MYR 1010
`Myriad Genetics, Inc. et al. (Petitioners) v. The Johns Hopkins University (Patent Owner)
`IPR For USPN 7,824,889
`
`Page 1 of 1237
`
`

`

`PTO/SB/57 (02-13)
`Approved for use through 07/31/2015. OMB 0651 -0064
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Underthe Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unlessit displays a valid OMB control number.
`
`13.
`
`The attached detailed request includes at least the following items:
`
`a. A statement identifying each substantial new question of patentability based on prior patents and printed
`publications. 37 CFR 1.510(b)(1).
`
`b. An identification of every claim for which reexamination is requested, and a detailed explanation of the pertinency
`and manner of applying the cited art to every claim for which reexamination is requested. 37 CFR 1.510(b)(2).
`
`14. __ A proposed amendmentis included (only where the patent owner is the requester). 37 CFR 1.510(e).
`
`15.
`
`a. It is certified that a copy of this request(if filed by other than the patent owner) has been servedin its entirety on
`the patent owner as provided in 37 CFR 1.33(c).
`The name and addressof the party served and the date of service are:
`Banner & Witcoff, Ltd., Attorneys for client 001107, 1100 13th Street N.W., Suite 1200, Washington DC 20005-4051
`
`
`Date of Service:
`;or
`
`| b. A duplicate copy is enclosed since service on patent owner wasnot possible. An explanation of the efforts
`made to serve patent owner is attached. See MPEP § 2220.
`
`16. Correspondence Address: Direct all communication about the reexamination to:
`
`[v.
`OR
`
`[|
`
`Address
`
`The address associated with Customer Number:
`
`52059
`
`Firm or
`Individual Name
`
`
`
`| For Patent Owner Requester “v For Third Party Requester
`
`17. v| The patentis currently the subject of the following concurrent proceeding(s):
` | a. Copending reissue Application No.
`
`_v|b. Copending reexamination Control No. Concurrent requests in related patents 6440706 & 7824889
`[_] c. Copending Interference No.
`|v d.
`Copendinglitigation styled:
`United States District Court for the Middle District of North Carolina Greensboro Division (Esoterix Genetic Labs, LLC, & The
`
`
`
`Johns Hopkins Univ. vs. Life Techs. Corp., Applied Biosystems, LLC, and lon Torrent Systems, Inc., Case No. 12-1173 (Oct 31, 2012)
`
`WARNING: Information on this form may becomepublic. Credit card information should not be
`included on this form. Provide credit card information and authorization on PTO-2038.
`
`6/17/13
`/Ashita A. Doshi/
`
`Authorized Signature
`Date
`
`Ashita Doshi
`
`Typed/Printed Name
`
`57,327
`Registration No.
`
`[Page 2 of 2]
`
`Page 2 of 1237
`
`Page 2 of 1237
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`

`

`IN THE UNITED STATES PATENT AND TRADEMARKOFFICE
`
`In re Ex Parte Reexamination of
`U.S. Patent No. 7,915,015
`
`Examiner: To Be Assigned
`
`Control No.: To Be Assigned
`
`Art Unit: To Be Assigned
`
`Reexam Filing Date: To Be Assigned
`
`Confirmation No.: To Be Assigned
`
`For: DIGITAL AMPLIFICATION
`
`REQUEST FOR EX PARTE REEXAMINATION UNDER37 C.F.R. §1.510
`
`Mail Stop Ex Parte Reexam
`Commissionerfor Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`DearSir:
`
`On behalf of Life Technologies Corp. (hereinafter "Requester"), under provisions
`
`of 37 C.F.R. §1.510 et seq., the undersigned hereby submits a Request for Reexamination
`
`of claims 1-18 of U.S. Patent No. 7,915,015 entitled "DIGITAL AMPLIFICATION"
`
`("the '015 patent"). The '015 patent indicates on its face thatit is assigned to The Johns
`
`Hopkins University.
`
`Entry and consideration are respectfully requested.
`
`Pursuant to 37 C.F.R §1.510, included with this Request are:
`
`e
`
`°
`
`the fee for requesting ex parte reexamination (37 C.F.R. §1.20(c)(1));
`
`an identification of the reexamined patent by patent number and every
`
`claim for which reexamination is requested;
`
`Page 3 of 1237
`
`Page 3 of 1237
`
`

`

`°
`
`°
`
`e
`
`°
`
`e
`
`°
`
`a citation of the patents and printed publications that are presented to
`
`provide a substantial new question of patentability, listed on form
`
`PTO/SB/08A;
`
`a statement identifying each substantial new question of patentability
`
`based on the cited patents and printed publications, and a detailed
`
`explanation of the pertinence and manner of applying the patents and
`
`printed publications to every claim for which reexamination is requested;
`
`a copy of every patent or printed publication relied upon or referred to in
`
`the Request;
`
`a copy ofthe entire patent including the front face, drawings, and
`
`specification/claims (in double-column format) for which reexamination is
`
`requested, and a copy of any disclaimer, certificate of correction, or
`
`reexamination certificate issued in the patent as Exhibit 1;
`
`a certification that the Request has been servedin its entirety on the patent
`
`owner(through the attorney of record during prosecution) at the address
`
`shownin the accompanying Certificate of Service;
`
`a showingthat the attorneyfiling this request has the authority to act on
`
`behalf of the real party in interest pursuant to 37 C.F.R. §1.34(a) under
`
`either a powerof attorney from that party or in a representative capacity
`
`pursuant to $1.34.
`
`Page 4 of 1237
`
`ii
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`Page 4 of 1237
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`

`

`TABLE OF CONTENTS
`
`Page
`
`I.
`
`Il.
`
`IDENTIFICATION OF CLAIMS FOR WHICH REEXAMINATIONIS
`REQUESTED AND BRIEF LISTING OF THE APPLIED ART,
`SUBSTANTIAL NEW QUESTIONS OF PATENTABILITY AND
`PROPOSED REJECTIONS .oo..ccccccccccccccccessceseceeseeesseceseceeeeeeseecssecsseseeeeeseeessecsseees 1
`
`CONCURRENTLITIGATION AND REEXAMINATION
`PROCEEDINGS: THE CLAIMS OF THE '015 PATENT ARE GIVEN
`THEIR BROADEST REASONABLE INTERPRETATION IN
`REEXAMINATION, UNLIKE THE STANDARDS APPLICABLE IN
`THE CONCURRENTLITIGATION w......cccccccccccccccesscesecsseeseeeseseeesseeeseessesseeesees 3
`
`Il.
`
`SUMMARYOF THE CLAIMS .......cccccccccccccssccssesscesecesecsseeseseeeesesesecssecseeeseseeseaees 6
`
`IV.
`
`PROSECUTION HISTORY OF THE '015 AND PARENT'706
`PATENTS 200. .eececccecccsceeseeeeeeeeesecaecaeesseseceseceaeceaecaeesaeseeesseeeaeceaeeaeesaeeeseseeeseeeaeenseeas 8
`
`V.
`
`SUBSTANTIAL NEW QUESTIONS OF PATENTABILITY.............0.cccce 10
`
`A.
`
`B.
`
`C.
`
`D.
`
`SNQ No. 1: Bischoff anticipates claims 1, 4, 5, 7-11 & 16-
`17 under 35 U.S.C. § 102(D) oo. eceeceesecececneeeseeeeeeeeceseceaeeaeeeaeeeeeeereaes 10
`
`SNQ No. 2: Claims 2, 3, 14 and 15 of the '015 patent are
`obvious under 35 U.S.C. § 103(a) over Bischoff in view of
`Kalina... ceccccccccesccesseceseceseceeseeesseceseceeseeessecseceseeeeseeessecssecseeeeeseeesies 11
`
`SNQ No. 3: Claims 12 & 13 of the '015 patent are obvious
`under 35 U.S.C. § 103(a) over Bischoff in view of Lin... cece 12
`
`SNQ No. 4: Claims 6 & 18 of the '015 patent are obvious
`under 35 U.S.C. § 103(a) over Bischoff in view of Ruano IU.............0.4. 13
`
`VI.
`
`MANNEROF APPLYING THE CITED PRIOR ART AND PROPOSED
`REJECTIONS 0... cecccceccceecceseceseeseeeseeeeeeseeeaeceaecaeeeseseeeeseceaecaecaeeeseseeenseeeaeeneeeeeeeees 14
`
`A.
`
`Proposed rejection 1: Bischoff anticipates claims 1, 4, 5, 7-
`11 & 16-17 under 35 U.S.C. § 102(D) o.oo eecccccccccrseceneceeeeeeeeeeseeeseees 14
`
`1.
`
`2.
`
`3.
`
`Short introductory overview ofrelevant portions of
`Bischoff's disclosure ..........ccccccccesccescseessecsseceseeeeseeeseeesseeeseeeeseeessees 14
`
`Detailed explanation of the pertinency and manner of
`applying Bischoff to independent claim 1.0.0... ee eeceeeeeeeteeees 18
`
`Detailed explanation of the pertinency and mannerof
`applying Bischoff to independent claim 8 ...........ceeeeeeseeeeeteeeee 38
`
`Page 5 of 1237
`
`ill
`
`Page 5 of 1237
`
`

`

`4.
`
`5.
`
`Detailed explanation of the pertinency and mannerof
`applying Bischoff to claims 7 and 9 o.oo... eceeceeceseeseeseeeeeeeeeeees 42
`
`Detailed explanation of the pertinency and mannerof
`applying Bischoff to claims 4, 5, 10, 11, 16 and 17... 43
`
`B.
`
`C.
`
`D.
`
`Proposedrejection 2: Bischoff renders obviousclaims2, 3,
`14, and 15 in view of Kalinina under 35 U.S.C. § 103(a) .....e eee 46
`
`Proposed rejection 3: Bischoff renders claims 12 & 13
`obvious in view of Li under 35 U.S.C. § 103(8)..... ce eececeesteeeteeeeeeeeees 53
`
`Proposed rejection 4: Bischoff renders claims 6 & 18
`obvious in view of Ruano IT under 35 U.S.C. § 103(8) occ ee eeeeeeeee 57
`
`VIL.
`
`CONCLUSION 200. icccccccccccceesceeseeeecesecneecaeeeeeseeeeseceaeceaeaecaeesaeeeeeseeeaeceaeeeeeaeeeeees 63
`
`VUI. CONCURRENT LITIGATION AND REEXAMINATION
`PROCEEDINGS 1.000. .ececcceccceceescesseeeecesecaecaceeseeeeeeseeeaecaaecaecaaecaeeeeeseeenaeeeaeeneeeaeeenees 63
`
`IX.
`
`AUTHORITY TO ACT AND CORRESPONDENCE ADDRESS .........0...0005 63
`
`X.
`
`REQUIRED FEES AND DEPOSIT ACCOUNT AUTHORIZATION............... 64
`
`Page 6 of 1237
`
`iv
`
`Page 6 of 1237
`
`

`

`TABLE OF EXHIBITS
`
`Patent for which Inter Partes Reexamination Is Requested
`
`Exhibit 1:
`
`U.S. Pat. No. 7,915,015 to Vogelstein et al., titled "Digital
`Amplification,” issued on March 29, 2011, with a priority date of
`August 2, 1999 and terminal disclaimer filed October 6, 2010.
`
`Prior Art References Relied Upon for SNOs
`
`Exhibit PA-1:
`
`Bischoff et a/., Hum Mol Genet. 4(3):395-9 (Mar 1995)
`
`Exhibit PA-2:
`
`Kalinina et al., Nuc. Acids Res. 25(10):1999-2004 (May 1997)
`
`Exhibit PA-3:
`
`Li et al., Nature. 29;335(6189):414-7 (Sep 29, 1988)
`
`Exhibit PA-4:
`
`Ruanoet al., Nucleic Acids Res. 17(20):8392 (Oct 25, 1989)
`
`Additional Exhibits
`
`Exhibit 2:
`
`PTO Form SB/08A
`
`Exhibit 3:
`
`Relevant portions of prosecution history of U.S. Pat. No. 7,915,015
`
`Exhibit 4:
`
`Relevant portions of prosecution history of U.S. Pat. No. 6,440,706
`
`Exhibit 5:
`
`Lapiduset al., U.S. Pat No 5,928,870
`
`Exhibit 6:
`
`Ruanoet al., PNASvol. 87 pp. 6296-6300, August 1990.
`
`Exhibit 7:
`
`U.S. Pat. No. 7,915,015
`
`Exhibit 8:
`
`Brenneret al., Cancer Res. 55, 2892-2895 (July 1, 1995)
`
`Exhibit9:
`
`Cheunget al., PNAS vol. 93 no. 25, pages 14676-14679 (Dec. 1996)
`
`Exhibit 10:
`
`von Eggeling et al., Hum. Genet. 99(2), pp 266-270 (Jan. 1997)
`
`Exhibit 11:
`
`Prosecution history of continuing App. No. 13/071,105
`
`Page 7 of 1237
`
`Page 7 of 1237
`
`

`

`1
`
`IDENTIFICATION OF CLAIMS FOR WHICH REEXAMINATIONIS
`REQUESTED AND BRIEF LISTING OF THE APPLIED ART,
`SUBSTANTIAL NEW QUESTIONS OF PATENTABILITY AND
`PROPOSED REJECTIONS
`
`Ex parte reexamination is respectfully requested under 35 U.S.C. §§302-307 and
`
`37 C.F.R. §1.510 of claims 1-18 of U.S. Patent No. 7,915,015 to Vogelstein et al. ("the
`
`‘015 patent"), and currently assigned to The Johns Hopkins University. The '015 patent
`
`issued on November2, 2010, with a priority date of August 2, 1999.
`
`Reexamination of claims 1-18 is requested in view of one or more of the
`
`references applied herein. The SNQs listed in Table II are based on the applied
`
`references cited herein and summarized in Table I below. The proposedrejections for
`
`each SNQ are summarized in Table ITI below.
`
`Page 8 of 1237
`
`Page 8 of 1237
`
`

`

`
`Table I: Summary of References Applied!
`
`
`Originally
`Art|Originally| Relied On
`Reference
`Under:
`Cited?
`Or
`Discussed?
`
`
`
`. SCHO
`"BISCHOFF"
`Bischoffet al.,
`Hum MolGenet. 4(3):395-9 (Mar 1995)
`
`"KALININA"
`_
`Kalinina et al.,
`Nucleic Acids Res. 25(10):1999-2004 (May 1997)
`
`"Ty"
`.
`Liet al,
`Nature. 29;335(6189):414-7 (Sep 29, 1988)
`UANO
`"RUA
`Ir"
`Ruano et al.,
`Nucleic Acids Res. 17(20):8392 (Oct 25, 1989)
`
`102(B)/
`103
`
`102(B)/
`103
`
`102(B)/
`103
`
`102(B)/
`103
`
`NO
`
`NO
`
`YES
`
`NO
`
`NO
`
`NO
`
`NO
`
`NO
`
`
`
`Table Il: Summary of SNQs
`
`
`SNQ No. I:
`
`Bischoff anticipates claims 1, 4, 5, 7-11 & 16-17 under 35 U.S.C. §
`102(b)
`
`SNQ No. 2:
`
`SNQ No. 3:
`
`SNQ No. 4:
`
`Claims 2, 3, 14 & 15 of the '015 patent are obvious under 35 U.S.C.
`§ 103(a) over Bischoff in view of Kalinina
`
`Claims 12 & 13 of the '015 patent are obvious under 35 U.S.C. §
`103(a) over Bischoff in view of Li
`
`Claims 6 & 18 of the '015 patent are obvious under 35 U.S.C. §
`103(a) over Bischoff in view of RuanoIT
`
`1 A
`
`Table III
`
`Proposed Rejections
`
`Proposed Rejection No. 1:
`
`Bischoff anticipates claims 1, 4, 5, 7-11 & 16-17 under
`
`pplied references that are newly cited in this request are listed on the attached form
`SB/08A (Exhibit 2).
`
`Page 9 of 1237
`
`Page 9 of 1237
`
`

`

`
`
`35 U.S.C. § 102(b)
`
`
`Proposed Rejection No. 2:
`
`Claims 2, 3, 14 & 15 of the '015 patent are obvious
`under 35 U.S.C. § 103(a) over Bischoff in view of
`Kalinina
`
`Proposed Rejection No. 3:
`
`Claims 12 & 13 of the '015 patent are obvious under 35 U.S.C. § 103(a) over Bischoff in view of Li
`
`Claims 6 & 18 of the '015 patent are obvious under 35
`Proposed Rejection No. 4:
`U'S.C. § 103(a) over Bischoff in view of RuanoII
`
`I.
`
`CONCURRENT LITIGATION AND REEXAMINATION
`PROCEEDINGS: THE CLAIMS OF THE '015 PATENT ARE GIVEN
`THEIR BROADEST REASONABLE INTERPRETATIONIN
`REEXAMINATION, UNLIKE THE STANDARDS APPLICABLEIN
`THE CONCURRENT LITIGATION
`
`The '015 patent is presently involvedin litigation in the United States District
`
`Court for the Middle District of North Carolina Greensboro Division (Esoterix Genetic
`
`Laboratories, LLC and The Johns Hopkins University vs. Life Technologies Corporation,
`
`Applied Biosystems, LLC, and Ion Torrent Systems, Inc., Case No. 12-1173 (filed
`
`October 31, 2012)).
`
`The claims of the '015 Patent do not need to be "interpreted" in any particular
`
`manner to be found unpatentable overthe priorart (e.g., by their plain terms each of the
`
`limitations is found in the prior art). Nevertheless, claim interpretation in the
`
`reexamination process differs from that in other contexts, such as litigation in the federal
`
`courts. Therefore, Requester here summarizes the standards applicable in reexamination
`
`and emphasizesthat this Request addresses the claims using that claim interpretation
`
`standard, rather than the standards that are applicable outside the reexamination context.
`
`In the context of reexamining patent claims, "the PTO must apply the broadest
`
`reasonable meaning to the claim language, taking into account any definitions presented
`
`Page 10 of 1237
`
`Page 10 of 1237
`
`

`

`in the specification.” In re Bass, 314 F.3d 575, 577 (Fed. Cir. 2002) (citing In re
`
`Yamamoto, 740 F.2d 1569, 1571 (Fed. Cir. 1984)); see also 37 C.F.R. § 1.555(b). Giving
`
`claims their broadest reasonable construction "serves the public interest by reducing the
`
`possibility that claims, finally allowed, will be given broader scopethan is justified." Jn
`
`re Yamamoto, 740 F.2d at 1571. "Construing claims broadly during prosecution is not
`
`unfair to the applicant(or, in this case, the patentee), because the applicant has the
`
`opportunity to amendthe claims to obtain moreprecise claim coverage." In re Am. Acad.
`
`ofSci. Tech Ctr., 367 F.3d 1359, 1363 (Fed. Cir. 2004) (citing Yamamoto, 740 F.2d at
`
`1571-72).
`
`While district courts interpret claim language in issued patents in light of the
`
`specification, prosecution history, prior art and other claims, this is not the mode of claim
`
`interpretation to be applied during examination, including reexamination. During
`
`examination, the claims must be interpreted as broadly as their terms reasonably allow.
`
`"The USPTOusesa different standard for construing claims than that used by district
`
`courts; during examination the USPTO mustgive claimstheir broadest reasonable
`
`interpretations." MPEP § 2111.01 (citing Am. Acad. ofSci. Tech Ctr., 367 F.3d at 1363).
`
`The words of the claim must be given their plain meaning unless the applicant has
`
`provideda clear definition in the specification. Jn re Zletz, 893 F.2d 319, 321, 13
`
`U.S.P.Q.2d 1320, 1322 (Fed. Cir. 1989). "[I]n proceedings before the PTO, claims in an
`
`application are to be given their broadest reasonable interpretation consistent with the
`
`specification .
`
`.
`
`. as it would be interpreted by one ofordinary skill in the art." Jn re
`
`Cortright, 165 F.3d 1353, 1359 (Fed. Cir. 1999)(citing In re Bond, 910 F.2d 831, 833
`
`Page 11 of 1237
`
`Page 11 of 1237
`
`

`

`(Fed. Cir. 1990)). Thus, in the analysis and discussion presented below,the identified
`
`claimsare given their broadest reasonable interpretation.
`
`Becausethe standards of claim interpretation used in the courts in patent litigation
`
`are different from the claim interpretation standards used in the Office in claim
`
`examination proceedings (including reexamination), any andall claim interpretations
`
`discussed or submitted herein, and all applications ofthe prior art to the claims, are under
`
`the broadest reasonable interpretation specifically for the purpose of demonstrating a
`
`SNQ for reexamination within the PTO andare neither binding upon Requester in any
`
`litigation related to the '015 patent, nor necessarily the construction of the claims that
`
`would result under legal standards that are mandated to be used by the Courts in
`
`litigation. See 35 U.S.C. § 314; see also MPEP § 2686.04 II (determination of a SNQ is
`
`made independently of a Court’s decision on validity because of different standards of
`
`proof and claim interpretation employed by the District Courts and the Office); see also
`
`Trans Texas, 498 F.3d at 1297-98; In re Zletz, 893 F.2d 319, 322 (Fed. Cir. 1989).
`
`The interpretation and/or construction of the claims in the '015 patent presented
`
`either implicitly or explicitly herein should not be viewedas constituting, in whole or in
`
`part, Requester's own interpretation and/or construction of such claims, but instead
`
`should be viewed as constituting an interpretation and/or construction required by the
`
`standards applicable in the reexamination context and by Patent Owner's use of broad
`
`(and often expansive and undefined) terminology in the claims. Furthermore, Requester
`
`expressly reservesthe right to present its own interpretation of such claimsat a later time
`
`during the related litigation, which interpretation may differ, in whole orin part, from
`
`that presented herein.
`
`Page 12 of 1237
`
`Page 12 of 1237
`
`

`

`Tl.
`
`SUMMARY OF THE CLAIMS
`
`USS. Patent No. 7,915,015 (the '015 patent) is generally drawn to methods of
`
`determining allelic imbalance. The claims for which reexamination is requested read as
`
`follows:
`
`1. A method for determining an allelic imbalance in a biological
`sample, comprising the stepsof:
`amplifying template molecules within a set comprisinga plurality
`of assay samples to form a population of amplified molecules in each of
`the assay samples of the set, wherein the template molecules are obtained
`from the biological sample;
`analyzing the amplified molecules in the assay samples ofthe set
`to determine a first number of assay samples which containafirst allelic
`form of a marker and a second numberof assay samples which contain a
`second allelic form of the marker, wherein between 0.1 and 0.9 of the
`assay samples yield an amplification product;
`comparing the first number to the second numberto ascertain an
`allelic imbalance in the biological sample; and
`identifying an allelic imbalance in the biological sample.
`
`2. The method of claim 1 wherein the step of amplifying employs
`real-time polymerase chain reactions.
`
`3. The method of claim 2 wherein the real-time polymerase chain
`reactions comprise a dual-labeled fluorogenic probe.
`
`4. The method of claim 1 wherein between 0.1 and 0.9 of the assay
`samples yield an amplification product as determined by amplification of
`the first allelic form of the marker.
`
`5. The method of claim 1 wherein between 0.1 and 0.9 of the assay
`samples yield an amplification product as determined by amplification of
`the secondallelic form of the marker.
`
`6. The method of claim 1 wherein the amplified molecules in each
`of the assay samples within the first and second numbers of assay samples
`are homogeneoussuchthat the first number of assay samples do not
`contain the secondallelic form of the marker and the second number of
`assay samples do not contain thefirst allelic form of the marker.
`
`7. The method of claim 1 wherein the sample is from blood.
`
`8. A method for determining an allelic imbalance in a biological
`sample, comprising the stepsof:
`
`Page 13 of 1237
`
`Page 13 of 1237
`
`

`

`distributing nucleic acid template molecules from a biological
`sample to form a set comprising a plurality of assay samples;
`amplifying the template molecules within the assay samples to
`form a population of amplified molecules in the assay samplesoftheset;
`analyzing the amplified molecules in the assay samples of the set
`to determine a first number of assay samples which containafirst allelic
`form of a marker and a second numberof assay samples which contain a
`secondallelic form of the marker;
`comparing the first number of assay samples to the second number
`of assay samples to ascertain an allelic imbalance betweenthefirst allelic
`form and the secondallelic form in the biological sample.
`
`9. The method of claim 8 wherein the sample is from blood.
`
`10. The method of claim 1 or 8 wherein between 0.1 and 0.6 of the
`assay samples yield an amplification product.
`
`11. The method of claim 1 or 8 wherein between 0.3 and 0.5 of the
`assay samples yield an amplification product.
`
`12. The method of claim 1 or 8 wherein the set comprisesat least
`500 assay samples.
`
`13. The method of claim 1 or 8 wherein the set comprisesat least
`1000 assay samples.
`
`14. The method of claim 8 wherein the step of amplifying employs
`real-time polymerase chain reactions.
`
`15. The method of claim 14 wherein the real-time polymerase
`chain reactions comprise a dual-labeled fluorogenic probe.
`
`16. The method of claim 8 wherein between 0.1 and 0.9 of the
`assay samples yield an amplification product as determined by
`amplification ofthe first allelic form of the marker.
`
`17. The method of claim 8 wherein between 0.1 and 0.9 of the
`assay samples yield an amplification product as determined by
`amplification of the secondallelic form of the marker.
`
`18. The method of claim 8 wherein the amplified molecules in
`each of the assay samples within the first and second numbers of assay
`samples are homogeneoussuchthat the first number of assay samples do
`not contain the secondallelic form of the marker and the second number
`of assay samples do not contain the first allelic form of the marker.
`
`Page 14 of 1237
`
`Page 14 of 1237
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`IV.
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`PROSECUTION HISTORY OF THE '015 AND PARENT '706
`PATENTS
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`During prosecution of the '015 patent, no prior art was applied against the '015
`
`claims (except for the claims of the grandparent patent No. 6,440,706 in a double-
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`patenting rejection).” The references provided and addressedin this reexamination
`
`request present substantial new questions of patentability because, among other things,
`
`they teach one or more elements of the '015 claims, and either anticipate or render these
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`claims obvious.
`
`Noart was applied against the '015 claims during original prosecution, or against
`
`the claims of its immediate parent, now U.S. Pat. No. 7,824,889 But art was applied
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`against the claims of a grandparent patent (U.S. 6,440,706, hereafter the "706 patent, for
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`which Requester is concurrently requesting reexamination). For the purposes of
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`patentability in this reexamination, the '706 claims were substantially similar to the '015
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`claims. Generally speaking, claims of both the '706 and '015 patents recite a method
`
`requiring four steps: (1) forming a set of assay samples containing template molecules
`
`from a biological sample (e.g., by "distributing"); (2) amplifying the template molecules
`
`in the assay samples; (3) analyzing the amplified molecules to determine a first number
`
`of assay samples that contain one sequence and a second numberof assay samplesthat
`
`contain a different sequence; and (4) comparing the numbers of assay samples. The '706
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`claims generally require that the last comparing step is performedto ascertain a ratio that
`
`Prosecution history of the '015 patent, Office Action mailed September 23, 2010, at page
`°
`5 (Exhibit 3).
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`reflects the composition of the biological sample, whereas the '015 claims generally
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`require that the comparing is performedto ascertain an allelic imbalance.
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`During original prosecution of the '706 claims, the PTO rejected multiple claims
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`of the '706 claims as obviousovera reference by Lapidusetal.” in view ofa publication
`
`by Ruano (“Ruano I”).’ In particular, the PTO found that Lapidustaughtall steps of
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`selected '706 claims except for an initial set/forming/diluting step, whereas Ruano I
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`taught single-molecule dilution, and it would have been obvious to combine Lapidus and
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`RuanoI to arrive at the claimed method.” In response, the '706 applicants argued that
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`neither Lapidus nor Ruano I counted numbersof assay samples. In particular, the
`
`applicants arguedthat:
`
`teach determining a number of assay
`Lapidus does not
`samples
`containing genetic
`sequences. Lapidus
`instead
`teaches determining concentration. The Office Action refers
`to this
`teaching of Lapidus
`as
`“enumerating number
`molecules of a target,” citing col. 2,
`lines 58-66. This,
`however, is different from determining the numberof assay
`samples containing a genetic sequence. Since the numbers of
`assay samples are not determined according to Lapidus,
`neither are the numbers compared,as required in step 4.°
`
`The PTO ultimately allowed the claims on the groundsthat the closest prior art
`
`(Lapidus) taught amplification and concentration determination of a reference and target
`
`Lapiduset al.. U.S. Pat No 5,928,870 (Exhibit 5).
`Ruanoet al., PNAS vol. 87 pp. 6296-6300, August 1990 (Exhibit 6). A different
`publication by Ruanoet al., (Ruano II) is being applied as a secondary referencein this request.
`>
`'706 patent prosecution history, Office Action issued April 12, 2001, at page 6 (Exhibit 4)
`°
`1706 patent prosecution history, Amendmentdated July 12, 2001, at page 12 (Exhibit 4).
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`Page 16 of 1237
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`nucleic acid, but that Lapidus’ "determination of concentration is within a sample"’ and
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`... did not teach or suggest forming a set of assay samples by dilution.
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`The references applied in this reexamination request teach the elements that the
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`'706 applicants asserted were missing from the prior art during prosecution ofthe
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`grandparent '706 patent(i.e., forming a set of a plurality of assay samples, for example by
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`dilution). In contrast to Lapidus, the primary references and most of the secondary
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`references applied herein do teach determining a numberof assay samples.
`
`Vv.
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`SUBSTANTIAL NEW QUESTIONS OF PATENTABILITY
`
`This section demonstrates how the applied prior art references, either alone orin
`
`combination raise substantial new questions ("SNQs") of patentability with respect to
`
`each claim of the '015 patent for which reexamination is sought. Ex parte reexamination
`
`of claims 1-18 of the '015 patent is respectfully requested. These references were either
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`not of record and/or not considered by the Examiner. These references raise substantial
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`new questions ("SNQs") of patentability and render the claims unpatentable. A brief
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`statement of the SNQsofpatentability is set forth immediately below. A detailed
`
`explanation of the pertinence and manner of applying the cited prior art to each claim for
`
`which reexamination is sought is presented in Section VI below.
`
`A.
`
`SNO No. 1: Bischoff anticipates claims 1, 5, 7-11 & 16-17 under 35 4,
`
`U.S.C. § 102(b)
`
`
`
`Bischoff* was published in March 1995 andis thuspriorart to the '015 patent
`
`under 35 U.S.C. § 102(b). Bischoff is newly cited in the present request. Under the
`
`1706 patent prosecution history, Supplemental Notice of Allowability mailed March 26,
`7
`2002, at page 2 (Exhibit 4).
`
`Page 17 of 1237
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`broadest reasonable interpretation of the claims, Bischoff discloses methods that meet all
`
`of the limitations of the methods of claims 1, 4, 5, 7-11 & 16-17.
`
`SNQ No. 1 based on Bischoff is new for at least two reasons:
`
`(i) Bischoffis
`
`newly cited in the present request and was not before the PTO during original
`
`prosecution; and(ii) the explanation presented herein of how Bischoff anticipates various
`
`claims presented herein wasnot before the original Examiner.
`
`SNQ No. | based on Bischoff is substantial at least because Bischoff teachesall
`
`aspects of claims 1, 4, 5, 7-11 & 16-17 and squarely anticipates these claims. In contrast,
`
`during the original prosecution of the '015 patent no art was found to anticipate the
`
`claims.
`
`Thus, a substantial new question of patentability based on Bischoffaloneis raised
`
`with respect to claims 1, 4, 5, 7-11 & 16-17.
`
`B.
`
`SNO No. 2: Claims2, 3, 14 and 15 of the '015 patent are obvious
`under 35 U.S.C. § 103(a) over Bischoff in view of Kalinina
`
`Bischoff has been discussed above in SNQ No. 1. Kalinina’ was published on
`
`May15, 1997 andispriorart to the '015 patent under 35 U.S.C. § 102(b). Kalininais
`
`newly cited in the present request.
`
`Bischoffet al., Single cell analysis demonstrating somatic mosaicism involving I Ip in a
`*
`patient with paternal isodisomy and Beckwith-Wiedemann syndrome. Hum. Mol Genet. 4(3):395-
`9 (Mar 1995), which formsprior art to the '015 patent under 35 U.S.C. § 102(b) (Exhibit PA-1).
`
`°—Kalinina et al., Nanoliter scale PCR with TaqMan detection. Nucleic Acids Res.
`25(10):1999-2004 (May 15, 1997), forming priorart to the '015 patent under 35 U.S.C. § 102(b)
`(Exhibit PA-2).
`
`Page 18 of 1237
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`Bischoff and Kalinina together raise a new question of patentability as to claims
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`2, 3, 14 and 15 because they were neither cited nor considered during the prosecution of
`
`the '015 patent or its parent '706 patent.
`
`Bischoff and Kalinina together raise a substantial question of patentability
`
`because it would have been obviousto those of ordinary skill in the art to practice the
`
`methods of claims 2, 3, 14 and 15 in light of the combined teachings of Bischoff and
`
`Kalinina. Exemplary rationales as to why Bischoff's and Kalinina's combined teachings
`
`would have rendered the claims obvious are presented in moredetail in the next section
`
`applying the art to the claims.
`
`Thus, a substantial new question of patentability based on Bischoff and Kalinina
`
`is raised with respect to claims 2, 3, 14 and 15.
`
`C.
`
`SNO No. 3: Claims 12 & 13 of the '015 patent are obvious under 35
`U.S.C. § 103(a) over Bischoff in view of Li
`
`Bischoff has been discussed above in SNQ No. 1. Li'° was published on
`
`September 29, 1988 andis priorart to the '015 patent under 35 U.S.C. § 102(b).
`
`Althoughcited by the applicants, Li was not relied on or discussed on record during
`
`original prosecution. In addition, Li has been cited against a related continuing
`
`application No. 13/071,105, as anticipating the pending claims, indicating thatit is highly
`
`likely that the examiner would also have rejected the claims of the’ 889 patent, which are
`
`similar to the rejected claims of the '105 application.
`
`'° Liet al., Amplification and analysis ofDNA sequencesin single human sperm and
`diploid cells. Nature. 29;335(6189):414-7 (Sep 29, 1988), which formspriorart to the '015 patent
`under 35 U.S.C. § 102(b) (Exhibit PA-4).
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`Page 19 of 1237
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`12
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`Bischoff and Li together raise a new question of patentability as to claims 12 &
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`13 at least because Bischoff wasneither cited nor considered during the prosecution of
`
`the '015 patent. Also, Li was not specifically discussed during original prosecution
`
`although it was cited by the applicants.
`
`Bischoff and Li togetherraise a substantial question of patentability becauseit
`
`would have been obviousto those of ordinary skill in the art to practice the methods of
`
`claims 12 & 13 in light of the combined teachings of Bischoff and Li. Exemplary
`
`rationales as to why Bischoff's and Li's combined teachings would have rendered the
`
`claims obviousare presented in more detail in the next section applying the art to the
`
`claims.
`
`Thus, a substantial new question of patentability based on Bischoff and Li is
`
`raised with respect to claims 12 & 13.
`
`SNO No. 4: Claims 6 & 18 of the '015 patent are obvious under 35
`D.
`U.S.C.§103(a) over Bischoff in view of Ruano II
`
`Bischoff has been discussed above in SNQ No. 1. Ruano II'' was published on
`
`October 25, 1989 andis prior art to the '015 patent under 35 U.S.C. § 102(b). RuanoIT is
`
`newly cited in the present request.
`
`Bischoff and RuanoII together raise a new question of patentability as to claims 6
`
`& 18 because they were neither cited nor considered during the prosecution of the '015
`
`patent.
`
`'! Ruano et al., Nucleic Acids Res. 17(20):8392 (Oct 25, 1989), which formsprior art to the
`'015 patent under 35 U.S.C. § 102(b) (Exhibit PA-5).
`
`Page 20 of 1237
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`13
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`Page 20 of 1237
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`Bischoff and RuanoII raise a substantial question of patentability becauseit
`
`would have been obviousto those of ordinary skill in the art to practice the methods of
`
`claims 6 & 18 in light of the combined teachings of Bischoff and Ruano II. Exemplary
`
`rationales as to why Bischoff's and RuanoII's combined teachings would have rendered
`
`the claims obviousare presented in more detail in the next section applying the art to the
`
`claims.
`
`Thus, a substantial new question of patentabil