`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Paper No. 1
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`
`SEQUENOM, INC.,
`Petitioner
`
`v.
`
`THE BOARD OF TRUSTEES OF
`THE LELAND STANFORD JUNIOR UNIVERSITY,
`Patent Owner
`
`Patent No. 8,195,415
`Issued: June 5, 2012
`Filed: January 29, 2010
`Inventors: Hei-Mun Christina Fan and Stephen R. Quake
`Title: NONINVASIVE DIAGNOSIS OF FETAL ANEUPLOIDY BY
`SEQUENCING
`____________________
`
`Inter Partes Review No. 2014-00337
`__________________________________________________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,195,415
`
`
`
`

`

`
`
`Table of Contents
`
`Table of Authorites .................................................................................................... v
`
`I.
`
`Compliance with Requirements of an Inter Partes Review Petition .............. 1
`
`A.
`
`Certification that the Patent May Be Contested via Inter Partes
`Review by the Petitioner ....................................................................... 1
`
`B.
`
`Fee for Inter Partes Review (§ 42.15(a)) .............................................. 1
`
`C. Mandatory Notices (37 C.F.R. § 42.8(b)) ............................................. 2
`
`1.
`
`2.
`
`3.
`
`4.
`
`Real Party in Interest (§ 42.8(b)(1)) ............................................ 2
`
`Other Proceedings (§ 42.8(b)(2)) ................................................ 2
`
`Lead and Back-Up Lead Counsel ............................................... 4
`
`Service on Petitioner ................................................................... 4
`
`D.
`
`Proof of Service (§§ 42.6(e) and 42.105(a)) ......................................... 5
`
`II.
`
`Identification of Claims Being Challenged (§ 42.104(b)) ............................... 5
`
`III. Relevant Information Concerning the Contested Patent ................................. 6
`
`IV. Person of Ordinary Skill in the Art .................................................................. 8
`
`V.
`
`Construction of Terms Used in the Claims ..................................................... 8
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`“Chromosome Portion” ......................................................................... 9
`
`“Window” and “Sliding Window” ........................................................ 9
`
`“Sequence Tag Density” ..................................................................... 12
`
`“Sequence Tag” ................................................................................... 12
`
`“Massively Parallel Sequencing” ........................................................ 12
`
`“Mixed Sample” .................................................................................. 13
`
`VI. Precise Reasons for Relief Requested ........................................................... 14
`
`- ii -
`
`

`

`
`
`A.
`
`Claims 1-6 and 8-12 Would Have Been Obvious Over Lo I in
`View of Shimkets ................................................................................. 14
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 1 ...................................................................................... 16
`
`Claim 2 ...................................................................................... 23
`
`Claim 3 ...................................................................................... 24
`
`Claim 4 ...................................................................................... 25
`
`Claim 5 ...................................................................................... 25
`
`Claim 6 ...................................................................................... 26
`
`Claim 8 ...................................................................................... 26
`
`Claim 9 ...................................................................................... 27
`
`Claim 10 .................................................................................... 27
`
`10. Claim 11 .................................................................................... 28
`
`11. Claim 12 .................................................................................... 28
`
`Claim 7 Is Obvious Over Lo I and Shimkets in Further View of
`One or More of Tarasov, Hillier, and Smith ....................................... 29
`
`Claims 13 and 16 Are Obvious Over Lo I and Shimkets in
`Further View of Wang ......................................................................... 30
`
`1.
`
`2.
`
`Claim 13 .................................................................................... 30
`
`Claim 16 .................................................................................... 37
`
`Claim 14 Is Obvious Over Lo I and Shimkets or Lo I and
`Shimkets in Further View of Dohm ..................................................... 38
`
`Claim 15 Is Obvious Over Lo I and Shimkets in Further View of
`Quake ................................................................................................... 38
`
`Claim 17 Is Obvious Over Lo I, Shimkets and Wang in Further
`View of One or More of Tarasov, Hillier, and/or Smith..................... 39
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`- iii -
`
`

`

`
`
`G.
`
`Claims 1-6 and 8-12 Would Have Been Obvious Over Lo I in
`View of Shimkets and Green ............................................................... 39
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 1 ...................................................................................... 41
`
`Claim 2 ...................................................................................... 46
`
`Claim 3 ...................................................................................... 47
`
`Claim 4 ...................................................................................... 47
`
`Claim 5 ...................................................................................... 48
`
`Claim 6 ...................................................................................... 48
`
`Claim 8 ...................................................................................... 49
`
`Claim 9 ...................................................................................... 49
`
`Claim 10 .................................................................................... 50
`
`10. Claim 11 .................................................................................... 51
`
`11. Claim 12 .................................................................................... 51
`
`Claim 7 Is Obvious Over Lo I, Shimkets and Green in Further
`View of One or More of Tarasov, Hillier, and Smith ......................... 52
`
`Claims 13 and 16 Are Obvious Over Lo I, Shimkets, and Green
`in Further View of Wang ..................................................................... 52
`
`1.
`
`2.
`
`Claim 13 .................................................................................... 52
`
`Claim 16 .................................................................................... 58
`
`Claim 14 Is Obvious Over Lo I in View of Shimkets and Green,
`and/or Lo I in View of Shimkets and Green in Further View of
`Dohm ................................................................................................... 59
`
`Claim 15 Is Obvious over Lo I in View of Shimkets and Green
`in Further View of Quake .................................................................... 59
`
`H.
`
`I.
`
`J.
`
`K.
`
`- iv -
`
`

`

`
`
`L.
`
`Claim 17 Is Obvious Over Lo I in View of Shimkets, Green and
`Wang and in Further View of One or More of Tarasov, Hillier,
`and Smith ............................................................................................. 60
`
`VII. Conclusion ..................................................................................................... 60
`
`- v -
`
`

`

`
`
`
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Ex parte Yamaguchi,
`No. 2007-4412, 2008 WL 4233306 (B.P.A.I. Aug. 29, 2008) ..................................2
`
`KSR Int’l v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................................... passim
`
`Verinata Health, Inc. v. Sequenom, Inc.,
`No. 3:12-cv-00865-SI (N.D. Cal.). ...........................................................................1, 3, 9
`
`STATUTES
`
`35 U.S.C. § 102(a) .............................................................................................................29, 38
`
`35 U.S.C. § 102(b) ..................................................................................................15, 29, 30, 39
`
`35 U.S.C. § 102(e) ...............................................................................................................2, 14
`
`35 U.S.C. § 103 ...........................................................................................................5, 6, 14, 39
`
`35 U.S.C. § 103(a) ............................................................................................................ passim
`
`35 U.S.C. § 315(b) ......................................................................................................................4
`
`OTHER AUTHORITIES
`
`37 C.F.R. § 42.6(e) .....................................................................................................................5
`
`37 C.F.R. § 42.8(b) .....................................................................................................................2
`
`37 C.F.R. § 42.8(b)(1) ................................................................................................................2
`
`37 C.F.R. § 42.8(b)(2) ................................................................................................................2
`
`37 C.F.R. § 42.15(a) ...................................................................................................................1
`
`37 C.F.R. § 42.100(b) ................................................................................................................9
`
`37 C.F.R. § 42.101(b) ................................................................................................................1
`
`- vi -
`
`

`

`
`
`37 C.F.R. § 42.104(b) ................................................................................................................5
`37 CPR. § 42.104(b) ................................................................................................................5
`
`37 C.F.R. § 42.105(a) .................................................................................................................5
`37 CPR. § 42.105(a) .................................................................................................................5
`
`37 C.F.R. § 42.122(b) ............................................................................................................1, 2
`37 CPR. § 42.122(b) ............................................................................................................ 1, 2
`
`M.P.E.P. § 2111.01 .....................................................................................................................9
`M.P.E.P. § 2111.01 .....................................................................................................................9
`
`
`
`- vii -
`
`-Vii-
`
`

`

`
`
`I.
`
`Compliance with Requirements of an Inter Partes Review Petition
`A. Certification that the Patent May Be Contested via Inter Partes
`Review by the Petitioner
`Petitioner certifies it is not barred or estopped from requesting inter partes
`
`review of U.S. Patent No. 8,195,415 (“the ’415 patent”) (Ex. 1001). Neither
`
`Petitioner, nor any party in privity with Petitioner, has filed a civil action
`
`challenging the validity of any claim of the ’415 patent. Although Petitioner was
`
`served with a complaint alleging infringement of the ’415 patent more than one
`
`year prior to the present date,1 the time period set forth in § 42.101(b) does not
`
`apply when the petition is accompanied by a request for joinder under § 42.122(b),
`
`which has been submitted concurrently with this petition. Paper No. 2. Also, the
`
`’415 patent has not been the subject of a finally concluded district court litigation.
`
`Fee for Inter Partes Review (§ 42.15(a))
`B.
`The Director is authorized to charge the fee specified by 37 C.F.R. §
`
`42.15(a) to Deposit Account No. 50-1597.
`
`
`1 As noted below in section I.C.2, the ’415 patent is involved in a district court
`
`litigation. See Case No. 3:12-cv-00865-SI (N.D. Cal.). The ’415 patent was added
`
`to the case via an amended complaint alleging infringement on June 27, 2012,
`
`which was served electronically that same day on Petitioner Sequenom, Inc. See
`
`Dkt. No. 34.
`
`1
`
`

`

`
`
`C. Mandatory Notices (37 C.F.R. § 42.8(b))
`Real Party in Interest (§ 42.8(b)(1))
`1.
`The real party of interest of this petition is Sequenom Inc. (“Sequenom”)
`
`located at 3595 John Hopkins Court, San Diego, California 92121.
`
`2. Other Proceedings (§ 42.8(b)(2))
`The ’415 patent is also involved in IPR No. 2013-00390, which was
`
`instituted on December 9, 2013, based on a petition filed by Petitioner. As
`
`discussed above, a request for joinder under § 42.122(b) with IPR No. 2013-00390
`
`is submitted concurrently with this petition. See Paper No. 2.
`
`The Patent Trial and Appeal Board (“the Board”) instituted IPR No. 2013-
`
`00390 on the ’415 patent based on the “Lo II” reference. The Board, however,
`
`declined to institute trial on grounds based on the “Lo I” reference, finding those
`
`grounds “redundant” to the grounds on which trial was instituted. Ex. 1017 at 21.
`
`In this petition, Petitioner again raises grounds based on Lo I.
`
`Lo I is a provisional U.S. patent application that is prior art to the ’415 patent
`
`under §§ 102(e)/103(a) as of its filing date for all it discloses. Ex parte
`
`Yamaguchi, No. 2007-4412, 2008 WL 4233306, at *9-11 (B.P.A.I. Aug. 29, 2008).
`
`Lo I is not cumulative to Lo II, a published U.S. patent publication, at least because
`
`Lo I has a filing date of July 23, 2007, which is one year earlier than Lo II’s filing
`
`date of July 23, 2008. During an interference proceeding involving the ’415
`
`patent, i.e., Interference No. 105,922, the ’415 patent Patent Owner indicated that it
`
`2
`
`

`

`
`
`intends to prove a conception date of December 18, 2007 for the subject matter of
`
`the count, which is claim 1 of the ’415 patent. Ex. 1014 at 2-3. This “priority
`
`statement” was filed on July 31, 2013, and was not available to Petitioner when
`
`Petitioner first commenced IPR2013-00390. Id. This alleged December 18, 2007
`
`conception date could antedate Lo II’s filing date if the Patent Owner provides
`
`sufficient evidence of an earlier invention; however, it would not antedate Lo I’s
`
`filing date. Thus, the Lo I reference is not cumulative to the Lo II reference for at
`
`least this reason, and the grounds presented in this petition based on the Lo I
`
`reference are not redundant to the instituted grounds in IPR No. 2013-00390 based
`
`on Lo II.
`
`Petitioner has filed a request for reconsideration of the Board’s decision not
`
`to institute a trial in IPR2013-00390 based on Lo I. See generally Ex. 1018. Even
`
`if the Board were to grant this Petition, the grounds of unpatentability set forth in
`
`this petition are not redundant or cumulative to the grounds of unpatentability set
`
`forth by Petitioner in IPR2013-00390 based on Lo I because the obviousness
`
`combinations set forth in the instant petition include references, i.e., Green and
`
`Tarasov (each discussed below), that were not relied upon in the earlier petition
`
`and like Lo I, are effective as prior art before the Patent Owner’s alleged
`
`conception date of the ’415 patent.
`
`The ’415 patent is also involved in Verinata Health, Inc. et al. v. Sequenom,
`
`3
`
`

`

`
`
`Inc. et al. See Case No. 3:12-cv-00865-SI (N.D. Cal.). As discussed, the ’415
`
`patent is also involved in Interference No. 105,922, declared on May 3, 2013.2
`
`U.S. Application No. 13/102,717 and U.S. Application No. 13/452,083, the
`
`latter of which has issued as U.S. Patent No. 8,296,076, each claim the benefit of
`
`priority of the filing date of the ’415 patent. In addition, the ’415 patent claims
`
`benefit of U.S. Application No. 12/560,708.
`
`Lead and Back-Up Lead Counsel
`
`3.
`Lead Counsel
`Jeffrey P. Kushan
`Reg. No. 43,401
`jkushan@sidley.com
`(202) 736-8914
`
`
`
`Back-Up Counsel
`Peter S. Choi
`Reg. No. 54,033
`peter.choi@sidley.com
`(202) 736-8000
`
`4.
`Service on Petitioner may be made by mail or hand delivery to: Sidley
`
`Service on Petitioner
`
`Austin LLP, 1501 K Street, N.W., Washington, D.C. 20005. The fax number for
`
`
`2 In the ’922 interference, Party Lo sought authorization to file a motion attacking
`
`the patentability of claims 1-17 of the ’415 patent based on many of the same prior
`
`art references forming the basis of this Petition. On June 14, 2013, the Board
`
`deferred that motion to the priority phase of the interference. In view of the
`
`pending time period provided by 35 U.S.C. § 315(b), Petitioner has filed this
`
`petition to preserve its rights.
`
`4
`
`

`

`
`
`Petitioner’s counsel is (202) 736-8711.
`
`Proof of Service (§§ 42.6(e) and 42.105(a))
`D.
`Proof of service of this petition is provided in Attachment A.
`
`II.
`
`Identification of Claims Being Challenged (§ 42.104(b))3
`The claims of the ’415 patent are unpatentable as being obvious in view of
`
`the prior art under 35 U.S.C. § 103. Specifically:
`
`Ground
`1
`
`Claims
`1-6, 8-12
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`7
`
`13, 16
`
`14
`
`15
`
`17
`
`1-6, 8-12
`
`7
`
`Description
`Obvious under 35 U.S.C. § 103 over Lo I
`and Shimkets
`Obvious under 35 U.S.C. § 103 over Lo I
`and Shimkets in view of one or more of
`Tarasov, Hillier, and Smith
`Obvious under 35 U.S.C. § 103 over Lo
`I, Shimkets, and Wang
`Obvious under 35 U.S.C. § 103 over Lo I
`and Shimkets, and/or Lo I, Shimkets, and
`Dohm
`Obvious under 35 U.S.C. § 103 over Lo
`I, Shimkets, and Quake
`Obvious under 35 U.S.C. § 103 over Lo
`I, Shimkets and Wang in view of one or
`more of Tarasov, Hillier, and Smith
`Obvious under 35 U.S.C. § 103 over Lo
`I, Shimkets, and Green
`Obvious under 35 U.S.C. § 103 over Lo
`I, Shimkets, and Green in view of one or
`
`
`3 Petitioner has not necessarily raised all challenges to the ’415 patent, given the
`
`limitations imposed by the Rules. Petitioner reserves all rights and defenses.
`
`5
`
`

`

`
`
`
`
`Ground
`
`Claims
`
`9
`
`10
`
`11
`
`12
`
`13, 16
`
`14
`
`15
`
`17
`
`Description
`more of Tarasov, Hillier and/or Smith
`Obvious under 35 U.S.C. § 103 over Lo
`I, Shimkets, Green, and Wang
`Obvious under 35 U.S.C. § 103 over Lo
`I, Shimkets, and Green, and/or Lo I,
`Shimkets, and Green, and Dohm
`Obvious under 35 U.S.C. § 103 over Lo
`I, Shimkets, Green, and Quake
`Obvious under 35 U.S.C. § 103 over Lo
`I, Shimkets, Green, and Wang in view of
`one or more of Tarasov, Hillier, and
`Smith
`
`Petitioner’s proposed construction of the claims, the evidence relied upon, and the
`
`precise reasons why the claims are unpatentable are provided in § IV, below. A
`
`list of evidence relied upon in support of this petition is set forth in Attachment B.
`
`III. Relevant Information Concerning the Contested Patent
`The ’415 patent was filed on January 29, 2010, as a division of U.S.
`
`Application No. 12/560,708 (“the ’708 application”). Ex. 1001 at 1:7-11. The
`
`’708 application was filed on September 16, 2009. Id. The ’415 patent and the
`
`’708 application each claim benefit to U.S. Provisional Application No.
`
`61/098,758, filed on September 20, 2008. Id.
`
`The ’415 patent is directed to “a method to achieve digital quantification of
`
`DNA (i.e., counting differences between identical sequences) using direct shotgun
`
`sequencing followed by mapping to the chromosome of origin and enumeration of
`
`6
`
`

`

`
`
`fragments per chromosome.” Id. at Abstract. “Shotgun sequencing” refers to
`
`random sequencing of nucleic acid fragments in a sample. According to the ’415
`
`patent, “[t]here is ... a desire to develop non-invasive genetic tests for fetal
`
`chromosomal abnormalities.” Id. at 1:52-54. The ’415 patent addresses that desire
`
`by providing methods for analyzing a maternal sample, such as blood, which
`
`contains maternal and fetal DNA, for detecting fetal aneuploidy. See, e.g., id. at
`
`10:55-68.
`
`As explained in the ’415 patent, “[t]he abnormal distribution of a fetal
`
`chromosome or portion of a chromosome (i.e., a gross deletion or insertion) may
`
`be determined in the present method by enumeration of sequence tags as mapped
`
`to different chromosomes.” Id. at 3:64-4:1. The methods entail “carr[ying] out
`
`sequence determinations on the DNA fragments in the sample, obtaining sequences
`
`from multiple chromosome portions of the mixed sample to obtain a number of
`
`sequence tags of sufficient length of determined sequence to be assigned to a
`
`chromosome location within a genome and of sufficient number to reflect
`
`abnormal distribution. Using a reference sequence, one assigns the sequence tags
`
`to their corresponding chromosomes including at least the specified chromosome
`
`by comparing the sequence to reference genomic sequence.” Id. at 4:34-44.
`
`The ’415 patent applies conventional statistical data analysis techniques to
`
`the sequencing data obtained from the methods. For example, according to the
`
`7
`
`

`

`
`
`’415 patent, one may normalize the data obtained from the disclosed methods to
`
`provide more robust and statistically significant results. In one approach, non-
`
`uniform distribution of sequence tags to different chromosomal portions may be
`
`corrected by using windows of defined length to subdivide the chromosomes. Id.
`
`at 4:51-67. This same approach to data analysis can be used to correct for the
`
`known bias resulting from the G/C content of the maternal and fetal DNA
`
`sequenced in the methods claimed in the ’415 patent. Id. at 5:23-30.
`
`IV. Person of Ordinary Skill in the Art
`The person of ordinary skill in the art would have a multi-disciplinary
`
`background with at least a bachelor’s degree in a life sciences area (e.g., biology,
`
`cell biology, genetics, and molecular biology) and at least a master’s degree of
`
`Ph.D. in computational biology, mathematics or statistics, or equivalent training.
`
`Ex. 1010 at ¶ 22. A person of ordinary skill in the art would have understood both
`
`the operation and application of massively parallel DNA sequencing platforms, and
`
`have significant direct experience at performing and applying these techniques.
`
`Further, a person of ordinary skill in the art would have understood and would
`
`have had experience with techniques for aligning sequence reads generated by
`
`massively parallel sequencing to a reference genome. Id.
`
`V. Construction of Terms Used in the Claims
`In an IPR, claims must be given their broadest reasonable construction in
`
`8
`
`

`

`
`
`light of the specification. See 37 C.F.R. § 42.100(b); M.P.E.P. § 2111.01.4
`
`A.
`
`“Chromosome Portion”
`
`Independent claims 1 and 13 recite testing for or determining a
`
`“chromosome portion.” Ex. 1001 at 33:53-34:58; 36:1-17. According to the ’415
`
`patent, “[t]he term ‘chromosome portion’ is used herein to denote either an entire
`
`chromosome or a significant fragment of a chromosome.” Id. at 4:5-7. The term
`
`“chromosome portion” should be construed in accordance with this definition. Ex.
`
`1010 at ¶ 30-31. The Board adopted this construction of the term “chromosome
`
`portion” in IPR No. 2013-00390. Ex. 1017 at 7.
`
`B.
`
`“Window” and “Sliding Window”
`
`The ’415 patent treats the terms “window” and “bin” as equivalent. Ex.
`
`1001, 7:37. Although “window” and “bin” are not expressly defined in the ’415
`
`patent, the patent states that “[e]ach autosome (chr. 1-22) is computationally
`
`
`4 Some of the claim terms of the ’415 patent were construed by the district court in
`
`Verinata Health, Inc. et al. v. Sequenom, Inc. et al. See Case No. 3:12-cv-00865-
`
`SI (N.D. Cal.). Ex. 1016 at 25-31. For the purposes of the IPR, the Board must,
`
`however, apply the broadest reasonable construction of the claim terms in light of
`
`the specification. In IPR No. 2013-00390, the Board has already construed the
`
`claim terms set forth below. Ex. 1017 at 7-9.
`
`9
`
`

`

`
`
`segmented into contiguous, non-overlapping windows” and that “[e]ach window is
`
`of sufficient length to contain a significant number of reads (sequence tags, having
`
`about 20-100 by of sequence)….” Ex. 1001, 5:4-9. Further, the ’415 patent
`
`informs the person of ordinary skill in the art that “where a number of windows of
`
`defined length are created along a chromosome, the windows being on the order of
`
`kilobases in length, whereby a number of sequence tags will fall into many of the
`
`windows and the windows covering each entire chromosome in question, with
`
`exceptions for non-informative regions, e.g., centromere regions and repetitive
`
`regions.” Id. at 4:53-59. Based on the specification of the ’415 patent, in
`
`IPR2013-00390, Petitioner asserted that a person of ordinary skill in the art would
`
`understand the meaning of “window” as used in the ’415 patent to mean a
`
`predefined subsection of a chromosome. Ex. 1017 at 7; Ex. 1010, ¶ 32-33. The
`
`Board, however, adopted slightly different constructions of the term “window” in
`
`IPR No. 2013-00390. Ex. 1017 at 8. The Board construed “window” to mean “a
`
`predefined subsection of a chromosome of sufficient length to allow determination
`
`of an abnormal chromosome distribution, if present, based on the number of
`
`sequence tags mapping to that chromosomal subsection.” Id.
`
`Claim 13 of the ’415 patent refers to a particular type of window, a “sliding
`
`window.” Ex. 1001, 36:1-17. An express definition for “sliding window” is not
`
`provided in the ’415 patent. At column 5, lines 4-6, the ’415 patent states: “[e]ach
`
`10
`
`

`

`
`
`autosome (chr. 1-22) is computationally segmented into contiguous, non-
`
`overlapping windows. (A sliding window could also be used).” This passage
`
`suggests that a “sliding window” can include contiguous, overlapping windows.
`
`Ex. 1010, ¶ 34-35.
`
`In Example 4, the ’415 patent states that “we divided the length of each
`
`chromosome into non-overlapping sliding window with a fixed width (in this
`
`particular analysis, a 50 kbp window was used), skipping regions of genome
`
`assembly gaps and regions with known microsatellite repeats.” Ex. 1001; 23:16-
`
`20. This passage suggests that, in addition to contiguous, overlapping windows,
`
`that “sliding window” also includes contiguous, non-overlapping windows. Ex.
`
`1010 at ¶ 34-35. Based on the teaching of the ’415 patent, Petitioner asserted in
`
`IPR2013-00390 that “sliding window” should be broadly construed as meaning
`
`contiguous, overlapping or non-overlapping, predefined subsections of a
`
`chromosome. Ex. 1017 at 8-9; Ex. 1010 at ¶ 34-35. The Board, however,
`
`construed “sliding window” to mean “a contiguous, overlapping or non-
`
`overlapping, predefined subsection of a chromosome of sufficient length to allow
`
`determination of an abnormal chromosome distribution, if present, based on the
`
`number of sequence tags mapping to that chromosomal subsection.” Ex. 1017 at
`
`8-9.
`
`
`
`11
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`

`

`
`
`C.
`
`“Sequence Tag Density”
`
`The ’415 patent defines “sequence tag density” as “the normalized value of
`
`sequence tags for a defined window of a sequence on a chromosome … where the
`
`sequence tag density is used for comparing different samples and for subsequent
`
`analysis.” Ex. 1001 at 8:50-54. The term “sequence tag density” should be
`
`broadly construed in accordance with this definition provided in the ’415 patent.
`
`Ex. 1010, ¶ 36-37. The Board adopted this construction of the term “sequence tag
`
`density” in IPR No. 2013-00390. Ex. 1017 at 7.
`
`D.
`
`“Sequence Tag”
`
`The term “sequence tag” is also defined in the ’415 patent. The term means
`
`“a DNA sequence of sufficient length that it may be assigned specifically to one of
`
`chromosomes 1-22, X, or Y.” Ex. 1001, 8:54-56. The term “sequence tag” should
`
`be construed in accordance with this definition provided in the ’415 patent. Ex.
`
`1010, ¶ 38-40. The Board adopted this construction of the term “sequence tag” in
`
`IPR No. 2013-00390. Ex. 1017 at 7.
`
`E.
`
`“Massively Parallel Sequencing”
`
`As defined in the ’415 patent, “‘[m]assively parallel sequencing’ means
`
`techniques for sequencing millions of fragments of nucleic acids….” Ex. 1001,
`
`9:19-25. As an example of instrumentation for performing massively parallel
`
`sequencing the ’415 patent identifies products offered by Illumina, Inc. Id. at 9:26-
`
`12
`
`

`

`
`
`29. The ’415 patent further admits that the protocol for whole genome sequencing
`
`using Illumina’s Solexa platform technology was known in the art as of December
`
`2006. Id. at 9:48-52.
`
`Given the teaching of the ’415 patent, “massively parallel sequencing” is
`
`properly broadly construed as meaning any technique available as of the effective
`
`filing date of the ’415 patent for sequencing millions of fragments of nucleic acids.
`
`Ex. 1010, ¶ 41-43. The Board adopted this construction of the term “massively
`
`parallel sequencing” in IPR No. 2013-00390. Ex. 1017 at 7.
`
`F.
`
`“Mixed Sample”
`
`All of the claims in the ’415 patent refer to a “mixed sample,” a term that is
`
`not expressly defined in the patent. The ’415 patent states that “the present
`
`invention comprises, in certain aspects, a method of testing for an abnormal
`
`distribution of a specified chromosome portion in a mixed sample of normally and
`
`abnormally distributed chromosome portions obtained from a single subject, such
`
`as a mixture of fetal and maternal DNA in a maternal plasma sample.” Ex. 1001,
`
`4:29-34. The patent goes on to state that “[o]ne then may determine a first number
`
`of sequence tags mapped to at least one normally distributed chromosome portion
`
`and a second number of sequence tags mapped to the specified chromosome
`
`portion, both chromosomes being in one mixed sample.” Id. at 4:46-50. In view
`
`of this disclosure, a person of ordinary skill in the art would understand that
`
`13
`
`

`

`
`
`“mixed sample” as used in the ’415 patent means a sample containing DNA from
`
`two different populations, e.g., DNA from a mother and a fetus, or DNA from
`
`normal and tumor cells. Ex. 1010, ¶ 44-46. The Board adopted this construction
`
`of the term “mixed sample” in a previous decision instituting inter partes review of
`
`the ’415 patent, IPR No. 2013-00390. Ex. 1017 at 7.
`
`VI. Precise Reasons for Relief Requested
`A. Claims 1-6 and 8-12 Would Have Been Obvious Over Lo I in View
`of Shimkets
`
`Lo I and Shimkets teach all of the features in claims 1-6 and 8-12. Ex. 1010
`
`at ¶ 47. As a result, these claims are invalid as obvious under 35 U.S.C. § 103. Lo
`
`I is U.S. provisional patent application filed on July 23, 2007. Lo I is available as a
`
`§§ 102(e)/103(a) reference as of its filing date for all it discloses.
`
`Lo I provides, among other things, methods “for determining whether a
`
`nucleic acid sequence imbalance (e.g., allelic imbalance) exists within a biological
`
`sample.” Ex. 1003 at [0010]; Ex. 1010 at ¶ 48. A “biological sample” is “any
`
`sample that is taken from a subject (e.g., a human, such as a pregnant woman) and
`
`contains one or more nucleic acid sof [sic] of interest.” Ex. 1003 at [0030]; Ex.
`
`1010 at ¶ 48. The biological sample may be maternal plasma, which contains both
`
`fetal and maternal nucleic acid sequences. Ex. 1003 at [0044]; Ex. 1010 at ¶ 48.
`
`The methods described in Lo I utilize methods to quantify nucleic acids in
`
`order to detect, among other things, fetal aneuploidy (i.e., Down Syndrome). Ex.
`
`14
`
`

`

`
`
`1003 at [0056]; Ex. 1010 at ¶ 49. Lo I recognizes that the fetal DNA will be found
`
`in maternal plasma or serum against a “background of maternal nucleic acid
`
`sequences.” Ex. 1003, [0010, 0044]; Ex. 1010 at ¶ 49. To demonstrate that a
`
`small portion of fetal nucleic acid can be analyzed accurately in the presence of
`
`background maternal material, Lo I discloses that the “experimental and simulation
`
`data show that digital RNA-SNP is an effective and accurate method for trisomy
`
`21 detection. ” Ex. 1003 at [0128]; Ex. 1010 at ¶ 50.
`
`Lo I further provides a description of applying random MPS of fragments of
`
`DNA, in a mixture of fetal and maternal DNA, rather than PCR of specific regions,
`
`in order to detect