Paper No.
`Filed: June 26, 2013
`
`
`Filed on behalf of: Sequenom, Inc.
`By: Steven P. O’Connor
`
`Michele C. Bosch
`FINNEGAN, HENDERSON, FARABOW,
` GARRETT & DUNNER, L.L.P.
`901 New York Avenue, NW
`Washington, DC 20001-4413
`Telephone: 202-408-4000
`Facsimile: 202-408-4400
`E-mail: steven.oconnor@finnegan.com
`
` michele.bosch@finnegan.com
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`SEQUENOM, INC.
`Petitioner
`
`v.
`
`THE BOARD OF TRUSTEES OF
`THE LELAND STANFORD JUNIOR UNIVERSITY
`Patent Owner
`____________________
`
`
`Patent 8,195,415
`
`____________________
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,195,415
`
`
`
`

`
`
`
`Table of Contents
`
`Table of Authorites ............................................................................................... iv
`
`I.
`
`Introduction .................................................................................................. 1
`
`II. Mandatory Notices Under 37 C.F.R. § 42.8 .................................................. 1
`
`III.
`
`Payment of Fees Under 37 C.F.R. §§ 42.15(a) and 42.103 ............................ 2
`
`IV. Grounds for Standing .................................................................................... 3
`
`V.
`
`Identification of Challenge ............................................................................ 3
`
`VI. Background and Overview of the ’415 Patent ............................................... 5
`
`VII. Claim Construction ....................................................................................... 8
`
`A.
`
`Chromosome Portion .......................................................................... 9
`
`B. Window and Sliding Window ............................................................. 9
`
`C.
`
`D.
`
`Sequence Tag Density ....................................................................... 11
`
`Sequence Tag .................................................................................... 11
`
`E. Massively Parallel Sequencing .......................................................... 11
`
`F. Mixed Sample ................................................................................... 12
`
`VIII. Detailed Explanation of Grounds for Unpatentability Under the
`Broadest Reasonable Construction .............................................................. 13
`
`A. Ground 1: Claims 1-6 and 8-12 Are Anticipated by Lo II ................ 13
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Claim 1 ................................................................................... 13
`
`Claim 2 ................................................................................... 17
`
`Claim 3 ................................................................................... 18
`
`Claim 4 ................................................................................... 18
`
`Claim 5 ................................................................................... 19
`
`- i -
`
`

`
`
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 6 ................................................................................... 19
`
`Claim 8 ................................................................................... 19
`
`Claim 9 ................................................................................... 20
`
`Claim 10 ................................................................................. 20
`
`10. Claim 11 ................................................................................. 21
`
`11. Claim 12 ................................................................................. 22
`
`B.
`
`C.
`
`Ground 2: Claim 7 Is Obvious over Lo II, Hillier, and/or Smith ....... 22
`
`Ground 3: Claims 13 and 16 Are Obvious over Lo II and Wang ...... 24
`
`1.
`
`2.
`
`Claim 13 ................................................................................. 24
`
`Claim 16 ................................................................................. 30
`
`D. Ground 4: Claim 14 Is Obvious over Lo II, Shimkets, and/or
`Dohm ................................................................................................ 30
`
`E.
`
`F.
`
`Ground 5: Claim 15 Is Obvious over Lo II and Quake ..................... 31
`
`Ground 6: Claim 17 Is Obvious over Lo II, Wang, Hillier,
`and/or Smith ...................................................................................... 32
`
`G. Ground 7: Claims 1-6 and 8-12 Are Obvious over Lo II and
`Wang ................................................................................................ 34
`
`H. Ground 8: Claim 7 Is Obvious over Lo II, Wang, Hillier, and/or
`Smith ................................................................................................. 36
`
`I.
`
`J.
`
`Ground 9: Claim 14 Is Obvious over Lo II, Wang, Shimkets,
`and /or Dohm .................................................................................... 36
`
`Ground 10: Claim 15 Is Obvious over Lo II, Wang, and Quake ....... 37
`
`K. Ground 11: Claims 1-6 and 8-12 Are Obvious over Lo I and
`Shimkets ............................................................................................ 37
`
`1.
`
`2.
`
`Claim 1 ................................................................................... 38
`
`Claim 2 ................................................................................... 45
`
`- ii -
`
`

`
`
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Claim 3 ................................................................................... 46
`
`Claim 4 ................................................................................... 46
`
`Claim 5 ................................................................................... 47
`
`Claim 6 ................................................................................... 47
`
`Claim 8 ................................................................................... 48
`
`Claim 9 ................................................................................... 48
`
`Claim 10 ................................................................................. 49
`
`10. Claim 11 ................................................................................. 49
`
`11. Claim 12 ................................................................................. 50
`
`L.
`
`Ground 12: Claim 7 Is Obvious over Lo I, Shimkets, Hillier,
`and/or Smith ...................................................................................... 50
`
`M. Ground 13: Claims 13 and 16 Are Obvious over Lo I,
`Shimkets, and Wang .......................................................................... 51
`
`1.
`
`2.
`
`Claim 13 ................................................................................. 51
`
`Claim 16 ................................................................................. 58
`
`N. Ground 14: Claim 14 Is Obvious over Lo I, Shimkets, and/or
`Dohm ................................................................................................ 59
`
`O. Ground 15: Claim 15 Is Obvious over Lo I, Shimkets, and
`Quake ............................................................................................... 59
`
`P.
`
`Ground 16: Claim 17 Is Obvious over Lo I, Shimkets, Wang,
`Hillier, and/or Smith ......................................................................... 60
`
`IX. Conclusion .................................................................................................. 60
`
`
`
`- iii -
`
`

`
`
`
`Table of Authorities
`
`
`FEDERAL CASES
`SAP Am., Inc. v. Versada Dev. Group, Inc.,
`No. CBM2012-00001 (PTAB Jun. 11, 2013) ..................................................... 8
`
`Page(s)
`
`KSR International Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) .................................................................................. passim
`
`Ex parte Yamaguchi,
`No. 2007-4412, 2008 WL 4233306, at *9-11 (B.P.A.I. Aug. 29, 2008) ............ 37
`
`FEDERAL STATUTES
`
`35 U.S.C. § 102 ............................................................................................. passim
`
`35 U.S.C. § 103 ............................................................................................. passim
`
`FEDERAL REGULATIONS
`
`37 C.F.R. § 42.8 ...................................................................................................... 1
`
`37 C.F.R. § 42.15(a) ............................................................................................... 2
`
`37 C.F.R. § 42.100(b) ............................................................................................. 8
`
`37 C.F.R. § 42.103 .................................................................................................. 2
`
`37 C.F.R. § 42.104(a) ............................................................................................. 3
`
`- iv -
`
`

`
`
`
`I.
`
`Introduction
`Sequenom, Inc. (“Petitioner”) requests inter partes review of all claims of
`
`U.S. Patent No. 8,195,415 (“the ’415 patent”) (Ex. 1001) assigned on its face to
`
`The Board of Trustees of the Leland Stanford Junior University (“Patent Owner”).
`
`This Petition shows by a preponderance of the evidence that there is a reasonable
`
`likelihood that Petitioner will prevail in demonstrating that all claims of the ’415
`
`patent are unpatentable over prior art that the Office did not fully consider during
`
`prosecution. Claims 1-17 of the ’415 patent should be found unpatentable and
`
`canceled.
`
`II. Mandatory Notices Under 37 C.F.R. § 42.8
`Real Party-in-Interest: Sequenom, Inc. is the real party-in-interest.
`
`Related Matters: The ’415 patent is involved in VERINATA HEALTH,
`
`INC. and THE BOARD OF TRUSTEES OF THE LELAND STANFORD
`
`JUNIOR UNIVERSITY v. SEQUENOM, INC., and SEQUENOM CENTER FOR
`
`MOLECULAR MEDICINE LLC., United States District Court for the Northern
`
`District of California, Case No. 3:12-cv-00865-SI.
`
`The ’415 patent is also involved in Interference No. 105,922, declared on
`
`May 3, 2013.1
`
`1 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
`
`(continued…)
`
`1
`
`

`
`
`
`U.S. Application Nos. 13/102,717 and 13/452,083, issued as U.S. Patent No.
`
`8,296,076, claim the benefit of priority of the filing date of the ’415 patent and
`
`may be affected by a decision in this proceeding. In addition, the ’415 patent
`
`claims benefit of U.S. Application No. 12/560,708, which may be affected by a
`
`decision in this proceeding.
`
`Lead and Back-Up Counsel and Service Information:
`
`Lead Counsel
`Steven P. O’Connor (Reg. No. 41,225)
`Finnegan, Henderson, Farabow,
` Garrett & Dunner, L.L.P.
`901 New York Avenue, NW
`Washington, DC 20001-4413
`Telephone: 571-203-2718
`Facsimile: 202-408-4400
`Email: steven.oconnor@finnegan.com
`
`Back-Up Counsel
`Michele C. Bosch (Reg. No. 40,524)
`Finnegan, Henderson, Farabow,
` Garrett & Dunner, L.L.P.
`901 New York Avenue, NW
`Washington, DC 20001-4413
`Telephone: 202-408-4193
`Facsimile: 202-408-4400
`Email: michele.bosch@finnegan.com
`
`
`III. Payment of Fees Under 37 C.F.R. §§ 42.15(a) and 42.103
`The required fees are submitted herewith. If any additional fees are due at
`
`any time during this proceeding, the Office is authorized to charge such fees to
`
`(…continued)
`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 right to have the unpatentability of the claims of the ‘415
`
`patent timely decided by the PTAB.
`
`2
`
`

`
`
`
`Deposit Account No. 06-0916.
`
`IV. Grounds for Standing
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’415 patent is
`
`available for inter partes review, and Petitioner is not barred or estopped from
`
`requesting inter partes review of the ’415 patent on the grounds identified.2
`
`V.
`
`Identification of Challenge3
`Petitioner challenges claims 1-17 of the ’415 patent and requests that these
`
`claims be found unpatentable and canceled in view of the following prior art:
`
`Exhibit Description
`Ex. 1002 U.S. Patent Application Publication No.
`2009/0029377 to Lo et al. (“Lo II”)
`Ex. 1003 U.S. Provisional Patent Application No. 60/951,438
`to Lo et al. (“Lo I”)
`Ex. 1004 U.S. Patent Application Publication No.
`2005/0221341 to Shimkets et al. (“Shimkets”)
`Ex. 1005 Tian-Li Wang et al., “Digital karyotyping,” Proc.
`
`Publication/
`Filing Date
`Jan. 29, 2009/
`Jul. 23, 2008
`Jul. 23, 2007
`
`Oct. 6, 2005
`
`Dec. 10, 2002
`
`
`2 As noted above in section II, the ’415 patent is involved in district court
`
`Case No. 3:12-cv-00865-SI. 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.
`
`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.
`
`3
`
`

`
`
`
`Exhibit Description
`Natl. Acad. Sci. USA, 99(25):16156-61 (“Wang”)
`Ex. 1006 LaDeana W. Hillier, “Whole-genome sequencing and
`variant discovery in C. elegans,” Nature Methods,
`5(2):183-88 (and on-line supplementary information)
`(“Hillier”)
`Ex. 1007 Juliane C. Dohm et al., “Substantial biases in ultra-
`short read data sets from high-throughput DNA
`sequencing,” Nucleic Acids Res., 36(16):e105
`(“Dohm”)
`Ex. 1008 U.S. Patent No. 7,888,017 to Quake and Fan
`(“Quake”)
`Ex. 1009 Andrew D. Smith et al., “Using quality scores and
`longer reads improves accuracy of Solexa read
`mapping,” BMC Bioinformatics, 9:128 (“Smith”)
`
`Publication/
`Filing Date
`
`Jan. 20, 2008
`
`Jul. 26, 2008
`
`Feb. 15, 2011/
`Feb. 2, 2007
`Feb. 28, 2008
`
`
`Petitioner requests cancellation of claims 1-17 on the following grounds:
`
`Ground Claims
`1
`1-6, 8-12
`2
`7
`
`3
`4
`
`5
`6
`
`7
`8
`
`9
`
`10
`
`13, 16
`14
`
`15
`17
`
`1-6, 8-12
`7
`
`14
`
`15
`
`Description
`Anticipated under 35 U.S.C. § 102(e) by Lo II
`Obvious under 35 U.S.C. § 103 over Lo II, Hillier, and/or
`Smith
`Obvious under 35 U.S.C. § 103 over Lo II and Wang
`Obvious under 35 U.S.C. § 103 over Lo II, Shimkets,
`and/or Dohm
`Obvious under 35 U.S.C. § 103 over Lo II and Quake
`Obvious under 35 U.S.C. § 103 over Lo II, Wang, Hillier,
`and/or Smith
`Obvious under 35 U.S.C. § 103 over Lo II and Wang
`Obvious under 35 U.S.C. § 103 over Lo II, Wang, Hillier,
`and/or Smith
`Obvious under 35 U.S.C. § 103 over Lo II, Wang,
`Shimkets, and/or Dohm
`Obvious under 35 U.S.C. § 103 over Lo II, Wang, and
`Quake
`
`4
`
`

`
`
`
`
`
`Sections VII and VIII A.-J., respectively, explain how the claims should be
`
`construed and how each claim element is found in the prior art. If the Patent
`
`Owner is able to provide sufficient evidence establishing that Lo II is not prior art
`
`to the ’415 patent under 35 U.S.C. § 102(e) as of Lo II’s July 23, 2008, filing date,
`
`then Petitioner submits these additional grounds supporting the cancellation of
`
`claims 1-17 (see infra Sections VIII K.-P.):
`
`Ground Claims
`11
`1-6, 8-12
`12
`7
`
`13
`
`14
`
`15
`
`16
`
`13, 16
`
`14
`
`15
`
`17
`
`Description
`Obvious under 35 U.S.C. § 103 over Lo I and Shimkets
`Obvious under 35 U.S.C. § 103 over Lo I, Shimkets,
`Hillier, and/or Smith
`Obvious under 35 U.S.C. § 103 over Lo I, Shimkets, and
`Wang
`Obvious under 35 U.S.C. § 103 over Lo I, Shimkets, and/or
`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,
`Wang, Hillier, and/or Smith
`
`
`VI. Background and Overview of the ’415 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, 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
`
`5
`
`

`
`
`
`DNA (i.e., counting differences between identical sequences) using direct shotgun
`
`sequencing followed by mapping to the chromosome of origin and enumeration of
`
`fragments per chromosome.” Id., Abstract. “Shotgun sequencing” refers to
`
`random sequencing of nucleic acid fragments in a sample. According to the ’415
`
`patent, “[t]here is therefore a desire to develop non-invasive genetic tests for fetal
`
`chromosomal abnormalities.” Id., 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. 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., 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 [by comparison to a reference sequence] and of sufficient number to
`
`reflect abnormal distribution.” Id., 4:34-43.
`
`The ’415 patent applies conventional statistical data analysis techniques to
`
`the sequencing data obtained from the methods. For example, according to the
`
`’415 patent, one may normalize the data obtained from the disclosed methods to
`
`6
`
`

`
`
`
`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.,
`
`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., 5:23-30.
`
`During prosecution of the ’415 patent, the Examiner rejected then-pending
`
`application claims 1-42 as anticipated by U.S. Patent Application Publication
`
`2010/0112590 to Lo et al. (“the Lo ’590 publication”), which is a continuation-in-
`
`part application of Lo II.4 In response, the Patent Owner canceled the rejected
`
`claims and entered new claims 43-59 (which, with subsequent amendments, issued
`
`as claims 1-17 of the ’415 patent). The Patent Owner asserted in an Amendment
`
`filed January 9, 2012, that its application was entitled to an effective filing date of
`
`September 16, 2009, and therefore the Lo ’590 publication “is only prior art to the
`
`
`4 This rejection is consistent with rejections made during prosecution of
`
`other members of the ’415 patent family. For example, Application No.
`
`12/560,708, the parent application to the ’415 patent, was withdrawn from issue
`
`and the pending claims currently stand rejected as anticipated by Lo II, or as
`
`obvious over Lo II in view of Dohm and another reference.
`
`7
`
`

`
`
`
`present application to the extent that it finds support in its parent application, Lo
`
`‘181 [Lo II].” Addressing the teaching of Lo II, the Patent Owner stated,
`
`incorrectly, that “this document does not disclose, for example, the step of
`
`‘determining values for numbers of sequence tags mapping to chromosome
`
`portions by using a number of windows of defined length within normally and
`
`abnormally distributed chromosome portions,’ as recited in claim 43 [’415 patent
`
`claim 1], or, for example, ‘determining numbers of sequence tags mapped to each
`
`sliding window on at least each autosome,’ as recited in claim 55 [’415 patent
`
`claim 13].” Following entry of this Amendment, the Examiner allowed the claims.
`
` The use of chromosomal windows to normalize nucleotide sequence data in
`
`methods for detecting chromosomal abnormalities was well known in the art
`
`before the earliest filing date of the ’415 patent as is shown supra. The claimed
`
`features the Patent Owner relied on to distinguish Lo II were well known at the
`
`time of the invention and cannot provide a basis for patentability. See Ex. 1010,
`
`¶¶38, 59-71, 85-90, 101-107, and 147-156..
`
`VII. Claim Construction
`A claim subject to inter partes review receives the “broadest reasonable
`
`construction in light of the specification of the patent in which it appears.”
`
`37 C.F.R. § 42.100(b). See SAP Am., Inc. v. Versada Dev. Group, Inc., No.
`
`CBM2012-00001 (PTAB Jun. 11, 2013) (slip. op. at 10). Here, the claim terms of
`
`8
`
`

`
`
`
`the ’415 patent should be given their broadest reasonable construction in light of
`
`the specification, and a few terms that warrant construction are discussed below.
`
`A. Chromosome Portion
`
`Independent claims 1 and 13 recite
`
`testing for or determining a
`
`“chromosome portion.” Ex. 1001, 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., 4:5-7. The term
`
`“chromosome portion” should be construed in accordance with this definition. Ex.
`
`1010, ¶30.
`
`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
`
`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
`
`9
`
`

`
`
`
`exceptions for non-informative regions, e.g., centromere regions and repetitive
`
`regions.” Id., 4:53-59. Based on the specification of the ’415 patent, 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. 1010, ¶31.
`
`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
`
`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, ¶32.
`
`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,
`
`¶32. Based on the teaching of the ’415 patent, “sliding window” should be broadly
`
`construed as meaning contiguous, overlapping or non-overlapping, predefined
`
`subsections of a chromosome. Ex. 1010, ¶32.
`
`10
`
`

`
`
`
`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, 8:50-54. The term “sequence tag density” should be broadly
`
`construed in accordance with this definition provided in the ’415 patent. Ex. 1010,
`
`¶33.
`
`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, ¶34.
`
`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., 9:26-
`
`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
`
`11
`
`

`
`
`
`2006. Id., 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, ¶35.
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`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
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`distribution of a specified chromosome portion in a mixed sample of normally and
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`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,
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`4:29-34. The patent goes on to state that “[o]ne then may determine a first number
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`of sequence tags mapped to at least one normally distributed chromosome portion
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`and a second number of sequence tags mapped to the specified chromosome
`
`portion, both chromosomes being in one mixed sample.” Id., 4:46-50. In view of
`
`this disclosure, a person of ordinary skill in the art would understand that “mixed
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`sample” as used in the ’415 patent means a sample containing DNA from two
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`different populations, e.g., DNA from a mother and a fetus, or DNA from normal
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`and tumor cells. Ex. 1010, ¶36.
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`VIII. Detailed Explanation of Grounds for Unpatentability Under the
`Broadest Reasonable Construction
`
`Claims 1-17 of the ’415 patent are invalid on multiple grounds. The
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`references relied on provide technical disclosures that the Office believed to be
`
`absent in the prior art. The references and grounds are also not cumulative to each
`
`other given the different disclosures of the references. A reasonable examiner
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`would consider these references to be important in deciding whether the claims are
`
`patentable, and this Petition demonstrates a reasonable likelihood that the
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`Petitioner will prevail in demonstrating the unpatentability of each claim of the
`
`’415 patent.
`
`A. Ground 1: Claims 1-6 and 8-12 Are Anticipated by Lo II
`
`Lo II discloses all of the features in claims 1-6 and 8-12. See Ex. 1002; Ex.
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`1010, ¶¶37-48. As a result, these claims are invalid as anticipated by Lo II under
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`35 U.S.C. § 102(e).
`
`a)
`
`Claim 1
`
`1.
`“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 subject, comprising:”
`Lo II discloses methods “for determining whether a nucleic acid sequence
`
`imbalance (e.g., chromosome imbalance) exists within a biological sample
`
`obtained from a pregnant female.” Ex. 1002, [0014]; Ex. 1010, ¶38. Lo II goes on
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`to disclose that the “dosage imbalance of a particular chromosome or chromosomal
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`13
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`
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`regions can be quantitatively determined … from the percentage representation of
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`the said locus among other mappable sequenced tags of the specimen.” Ex. 1002,
`
`[0067]; Ex. 1010, ¶38.
`
`Lo II discloses that “nucleic acid molecules from the fetus and the pregnant
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`female” are contained in the biological sample, and “the nucleic acid molecules
`
`may be fragments from chromosomes.” Ex. 1002, [0054]; Ex. 1010, ¶38.
`
`b)
`
`“(a) sequencing DNA from the mixed sample to obtain
`sequences from multiple chromosome portions, wherein
`said sequences comprise a number of sequence tags of
`sufficient length of determined sequence to be assigned to a
`chromosome location within a genome;”
`Lo II discloses that “[a] portion of the nucleic acid presence of abnormal
`
`molecules contained in the biological sample are sequenced.” Ex. 1002, [0015];
`
`Ex. 1010, ¶38. Lo II discloses that the sequencing is done at random, that is “[t]he
`
`origin of a particular fragment is not selected ahead of time.” Ex. 1002, [0080];
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`Ex. 1010, ¶38. Because “[t]he sequencing is done at random … a database search
`
`may be performed to see where a particular fragment is coming from[,]” indicating
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`that the sequence tag must be of sufficient length to assign the sequence to a
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`location on chromosome of the genome. Ex. 1002, [0080]; Ex. 1010, ¶38.
`
`c)
`
`to corresponding
`tags
`the sequence
`“(b) assigning
`chromosome portions including at least the specified
`chromosome by comparing the determined sequence of the
`sequence tags to a reference genomic sequence;”
`Lo II discloses that in its methods “[t]he short sequence tags generated were
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`14
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`
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`aligned to the human reference genome sequence and the chromosomal origin was
`
`noted.” Ex. 1002, [0070]; Ex. 1010, ¶38. Similarly, Lo II discloses that “[a]fter
`
`the massively parallel sequencing, bioinformatics analysis was performed to locate
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`the chromosomal origin of the sequenced tags.” Ex. 1002, [0074]; Ex. 1010, ¶38;
`
`see also Ex. 1002, [0080]; Ex. 1010, ¶38.
`
`d)
`
`“(c) determining values for numbers of sequence tags
`mapping to chromosome portions by using a number of
`windows of defined length within normally and abnormally
`distributed chromosome portions to obtain a first value and
`a second value therefrom; and”
`Lo II discloses, in the context of sequence data analysis, normalizing the
`
`frequency of sequences that are from a chromosome involved in aneuploidy and
`
`sequences that are from the other chromosomes. Ex. 1002, [0069]; Ex. 1010, ¶38.
`
`Lo II discloses, in the same context, that particular “chromosomal regions”
`
`are distinct from chromosomes: “There are a number of ways of determining the
`
`amounts of the chromosomes, including but not limited to counting the number of
`
`sequenced tags, the number of sequenced nucleotides (basepairs) or the
`
`accumulated lengths of sequenced nucleotides (basepairs) originating from
`
`particular chromosome(s) or chromosomal regions.” Ex. 1002, [0060]; Ex. 1010,
`
`¶38. Lo II discloses using chromosomal regions, or sets of chromosomal regions,
`
`to determine if aneuploidy exists. Ex. 1002, [0050]; Ex. 1010, ¶38. A person of
`
`ordinary skill in the art would understand that the disclosure of “chromosomal
`
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`regions” in Lo II is a disclosure of using “windows” to analyze the data. Ex. 1010,
`
`¶38.
`
`Lo II also discloses that “dosage imbalance of a particular chromosome or
`
`chromosomal regions can be quantitatively determined. In other words, the dosage
`
`imbalance of the chromosome or chromosomal regions is inferred from the
`
`percentage representation of the said locus among other mappable sequenced tags
`
`of the specimen.” Ex. 1002, [0067], Ex. 1010, ¶65.
`
`e)
`
`“(d) using the values from step (c) to determine a
`differential, between the first value and the second value,
`which is determinative of whether or not the abnormal
`distribution exists.”
`Lo II discloses using the sequencing results to determine first and second
`
`amounts of sequences identified as originating from a first and a second
`
`chromosome. From those amounts, “[a] parameter from the first amount and the
`
`second amount is then compared to one or more cutoff values. Based on the
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`comparison, a classification of whether a fetal chromosomal aneuploidy exists for
`
`the first chromosome is determined.” Ex. 1002, [0016]; Ex. 1010, ¶38.
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`16
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`a)
`
`Claim 2
`
`2.
`“The method of claim 1 wherein to determine a differential
`includes the step of comparing a normalized sequence tag
`density of the