such statement
`
`Statement
`
`Novelty (N)
`
`Inventive step (IS)
`
`15-39
`
`
`1—14, 40-41
`
`
`17-39
`
`1 -16 , 4041
`
`Industrial applicability (IA)
`
`
`1‘41
`
`None
`
`-'**-Continued Within the Next Supplemental Box-“'—
`
`Citations and explanations:
`2‘
`Claims 1-14 and 40-41 lack novelty under PCT Article 33(2) as being anticrpated by US 2015/0073258 A1 (MAZER, A et al.)
`
`As per claim 1, MAZER discloses a method for determining a disorder state of brain tissue in a brain of a subject (comparing tissue
`properties, including tissue volume (TV) and volume of interacting protons (VlP), based on proton density, PD, and T1 map data, is used
`to detect degenerative processes in soft tissue, such as the brain; the degenerative processes are indicative of a neurodegenerative
`disease; paragraphs [0008], [0111]), comprising: (a) obtaining magnetic resonance imaging (MRl) data comprising at least one MRl
`image of the brain (microstructure of brain white matter is imaged using MRl to obtain a series of MRI images, Le. maps; figure 8;
`paragraphs [00091-[0010], [0029], [0105], [0108]), the MRI image comprising a plurality of voxels (images comprise a plurality of voxels of
`2 mm‘3 in size; figure 8; paragraphs [[0059], [0105]), a voxel of the plurality of voxels being associated with the brain tissue of the brain
`of the subject (gray scale of voxels shows values, eg. PD values associated with the brain slice of the image; figure 8; paragraphs
`[0037], [0059]) and comprising one or more measured MRl parameters in the MRI data (tissue specific MRI parameters measured such
`as TV, ViP as seen in figure 11 and PD of figure 19 for comparison; paragraphs [0008], [0029], [0037], [0049]);
`(b) for the voxel of the plurality of voxels (units used for the maps are voxels; determinations are made for each voxel; paragraphs [0109],
`[0118]), using one or more computer processors to process the one or more measured MRI parameters with one or more simulated MRI
`parameters for the voxel (set of simulations is used to estimate values, in particular PD. (measured MRl parameter) with multi-coil data to
`characterize the measured value of the voxel: figures 12, 13, paragraphs [0031], [0167]), the one or more simulated MRl parameters
`being generated from one or more microstructural models at the voxel (simulations are generated from data based on tissue types
`characterized by properties of very small structures across a voxel, erg. white matter microstructures: figure 16; paragraphs [0034],
`[0158], [0161], [0167]); (c) for the voxel of the plurality of voxels (units used for the maps are voxels; determinations are made for each
`voxel; paragraphs [0109], [0113]), selecting a diagnostic model from the one or more microstructural models (mapping the PD
`quantitatively allows building of a model of the tissue properties which are correlated to degenerative process; images for microstructural
`models included models from 3 MS sub]ects having distinguishable differences along the white matter tract; figure 11; paragraphs [0008],
`[0029], [0217]—[0219], [0224]), the diagnostic model meeting a threshold congruence between the one or more measured MRl parameters
`and the one or more simulated MRl parameters associated with the diagnostic model (a substrate PD measured by all the coils and a PD
`is obtained from M0 images from four simulated coils (simulated parameter) and these are matched (congruence); models include those
`from the 3 MS subjects (diagnostic model): figures 13, 19; paragraphs [0037], [0180], [0194], [0217]); and (d) for the voxel of the plurality
`of voxels (units used for the maps are voxels; determinations are made for each voxel; paragraphs [0109], [0118]), using the diagnostic
`model to determine the disorder state of the brain tissue associated with the voxel (comparing tissue properties, based on T1-weighted
`protein density, is used to detect degenerative processes in soft tissue, such as the brain; the degenerative processes are indicative of a
`neurodegenerative disease; paragraphs [0008], [0111]).
`
`As per claim 2, MAZER discloses the method of claim 1. MAZER further discloses wherein each voxel comprises a plurality of measured
`MRl parameters (tissue specific MRl parameters of each voxel are measured such as PD, relaxation time T1, transverse relaxation T2,
`non—water tissue volume, TV and volume of interacting protons, VlP; paragraphs [0049], [0071]).
`
`As per claim 3, MAZER discloses the method of claim 2. MAZER further discloses wherein the one or more measured MRI parameters
`are a plurality of measured MRl parameters (preferably more than one tissue specific MRl parameters of each voxel are measured
`particularly, PD, relaxation time T1, transverse relaxation T2, non-water tissue volume, W and volume of interacting protons, VIP;
`paragraphs [0049], [0071], [0152]),
`
`As per claim 4, MAZER discloses the method of claim 3. MAZER further discloses wherein the one or more simulated MRl parameters
`are a plurality of simulated MRI parameters (1250 M0 data sets simulated; paragraphs [0033], [0059]).
`
`As per claim 5, MAZER discloses the method of claim 4, MAZER further discloses comprising repeating (b)-(d) one or more times for
`additional voxels of the plurality of voxels (over a thousand repeats to estimate the map from a plurality of voxels; paragraphs
`[0033]-[0034], [0059], [0105])
`
`Form PCT/lSA/237 (Box No. V) (January 20l5)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`
`PCT/USlT/64745
`
`Supplemental Box
`
`In case the space in any of the preceding boxes is not sufficient.
`Continuation of:
`
`»‘“—Continued from Box V: Citations and Explanations-"‘—
`
`As per claim 6, MAZER discloses the method of claim 5. MAZER further discloses comprising repeating (b)-(d) for all other voxels of the
`plurality of voxels (over a thousand repeats to estimate the map from a plurality of voxels over the entire brain; paragraphs [0033]-[0034],
`[0059], [0220]).
`
`As per claim 7, MAZER discloses the method of claim 5. MAZER further discloses comprising repeating (b)-(d) for all voxels associated
`with a specified region of the brain (over a thousand repeats to estimate the map from a plurality of voxels containing largely suboortical
`region; paragraphs [0033]-[0034], [0059]. [0220]).
`
`As per claim 8, MAZER discloses the method of claimt5. MAZER further discloses comprising repeating (b)—(d) for all voxels associated
`with an entirety of the brain (over a thousand repeats to estimate the map from a plurality of voxels over the entire brain; paragraphs
`[0033]-[0034], [0059], [0220]).
`
`As per claim 9, MAZER discloses the method of claim 5. MAZER further discloses comprising repeating (a)-(d) tor a plurality of MRI
`Images, each MRI image of the plurality of MRI images associated with a brain selected from a plurality of brains, each brain of the
`plurality of brains associated with a subject selected from a plurality of subjects (the method includes acquiring MRI images for the
`brains (plurality of brains) of 11 controls and at least one MS subject (plurality of subjects) and measuring and comparing parameters for
`these subjects; figures 8, 11; paragraphs [0026], [0029]).
`
`As per claims 10/6—9, MAZER discloses the method of claims 6-9. MAZER further discloses wherein the MRI image is selected from the
`group consisting of: a longitudinal relaxation time (T1)‘weighted MRI image (relaxation time. T1-regularized; paragraphs [0049], [0055]),
`a transverse relaxation time (T2)-weighted MRI image (T—2 weighted; paragraph [0055]), and a diffusion-weighted MRI image (diffusion
`weighted: paragraph [0116]).
`
`As per claims 11/10/6~9. MAZER discloses the method of claims 1016-9. MAZER further discloses wherein the measured MRI parameter
`is selected from the group consisting of: a longitudinal relaxation time (T1) (comparing tissue properties, including tissue volume (TV)
`and volume of interacting protons (VIP), based on proton density, PD. and T1 map data; paragraphs [0008], [0111]). a transverse
`relaxation time (T2) (T-2 data: paragraph [0049]), and a diffusion coefficient (paragraph [0158]).
`
`As per claims 12/11/10/6-9, MAZER discloses the method of claims 11/10/6-9. MAZER further discloses wherein the simulated MRI
`parameter is selected from the group consisting of: a longitudinal relaxation time (T1) (comparing tissue properties, including tissue
`volume (TV) and volume of interacting protons (VIP), based on proton density, PD, and T1 map data; paragraphs [0008], [0111]), a
`transverse relaxation time (T2), and a diffusion coefficient (paragraphs [0158], [0175]).
`
`As per claims 13/12/11/10/643, MAZER discloses the method of claims 12/11/10/6-9. MAZER further discloses wherein the one or more
`microstructural models comprise information regarding a parameter selected from the group consisting of: intracellular content.
`extracellular content, distribution of extracellular content within interstitial space, distribution of intracellular content within intracellular
`space (tissue volume (TV) and volume of interacting protons (VIP), based on proton density, PD; paragraphs [0008], [0111]), and tissue
`geometry.
`
`As per claims 14/13/12/11/10/6-9, MAZER discloses the method of claims 13/ 12/1 1/10/6—9. MAZER further discloses wherein the one or
`more microstructural models comprise measured or predicted values of a parameter selected from the group consisting of: cell density,
`cell shape, cell geometry, cell size, cell distribution, intercellular spacing, extracellular matrix homogeneity, interstitial tortuosity, water to
`protein ratio, water to lipid ratio (T1 weighted values of PD take into account water protons and the volume of these protons in relation to
`proteins and lipids (water to protein ratio or water to lipid ratio; paragraph [0123]), water to carbohydrate ratio, protein to lipid ratio ,
`protein to carbohydrate ratio. and lipid to carbohydrate ratio.
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`170rm PCT/ISA/237 (Supplemental Box) (January 2015)
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`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US17/64745
`
`Supplemental Box
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`In case the space in any of the preceding boxes is not sufficient.
`Continuation of:
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`As per claim 40, MAZER discloses a method for determining a disorder state of a tissue in a portion of a body of a subject (comparing
`tissue properties, including tissue volume (TV) and volume of interacting protons (VlP). based on proton density. PD, and T1 map data,
`is used to detect degenerative processes in soft tissue, such as the brain; the degenerative processes are indicative of a
`neurodegenerative disease; paragraphs [0008], [0111]), comprising: (a) obtaining magnetic resonance imaging (MRI) data comprising at
`least one MRI image of the tissue (microstructure of brain white matter is imaged using MRI to obtain a series of MR] images, lei maps;
`figure 8; paragraphs [0009]-[0010], [0029], [0105], [0108]), the MRI image comprising a plurality of voxels (images comprise a plurality
`of voxels 012 mm"3 in size; figure 8: paragraphs [0059], [0105]), a voxel of the plurality of voxels being associated with the tissue of the
`subject (gray scale of voxels shows values, eg PD values associated with the brain slice of the image; figure 8; paragraphs [0037],
`[0059]) and comprising one or more measured MRI parameters in the MRI data (tissue specific MRI parameters measured such as TV,
`VIP as seen in figure 11 and PD. of figure 19 for comparison; paragraphs [0008], [0029], [0037], [0049]); (b) for the voxel of the plurality
`of voxels, using one or more computer processors to process the one or more measured MRI parameters with one or more simulated
`MRl parameters for the voxel (set of simulations is used to estimate values, in particular PD. (measured MR1 parameter) with multl-coil
`data to characterize the measured value of the voxel; figures 12, 13, paragraphs [0031]. [0167]), the one or more simulated MRl
`parameters being generated from one or more microstructural models at the voxel (simulations are generated from data based on tissue
`types to characterize properties of very small structures across a voxel, particularly white matter microstructures; figure 16; paragraphs
`[0034], [0158], [0161], [0157]); (c) for the voxel of the plurality of voxels (units used for the maps are voxels: determinations are made for
`each voxel; paragraphs [0109], [0118]), selecting a diagnostic model from the one or more microstructural models (mapping the PD
`quantitatively allows building of a model of the tissue properties which are correlated to degenerative process; images for
`microstructural models included models from 3 MS subjects having distinguishable differences along the white matter tract; figure 11;
`paragraphs [0008]. [0029]. [0217]»[0219], [0224]), the diagnostic model meeting a threshold congruence between the one or more
`measured MRI parameters and the one or more simulated MRI parameters associated with the diagnostic model (a substrate PD
`measured by all the coils and a PD is obtained from M0 images from four simulated coils (simulated parameter) and these are matched
`(congruence); models include those from the 3 MS subjects (diagnostic model); figures 13, 19; paragraphs [0037], [0180], [0194],
`[0217]); and (d) for the voxel of the plurality of voxels (units used for the maps are voxels; determinations are made for each voxel;
`paragraphs [0109], [0118]), using the diagnostic model to determine the disorder state of the tissue associated with the voxel
`(comparing tissue properties, based on T1-weighted protein density, is used to detect degenerative processes in soft tissue, such as the
`brain; the degenerative processes are indicative of a neurodegenerative disease; paragraphs [0008], [0111]).
`
`As per claim 41, MAZER discloses the method of claim 40. MAZER further discloses wherein the tissue is selected from the group
`consisting of: spinal cord tissue, heart tissue, vascular tissue, lung tissue, liver tissue, kidney tissue, esophageal tissue, stomach tissue,
`intestinal tissue, pancreatic tissue. thyroid tissue, adrenal tissue, spleen tissue, lymphatic tissue, appendix tissue, breast tissue, bladder
`tissue, vaginal tissue, ovarian tissue, uterine tissue, penile tissue, testicular tissue. prostatic tissue, skeletal muscle tissue, skin, and
`non-brain tissue of the head and neck (soft tissue in the embodiments includes cartilage, fatty tissue and peripheral nerve tissue
`(non-brain tissue); paragraphs [0009]),
`
`Claims 15/14/13/12/11/10/6-9 and 16/ 15/14/13/1 2/1 1/10/6-9 lack an inventive step under PCT Article MAZER in view of "Diagnostic
`neuroimaging across diseases” to KLOPPEL, et al. hereinafter “KLOPPEL”.
`
`As per claims 15/14/13/12/11/10/6—9, MAZER discloses the method of claims 14/13/12/11/10/6-9. MAZER further discloses the models
`are microstructural models (simulations are generated from data based on tissue types characterized by properties of very small
`structures across a voxel, e.g. white matter microstructures; figure 16; paragraphs [0034], [0158], [0161], [0167]) MAZER does not
`disclose wherein the one or more models are selected from a model library. KLOPPEL discloses wherein the one or more models are
`selected from a model library (methods of analyzing MRl-based recognition models to diagnose neurodegenerative disorders include
`the goal of acquiring a training data set to form a library of the disease specific patterns, e,g. models; page 458, column 1, paragraph 5).
`It would have been obvious to one of ordinary skill in the art to modify the microstructural model of MAZER with a library of such models
`as taught by KLOPPEL for the advantage of a large enough data set to reliably diagnose the pattem of the disease against the
`variability of the disease from subjectto subject (KLOPPEL: page 458, column 1, paragraph 5).
`
`As per claims 16/15/14/13l12/11/10/6—9, MAZER and KLOPF’EL in combination, disclose the method of claims 15/14/13/12/11/10/6-9.
`MAZER further discloses the models are microstructural models (simulations are generated from data based on tissue types
`characterized by properties of very small structures across a voxel, e.g, white matter microstructures; figure 16; paragraphs [0034],
`[0158], [0161], [0167]), MAZER does not disclose wherein the model library comprises at least 100 models. KLOPPEL discloses
`wherein the model library comprises at least 100 models (advanced pattern recognition study based on MRI image analysis of 69
`schizophrenic patients and 79 healthy controls for a total of at least 148 models, one from each subject, to be considered in the training
`algorithm; page 460. column 1, paragraph 1),
`it would have been obvious to one of ordinary skill in the art to modify the microstructural
`m