`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMIVHSSIONER FOR PATENTS
`PO. Box 1450
`Alexandria1 Virginia 22313-1450
`wwwusptogov
`
`
`
`
`
`13/521,683
`
`07/11/2012
`
`Toshifumi Nanjoh
`
`061352—0478
`
`2288
`
`McDermott Will and Emery LLP
`The McDermott Building
`500 North Capitol Street, NW.
`WASHINGTON, DC 20001
`
`WANG, CHANG YU
`
`1649
`
`PAPER NUMBER
`
`NOTIFICATION DATE
`
`DELIVERY MODE
`
`06/04/2015
`
`ELECTRONIC
`
`Please find below and/0r attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`Notice of the Office communication was sent electronically on above—indicated "Notification Date" to the
`following e—mail address(es):
`
`mweipdocket @ mwe.com
`
`PTOL—90A (Rev. 04/07)
`
`

`

`
`Application No.
`Applicant(s)
`
` 13/521,683 NANJOH ET AL.
`Examiner
`Art Unit
`AIA (First Inventorto File)
`Office Action Summary
`
`1649Chang-Yu Wang a?”
`
`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address --
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE g MONTHS FROM THE MAILING DATE OF
`THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR 1.136(a).
`after SIX (6) MONTHS from the mailing date of this communication.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication.
`Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1.704(b).
`
`In no event, however, may a reply be timely filed
`
`-
`-
`
`Status
`
`1)IXI Responsive to communication(s) filed on 5/18/15.
`[I A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filed on
`
`2b)|:| This action is non-final.
`2a)IZ| This action is FINAL.
`3)I:I An election was made by the applicant in response to a restriction requirement set forth during the interview on
`
`
`; the restriction requirement and election have been incorporated into this action.
`
`4)|:I Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
`closed in accordance with the practice under EX parte Quay/e, 1935 CD. 11, 453 O.G. 213.
`
`Disposition of Claims*
`
`5)IXI C|aim(s) 1-9 12—17and 20-24 is/are pending in the application.
`5a) Of the above claim(s)
`is/are withdrawn from consideration.
`6 III Claim s) _ is/are allowed.
`
`1-9 12—1 7 and 20-24 is/are rejected.
`
`is/are objected to.
`
`
`
`are subject to restriction and/or election requirement.
`* If any claims have been determined allowable, you may be eligible to benefit from the Patent Prosecution Highway program at a
`
`participating intellectual property office for the corresponding application. For more information, please see
` S
`htt
`://www.usoto. ov/ atents/init events) .h/index.‘
`
`
`
`, or send an inquiry to PF"I-Ifeedback{<‘buspto.qov.
`
`Application Papers
`
`10)I:I The specification is objected to by the Examiner.
`11)|:I The drawing(s) filed on _ is/are: a)I:I accepted or b)I:I objected to by the Examiner.
`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121 (d).
`
`Priority under 35 U.S.C. § 119
`12)I:I Acknowledgment is made of a claim for foreign priority under 35 U.S.C. §119(a)-(d) or (f).
`Certified copies:
`
`b)I:I Some” c)I:I None of the:
`a)I:I All
`1.I:I Certified copies of the priority documents have been received.
`2.I:I Certified copies of the priority documents have been received in Application No.
`3.I:I Copies of the certified copies of the priority documents have been received in this National Stage
`
`application from the International Bureau (PCT Rule 17.2(a)).
`** See the attached detailed Office action for a list of the certified copies not received.
`
`Attachment(s)
`
`
`
`3) D Interview Summary (PT0_413)
`1) E Notice of References Cited (PTO-892)
`Paper No(s)/Mai| Date.
`.
`.
`—
`4) I:I Other'
`2) D Information Disclosure Statement(s) (PTO/SB/08a and/or PTO/SB/08b)
`
`Paper No(s)/Mai| Date .
`U.S. Patent and Trademark Office
`PTOL-326 (Rev. 11-13)
`
`Office Action Summary
`
`Part of Paper No./Mai| Date 20150527
`
`

`

`Application/Control Number: 13/521 ,683
`
`Page 2
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`Art Unit: 1649
`
`1.
`
`The present application is being examined under the pre-AlA first to invent
`
`provisions.
`
`DETAILED ACTION
`
`RESPONSE TO AMENDMENT
`
`Status of Application/Amendments/claims
`
`2.
`
`Applicant’s amendment filed 5/18/15 is acknowledged. Claims 10, 11, 18 and 19
`
`are canceled. Claims 1, 3 and 24 are amended. Claims 1-9, 12-17 and 20-24 are
`
`pending in this application and under examination in this office action.
`
`3.
`
`Applicant’s arguments filed on 5/18/15 have been fully considered but they are
`
`not deemed to be persuasive for the reasons set forth below.
`
`Claim Rejections/Objections Withdrawn
`
`4.
`
`The rejection of claims 1-10 and 12-24 under pre-AlA 35 U.S.C. 103(a) as being
`
`unpatentable over US2009/0123952 (Slemmon, published on May 14, 2009, priority
`
`Nov 12, 2004) in view of EP1882944 or US2010/0129847 (Navarrete et al., published
`
`on Jan 30, 2008, as in IDS), Gupta et al. (Neurosci. Lett. 2007, 429: 75-80) and
`
`Yamagishi et al. (Ann Otol. Rhinol. Laryngol. 1994. 103: 421 -7) is withdrawn in
`
`response to Applicant’s amendment to the claims and cancellation of claims 10, 18 and
`
`19.
`
`The rejection of claims 10, 18 and 19 under 35 U.S.C. 112(d) or pre-AlA 35
`
`U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further
`
`

`

`Application/Control Number: 13/521 ,683
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`Page 3
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`Art Unit: 1649
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`limit the subject matter of the claim upon which it depends is moot because the claims
`
`are canceled.
`
`The rejection of claims 10, 18 and 19 under 35 U.S.C. 101 because the claimed
`
`invention is directed to a judicial exception (Le, a law of nature, a natural phenomenon,
`
`or an abstract idea) without significantly more is moot because the claims are canceled.
`
`Claim Rejections/Objections Maintained
`
`In view of the amendment filed on 5/18/15, the following rejections are maintained.
`
`Claim Rejections - 35 USC § 101
`
`5.
`
`35 U.S.C. 101 reads as follows:
`
`Whoever invents or discovers any new and useful process, machine, manufacture, or composition of
`matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the
`conditions and requirements of this title.
`
`Claims 1-9, 12-17 and 20-24 stand rejected under 35 U.S.C. 101 because the
`
`claimed invention is directed to a judicial exception (Le, a law of nature, a natural
`
`phenomenon, or an abstract idea) without significantly more. Claim(s) 1-9, 12-17 and
`
`20-24 is/are directed to an amyloid [3 measurement method. The claim(s) does/do not
`
`include additional elements that are sufficient to amount to significantly more than the
`
`judicial exception because the claims are based on a correlation between different
`
`expression levels of Abeta peptides in the brain or a body fluid and patients suffering
`
`from Alzheimer’s disease and the claims recite elements/steps in addition to the judicial
`
`exception(s) that are well-understood, purely conventional or routine in the relevant
`
`field, the elements/steps recited in the claims in addition to the judicial exception(s) that
`
`

`

`Application/Control Number: 13/521 ,683
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`Page 4
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`Art Unit: 1649
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`are insignificant extra-solution activity, are merely appended to the judicial exception(s)
`
`and amount to nothing more than a mere field of use.
`
`Claims 1-2, 4-8, 12 and 21 -23 as amended are drawn to an amyloid [3
`
`measurement method comprising the following steps in the following order: a sample
`
`preparation step in which a sample comprising amyloid [3 is placed in a sample
`
`treatment vessel, wherein the sample is an irrigation solution obtained by irrigation of
`
`living tissue; a concentration step in which a solubilizer that solubilizes amyloid [3 is
`
`added to the sample in the sample treatment vessel and an amount of solvent
`
`contained in the sample is reduced without drying and solidifying the sample by a
`
`concentration operation to provide a concentrated sample, wherein the solubilizer is in
`
`an effective amount to dissociate amyloid [3 oligomers into amyloid [3 monomers; a
`
`neutralization step in which the concentrated sample is contacted with a neutralizing
`
`agent that neutralizes the solubilizer and provides a neutralized treated sample solution;
`
`and a measurement step in which the amyloid [3 monomers contained in the neutralized
`
`treated sample solution are quantitatively measured based on an antigen-antibody
`
`reaction.
`
`Claims 3, 9, 13-17 and 20 as amended are drawn to an amyloid [3 measurement
`
`method comprising the following steps in the following order: a sample treatment vessel
`
`preparation step in which an additive to be attached to amyloid [3 oligomers is placed in
`
`a sample treatment vessel; a sample preparation step in which a sample comprising
`
`amyloid [3 is placed in the sample treatment vessel, wherein the sample is an irrigation
`
`solution obtained by irrigation of living tissue; a first concentration step in which the
`
`

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`Application/Control Number: 13/521 ,683
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`Page 5
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`Art Unit: 1649
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`sample in the sample treatment vessel is concentrated; a second concentration step in
`
`which a solubilizer that solubilizes amyloid [3 is added to the sample concentrated in the
`
`first concentration step and an amount of solvent contained in the sample is reduced
`
`without drying and solidifying the sample by a concentration operation to provide a
`
`concentrated sample, wherein the solubilizer is in an effective amount to dissociate
`
`amyloid [3 oligomers into amyloid [3 monomers; a neutralization step in which the
`
`concentrated sample is contacted with a neutralizing agent that neutralizes the
`
`solubilizer and provides a neutralized treated sample solution; and a measurement step
`
`in which the amyloid [3 monomers contained in the neutralized treated sample solution
`
`are quantitatively measured based on an antigen-antibody reaction.
`
`Claim 24 as amended is drawn to an amyloid [3 measurement method
`
`comprising: a sample preparation step in which a sample comprising amyloid [3 is
`
`placed in a sample treatment vessel; a concentration step in which a solubilizer that
`
`solubilizes amyloid [3 is added to the sample in the sample treatment vessel and an
`
`amount of solvent contained in the sample is reduced without drying and solidifying the
`
`sample by a concentration operation to provide a concentrated sample, wherein the
`
`solubilizer is an organic acid in an amount effective to dissociate amyloid [3 oligomers
`
`into amyloid [3 monomers; a neutralization step in which the concentrated sample is
`
`contacted with a neutralizing agent that neutralizes the solubilizer and provides a
`
`neutralized treated sample solution; and a measurement step in which the amyloid [3
`
`monomers contained in the neutralized treated sample solution are quantitatively
`
`measured based on an antigen-antibody reaction.
`
`

`

`Application/Control Number: 13/521 ,683
`
`Page 6
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`Art Unit: 1649
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`On p. 9-10 of the response, Applicant argues that independent claims 1, 3 and
`
`24 recite a concentration step or a second concentration step in which a solublizer that
`
`solubilizes Abeta is added to the sample in the sample treatment vessel, and an amount
`
`of solvent contained in the sample is reduced without drying and solidifying the sample
`
`by a concentration operation. Applicant argues that the claimed steps are not
`
`conventional, the primary reference, Slemmon teaches away from this step and the
`
`combined references would not have expected the advantages of the claimed method.
`
`Applicant’s arguments have been fully considered but they are not persuasive.
`
`Contrary to Applicant’s arguments, the examiner asserts that the claimed invention is
`
`directed to a judicial exception (Le, a law of nature, a natural phenomenon, or an
`
`abstract idea) without significantly more because because the claims are based on a
`
`correlation between different expression levels of Abeta peptides in the brain or a body
`
`fluid and patients suffering from Alzheimer’s disease and the claims recite
`
`elements/steps in addition to the judicial exception(s) that are well-understood, purely
`
`conventional or routine in the relevant field, the elements/steps recited in the claims in
`
`addition to the judicial exception(s) that are insignificant extra-solution activity, are
`
`merely appended to the judicial exception(s) and amount to nothing more than a mere
`
`field of use.
`
`As previously made of record, the additional steps “a sample preparation step in
`
`which a sample comprising amyloid [3 is placed in a sample treatment vessel, wherein
`
`the sample is an irrigation solution obtained by irrigation of living tissue; a concentration
`
`step in which a solubilizer that solubilizes amyloid [3 is added to the sample
`
`a
`
`

`

`Application/Control Number: 13/521 ,683
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`Page 7
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`Art Unit: 1649
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`neutralization step
`
`and a measurement step
`
`as recited in independent claims 1, 3
`
`and 24 are well-understood steps and purely routine as evidenced by US2009/0123952
`
`(Slemmon, published on May 14, 2009, priority Nov 12, 2004) in view of EP1882944 or
`
`US2010/0129847 (Navarrete et al., published on Jan 30, 2008, as in IDS), Gupta et al.
`
`(Neurosci. Lett. 2007, 429: 75-80) and Yamagishi et al. (Ann Otol. Rhinol. Laryngol.
`
`1994. 103: 421-7). In addition, newly added limitation “an amount of solved contained in
`
`the sample is reduced without drying and solidifying the sample by a concentration
`
`operation" is also well-understood steps and purely routine in the relevant field as
`
`evidenced by US2007/0172846 (Zhang et al., published Jul 26, 2007).
`
`US2007/0172846 (Zhang et al.) teaches a step to concentrate a solution by
`
`ultrafiltration, which is not to reduce the amount of solvent contained in the sample
`
`without drying and solidifying the sample (see [0278]-[0279], in particular). The
`
`additional steps/elements recited in the claims in addition to the judicial exception(s)
`
`that are well-understood, purely conventional or routine in the relevant field, the
`
`elements/steps recited in the claims in addition to the judicial exception(s) that are
`
`insignificant extra-solution activity, are merely appended to the judicial exception(s) and
`
`amount to nothing more than a mere field of use as evidenced by US2009/0123952
`
`(Slemmon, published on May 14, 2009, priority Nov 12, 2004) US2007/0172846 (Zhang
`
`et al.), EP1882944 or US2010/0129847 (Navarrete et al., published on Jan 30, 2008, as
`
`in IDS), Gupta et al. (Neurosci. Lett. 2007, 429: 75-80) and Yamagishi et al. (Ann Otol.
`
`Rhinol. Laryngol. 1994. 103: 421-7). Thus, the steps recited in independent claims are
`
`well-understood and purely routine and are no more than a field of use or merely involve
`
`

`

`Application/Control Number: 13/521 ,683
`
`Page 8
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`Art Unit: 1649
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`insignificant extrasolution activity. Thus, the additional elements or steps in the claim do
`
`not integrate the natural principle into the method and the additional elements or steps
`
`in the claim are not sufficient to ensure that the claim amounts to significantly more than
`
`the natural principle itself. These additional elements or steps are mere field of use that
`
`impose no meaningful limit on the performance of the method and are no more than
`
`well-understood, purely conventional, and routinely taken by others in order to apply the
`
`natural principle. Accordingly, the instant claims are directed to a judicial exception (Le,
`
`a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
`
`Thus, Claims 1-9, 12-17 and 20-24 are not patent-eligible. Accordingly, the rejection of
`
`claims 1-9, 12-17 and 20-24 under 35 U.S.C. 101 because the claimed invention is
`
`directed to a judicial exception (Le, a law of nature, a natural phenomenon, or an
`
`abstract idea) without significantly more is maintained.
`
`New Grounds of Rejection Necessitated by the Amendment
`
`The following rejections are new grounds of rejections necessitated by the amendment
`
`filed on 5/18/15.
`
`Claim Rejections - 35 USC § 103
`
`6.
`
`The following is a quotation of pre-AlA 35 U.S.C. 103(a) which forms the basis
`
`for all obviousness rejections set forth in this Office action:
`
`(a) A patent may not be obtained though the invention is not identically disclosed or described
`as set forth in section 102 of this title, if the differences between the subject matter sought to
`be patented and the prior art are such that the subject matter as a whole would have been
`obvious at the time the invention was made to a person having ordinary skill in the art to which
`said subject matter pertains. Patentability shall not be negatived by the manner in which the
`invention was made.
`
`

`

`Application/Control Number: 13/521 ,683
`
`Page 9
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`Art Unit: 1649
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`The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148
`
`USPQ 459 (1966), that are applied for establishing a background for determining
`
`obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
`
`1. Determining the scope and contents of the prior art.
`2. Ascertaining the differences between the prior art and the claims at issue.
`3. Resolving the level of ordinary skill in the pertinent art.
`4. Considering objective evidence present in the application indicating
`obviousness or nonobviousness.
`
`This application currently names joint inventors. In considering patentability of the
`
`claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter
`
`of the various claims was commonly owned at the time any inventions covered therein
`
`were made absent any evidence to the contrary. Applicant is advised of the obligation
`
`under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was
`
`not commonly owned at the time a later invention was made in order for the examiner to
`
`consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C.
`
`102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
`
`Claims 1-9, 12-17 and 20-24 are rejected under pre-AIA 35 U.S.C. 103(a) as
`
`being unpatentable over US2009/0123952 (Slemmon, published on May 14, 2009,
`
`priority Nov 12, 2004, cited previously) in view of US2007/0172846 (Zhang et al.,
`
`published Jul 26, 2007), EP1882944 or US2010/0129847 (Navarrete et al., published
`
`on Jan 30, 2008, as in IDS), Gupta et al. (Neurosci. Lett. 2007, 429: 75-80, cited
`
`previously) and Yamagishi et al. (Ann Otol. Rhinol. Laryngol. 1994. 103: 421-7, cited
`
`

`

`Application/Control Number: 13/521 ,683
`
`Page 10
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`Art Unit: 1649
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`previously). The rejection is maintained for the reasons made of record and the reasons
`
`set forth below.
`
`Claims 1-2, 4-8, 12 and 21 -23 as amended are drawn to an amyloid [3
`
`measurement method comprising the following steps in the following order: a sample
`
`preparation step in which a sample comprising amyloid [3 is placed in a sample
`
`treatment vessel, wherein the sample is an irrigation solution obtained by irrigation of
`
`living tissue; a concentration step in which a solubilizer that solubilizes amyloid [3 is
`
`added to the sample in the sample treatment vessel and an amount of solvent
`
`contained in the sample is reduced without drying and solidifying the sample by a
`
`concentration operation to provide a concentrated sample, wherein the solubilizer is in
`
`an effective amount to dissociate amyloid [3 oligomers into amyloid [3 monomers; a
`
`neutralization step in which the concentrated sample is contacted with a neutralizing
`
`agent that neutralizes the solubilizer and provides a neutralized treated sample solution;
`
`and a measurement step in which the amyloid [3 monomers contained in the neutralized
`
`treated sample solution are quantitatively measured based on an antigen-antibody
`
`reaction.
`
`Claims 3, 9, 13-17 and 20 as amended are drawn to an amyloid [3 measurement
`
`method comprising the following steps in the following order: a sample treatment vessel
`
`preparation step in which an additive to be attached to amyloid [3 oligomers is placed in
`
`a sample treatment vessel; a sample preparation step in which a sample comprising
`
`amyloid [3 is placed in the sample treatment vessel, wherein the sample is an irrigation
`
`solution obtained by irrigation of living tissue; a first concentration step in which the
`
`

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`Application/Control Number: 13/521 ,683
`
`Page 11
`
`Art Unit: 1649
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`sample in the sample treatment vessel is concentrated; a second concentration step in
`
`which a solubilizer that solubilizes amyloid [3 is added to the sample concentrated in the
`
`first concentration step and an amount of solvent contained in the sample is reduced
`
`without drying and solidifying the sample by a concentration operation to provide a
`
`concentrated sample, wherein the solubilizer is in an effective amount to dissociate
`
`amyloid [3 oligomers into amyloid [3 monomers; a neutralization step in which the
`
`concentrated sample is contacted with a neutralizing agent that neutralizes the
`
`solubilizer and provides a neutralized treated sample solution; and a measurement step
`
`in which the amyloid [3 monomers contained in the neutralized treated sample solution
`
`are quantitatively measured based on an antigen-antibody reaction.
`
`Claim 24 as amended is drawn to an amyloid [3 measurement method
`
`comprising: a sample preparation step in which a sample comprising amyloid [3 is
`
`placed in a sample treatment vessel; a concentration step in which a solubilizer that
`
`solubilizes amyloid [3 is added to the sample in the sample treatment vessel and an
`
`amount of solvent contained in the sample is reduced without drying and solidifying the
`
`sample by a concentration operation to provide a concentrated sample, wherein the
`
`solubilizer is an organic acid in an amount effective to dissociate amyloid [3 oligomers
`
`into amyloid [3 monomers; a neutralization step in which the concentrated sample is
`
`contacted with a neutralizing agent that neutralizes the solubilizer and provides a
`
`neutralized treated sample solution; and a measurement step in which the amyloid [3
`
`monomers contained in the neutralized treated sample solution are quantitatively
`
`measured based on an antigen-antibody reaction.
`
`

`

`Application/Control Number: 13/521 ,683
`
`Page 12
`
`Art Unit: 1649
`
`Dependent claims are directed to an additive to be attached to amyloid b placed
`
`in a sample treatment vessel (claims 2, 3), wherein the solubilizer is formic acid or
`
`organic acid (claims 4, 13, 21 and 24), an additive containing formic acid and S-allyl-L-
`
`cysteine (claims 5 and 14), a blocking agent including BSA (claims 6-7 and 15-16), an
`
`inner wall surface inhibiting adsorption of amyloid [3 (claims 8 and 17), concentration
`
`performed without insolubilizing amyloid [3 (claims 9), wherein the living tissue is nasal
`
`mucosa (claim 12), amyloid monomers are amyloid [342 monomers and/or amyloid [340
`
`monomers (claim 22), wherein the solubilizer is added to the sample to obtain a mixture
`
`and the mixture is subjected to the concentration operation to reduce the amount of
`
`solvent contained in the sample (claim 23).
`
`Slemmon (US2009/0123952) teaches quantitative methods of measuring the
`
`amount of at least one Abeta species in a sample of biological fluid, which comprises
`
`the steps of contacting the sample with a denaturing agent comprising guanidine
`
`hydrochloride; extracting a peptide pool from the sample-denaturing agent mixture by
`
`solid phase extraction; separating the Abeta species from the peptide pool by reverse
`
`phase HPLC; and determining the amount of the Abeta species separated from the
`
`peptide pool by an immunoassay (see p.2-4; p. 6-8, in particular). Slemmon teaches an
`
`amyloid [3 measurement method comprising: a sample preparation step in which a
`
`sample possibly containing amyloid [3 is placed in a sample treatment vessel; a
`
`concentration step in which a solubilizer that solubilizes amyloid [3 is added to the
`
`sample in the sample treatment vessel and an amount of solvent contained in the
`
`

`

`Application/Control Number: 13/521 ,683
`
`Page 13
`
`Art Unit: 1649
`
`sample is reduced by a concentration operation; a neutralization step in which the
`
`solubilizer in a treated sample solution obtained in the concentration step is neutralized;
`
`and a measurement step in which amyloid [3 possibly contained in a neutralized treated
`
`sample solution is quantitatively measured based on an antigen-antibody reaction as
`
`realted to claims 1-9, 12-17 and 20-24 (see p. 2—3; p. 6-9; claims 1-25 in particular).
`
`Slemmon teaches an additive to be attached to amyloid [3 placed in a sample treatment
`
`vessel as in claims 2 and 3, a solubilizer including guanidine HCL as in claims 1-3 (see
`
`p. 2—3; p.6-9, in particular), a blocking agent including BSA as in claims 6-7 and 15-16
`
`(see p. 2—3; p. 6-9, [OO65]-[0068], in particular), an inner wall surface inhibiting
`
`adsorption of amyloid [3 as in claims 8 and 17 (see p. 6-9; [0059]-[OO65], in particular),
`
`concentration performed without insolubilizing amyloid [3 as in claims 9 (see p. 2—3; p. 6-
`
`9;
`
`[0059]-[0065], in particular). Slemmon teaches that peptides in the supernatant were
`
`concentrated and desalted by solid-phase extraction over two C18 SepPak Plus
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`cartridges (Waters, Milford, Mass.) coupled in series. The cartridges had been
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`equilibrated prior to use in 0.1% trifluoroacetic acid in water and unbound material was
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`removed by washing cartridges in the same buffer (see [OO68]-[OO70], in particular).
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`But Slemmon (U82009/0123952) fails to teach the limitation “without drying and
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`solidifying the sample by a concentration operation” as in claims 1, 3 and 24. Slemmon
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`(U82009/O123952) fails to teach an irrigation solution obtained by irrigating of living
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`tissue as in independent claims 1 and 3 (see p. 6-9; [0059]-[0065], in particular formic
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`acid or organic acid as solubilizers as in claims 4, 13, 21 and 24, an additive containing
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`formic acid and S—allyl-L-cysteine as in claims 5 and 14, and also fail to teach nasal
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`mucosa as in claims 12 and 20.
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`Although Slemmon (U82009/0123952) does not teach the limitation “without
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`drying and solidifying the sample by a concentration operation” as in claims 1, 3 and 24,
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`the new limitation “an amount of solvent contained in the sample is reduced without
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`drying and solidifying the sample by a concentration operation" is also well-known steps
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`and purely routine in the art because US2007/0172846 (Zhang et al.) teaches a step of
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`concentrating polypeptides/peptides in a solution by ultrafiltration, which is not to
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`reduce the amount of solvent contained in the sample without drying and solidifying the
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`sample as recited in claims 1, 3 and 24 (see [O278]-[O279], in particular).
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`It would have
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`been obvious to a skilled artisan at the time the instant invention was made to
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`incorporate the teaching of US2007/0172846 (Zhang et al.) into the method of Slemmon
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`(US2009/0123952) to concentrate peptides in the supernatant by reducing the amount
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`of solvent contained in the sample without drying and solidifying the sample by
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`ultrafiltration to concentrate and desalt the peptides in the supernatant or in the sample.
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`The skilled artisan would have been motivated to do so with an expectation of success
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`because the step of reducing the amount of solvent contained in the sample to
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`concentrate the peptide in the sample without drying and solidifying the sample by
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`ultrafiltration has been used and known in the art as taught by US2007/0172846 (Zhang
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`et al.).
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`In addition, Slemmon (US2009/0123952) and US2007/0172846 (Zhang et al.) fail
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`to teach an irrigation solution obtained by irrigating of living tissue as in independent
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`claims 1 and 3, formic acid or organic acid as solubilizers as in claims 4, 13, 21 and 24,
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`an additive containing formic acid and S-allyl-L-cysteine as in claims 5 and 14, and also
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`fail to teach nasal mucosa as in claims 12 and 20.
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`Navarrete Santos (EP1882944 or US2010/0129847) teaches a method for the
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`detection marker of the Alzheimer's disease, namely the amyloid-beta oligomers in
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`human CSF and accurate quantification of Abeta oligomers, using a combination of
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`steps including demasking the epitopes responsible for antibody binding on the Abeta
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`peptide oligomers as well as detecting fluorescently marked antibodies binding to said
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`epitopes, which meets the limitations recited in instant claims (see abstract; p. 1-3; p. 4-
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`5, examples 1-7; p. 6-7, claims 11-25, in particular). Navarrete teaches an amyloid [3
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`measurement method comprising: a) providing a sample of a body fluid to be tested
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`with respect to the presence of amyloid-beta peptide oligomers (Le. a sample
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`preparation step in which a sample possibly containing amyloid [3 is placed in a sample
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`treatment vessel); b) demasking the epitopes responsible for antibody binding on said
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`amyloid-beta peptide oligomers using different agents and detergents and proteinase
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`inhibitors (Le. a concentration step in which a solubilizer that solubilizes amyloid [3 is
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`added to the sample in the sample treatment vessel and an amount of solvent
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`contained in the sample is reduced by a concentration operation); c) contacting said
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`sample after said demasking step with one antibody comprising an antibody population
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`binding to one epitope on said amyloid-beta peptide oligomer, one part of the antibody
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`population being labeled with a first fluorescence marker and the other part of the
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`antibody population being labeled with a second fluorescence marker, or contacting
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`said sample after said demasking step with at least two antibodies binding to at least
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`two different epitopes on said amyloid-beta peptide oligomers, the first antibody being
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`labeled with a first fluorescence marker and the at least second antibody being labeled
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`with a second fluorescence marker, wherein said first fluorescence marker acts as
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`donor transferring its energy to said second fluorescence marker acting as acceptor (Le.
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`a neutralization step in which the solubilizer in a treated sample solution obtained in the
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`concentration step is neutralized); and d) determining the intensity of the fluorescence
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`resonance energy transfer signal emitted by said fluorescence labeled sample to detect
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`amyloid-beta peptide oligomers present in said body sample (Le. a measurement step
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`in which amyloid [3 possibly contained in a neutralized treated sample solution is
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`quantitatively measured based on an antigen-antibody reaction) (see abstract; p. 1-3; p.
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`4-5, examples 1-7; p. 6-7, claims 11-25, in particular). Navarrete also teaches an
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`additive to be attached to amyloid [3 placed in a sample treatment vessel as in claims 2
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`and 3 (Le. proteinase inhibitors; see [0027], in particular), a solubilizer including formic
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`acid (i.e. organic acid) as in claims 4,13, 21 and 24 (Le. different detergents including
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`formic acid, see [0023]—[[0043], in particular), a blocking agent as in claims 6 and 15 (Le.
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`Hepes, see [0065], [0068], in particular). Navarrete Santos teaches an inner wall
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`surface inhibiting adsorption of amyloid beta as in claims 8 and 17 (see p. 1-7, in
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`particular). Navarrete teaches that the concentration is performed without insolubilizing
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`amyloid beta as in claims 9 (see p. 1-7, in particular).
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`Yamagishi et al. teach that a senile plaque-like extracellular mass was found in
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`the olfactory epithelium, and it reacted strongly to an anti-Tau antiserum and weakly to
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`an anti-amyloid-beta protein antiserum. The same pathologic changes in the brain are
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`also present in the olfactory mucosa of patients with AD. Not only disruption of the
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`central olfactory pathway, but also an olfactory disturbance of AD patients is caused by
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`peripheral changes. Furthermore, an olfactory mucosal biopsy is a useful method for a
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`definitive diagnosis of AD (see p. 421, abstract, in particular). Yamagishi et al. teach
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`olfactory mucosa was obtained from AD patients and Abeta immunoreactivity can be
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`found in the olfactory mucosa (see p. 423; p. 425 and table, in particular).
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`Gupta et al. teach that S-allyl-L-cysteine (SAC) can prevent cognitive decline