`
`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
`
`02/20/2015
`
`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 3/19/14.
`[I A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filed on
`
`2b)lX| This action is non-final.
`2a)I:| 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.
`
`1) E Notice of References Cited (PTO-892)
`3) I] Interview Summary (PTO-413)
`.
`.
`Paper No(s)/Mai| Date.
`2) E Information Disclosure Statement(s) (PTO/SB/08a and/or PTO/SB/08b)
`Paper No(s)/Mai| Date 4/24/14. 4) D Other: —-
`
`U.S. Patent and Trademark Office
`PTOL-326 (Rev. 11-13)
`
`Office Action Summary
`
`Part of Paper No./Mai| Date 20150211
`
`Disposition of Claims*
`5)IXI C|aim(s) 1-10 and 12-24 is/are pending in the application.
`5a) Of the above claim(s)
`is/are withdrawn from consideration.
`6 III Claim s) _ is/are allowed.
`s 1-10 and 12-24 is/are rejected.
`
`is/are objected to.
`
`) )
`
`_
`
`
`are subject to restriction and/or election requirement.
`9)|:l Claim(s
`)
`* 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.
`
`Attach ment(s)
`
`
`
`

`

`Application/Control Number: 13/521 ,683
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`Page 2
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`Art Unit: 1649
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`The action dated 02/13/2015 is incomplete due to a system error and is thus vacated.
`The instant office action replaces the vacated action.
`
`The present application is being examined under the pre-AIA first to invent
`1.
`provisions.
`
`DETAILED ACTION
`
`RESPONSE TO AMENDMENT
`
`2.
`
`A request for continued examination under 37 CFR 1.114, including the fee set
`
`forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this
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`application is eligible for continued examination under 37 CFR 1.114, and the fee set
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`forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action
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`has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/19/14
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`has been entered.
`
`Status of Application/Amendments/claims
`
`3.
`
`Applicant’s amendment filed 3/19/14 is acknowledged. Claim 11 is canceled.
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`Claims 1, 3 and 12 are amended. Claim 24 is newly added. Claims 1-10, 12-23 and
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`newly added claim 24 are pending in this application and under examination in this
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`office action.
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`4.
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`Applicant’s arguments filed on 3/19/14 have been fully considered but they are
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`not deemed to be persuasive for the reasons set forth below.
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`

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`Application/Control Number: 13/521 ,683
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`Page 3
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`Art Unit: 1649
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`Claim Rejections/Objections Withdrawn
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`5.
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`The rejection of claim 1-3, 6-11, 15-19 and 21-23 pre-AIA 35 U.S.C. 102 (b) as
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`being anticipated by US2009/0123952 (Slemmon, published on May 14, 2009, priority
`
`Nov 12, 2004) is withdrawn in response to Applicant’s amendment to the claims and
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`arguments on p. 7 of the response.
`
`The rejection of claim 11 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) in
`
`view of EP1882944 or US2010/0129847 (Navarrete Santos 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 moot because the claim is canceled.
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`Claim Rejections/Objections Maintained
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`In view of the amendment filed on 3/19/14, the following rejections are maintained.
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`Claim Rejections - 35 USC § 103
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`6.
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`The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis
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`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.
`
`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
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`obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
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`Page 4
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`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
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`not commonly owned at the time a later invention was made in order for the examiner to
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`consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C.
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`102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
`
`Claims 1-10 and 12-24 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) 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). The rejection is
`
`maintained for the reasons made of record and the reasons set forth below.
`
`Claims 1-2, 4-8, 10, 12 and 21 -23 are drawn to an amyloid [3 measurement
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`method comprising: a sample preparation step in which a sample comprising amyloid [3
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`is placed in a sample treatment vessel, wherein the sample is an irrigation solution
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`obtained by irrigation of living tissue; a concentration step in which a solubilizer that
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`solubilizes amyloid [3 is added to the sample in the sample treatment vessel and an
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`amount of solvent contained in the sample is reduced by a concentration operation to
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`provide a concentrated sample, wherein the solubilizer is in an effective amount to
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`dissociate amyloid [3 oligomers into amyloid [3 monomers; a neutralization step in which
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`the concentrated sample is contacted with a neutralizing agent that neutralizes the
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`solubilizer and provides a neutralized treated sample solution; and a measurement step
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`in which the amyloid [3 monomers contained in the neutralized treated sample solution
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`are quantitatively measured based on an antigen-antibody reaction.
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`Claims 3, 9, 13-20 are drawn to an amyloid [3 measurement method comprising:
`
`a sample treatment vessel preparation step in which an additive to be attached to
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`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
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`concentration step in which the sample in the sample treatment vessel is concentrated;
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`a second concentration step in which a solubilizer that solubilizes amyloid [3 is added to
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`the sample concentrated in the first concentration step and an amount of solvent
`
`contained in the sample is reduced 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
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`in which the amyloid [3 monomers contained in the neutralized treated sample solution
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`are quantitatively measured based on an antigen-antibody reaction.
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`Claim 24 is drawn to an amyloid [3 measurement method comprising: a sample
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`preparation step in which a sample comprising amyloid [3 is placed in a sample
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`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 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.
`
`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
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`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
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`performed without insolubilizing amyloid [3 (claims 9), a body fluid (claims 10 and 18), an
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`irrigation solution obtained by irrigating of living tissue (claims 11 and 19), amyloid
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`monomers are amyloid [342 monomers and/or amyloid [340 monomers (claim 22),
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`wherein the solubilizer is added to the sample to obtain a mixture and the mixture is
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`subjected to the concentration operation to reduce the amount of solvent contained in
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`the sample (claim 23).
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`Slemmon (U82009/O123952) 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
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`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
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`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
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`sample in the sample treatment vessel and an amount of solvent contained in the
`
`sample is reduced by a concentration operation; a neutralization step in which the
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`solubilizer in a treated sample solution obtained in the concentration step is neutralized;
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`and a measurement step in which amyloid [3 possibly contained in a neutralized treated
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`sample solution is quantitatively measured based on an antigen-antibody reaction as in
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`1-3, 6-11, and 15-19 (see p. 2—3; p. 6-9; claims 1-25 in particular). Slemmon 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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`3, a solubilizer including guanidine HCL as in claims 1-3 (see p. 2—3; p.6-9, in particular),
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`a blocking agent including BSA as in claims 6-7 and 15-16 (see p. 2—3; p. 6-9, [0065]-
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`[0068], in particular), an inner wall surface inhibiting adsorption of amyloid b as in claims
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`

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`8 and 17 (see p. 6-9; [0059]-[0065], in particular), concentration performed without
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`insolubilizing amyloid [3 as in claims 9 (see p. 2-3; p. 6-9;
`
`[0059]-[OO65], in particular), a
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`body fluid as in claims 10 and 18 (see p. 2-3; p. 6-9;
`
`[0059]-[OO65], in particular).
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`But Slemmon (US2009/0123952) fails to teach an irrigation solution obtained by
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`irrigating of living tissue as in independent claims 1, 3 and 19 (see p. 6-9; [0059]-[0065],
`
`in particular formic acid or organic acid as solubilizers as in claims 4, 13, 21 and 24, an
`
`additive containing formic acid and S—allyl-L-cysteine as in claims 5 and 14, and also fail
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`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
`
`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
`
`steps including demasking the epitopes responsible for antibody binding on the Abeta
`
`peptide oligomers as well as detecting fluorescently marked antibodies binding to said
`
`epitopes, which meets the limitations recited in instant claims (see abstract; p. 1-3; p. 4-
`
`5, examples 1-7; p. 6-7, claims 11-25, in particular). Navarrete teaches an amyloid [3
`
`measurement method comprising: a) providing a sample of a body fluid to be tested
`
`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
`
`treatment vessel); b) demasking the epitopes responsible for antibody binding on said
`
`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
`
`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
`
`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.
`
`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
`
`and 3 (Le. proteinase inhibitors; see [0027], in particular), a solubilizer including formic
`
`acid (i.e. organic acid) as in claims 4,13, 21 and 24 (Le. different detergents including
`
`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). Navarrete teaches a body fluid as
`
`in claims 10 and 18 (see [0023]-[OO27], in particular) and an irrigation solution obtained
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`by irrigating of living tissue as in claims 11 and 19 (see [0023]-[OO27]; in particular).
`
`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
`
`found in the olfactory mucosa (see p. 423; p. 425 and table, in particular).
`
`Gupta et al. teach that S-allyl-L-cysteine (SAC) can prevent cognitive decline by
`
`protecting neurons from Abeta induced neuronal apoptosis. Gupta et al. teach that SAC
`
`dose-dependently inhibited Abeta fibrillation and also destabilized performed Abeta
`
`fibrils (see p. 75, abstract, in particular). Gupta et al. teach that SAC acts as a breaker
`
`of the preformed Abeta fibrils and prevent the self-oligomerization of Abeta (see p. 79,
`
`in particular).
`
`It would have been obvious to a skilled artisan at the time the instant invention
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`was made to incorporate the teaching of Navarrete Santos (US2010/0129847) and
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`Gupta to include Formic acid and SAC as an additive in the method of to solubilize
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`Abeta oligomers or fibril and to prevent Abeta from further oligomerization, increase
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`solubilization and reveal more epitopes of Abeta in a solution. The skilled artisan would
`
`have been motivated to do so with an expectation of success because SAC has been
`
`shown to inhibit Abeta oligomerization in solution.
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`In addition, it would have been obvious to one of ordinary skill in the art at the
`
`time the instant invention was made to incorporate the teaching of Yamagishi et al. and
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`Navarrete Santos (U82010/O129847) in the method of Slemmon (U82009/O123952) to
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`measure Abeta in nasal mucosa by irrigation of nasal mucosa with an irrigation solution.
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`The skilled artisan would have been motivated to do so with an expectation of success
`
`because Abeta deposits can be found in nasal mucosa, the same pathologic changes in
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`the brain are also present in the olfactory mucosa of patients with AD, and thus an
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`olfactory mucosal biopsy can be a useful method for a definitive diagnosis of AD.
`
`On p. 8-10 of the response, Applicant argues that Slemmon fails to teach each
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`and every element of claims 1 and 3 and Navarrete and Gupta fail to cure the
`
`deficiencies of Slemmon because Navarrete and Gupta fail to teach or suggest a
`
`method of measuring Abeta in a sample wherein the sample is an irrigation solution
`
`obtained by irrigation of living tissue. Applicant also argues that Yamagashi also fails to
`
`cure the deficiency because Yamagashi is an invitation to research and does not teach
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`the detection of amyloid beta monomers in an olfactory mucosal biopsy sample.
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`Applicant further cites Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino in
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`support of the arguments. Applicant argues that the amount of Abeta in an irrigation
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`solution such as that of nasal mucus is extremely low; and thus a skilled artisan would
`
`not have predicted claims 1-10 and 12-23 from the teachings of Slemmon, Navarrete,
`
`Gupta and Yamagashi. Applicant further argues that Slemmon, Navarrete, Gupta and
`
`Yamagashi fail to teach or suggest an Abeta measurement method in which “..a
`
`solubilizer (an organic acid) that solubilizes amyloid beta oligomer..." as in claim 24.
`
`Applicant argues that Slemmon not only fails to teach or suggest an organic acid
`
`solubilizer but also fails to teach a concentration step in which "a solubilizer that
`
`solubilizes amyloid beta oligomers is added to sample...wherein the solubilizer is in an
`
`amount effective to dissociate amyloid beta oligomers into amyloid beta monomers.
`
`Applicant further cites In re Robertson in support of the arguments. Applicant argues
`
`that Slemmon does not inherently teach the claimed “concentration step.." because
`
`Slemmon requires dilution of the denaturing agent and that denaturing action of
`
`guanidine hydrochloride is reversible, and thus diluting guanidine hydrochloride would
`
`most likely result in Abeta monomers to self-associated or aggregate into oligomers
`
`and/or polymers. Applicant argues that Navarret, Gupta and Yamagashi fail to cure this
`
`deficiency in Slemmon because Navarrete only teaches formic acid as one of many
`
`detergents but fails to teach the use of formic acid in an amount effective to dissociate
`
`Abeta oligomers into Abeta monomers. Applicant argues that the detergent
`
`concentration is chosen not to dissociate Abeta oligomers into Abeta monomers
`
`because a low concentration (about 0.01 -2%) of detergent is used to demask Abeta
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`oligomer. Applicant further argues that Slemmon, Navarrete, Gupta and Yamagashi fail
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`to teach “a measurement step in which the amyloid beta monomers contained in the
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`neutralized treated sample solution are quantitatively measured based on an antigen-
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`antibody reaction because Slemmon is directed to a HPLC method and Navarrete's
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`method is incapable of detecting Abeta monomers. Applicant argues that Gupta and
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`Yamagashi fail to cure the deficiency in Slemmon and Navarrete.
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`Applicant's arguments have been fully considered but they are not persuasive.
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`Contrary to Applicant’s arguments, the examiner asserts that Slemmon does teach the
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`claimed method because Slemmon teaches the use of guanidine hydrochloride as an
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`agent to dissociate Amyloid beta oligomers into Amyloid beta monomers. Applicant's
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`interpretation on the use of guanidine hydrochloride is incorrect because Slemmon
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`teaches that it is preferred that the denaturing agent is also capable of causing release
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`of Amyloid beta peptides that are bonded to other proteins, peptides, or molecules in
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`the sample, and such a denaturing agent includes guanidine salts such as guanidine
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`hydrochloride (guanidine HCI) and urea (see [0021], in particular).
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`In addition, as set forth above, contrary to Applicant’s arguments, the examiner
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`asserts that Slemmon does teach “a neutralization step in which the concentrated
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`sample is contacted with a neutralizing agent that neutralizes the solubilizer and
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`provides a neutralized treated sample solution as in amended claims 1 and 3 because
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`Slemmon teaches that the peptides in the denaturing solution are re-dissolved in a
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`suitable medium containing acetic acid and trifluoroacetic acid is added in the final
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`solution for immunoassay such as ELISA and mass spec to measure the concentration
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`of Abeta monomers (see [OO24]—[OO28]; [0030]-[0037], in particular).
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`Application/Control Number: 13/521 ,683
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`Page 14
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`Art Unit: 1649
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`In addition, Applicant cannot show nonobviousness by attacking references
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`individually where the rejections are based on combinations of references. See In re
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`Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck& 00., 800 F.2d 1091,
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`231 USPQ 375 (Fed. Cir. 1986).
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`In this case, US2009/0123952 (Slemmon) teaches quantitative methods of
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`measuring the amount of at least one Abeta species in a sample of biological fluid,
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`which comprises the steps of contacting the sample with a denaturing agent comprising
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`guanidine hydrochloride; extracting a peptide pool from the sample-denaturing agent
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`mixture by solid phase extraction; separating the Abeta species from the peptide pool
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`by reverse phase HPLC; and determining the amount of the Abeta species separated
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`from the peptide pool by an immunoassay (see p.2-4; p. 6-8, in particular). The step of
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`solubilizing Abeta oligomers or fibril in the presence of guainidine hydrochloride meets
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`the limitation "wherein the solubilizer dissociates amyloid beta oligomers into amyloid
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`beta monomers”.
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`Although US2009/0123952 (Slemmon) does not teach formic acid or organic acid
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`as solubilizers as in claims 4, 13 and 21, and formic acid and S—allyl-L-cysteine (SAC)
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`as an additive as in claims 5 and 14, US2010/0129847 (Navarrete et al.) 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 as in claims 4 and 13 (Le. different detergents including formic acid, see [0023]-
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`[[0043], in particular), a blocking agent as in claims 6 and 15 (Le. Hepes, see [0065],
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`Application/Control Number: 13/521 ,683
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`Page 15
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`Art Unit: 1649
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`[0068], in particular), and Gupta et al. teach that S-allyl-L-cysteine (SAC) can prevent
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`cognitive decline by protecting neurons from Abeta induced neuronal apoptosis. Gupta
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`et al. teach that SAC dose-dependently inhibited Abeta fibrillation and also destabilized
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`performed Abeta fibrils (see p. 75, abstract, in particular). Gupta et al. teach that SAC
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`acts as a breaker of the preformed Abeta fibrils and prevent the self-oligomerization of
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`Abeta (see p. 79, in particular). It would have been obvious to one of ordinary skill in the
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`art at the time the instant invention was made to incorporate the teaching of
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`US2010/0129847 (Navarrete et al.) and Gupta to include Formic acid and SAC as an
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`additive in the method of US2009/0123952 (Slemmon) to solubilize Abeta oligomers or
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`fibril and to prevent Abeta from further oligomerization, increase solubilization and
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`reveal more epitopes of Abeta in a solution. The person of ordinary skill in the art would
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`have been motivated to do so with an expectation of success because SAC has been
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`shown to inhibit Abeta oligomerization in solution.
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`In addition, although US2009/0123952 (Slemmon) fails to teach nasal mucosa as
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`in claims 12 and 20, Yamagishi et al. teach that a senile plaque-like extracellular mass
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`was found in the olfactory epithelium, and it reacted strongly to an anti-Tau antiserum
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`and weakly to an anti-amyloid-beta protein antiserum. Yamagishi et al. teach that the
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`same pathologic changes in the brain are also present in the olfactory mucosa of
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`patients with AD. Not only disruption of the central olfactory pathway, but also an
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`olfactory disturbance of AD patients is caused by peripheral changes, and thus, an
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`olfactory mucosal biopsy could be a useful method for a definitive diagnosis of AD (see
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`p. 421, abstract, in particular). Thus, it would have been obvious to one of ordinary skill
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`Application/Control Number: 13/521 ,683
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`Page 16
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`Art Unit: 1649
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`in the art at the time the instant invention was made to incorporate the teaching of
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`Yamagishi et al. in the methods of US2009/0123952 (Slemmon) and US2010/0129847
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`(Navarrete) to measure Abeta in nasal mucosa. The person of ordinary skill in the art
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`would have been motivated to do so with an expectation of success because Abeta
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`deposits can be found in nasal mucosa, the same pathologic changes in the brain are
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`also present in the olfactory mucosa of patients with AD, and thus an olfactory mucosal
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`biopsy can be a useful method for a definitive diagnosis of AD.
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`Note that the motivation to combine can arise from the expectation that the prior
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`art elements will perform their expected functions to achieve their expected results
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`when combined for their common known purpose. MPEP. §2144.07. Specific
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`statements in the references themselves which would spell out the claimed invention
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`are not necessary to show obviousness, since questions of obviousness involve not
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`only what references expressly teach, but what they would collectively suggest to one of
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`ordinary skill in the art. See CTS Corp. v. Electro Materials Corp. of America 202 USPQ
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`22 (DC SNY 1979); and In re Burcke/201 USPQ 67 (CCPA 1979). It is not necessary
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`that the claimed invention be expressly suggested in any one or all of the references to
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`justify combining their teachings; rather the test is what the combined teachings of the
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`references would have suggested to those of ordinary skill in the art. In re Keller, 642
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`F.2d 413, 208 USPQ 871 (CCPA 1981). Accordingly, the rejection of claims 1-10 and
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`12-24 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US2009/0123952
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`(Slemmon) in view of US2010/0129847 (Navarrete et al.), Gupta et al. and Yamagishi et
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`al. is maintained.
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`Application/Control Number: 13/521,683
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`Page 17
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`Art Unit: 1649
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`New Grounds of Rejection
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`Claim Rejections - 35 USC § 1 12
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`7.
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`The following is a quotation of 35 U.S.C. 112(d):
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`(d) REFERENCE IN DEPENDENT FORMS—Subject to subsection (e), a claim in dependent
`form shall contain a reference to a claim previously set forth and then specify a further
`limitation of the subject matter claimed. A claim in dependent form shall be construed to
`incorporate by reference all the limitations of the claim to which it refers.
`
`The following is a quota