MYR 1009
`Myriad Genetics, Inc. et al. (Petitioners) v. The Johns Hopkins University (Patent Owner)
`IPR For USPN 7,824,889
`
`Page 1 of 1365
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`

`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 & 7015015
`[_] 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 1365
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`Page 2 of 1365
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`

`IN THE UNITED STATES PATENT AND TRADEMARKOFFICE
`
`In re Ex Parte Reexamination of
`U.S. Patent No. 7,824,889
`
`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 1-22 of U.S. Patent No. 7,824,889 entitled "DIGITAL AMPLIFICATION"
`
`("the '889 patent"). The '889 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 1365
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`Page 3 of 1365
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`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 1365
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`

`

`TABLE OF CONTENTS
`
`I.
`
`Il.
`
`IDENTIFICATION OF CLAIMS FOR WHICH REEXAMINATIONIS
`REQUESTED AND BRIEF LISTING OF THE APPLIED ART,
`SUBSTANTIAL NEW QUESTIONS OF PATENTABILITY AND
`PROPOSED REJECTIONS 000... cccccccecsecsceseeeeseeseeeeseeseeecneeaeeecneeseseeaeeecaeeaeeeeneeaeees 1
`
`CONCURRENTLITIGATION AND REEXAMINATION
`PROCEEDINGS: THE CLAIMSOF THE '889 PATENT ARE GIVEN
`THEIR BROADEST REASONABLE INTERPRETATIONIN
`REEXAMINATION, UNLIKE THE STANDARDS APPLICABLEIN
`THE CONCURRENTLITIGATION......ccecccceccccesecseeescceeeeeseeseeseesesaeeseeeeneeneenes 3
`
`TH.
`
`SUMMARY OF THE CLAIMS 2.00... cccccccccccseseeseeesceeeecceeeeeseeseesecsessecseeeesnseeeeees 6
`
`IV.
`
`PROSECUTION HISTORY OF THE '889 AND PARENT'706 PATENT........... 8
`
`V.
`
`SUBSTANTIAL NEW QUESTIONS OF PATENTABILITY......... cece 10
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`SNQ No. 1: Bischoff anticipates claims 1, 5, 8-15, 19, 20
`& 22 under 35 U.S.C. § 102(D) oe cceeseeecneeeeecneeseeecneeseeeeeeteteeeeeerenes 1]
`
`SNQ No. 2: Claims 2-3 of the '889 patent are obvious
`under 35 U.S.C. § 103(a) over Bischoff in view of Kalinina................... 12
`
`SNQ No. 3: Claims 4, 6 and 7 of the '889 patent are
`obvious under 35 U.S.C. § 103(a) over Bischoff in view of
`ZHANG ooo. eeeeeeeccccscccssecessceseceeseecsseceseceeceeeseecsseceeceeseeesseesseceseeseseeeseeesseesseeesges 12
`
`SNQ No. 4: Claims 16, 17 and 20 of the '889 patent are
`obvious under 35 U.S.C. § 103(a) over Bischoff in view of
`LA ei eeeeceeeeecnseesceseescesecseesecsevsecsevseceaeecceaessessecsessecaeveecneseeceaeeseesesseeaeeaeearens 13
`
`SNQ No. 5: Claims 18, 20 and 21 of the '889 patent are
`obvious under 35 U.S.C. § 103(a) over Bischoff in view of
`RuanLD eee eee eececeeeceeeeesseecaeceaeeeeeeeeacecsaeceaeeseceesaeeceaeceeeeseaeesaeeseaeeeeeeeeaes 14
`
`VI.
`
`MANNEROF APPLYING THE CITED PRIOR ART AND PROPOSED
`REJECTIONS 000. ceccececcsseesceseeseesessessecseveecneeeeceaeeseesessesaecaeseecnaeeeceaeeeeeaesateneenees 15
`
`A.
`
`Proposedrejection 1: Bischoff anticipates claims1, 5, 8-
`15, 19, 20 and 22 under 35 U.S.C. § 102(D) oo. cceecceetecneeeeeneeeeeteens 15
`
`1.
`
`2.
`
`Short introductory overview ofrelevant portions of
`Bischoff's disclosure ..........ccccceeceesseeceesceseceeeeeeeeseeeeeeeeceseeneeeeeeseees 15
`
`Detailed explanation of the pertinency and mannerof
`applying Bischoff to independent claim 1.0... eeeeeeeeeteeeee 19
`
`Page 5 of 1365
`
`iii
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`

`

`3.
`
`4.
`
`5.
`
`Detailed explanation of the pertinency and mannerof
`applying Bischoff to independent claim 19.0.0... ee eeeeseeeeees 42
`
`Detailed explanation of the pertinency and mannerof
`applying Bischoff to claims 5 and 22 0.0.0... ceeceeceeseeeceeseeeeeeeeeeees 46
`
`Detailed explanation of the pertinency and mannerof
`applying Bischoff to claims 8-15 and 20.0.0... ee eeeeseeseereeeeeeees 46
`
`B.
`
`C.
`
`D.
`
`E.
`
`Proposed rejection 2: Bischoff renders obvious claims 2
`and 3 in view of Kalinina under 35 U.S.C. § 103(a) oo... eeceeceeeteeeteees 50
`
`Proposed rejection 3: Bischoff renders claims 4, 6 and 7
`obvious under 35 U.S.C. § 103(a) in view of Zhang... eee eects 57
`
`Proposed rejection 4: Bischoff renders claims 16, 17 and
`20 obvious in view of Li under 35 U.S.C. § 103(a) 0. ec cecceteeeeeeeeee 60
`
`Proposed rejection 5: Bischoff renders claims 18, 20 and
`21 obvious in view of RuanoII under 35 U.S.C. § 103(a) wo... eee eee 66
`
`VIL.
`
`CONCLUSION 200. icccccccccccceesceeseeeecesecneecaeeeeeseeeeseceaeceaeaecaeesaeeeeeseeeaeceaeeeeeaeeeeees 72
`
`VUI. CONCURRENT LITIGATION AND REEXAMINATION
`PROCEEDINGS 1.000. .ececcceccceceescesseeeecesecaecaceeseeeeeeseeeaecaaecaecaaecaeeeeeseeenaeeeaeeneeeaeeenees 72
`
`IX.
`
`AUTHORITY TO ACT AND CORRESPONDENCE ADDRESS .........0...0005 73
`
`X.
`
`REQUIRED FEES AND DEPOSIT ACCOUNT AUTHORIZATION............... 73
`
`Page6 of 1365
`
`iv
`
`Page 6 of 1365
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`

`

`TABLE OF EXHIBITS
`
`Patent for which Inter Partes Reexamination Is Requested
`
`Exhibit 1:
`
`USS. Pat. No. 7,824,889 to Vogelstein et al., titled "Digital
`Amplification," issued on November 2, 2010, with a priority date of
`August 2, 1999 and terminal disclaimer filed March 12, 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:
`
`Zhanget al., PNAS USA, 89(13):5847-51 (July 1, 1992),
`
`Exhibit PA-4:
`
`Li et al., Nature. 29;335(6189):414-7 (Sep 29, 1988)
`
`Exhibit PA-S5:
`
`Ruano et 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. 7,824,889
`
`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 1365
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`

`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 1-22 of U.S. Patent No. 7,824,889 to Vogelstein et al. ("the
`
`'889 patent"), and currently assigned to The Johns Hopkins University. The '889 patent
`
`issued on November2, 2010, with a priority date of August 2, 1999.
`
`Reexamination of claims 1-22 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 1365
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`

`

`
`Table I: Summary of References Applied!
`
`Originally
`Art|Originally| Relied On
`Reference
`Under:
`Cited?
`Or
`Discussed?
`
`"
`
`"
`
`BISCHOFF
`Bischoffet al.,
`Hum MolGenet. 4(3):395-9 (Mar 1995)
`_ NIN
`"KALININA"
`Kalinina et al.,
`Nucleic Acids Res. 25(10):1999-2004 (May 1997)
`"NG
`"ZTHA
`Zhang et al,
`PNASUSA,89(13):5847-51 (July 1, 1992),
`
`
`
`102(B)/
`103
`
`102(B)/
`103
`
`102(B)/
`103
`
`102(B)/
`103
`
`102(B)/
`103
`
`"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)
`
`
`
`Table Il: Summary of SNQs
`
`
`SNQ No. I:
`
`Bischoff anticipates claims 1, 5, 8-15, 19, 20 & 22 under 35 U.S.C.
`§ 102(b)
`
`
`
`
`
`§ 103(a) over Bischoff in view of RuanoIT
`
`Claims 2-3 of the '889 patent are obvious under 35 U.S.C. § 103(a)
`over Bischoff in view of Kalinina
`
`Claims 4, 6 & 7 of the '889 patent are obvious under 35 U.S.C. §
`103(a) over Bischoff in view of Zhang
`
`Claims 16, 17 & 20 of the '889 patent are obvious under 35 U.S.C.
`§ 103(a) over Bischoff in view of Li
`
`Claims 18, 20 & 21 of the '889 patent are obvious under 35 U.S.C.
`
`' Applied references that are newly cited in this request are listed on the attached form
`SB/08A (Exhibit 2).
`
`Page 9 of 1365
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`

`Table HI
`
`Proposed Rejections
`
`
`Bischoff anticipates claims 1, 5, 8-15, 19, 20 & 22
`Proposed Rejection No. 1:
`under 35 U.S.C. § 102(b)
`
`
`Proposed Rejection No. 2:
`
`Claims 2-3 of the '889 patent are obvious under 35
`U'S.C. § 103(a) over Bischoff in view of Kalinina
`
`35 U.S.C. § 103(a) over Bischoff in view of Ruano IT
`
`
`
`Proposed Rejection No. 3:
`
`Proposed Rejection No. 4:
`
`Claims 4, 6 & 7 of the '889 patent are obvious under 35
`U'S.C. § 103(a) over Bischoff in view of Zhang
`
`Claims 16, 17 & 20 of the '889 patent are obvious under
`35 U.S.C. § 103(a) over Bischoff in view of Li
`
`Proposed Rejection No. 5:
`
`Claims 18, 20 & 21 of the '889 patent are obvious under
`
`I.
`
`CONCURRENT LITIGATION AND REEXAMINATION
`PROCEEDINGS: THE CLAIMS OF THE '889 PATENT ARE GIVEN
`THEIR BROADEST REASONABLE INTERPRETATIONIN
`REEXAMINATION, UNLIKE THE STANDARDS APPLICABLEIN
`THE CONCURRENT LITIGATION
`
`The '889 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 '889 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
`
`Page 10 of 1365
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`

`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
`
`in the specification." Jn re Bass, 314 F.3d 575, 577 (Fed. Cir. 2002) (citing Jn 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
`
`Page 11 of 1365
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`

`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
`
`(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 claim interpretations submitted
`
`herein for the purpose of demonstrating an SNQare neither binding upon Requester in
`
`any litigation related to the '889 patent, nor do such claim interpretations necessarily
`
`correspond to the construction of claims underlegal 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); In re Trans Texas Holdings Corp., 498 F.3d 1290 (Fed. Cir. 2007), at
`
`1297-98; In re Zletz, 893 F.2d at 322.
`
`The interpretation and/or construction of the claims in the '889 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
`
`Page 12 of 1365
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`

`during the related litigation, which interpretation may differ, in whole orin part, from
`
`that presented herein.
`
`Tl.
`
`SUMMARY OF THE CLAIMS
`
`U.S. Patent No. 7,824,889 (the '889 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 a biological sample;
`
`analyzing the amplified molecules in the assay samples of the set
`to determine a first number of assay samples which contain a selected
`genetic sequence on a first chromosomeand a second numberof assay
`samples which contain a reference genetic sequence on a second
`chromosome, wherein between 0.1 and 0.9 of the assay samples yield an
`amplification product;
`
`comparing the first number of assay samples to the second number
`of assay samples to ascertain 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 the selected genetic sequence
`and the reference genetic sequence are non-polymorphic markers.
`
`5. The method of claim 1 wherein the biological sample is from
`
`blood.
`
`6. The method of claim 1 wherein the selected genetic sequenceis
`a non-polymorphic marker.
`
`Page 13 of 1365
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`

`

`7. The method of claim 1 wherein the reference genetic sequence is
`a non-polymorphic marker.
`
`8. The methodof claim 1 wherein between 0.1 and 0.6 of the assay
`samples yield an amplification product.
`
`9. The method of claim 1 wherein between 0.3 and 0.5 of the assay
`samples yield an amplification product.
`
`10. 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 selected genetic sequence.
`
`11. 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 reference genetic sequence.
`
`12. The method of claim 1 wherein between 0.1 and 0.6 of the
`assay samples yield an amplification product as determined by
`amplification of the selected genetic sequence.
`
`13. The method of claim 1 wherein between 0.1 and 0.6 of the
`assay samples yield an amplification product as determined by
`amplification of the reference genetic sequence.
`
`14. The method of claim 1 wherein between 0.3 and 0.5 of the
`assay samples yield an amplification product as determined by
`amplification of the selected genetic sequence.
`
`15. The method of claim 1 wherein between 0.3 and 0.5 of the
`assay samples yield an amplification product as determined by
`amplification of the reference genetic sequence.
`
`16. The method of claim 1 wherein the set comprises at least 500
`assay samples.
`
`17. The method of claim 1 wherein the set comprises at least 1000
`assay samples.
`
`18. The method of claim 1 wherein the amplified molecules in
`each of the assay samples in the first and second numbers of assay
`samples are homogeneoussuchthat the first number of assay samples do
`not contain the reference genetic sequence and the second numberofassay
`samples do not contain the selected genetic sequence.
`
`19. A method for determining an allelic imbalancein a biological
`sample, comprising the stepsof:
`
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`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 samplesofthe set;
`
`analyzing the amplified molecules in the assay samples of the set
`to determine a first number of assay samples which contain a selected
`genetic sequence on a first chromosomeand a second numberof assay
`samples which contain a reference genetic sequence on a second
`chromosome;
`
`comparing the first number of assay samples to the second number
`of assay samples to ascertain an allelic imbalance betweenthefirst
`chromosomeand the second chromosomein the biological sample.
`
`20. The method of claim 19 wherein between 0.1 and 0.9 of the
`assay samples yield an amplification product.
`
`21. The method of claim 20 wherein between 0.1 and 0.9 of the
`assay samples yield a homogeneous amplification product.
`
`22. The method of claim 19 wherein the biological sample is
`
`blood.
`
`IV.
`
`PROSECUTION HISTORY OF THE '889 AND PARENT '706 PATENT
`
`During prosecution ofthe '889 patent, no prior art was applied against the '889
`
`claims (except for the claims of the parent patent No. 6,440,706 in a double-patenting
`
`rejection).” The references provided and addressedin this reexamination request present
`
`substantial new questions of patentability because, amongother things, they teach one or
`
`more elements of the '889 claims, and either anticipate or render these claims obvious.
`
`Although no art was applied against the '889 claims, during the prosecution ofthe
`
`parent patent (U.S. 6,440,706, hereafter the ‘706 patent, for which Requesteris
`
`concutrently requesting reexamination) art was applied to the claims. For the purposes of
`
`Prosecutionhistory ofthe '889 patent, Office Action mailed Dec. 29, 2009, at page 2
`>
`(Exhibit3).
`
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`patentability in this reexamination, the '706 claims were substantially similar to the '889
`
`claims. Generally speaking, claims of both the '706 and '889 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 contains one sequence and a second numberof assay samples that
`
`contains a different sequence; and (4) comparing the numbersof assay samples. The '706
`
`claims generally require that the last comparing step is performedto ascertain a ratio that
`
`reflects the composition of the biological sample, whereas the '889 claims generally
`
`require that the comparing is performedto ascertain an allelic imbalance.
`
`During original prosecution of the '706 claims, the PTO rejected the '706 claims
`
`as obviousover a reference by Lapidusetal.” in view of a publication by Ruano (“Ruano
`
`I”). In particular, the PTO found that Lapidus taughtall steps of '706 claims except for
`
`an initial set/forming/diluting step, whereas RuanoI taught single-molecule dilution, and
`
`it would have been obvious to combine Lapidus and RuanoI to arrive at the claimed
`
`method.” In response, the '706 applicants argued that neither Lapidus nor RuanoI
`
`counted numbers of assay samples. In particular, the applicants argued that:
`
`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
`
`Lapiduset al.. U.S. Pat No 5,928,870 (Exhibit 5).
`>
`Ruanoetal., PNASvol. 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)
`
`Page 16 of 1365
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`

`

`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 andtarget
`
`nucleic acid, but that Lapidus’ "determination of concentration is within a sample"’ and
`
`... did not teach or suggest forming a set of assay samples by dilution.
`
`The references applied in this reexamination request teach the elements that the
`
`‘706 applicants asserted were missing from the priorart (i.e., forming a set of a plurality
`
`of assay samples, for example by dilution). In contrast to Lapidus, the primary references
`
`and mostof the secondary references applied herein do teach determining a numberof
`
`assay samples.
`
`Vv.
`
`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 '889 patent for which reexamination is sought. Ex parte reexamination
`
`of claims 1-22 of the '889 patent is respectfully requested. These references were either
`
`not of record and/or not considered by the Examiner. These references raise substantial
`
`new questions ("SNQs") of patentability and render the claims unpatentable. A brief
`
`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.
`
`6 7
`
`'706 patent prosecution history, Amendmentdated July 12, 2001, at page 12 (Exhibit 4).
`'706 patent prosecution history, Supplemental Notice of Allowability mailed March 26,
`2002, at page 2 (Exhibit 4).
`
`Page 17 of 1365
`
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`
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`

`

`SNO No. 1: Bischoff anticipates claims 1, 5, 8-15, 19, 20 & 22 under
`
`A.
`35 U.S.C.§102(b
`
`Bischoff* was published in March 1995 andis thuspriorart to the '889 patent
`
`under 35 U.S.C. § 102(b). Bischoff is newly cited in the present request. Under the
`
`broadest reasonable interpretation of the claims, Bischoff discloses methods that meet all
`
`of the limitations of the methodsof claims 1, 5, 8-15, 19, 20 & 22.
`
`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, 5, 8-15, 19, 20 & 22 and squarely anticipates these claims. In
`
`contrast, during the original prosecution of the '889 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, 5, 8-15, 19, 20 & 22.
`
`Bischoffet al., Single cell analysis demonstrating somatic mosaicism involving I Ip in a
`*
`patient with paternal isodisomy and Beckwith-Wiedemann syndrome. Hum MolGenet. 4(3):395-
`9 (Mar 1995), which formsprior art to the '889 patent under 35 U.S.C. § 102(b) (Exhibit PA-1).
`
`Page 18 of 1365
`
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`
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`

`

`B.
`
`SNOQ No. 2: Claims 2-3 of the '889 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 '889 patent under 35 U.S.C. § 102(b). Kalininais
`
`newly cited in the present request.
`
`Bischoff and Kalinina together raise a new question of patentability as to claims 2
`
`and 3 because they were neither cited nor considered during the prosecution of the '889
`
`patentor 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 and 3 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 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 Kalinina
`
`is raised with respect to claims 2 and3.
`
`C.
`
`SNO No. 3: Claims 4, 6 and 7 of the '889 patent are obvious under 35
`U.S.C. § 103(a) over Bischoff in view of Zhang
`
`Bischoffhas been discussed above in SNQ No. 1. Zhang’? waspublished on July
`
`1, 1992 andisprior art to the '889 patent under 35 U.S.C. § 102(b).
`
`°—Kalinina et al., Nanoliter scale PCR with TaqMan detection. Nucleic Acids Res.
`25(10):1999-2004 (May 15, 1997), forming priorart to the '889 patent under 35 U.S.C. § 102(b)
`(Exhibit PA-2).
`
`Page 19 of 1365
`
`12
`
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`
`

`

`Bischoff and Zhang together raise a new question of patentability as to claims 4, 6
`
`& 7 at least because Bischoff was neither cited nor considered during the prosecution of
`
`the '889 patent. Zhang was not discussed or relied on during original prosecution
`
`although it was cited by the applicants.
`
`Bischoff and Zhang togetherraise a substantial question of patentability because
`
`it would have been obviousto those of ordinary skill in the art to practice the methods of
`
`claims 4, 6, and 7 in light of the combined teachings of Bischoff and Zhang. Exemplary
`
`rationales as to why Bischoff's and Zhang'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 Zhangis
`
`raised with respect to claims 4, 6 and 7.
`
`SNO No. 4: Claims 16, 17 and 20 of the '889 patent are obvious under
`D.
`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 '889 patent under 35 U.S.C. § 102(b).
`
`Although cited by the applicants, Li was not discussedor relied on during original
`
`prosecution. In addition, Li has been cited against a related continuing application No.
`
`13/071,105, as anticipating the pending claims, indicating that it is highly likely that the
`
`Zhanget al., Whole genome amplificationfrom a single cell: implicationsfor genetic
`‘0
`analysis. PNAS USA, 89(13):5847-51 (July 1, 1992), forming prior art under 35 U.S.C. § 102(b)
`to the '889 patent (Exhibit PA-3).
`Li et al., Amplification and analysis ofDNA sequences in single human sperm and
`diploid cells. Nature. 29;335(6189):414-7 (Sep 29, 1988), which formspriorart to the '& patent
`under 35 U.S.C. § 102(b) (Exhibit PA-4).
`
`Page 20 of 1365
`
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`

`examiner would also have rejected the claims of the’ 889 patent, which are similar to the
`
`rejected claims of the '105 application.
`
`Bischoff and Li