`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`PO. Box 1450
`Alexandria1 Virginia 22313- 1450
`wwwnsptogov
`
`APPLICATION NO.
`
`
`
`
` F ING DATE
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`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`
`
`
`CONF {MATION NO.
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`13/355,458
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`01/20/2012
`
`Ian Gibbons
`
`30696—733201
`
`1056
`
`21971
`
`7590
`
`01/23/2013
`
`WILSON, SONSINI, GOODRICH & ROSATI
`650 PAGE MILL ROAD
`PALO ALTO, CA 94304-1050
`
`EXAMINER
`
`REYES, CHRISTOPHER R
`
`ART UNIT
`
`1639
`
`MAIL DATE
`
`01/23/2013
`
`PAPER NUMBER
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`DELIVERY MODE
`
`PAPER
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`Please find below and/or attached an Office communication concerning this application or proceeding.
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`The time period for reply, if any, is set in the attached communication.
`
`PTOL—90A (Rev. 04/07)
`
`

`

`
`
`Office Action Summary
`
`Application No.
`
`Applicant(s)
`
`13/355,458
`
`GIBBONS ET AL.
`
`Examiner
`CHRISTOPHER REYES
`
`Art Unit
`1639
`
`-- 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 3 MONTH(S) OR THIRTY (30) DAYS,
`WHICHEVER IS LONGER, FROM THE MAILING DATE OF THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR1. 136( a).
`In no event however may a reply be timely filed
`after SIX () 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).
`
`Status
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`1)IZI Responsive to communication(s) filed on 11 December 2012.
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`2a)I:l This action is FINAL.
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`2b)IZ| This action is non-final.
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`3)I:I An election was made by the applicant in response to a restriction requirement set forth during the interview on
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`; the restriction requirement and election have been incorporated into this action.
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`4)|:l Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
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`closed in accordance with the practice under Exparte Quay/e, 1935 CD. 11, 453 O.G. 213.
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`Disposition of Claims
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`5)IZI Claim(s) fl is/are pending in the application.
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`5a) Of the above claim(s) 1-33 and 38-91 is/are withdrawn from consideration.
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`6)I:I Claim(s) _ is/are allowed.
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`7)|Zl Claim(s) 34-37is/are rejected.
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`8)IZI Claim(s)3—4and 35is/are objected to.
`
`
`9)I:l Claim((s)
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`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
`
`htt
`:/'/www.us to. ovI’Watents/init events/mnh/inq'exls or send an inquiry to PPeredback usntqt 0v.
`
`Application Papers
`
`10)|:l The specification is objected to by the Examiner.
`
`11)|Z| The drawing(s) filed on 20Januarz2012 and 03August2012 is/are: a)IZI accepted or b)|:l 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
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`12)I:I Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
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`a)|:l All
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`b)I:l Some * c)|:l None of:
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`1.|:I Certified copies of the priority documents have been received.
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`2.|:I Certified copies of the priority documents have been received in Application No. _
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`3.I:I Copies of the certified copies of the priority documents have been received in this National Stage
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`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)
`
`1) X Notice of References Cited (PTO-892)
`
`2) IX! Information Disclosure Statement(s) (PTO/SB/08)
`Paper No(s)/Mai| Date 28 August 2012.
`US. Patent and Trademark Office
`
`3) D Interview Summary (PTO-413)
`Paper No(s)/Mai| Date.
`4) D Other:
`
`PTOL-326 (Rev. 09-12)
`
`Office Action Summary
`
`Part of Paper No./Mai| Date 20130102
`
`
`
`

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`Application/Control Number: 13/355,458
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`Page 2
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`Art Unit: 1639
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`Claims 1-91 are pending.
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`DETAILED ACTION
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`Election/Restrictions
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`1.
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`Applicant's election with traverse of Invention IV (claims 34-37) in the reply filed
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`on 11 December 2012 is acknowledged. The traversal is on the ground(s) that
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`inventions I, IV, V, VI, and X have not been established to be mutually exclusive, and
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`that there is no search burden, and thus no reason for insisting on restriction. The
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`restriction requirement between elected Invention IV and nonelected inventions l, V, VI,
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`and X is maintained for the following reasons: 1) The search burden has been
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`established for the reasons listed on page 14 of the prior office action, which identifies
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`the inventions as having acquired separate status in the art in view of their different
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`classification, the inventions require different fields of search, and the prior art
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`applicable to one invention would likely not be applicable to another invention; and 2)
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`Applicants' argument of the Inventions not being mutually exclusive is based on the
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`assertion that a subset of one or more limitations are non-exclusive and/or overlapping
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`between the Inventions. This argument ignores the actual invention in each group of
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`claims, each of which is inclusive of other limitations. Applicants have not shown that
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`the inventions, each taken as a whole, encompass non-exclusive and/or overlapping
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`subject matter.
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`2.
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`Claims 1-33 and 38-91 are withdrawn from further consideration pursuant to 37
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`CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable
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`

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`Application/Control Number: 13/355,458
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`Page 3
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`Art Unit: 1639
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`generic or linking claim. Applicant timely traversed the restriction (election) requirement
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`in the reply filed on 11 December 2012.
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`The requirement is still deemed proper and is therefore made FINAL.
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`Claims 34-37 will be examined on the merits.
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`Claim Objections
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`3.
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`4.
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`Claims 34 and 35 are objected to because of the following informalities:
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`Claim 34 recites “predetermine” in line 8.
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`It appears that "predetermined" was
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`intended.
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`5.
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`Claim 35 recites "comprise" in line 1.
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`It appears that "comprises" was intended.
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`Appropriate correction is required.
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`Claim Rejections - 35 USC § 102
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`6.
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`The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that
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`form the basis for the rejections under this section made in this Office action:
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`A person shall be entitled to a patent unless —
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`(b) the invention was patented or described in a printed publication in this or a foreign country or in
`public use or on sale in this country, more than one year prior to the date of application for patent in
`the United States.
`
`7.
`
`Claims 34 and 35 are rejected under 35 U.S.C. 102(b) as being anticipated by
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`US 2003/0138140 (hereinafter ‘140).
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`8.
`
`Regarding claims 34 and 35, ‘140 teaches an image-based method of detecting
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`and quantitating molecular species of interest in a sample, as indicated in paragraph
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`[0092] (Le. a method for characterizing an analyte suspected to be present in a sample).
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`The method is described in greater detail in earlier paragraphs. Paragraph [0070]
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`Page 4
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`Art Unit: 1639
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`indicates recording an image that is comprised of a plurality of pixels arranged in a
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`Cartesian coordinate system wherein intensity values are measured at each pixel, and
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`paragraph [0071] teaches that intensity values are measured in red, green, and blue
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`channels for each pixel (i.e. the obtained image is a digital image that comprises at least
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`a two-dimensional array of pixels wherein each pixel comprises a plurality of intensity
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`values, each of which corresponds to a distinct detection spectral region). Figure 1 and
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`paragraph [0053] indicate that the device comprises a computer which, as indicated in
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`paragraph [0054], is configured to be capable of analyzing the image with respect to
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`each of the red, green, and blue channels (i.e. the method steps are executed with the
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`aid of a programmable device).
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`9.
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`Paragraph [0070] teaches that the intensity values measured for each pixel may
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`be applied directly in a calculation of a concentration using the well-known Beer-
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`Lambert law as described in equation (1) at the end of paragraph [0061], or in the case
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`of a system wherein multiple components are detected, the recorded intensity values
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`may be used to determine the concentration of individual components using either a
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`simple method of linear combination based on the Beer-Lambert Law as shown in
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`equations (3)-(5) at the end of paragraph [0066], or through a more computationally
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`rigorous method that relies on first characterizing each of the dyes of interest according
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`to paragraphs [0056]-[0059] to generate a table of values for each dye, subsequently
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`generating a table of values for a sample according to the same procedure, and
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`subsequently fitting the sample data as a combination of the tables from the dyes
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`according to the method described in paragraphs [0072]-[0075].
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`In the case of the
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`Page 5
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`Art Unit: 1639
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`Beer-Lambert law and derivatives thereof, the equations define predetermined sets of
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`values on the basis of a known path length and known extinction coefficients.
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`In the
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`case of the computational method, the reference teaches determining sets of values
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`before executing an analysis and thus a measured value is correlated with
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`predetermined sets of values. Thus the reference teaches a step of correlating with the
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`aid of a programmable device the obtained intensity values with a predetermined set of
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`values.
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`Further, paragraph [0071] teaches that the method handles a range of values
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`that is defined by a minimal intensity value of a "black image" that "will have an intensity
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`value approaching 0" in each channel and white light image that defines a maximum
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`intensity value that may be recorded in each channel, and thus defines a dynamic range
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`for each detection spectral region. Regarding step (c) of instant claim 34:”predicting the
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`presence and/or quantity of said analyte based on said correlating...” the Beer-Lambert
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`law allows calculation of concentration given optical density, extinction coefficient, and
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`path length. Since the latter three values are known or measured in the reference, it is
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`clear that application of this method must be used in a step of predicting the quantity of
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`said analyte in the sample.
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`10.
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`The '140 reference thus teaches all the limitations of and anticipates instant
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`claims 34 and 35.
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`Claim Rejections - 35 USC § 103
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`11.
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`The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all
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`obviousness rejections set forth in this Office action:
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`(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
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`

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`Page 6
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`Art Unit: 1639
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`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.
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`12.
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`The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148
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`USPQ 459 (1966), that are applied for establishing a background for determining
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`obviousness under 35 U.S.C. 103(a) are summarized as follows:
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`999?)?“
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`Determining the scope and contents of the prior art.
`Ascertaining the differences between the prior art and the claims at issue.
`Resolving the level of ordinary skill in the pertinent art.
`Considering objective evidence present in the application indicating
`obviousness or nonobviousness.
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`13.
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`This application currently names joint inventors.
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`In considering patentability of
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`the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of
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`the various claims was commonly owned at the time any inventions covered therein
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`were made absent any evidence to the contrary. Applicant is advised of the obligation
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`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 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g)
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`prior art under 35 U.S.C. 103(a).
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`14.
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`Claims 34 and 36 are rejected under 35 U.S.C. 103(a) as being unpatentable
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`over US 2003/0138140 as applied to claims 34 and 35 above, and further in view of
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`Tholouli et al. (hereinafter “Tholouli”) and US 2008/0038771 (hereinafter 771).
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`16.
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`‘140 teaches all the limitations of claims 34 and 35 above.
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`‘140 does not teach
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`selection and illumination of the sample by an illumination wavelength prior to or
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`concurrently with obtaining the digital image.
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`

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`Application/Control Number: 13/355,458
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`Page 7
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`Art Unit: 1639
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`17.
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`Tholouli teaches a method of imaging a histological sample using quantum dot-
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`labeled oligonucleotides as described in the abstract. Tholouli indicates in the first
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`paragraph of the left column on page 629 that quantum dots possess several desirable
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`properties including high fluorescence efficiency, long fluorescence lifetime, an
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`excitation wavelength that is constant, and a detection wavelength that is tunable. Thus
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`Tholouli claims quantum dots are "near-optimal for many fluorescent applications."
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`Tholouli’s method involves excitation of the sample at 490 nm followed by detection
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`through recording a series of images (i.e. selecting an illumination wavelength and
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`illuminating the sample with selected illumination wavelength prior to and/or
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`concurrently with obtaining the digital image), as described under the heading “Spectral
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`imaging" on page 630. The detection range covers 450 to 720 nm (which includes blue,
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`green, and red wavelengths), and an image is recorded every 5 nm within that range.
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`The paragraph indicates that “each image contains the complete spectral information for
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`every pixel" at a given wavelength. This is understood to indicate that each image at
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`least includes a value for the intensity of the corresponding wavelength at each pixel.
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`All images are subsequently assembled into a cube for deconvolution. The approach to
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`deconvolution is similar to what is found in the '140 reference. Tholouli explicitly
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`indicates in the cited paragraph that "a spectral library comprising the spectra of tissue
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`autofluorescence and that of each quantum dot used is created" and subsequently
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`applied in spectral unmixing.
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`18.
`
`The ‘771 considers in paragraphs [OO82]—[OO85] the relative virtues of RBG
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`image-based methods, such as those applied in the '140 reference, and the spectral
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`

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`Page 8
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`Art Unit: 1639
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`imaging-based methods, such as those applied by Tholouli.
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`In particular, '771 teaches
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`that "signal processing theory suggests that at least n if not n+1 measurements are
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`needed to unmix n signal" and that while an RGB sensor is adequate for separation of a
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`brown dye and a blue dye during subsequent image analysis, "it has proven extremely
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`difficult to unmix brown from red from blue (a typical combination of stains for a double-
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`labeled sample), using only RGB measurements,” thus indicating the need for
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`multispectral imaging approaches, such as those applied by Tholouli which, as indicated
`
`in paragraph [0084], allows the determination of precise optical spectra at every pixel
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`location. This is understood to indicate at least that intensity values for a plurality of
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`wavelengths of light may be known for each pixel in the resultant image of a
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`multispectral imaging approach. Paragraph [0085] teaches that “the key process, either
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`with RGB images or multispectral datasets, is to partition the overall signal in a given
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`pixel correctly into its components species.” Paragraph [0085] also indicates that
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`Lambert-Beer law analysis relating concentration to absorbance is also applied in a
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`linear unmixing algorithm regardless of whether the images are collected using as RGB
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`images or multispectral datasets and particularly indicates that in contrast to the
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`chromogens imaged in bright field, as shown by the '140 reference, fluorescent signals,
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`as applied in Tholouli, may be directly used in a linear unmixing algorithm. As the ‘140
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`reference and the ‘771 reference both teach, the signal obtained from chromogens
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`imaged in a bright field may be mathematically transformed to permit their application in
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`a linear unmixing algorithm.
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`

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`Application/Control Number: 13/355,458
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`Page 9
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`Art Unit: 1639
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`19.
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`It would have been obvious to one of ordinary skill in the art at the invention was
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`made to modify the invention of ‘140 by applying the method of Tholouli which uses
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`quantum dots and requires illumination of the sample with an appropriate excitation
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`wavelength. One of ordinary skill would have been motivated to do so because
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`quantum dots are indicated by Tholouli as possessing several characteristics that are
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`desirable for use in fluorescent application, including fluorescent detection of species in
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`histological samples. Furthermore, Tholouli's approach to image analysis is highly
`
`similar to the approach applied in the method taught by ‘140. A principle difference
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`would seem to be that the overall image collected by the method of Tholouli produces a
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`cube from a series of images to indicate the intensity of light at each pixel across a
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`range of discrete wavelengths, whereas the method of '140 appears to instead rely on
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`recording only one image from which all intensity data is extracted. Tholouli's approach
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`would seem to allow for greater characterization of a sample by permitting detection of
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`not only red, blue, and green wavelengths, but intermediate wavelengths as well.
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`It will
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`be clear to one of ordinary skill that the image of '140 may be recapitulated from the
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`images recorded in Tholouli's approach by selecting the images corresponding to the
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`desired wavelengths and combining the information contained therein into a single
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`image or array of values. Furthermore, the ‘771 reference indicates that Tholouli’s
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`application of a multispectral imaging process represents a technological improvement
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`to the invention of ‘140.
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`'771 also teaches that the fluorescent signals of Tholouli are
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`functionally equivalent to the chromagen signal of '140 and may also be used in a Beer-
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`Lambert type analysis to determine the concentrations of species contributing to
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`

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`Page 10
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`Art Unit: 1639
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`observed signals. Thus the invention as a whole would have been prima facie obvious
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`to one of ordinary skill in the art at the time the invention was made.
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`20.
`
`Claims 34, 36, and 37 are rejected under 35 U.S.C. 103(a) as being
`
`unpatentable over US 2003/0138140, Tholouli et al. and US 2008/0038771 as applied
`
`to claims 34-36 above, and further in view of Resch-Genger et al. (hereinafter “Resch-
`
`Genger”).
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`21.
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`The ‘140, Tholouli, and ‘771 references teach all the limitations of claims 34-36
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`as described above. The ‘140, Tholouli, and ‘771 references do not explicitly teach the
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`illumination of the sample by a second wavelength.
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`22.
`
`Tholouli does teach the use of multiple quantum dots. The section entitled
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`“Multiplexing” on page 630 references multiple quantum dots, and the section entitled
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`“Reagents" on page 629 indicates that quantum dots with different emission spectra
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`were used. Since Tholouli only describes one excitation wavelength, it is assumed that
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`all quantum dots used adequately absorb at the selected excitation wavelength.
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`23.
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`Resch-Genger reviews quantum dots (QDs) and organic dyes. Table 2 on page
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`766 conveniently provides a comparison of these two classes of fluorophore across a
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`variety of categories. A review of the table and other sections of the reference indicates
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`that while the application of quantum dots in fluorescent applications, such as imaging,
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`shows a lot of promise, there are some drawbacks, many of which seem to be rooted in
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`the newness of the technology. For instance, the reference states in the first paragraph
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`of the left column on page 767 that "to date, there are no consensus methods for
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`

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`Page 11
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`labeling biomolecules with QDs,” in the last paragraph of the right column on page 767
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`that “labeling of specific intracellular structures outside endocytosed vesicles or imaging
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`reactions in the cytoplasm or the nucleus requires more sophisticated tools, which still
`
`need to be worked out in detail,” and the second paragraph of the right column on page
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`770 indicates that it is not known to what extent there is leakage of toxic substances
`
`from the cores of QDs. On the other hand, as Table l indicates, means of binding
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`organic dyes to biomolecules are well-known, the first paragraph of the right column on
`
`page 767 indicates "several methods are well-established for delivery of organic dye
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`labels into cells" and that the ability to render the dyes cell permeant "is a huge
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`advantage for this class of labels," and in the second paragraph of the right column on
`
`page 770 that “cytotoxicity data for many traditional dyes are available." Resch-Genger
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`demonstrates representative absorption/emission spectra for several ODS and organic
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`dyes in figure 1.
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`It can be seen that while the absorption spectra of QDs show
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`considerable overlap, the overlap of absorption spectra for organic dyes is much more
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`variable (See, for instance, the poor overlap between the absorption spectra of Cy3 and
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`Cy5 in panel d of Figure 1).
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`24.
`
`It would have been obvious to one of ordinary skill in the art at the time the
`
`invention was made to substitute the quantum dots of Tholouli with organic dyes, and to
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`record two sets of images using multiple wavelengths as suggested by Resch-Genger.
`
`One of ordinary skill would have been motivated to do so because while quantum dots
`
`and organic dyes are functionally equivalent, and while it is true that quantum dots do
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`offer many desirable properties, one of ordinary skill may nonetheless choose to use
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`

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`Page 12
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`Art Unit: 1639
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`organic dyes because of their more thorough characterization. Organic dyes do not
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`necessarily enjoy the same convenient quality of possessing overlapping absorption
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`spectra, and it would be clear to one of ordinary skill applying only common sense that
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`election of dyes with poor overlap would likely require exciting each dye independently,
`
`thus requiring collection of multiple sets of images, one for excitation wavelength used
`
`to illuminate the sample. Both sets of images may subsequently be used to detect the
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`presence of an analyte in the sample based on the obtained intensity values from the
`
`digital images obtained from each round of spectral imaging. Thus the invention as a
`
`whole would have been prima facie obvious to one of ordinary skill in the art at the time
`
`the invention was made.
`
`Conclusion
`
`Any inquiry concerning this communication or earlier communications from the
`
`examiner should be directed to CHRISTOPHER REYES whose telephone number is
`
`(571 )272—7082. The examiner can normally be reached on Monday to Thursday, 8:00
`
`to 6:00 EST.
`
`If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
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`supervisor, Ardin Marschel can be reached on 571-272—0718. The fax phone number
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`for the organization where this application or proceeding is assigned is 571 -273-8300.
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`