`Filed July 7, 2014
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`Filed on behalf of: Sequenom, Inc.
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`By: Michael J. Wise (mwise@perkinscoie.com)
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`Patrick D. Morris (pmorris@perkinscoie.com)
`Perkins Coie LLP
`1888 Century Park East, Suite 1700
`Los Angeles, CA 90067-1721
`Telephone: (310) 788-3210
`Facsimile: (310) 788-3399
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`SEQUENOM, INC.
`Petitioner
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`v.
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`THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR
`UNIVERSITY
`Patent Owner
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`SEQUENOM REPLY TO PATENT OWNER RESPONSE
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`Case IPR2013-00390
`Patent 8,195,415
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`TABLE OF AUTHORITIES
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`IPR2013-00390
`8,195,415
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`I.
`II.
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`B.
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`Page
`INTRODUCTION .......................................................................................... 1
`CLAIMS 1-17 OF THE '415 PATENT ARE ANTICIPATED
`AND/OR OBVIOUS OVER THE CITED REFERENCES ........................... 2
`A.
`THE BROADEST REASONABLE INTERPRETATION OF "WINDOW"
`ENCOMPASSES ANY PREDEFINED SUBSECTION OF A
`CHROMOSOME ....................................................................................... 2
`LO II IS PRIOR ART AGAINST THE '415 PATENT ..................................... 4
`1.
`THE "CHROMOSOME PORTIONS" OF LO II ARE "WINDOWS" ........ 4
`2.
`LO II ENABLES THE USE OF "WINDOWS" .................................... 5
`3.
`PATENT OWNER HAS NOT ESTABLISHED AN ACTUAL
`REDUCTION TO PRACTICE PRIOR TO JULY 23, 2008 .................... 7
`C. WANG, HILLIER, AND SMITH ............................................................... 13
`III. CONCLUSION ............................................................................................. 15
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`i
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`TABLE OF AUTHORITIES
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`IPR2013-00390
`8,195,415
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`Page
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`CASES
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`Cooper v. Goldfarb,
`154 F.3d 1321 (Fed. Cir. 1998) ............................................................................ 8
`
`Hahn v. Wong,
`892 F.2d 1028 (Fed. Cir. 1989) ............................................................................ 8
`
`In re Borkowski,
`422 F.2d 904, 164 U.S.P.Q. 642 (C.C.P.A. 1970) ................................................ 6
`
`In re Garner,
`508 F.3d 1376 (Fed. Cir. 2007) ............................................................................ 8
`
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) ........................................................................ 8, 9
`
`Price v. Symsek,
`988 F.2d 1187 (Fed. Cir. 1993) ............................................................................ 8
`
`Reese v. Hurst v. Wiewiorowski,
`661 F.2d 1222 (C.C.P.A. 1981) ...................................................................... 8, 10
`
`Revson v. Cinque & Cinque, P.C.,
`221 F.3d 71 (2nd Cir. 2000) ............................................................................... 13
`
`Stampa v. Jackson,
`77 U.S.P.Q.2d 1105 (B.P.A.I. 2005) .................................................................. 13
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`IPR2013-00390
`Patent 8,195,415
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`I.
`
`INTRODUCTION
`The Petition filed on June 26, 2013 (Paper 1) shows that '415 Patent claims 1-
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`6 and 8-12 are anticipated by U.S. Patent Publ. No. 2009/0029377 ("Lo II," Ex.
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`1002), and that claims 7 and 13-17 are obvious over Lo II in combination with,
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`among others, U.S. Patent Publ. No. 2005/0221341 ("Shimkets," Ex. 1004), Wang
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`et al. Proc Natl Acad Sci USA 99(25):16156-61 (2002) ("Wang," Ex. 1005), Hillier
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`Nature Methods 5(2):183-8 (2008) ("Hillier," Ex. 1006), and Smith et al. BMC
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`Bioinformatics 9:128 (2008) ("Smith," Ex. 1009).
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`In its Response (Paper 24), Patent Owner proposes that its claim term
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`"windows" should include the unwritten limitation "of equal length." This
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`construction is at odds with the plain meaning of the term and the disclosure of the
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`'415 Patent, and would require the Board to reverse its construction from both the
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`Decision dated December 9, 2013 (Paper 7) and the Decision on Motions dated
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`April 7, 2014 in companion Interference No. 105,922 ("'922 Interference"). Patent
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`Owner asserts that Lo II does not enable "windows of defined length," and that
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`Wang does not disclose a "sliding window of predetermined length" and teaches
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`away from the alignment of sequence tags with a single mismatch. These positions
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`are based on minimal analysis and a fundamental misunderstanding of Lo II and
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`Wang. In particular, Patent Owner fails to address the state of the art in 2008, a
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`time at which the use of windows in conjunction with sequencing and alignment
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`was well known. Finally, Patent Owner asserts that Lo II is not prior art against
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`the '415 Patent because of an alleged earlier actual reduction to practice by Stephen
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`Quake ("Quake") and Hei-Mun Christina Fan ("Fan"). This assertion also lacks
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`1
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`IPR2013-00390
`Patent 8,195,415
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`support, relying entirely on inventor testimony (Fan) and the statements of a
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`contemporary witness (Yair Blumenfeld, "Blumenfeld") who fails to acknowledge
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`that he understood or was even aware of the specific steps of the claimed methods.
`II. CLAIMS 1-17 OF THE '415 PATENT ARE ANTICIPATED AND/OR
`OBVIOUS OVER THE CITED REFERENCES
`A. The Broadest Reasonable Interpretation of "Window" Encompasses
`Any Predefined Subsection of a Chromosome
`The Board has construed "window" to mean "a predefined subsection of a
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`chromosome of sufficient length to allow determination of an abnormal
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`chromosome distribution, if present, based on the number of sequence tags
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`mapping to that chromosomal subsection." Paper 7, p. 8, 2nd ¶. In the companion
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`'922 Interference, the Board construed "windows" as "predefined subsections of a
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`chromosome" or "chromosomal regions." Ex. 1088, p. 18, 2nd full ¶. Despite the
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`Board having ruled on this matter twice, Patent Owner argues that both decisions
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`are wrong and that "windows of defined length" are limited to windows of equal
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`length. Paper 24, pp. 3-10.
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`Patent Owner asserts that the "portions of the '415 patent specification,
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`including the examples and figures, that discuss the use of windows make it clear
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`that the windows are all of equal length in a given experiment." Paper 24, p. 4, 1st
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`full ¶. The Interference Board rejected this argument, stating "[w]hen we look to
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`the specification for guidance in construing claim terms, we avoid limitations that
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`are reflected only in specific embodiments, particularly if those embodiments are
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`not reflected in the claims." Ex. 1088, ¶ spanning pp. 16-17. Further, Example 8
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`in the '415 Patent contradicts Patent Owner's assertion regarding the examples by
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`IPR2013-00390
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`using two different sized windows (50 kb for aneuploidy detection and 20 kb for
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`GC content correction) in the same experiment, performed on the same sequencing
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`data from the same samples. Ex. 1001, 26:5-59; Ex. 1089, 104:17-108:20.
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`Patent Owner asserts the sentence "[t]his is explained in detail below, where a
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`number of windows of defined length are created along a chromosome…" in the
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`'415 Patent would be interpreted by one of ordinary skill in the art to refer
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`specifically to "the second to last sentence of the paragraph." Paper 24, p. 6, 1st
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`full ¶ to p. 7, 1st full ¶; Ex. 1001, 4:53-64. There is no credible basis for
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`interpreting "explained in detail below" to refer to a single cherry-picked sentence
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`rather than to the numerous ensuing references to windows in the '415 Patent.
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`Further, the second to last sentence of the paragraph merely states "by counting
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`sequence tags within a series of predefined windows of equal lengths along
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`different chromosomes, more robust and statistically significant results may be
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`obtained." Ex. 1001, 4:61-64. Thus, the use of equal length windows is not a
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`requirement, but an option to achieve better results.
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`Undeterred, Patent Owner asserts that the "only purpose" of the windows in
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`the '415 Patent "is to normalize data." Paper 24, p. 10, 2nd full ¶. However, as the
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`Interference Board found, "[t]he only purpose of the 'windows'…is to determine
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`'values' for numbers of sequence tags mapped to the chromosome portions,
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`specifically a 'first value and a second value,' which are then used…to determine
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`whether or not an abnormal distribution exists;" the claims do not expressly
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`indicate that the windows are to be used for normalization or that they must be of
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`equal length. Ex. 1088, p. 14, 1st full ¶. Even Patent Owner's own witness, Dr. J.
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`Chris Detter ("Detter"), testified numerous times that the windows of the '415
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`Patent have purposes beyond normalization, including mitigation of computational
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`demands of whole genome sequencing and more informative results due to
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`examination of smaller amounts of information. Ex. 2117, ¶41; Ex. 1087, ¶45; Ex.
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`1088, pp. 9-10, ¶¶5-6, p. 15, 1st full ¶.
`B. Lo II is Prior Art Against the '415 Patent
`1. The "Chromosome Portions" of Lo II are "Windows"
`Patent Owner asserts that the "windows" of the '415 Patent claims are distinct
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`from the "chromosomal regions" or "sets of chromosome regions" of Lo II. Paper
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`24, p. 13, 2nd full ¶ to ¶ spanning pp. 16-17. Patent Owner states that a
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`chromosomal region cannot be a window of defined length because it "is not
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`necessarily defined by size," and "may vary from person to person." Paper 24, ¶
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`spanning pp. 13-14. This does not distinguish the two terms because the '415
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`Patent does not define window size as a single objective number, but as an
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`arbitrary size "of sufficient length to contain a significant number of sequence
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`reads," typically "between 10 kb and 100 kb, more typically between 40 and 60
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`kb." Ex. 1001, 5:6-11. Thus, like a chromosomal region, the size of a window
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`may vary.
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`Patent Owner states "a chromosome portion is being tested for aneuploidy, but
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`a window is used to do that testing," and attempts to distinguish this from the
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`"chromosomal region" of Lo II, which Patent Owner defines as "a polynucleotide
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`sequence whose imbalance is itself being tested." Paper 24, p. 14, 1st full ¶; ¶
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`spanning pp. 15-16. This is a false distinction because windows themselves may
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`be tested for aneuploidy. Ex. 2001, 56:17-20, 57:15-19. Further, Lo II states that a
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`"clinically relevant chromosomal region" is "a polynucleotide sequence
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`corresponding to a segment of a larger genomic sequence whose potential
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`imbalance is being tested or to the larger genomic sequence itself." Ex. 1002,
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`¶¶0037, 0052. Thus, a "chromosomal region" of Lo II is not limited to a
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`"chromosome portion being tested for aneuploidy," but may be a region within
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`such a portion.
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`Finally, to support its assertion that chromosomal regions are not windows,
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`Patent Owner claims that one of ordinary skill in the art would understand the
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`windows of the '415 Patent to be used exclusively for normalization. Paper 24, p.
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`17, 1st full ¶ to ¶ spanning pp. 18-19. As discussed above, this assertion
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`contradicts the testimony of Patent Owner's own witness and the decision of the
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`Interference Board, which states "Fan has not directed us to evidence that
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`'windows' is a term of art that skilled artisans would have known inherently
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`indicates equal length or a specific normalization protocol." Ex. 2117, ¶41; Ex.
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`1087, ¶45; Ex. 1088, p. 14, 1st full ¶.
`2. Lo II Enables the Use of "Windows"
`Patent Owner asserts that Lo II lacks enablement because it requires undue
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`experimentation to practice the "windows" of the '415 Patent. Paper 24, p. 19, 1st
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`full ¶ to p. 21, 2nd ¶. To determine whether experimentation is undue, courts
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`typically use the Wands factors, which Patent Owner alludes to but makes no effort
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`to address. Patent Owner merely states that there are no working examples, and
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`concludes that Lo II "does not provide any guidance." Paper 24, p. 20, 1st full ¶ to
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`p. 21, 1st ¶; Ex. 1090, 157:18-158:25. The absence of working examples alone is
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`insufficient to establish a lack of enablement. In re Borkowski, 422 F.2d 904, 908,
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`164 U.S.P.Q. 642, 645 (C.C.P.A. 1970) ("The specification need not contain an
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`example if the invention is otherwise disclosed in such manner that one skilled in
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`the art will be able to practice it without an undue amount of experimentation.").
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`As fully set forth in the Petition for IPR (Paper 1) and confirmed by the Board
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`in Paper 7 and the Decision on Motions in the '922 Interference, Lo II discloses
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`how chromosomal regions (i.e., windows) are used to analyze sequence tags for
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`determination of aneuploidy. Paper 7, p. 10, 3rd full ¶ and ¶ spanning pp. 10-11;
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`Ex. 1088, p. 19, 2nd full ¶. This is supported by a more complete analysis of the
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`Wands factors. The level of skill in the relevant art was high when Lo II was filed,
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`and windows were conventional mathematical tools whose use in bioinformatics
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`was well known, predictable, and routine. Ex. 1090, 11:10-12:17, 153:21-25; Ex.
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`1010, ¶22. Neither Patent Owner nor Detter provide any analysis of the relevant
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`art in 2008, but references disclosing the use of windows in conjunction with
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`sequencing include, for example, Lander et al. Nature 409:860-921 (2001) (Ex.
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`1101, cited in the '415 Patent at 30:49-50), which discloses the use of windows of
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`various sizes to analyze G/C content, distribution of repeats, and correlation
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`between transposons and G/C content. Ex. 1101, p. 876, right col., 3rd full ¶ to p.
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`877, left col., 4th full ¶; p. 883, right col., 2nd full ¶; p. 884, left col., 1st full ¶;
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`Figs. 9, 13, 22, 36; Ex. 1090, 61:23-62:2. Other references disclosing windows in
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`conjunction with sequencing prior to 2008 include U.S. Patent Publication No.
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`2005/0221341 ("Shimkets," Ex. 1004), which discloses normalizing data for
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`aneuploidy detection by analyzing the distribution of genomic DNA fragments
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`using windows of defined length within a test chromosome and a normal
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`chromosome (see, e.g., ¶0007); Margulies et al. Proc Natl Acad Sci USA
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`102:3354-59 (2005) (Ex. 1091) (see, e.g., p. 3356, right col., 1st full ¶); Giladi et
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`al. Bioinformatics 18:873-9 (2002) (Ex. 1092) (see, e.g., Abstract); Fares et al. J
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`Mol Evol 55:509-21 (2002) (Ex. 1093) (see, e.g., Abstract, p. 512, ¶ spanning
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`columns); and Brickner et al. Mamm Genome 10:95-101 (1999) (Ex. 1094) (see,
`e.g., Abstract, p. 96, 3rd full ¶). Ex. 1010, ¶¶97, 98, 100, 102-106.1
`Based on the level of ordinary skill in the art, the nature of the invention, the
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`state of the prior art, and the level of predictability in the art, one of ordinary skill
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`in the art could have readily practiced sequencing and alignment using "windows
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`of defined length" based on the disclosure of Lo II without undue experimentation.
`3. Patent Owner Has Not Established an Actual Reduction to
`Practice Prior to July 23, 2008
`Patent Owner attempts to avoid Lo II by asserting an actual reduction to
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`practice by Quake and Fan prior to July 23, 2008. Paper 24, pp. 29-60. Quake's
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`declaration has been withdrawn, and Fan's allegation of a reduction to practice
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`1 Patent Owner does not dispute that U.S. Prov. Appl. No. 60/951,438 ("Lo I," Ex.
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`1003) discloses all but step (c) (windows of defined length) of '415 Patent claim 1.
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`Paper 24, p. 29, 1st ¶. Since each of the references listed above discloses the use
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`of windows in conjunction with sequencing (with Shimkets disclosing the use of
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`windows in conjunction with aneuploidy detection), claim 1 would be obvious
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`over any of these references in combination with Lo I.
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`lacks corroboration. Other than the Fan declaration (Ex. 2132), the only evidence
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`of an actual reduction to practice proffered by Patent Owner is an unwitnessed and
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`unsigned laboratory notebook (Ex. 2110), emails between the inventors and
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`various parties that fail to reference the specific steps of the '415 Patent claims, and
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`testimony by third parties who lack specific knowledge of the inventors' alleged
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`activities during the relevant time period (Detter) and fail to corroborate a
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`reduction to practice of the steps of the '415 Patent claims (Blumenfeld).
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`"[A]n inventor's testimony as to the facts of invention must be corroborated by
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`independent evidence." In re Garner, 508 F.3d 1376, 1380 (Fed. Cir. 2007), citing
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`Cooper v. Goldfarb, 154 F.3d 1321, 1330 (Fed. Cir. 1998). Corroborative
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`evidence may be "testimony of a witness, other than an inventor, to the actual
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`reduction to practice or it may consist of evidence of surrounding facts and
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`circumstances independent of information received from the inventor." Hahn v.
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`Wong, 892 F.2d 1028, 1032-1033 (Fed. Cir. 1989), quoting Reese v. Hurst v.
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`Wiewiorowski, 661 F.2d 1222, 1225 (C.C.P.A. 1981). "Sufficiency of
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`corroboration is determined by using a 'rule of reason' analysis, under which all
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`pertinent evidence is examined when determining the credibility of an inventor's
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`testimony." Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1170 (Fed. Cir. 2006),
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`citing Price v. Symsek, 988 F.2d 1187, 1195 (Fed. Cir. 1993). However, adoption
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`of the "rule of reason" has not altered the requirement that evidence of
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`corroboration must not depend solely on the inventor himself." Reese, 661 F.2d at
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`1225.
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`In support of its alleged actual reduction to practice, Patent Owner cites
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`Blumenfeld's declaration (Ex. 2134) and Ex. 2127, which purports to be an email
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`from Blumenfeld to Fan and Quake. Paper 24, p. 37, 2nd full ¶. The email
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`appears to be a response to a previous email from Fan in which she stated she was
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`"attaching a graph of the preliminary analysis of the full sequencing run" and the
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`recipients should "[p]ay attention to the distribution of chr21." Ex. 2127, p. 1. The
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`excerpt of Fan's email in Ex. 2127 does not refer to aligning, windows, or any of
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`the other specific steps of the '415 Patent claims; it does not even provide a cogent
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`summary of the experiment or its results. Blumenfeld's response consists of one
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`word: "[a]wesome!" Id. This is hardly sufficient to establish corroboration of the
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`claimed method.
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`When a claim is directed to a process, it is the successful reduction to practice
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`of the process that must be corroborated, not merely the successful end result.
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`Medichem, 437 F.3d at 1171. Neither the incomplete excerpt of Fan's original
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`email nor Blumenfeld's one word response include any suggestion of "determining
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`values for numbers of sequence tags mapping to chromosome portions by using a
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`number of windows of defined length with a normally and abnormally distributed
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`chromosome portions to obtain a first value and a second value therefrom." Even
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`if the original email had included such information, Blumenfeld's one word
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`response is insufficient to establish corroboration. In his declaration, Blumenfeld
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`does not elaborate on the meaning of his statement; he simply reiterates that he told
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`Fan the results were "awesome." Ex. 2134, ¶8. Blumenfeld never discusses the
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`specific steps of the '415 Patent claims or his understanding or mindset regarding
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`those steps in 2008, and never actually states that he was aware of a complete
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`reduction to practice.
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`Patent Owner also relies on the declaration of Detter (Ex. 2138). Despite
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`opining about the state of the art in 2008 and the mindset of Quake and Fan, Detter
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`admits he has no contemporaneous knowledge of the inventors' activities in 2008,
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`has not performed any searches to ascertain the state of the art in 2008, and has
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`relied exclusively on documentation provided by Patent Owner in reaching his
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`conclusions. Ex. 1090, 20:8-22:10, 61:23-62:2. Witness testimony cannot
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`corroborate an actual reduction to practice where the witness relies exclusively on
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`what they were told by the inventor. Reese, 661 F.2d at 1231. Detter admits he
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`does not know the legal definition of a reduction to practice, and when pressed on
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`this issue provided a definition that was muddled at best. Ex. 1090, 18:9-20:7,
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`22:12-27:15. As such, Detter's conclusions regarding Quake and Fan's alleged
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`reduction to practice are entitled to no weight.
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`Patent Owner cites a manuscript allegedly attached to a June 19, 2008 email
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`from Fan to Quake and Blumenfeld (Ex. 2113/2111) as evidence of its reduction to
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`practice. Paper 24, ¶ spanning pp. 38-39. The email refers to the attached
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`manuscript as a "very rough draft." Ex. 2113, p. 1. There is nothing on the face of
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`the exhibits to verify that the proffered attachments are the same ones that were
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`attached to the original email, and Patent Owner has not provided testimony from
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`Blumenfeld to confirm this point. Blumenfeld merely testifies that he received the
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`email and that it included manuscripts or data. Ex. 2134, ¶9. Further, all
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`Blumenfeld says about the manuscript in his declaration is that it was "based on
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`their first Solexa sequencing run and was to be submitted to the journal
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`Proceedings of the National Academy of Sciences, USA," and that he was listed as
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`an author on the paper along with Fan, Quake, Usha Chitkara ("Chitkara"), and
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`Louanne Hudgins ("Hudgins") when it ultimately published in 2008. Id. The mere
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`existence of this manuscript is insufficient to establish corroboration. Patent
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`Owner does not provide any contemporaneous emails from Blumenfeld discussing
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`the manuscript or even acknowledging its receipt, and Blumenfeld offers no
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`information in his declaration as to what he was actually aware of at the time the
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`manuscript was circulated. It is also notable given Patent Owner's reliance on the
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`manuscript that they do not reference the other authors on the eventual paper,
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`much less provide declarations from them.
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`Patent Owner goes on to cite a second manuscript attached to a July 9, 2008
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`email from Quake to Herzenberg, Fan, and Blumenfeld (Ex. 2112) as further
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`evidence of its alleged reduction to practice. Paper 24, p. 39, 2nd full ¶. Like the
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`manuscript in Ex. 2113/2111, there is no evidence that the document included in
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`Ex. 2112 is the same document that was attached to the original email.
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`Blumenfeld does not discuss Ex. 2112 in his declaration, citing it only once
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`without comment for the proposition that he discussed revisions to the manuscript
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`with Quake and Fan on July 7, 2008 (i.e., prior to the date of the email). Ex. 2134,
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`¶11. Blumenfeld does not describe these discussions, and again provides no
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`indication that he actually read the manuscript or that he was aware of the steps of
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`any aneuploidy detection methods.
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`In his declaration, Blumenfeld states that he received an additional graph from
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`Fan on July 1, 2008, and that he discussed the manuscript with Quake and Fan on
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`July 7, 2008. Ex. 2134, ¶¶10-11. In support of these assertions, Blumenfeld cites
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`a July 1, 2008 email from Fan (Ex. 2129), and July 7 and July 9, 2008 emails from
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`Quake (Ex. 2131 and 2112, respectively). However, there is nothing in Ex. 2129
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`or Ex. 2112 to prove that Blumenfeld actually received those messages at the time,
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`nor is there any indication in the exhibits or in Blumenfeld's declaration that he
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`discussed the results with the inventors or offered feedback. The only input
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`Blumenfeld provided in any of the cited emails was a statement in Ex. 2131 that he
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`had added "a little bit about the recent ACOG Practice Bulletin which recommends
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`that invasive testing now be offered to ALL women, regardless of risk factors. I
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`think it will play nicely with the need for a 'risk-free' non-invasive diagnostic test."
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`Ex. 2131, p. 1. There is nothing in this message to suggest that Blumenfeld
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`understood or was even aware of the various steps of the '415 Patent claims;
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`instead, it appears that Blumenfeld was merely providing information for the
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`background of the paper.
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`The burden is on Patent Owner to establish a corroborated reduction to
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`practice. By failing to supply a single shred of evidence showing what any third
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`party understood or knew about the steps of the claimed methods prior to July 23,
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`2008, Patent Owner has utterly failed to meet its burden. The declaration of
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`Blumenfeld is critically deficient because it provides no statement as to what
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`Blumenfeld actually knew and understood about the methods recited in the '415
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`Patent claims at the time of the alleged reduction to practice, and certainly no
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`evidence that he was aware of all of the steps or that he recognized a complete
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`reduction to practice. Further, Patent Owner fails to provide testimony from
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`Quake and Fan's alleged collaborators and coauthors Chu, Fischer, Chitkara, and
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`Hudgins, or from any of the other parties listed in the acknowledgement section of
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`their eventual PNAS paper (Sidow, Guang Shi, Norma Neff, Richard White III,
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`and Nick Ingolia). Ex. 2139, p. 1. Given the significant potential of such
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`testimony to corroborate the alleged reduction to practice, the Board is justified in
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`drawing an adverse inference against Patent Owner for failure to proffer such
`crucial testimony.2 Stampa v. Jackson, 77 U.S.P.Q.2d 1105, 1120 (B.P.A.I. 2005),
`citing Revson v. Cinque & Cinque, P.C., 221 F.3d 71, 81-82 (2nd Cir. 2000).
`C. Wang, Hillier, and Smith
`Patent Owner asserts that Wang "does not disclose a sliding window of
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`predetermined length as that term is properly construed." Paper 24, p. 22, 2nd ¶.
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`Patent Owner states that the length of the sliding windows in Wang "was
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`determined based on the number of virtual tags," and therefore the windows "were
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`not all of an equal length within a given experiment." As discussed at length
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`above, the windows of the '415 Patent do not have to be "of an equal length."
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`Patent Owner is attempting to distinguish Wang on the basis of a limitation that is
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`not present in the '415 Patent claims. Further, Wang's use of sliding windows of
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`1,000 virtual tags to normalize shows that, contrary to Patent Owner and Detter’s
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`assertions, windows do not need to be of fixed or equal length for normalization.
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`Ex. 1005, p, 16157, left col., 1st ¶; p.16159, Fig 2 legend. It is not surprising that
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`2 Similarly, the refusal of named '415 Patent co-inventor Quake to appear for cross-
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`examination in the U.S. is suspect and warrants a negative inference.
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`Detter gets this point wrong, as he has exhibited a complete lack of understanding
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`regarding Wang. For example, Detter testified that Wang does not disclose sliding
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`windows because it examined the chromosome as a whole. Ex. 2117, ¶157. Wang
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`plainly states that "sliding windows" were utilized, a term that has a clear meaning
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`and had that same clear meaning in 2002. Ex. 1005, p. 16157, left col., 1st ¶; p.
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`16159, ¶spanning columns; p. 16159, Fig. 2 legend; p. 16160, Fig. 3B legend.
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`Detter also exhibits a fundamental misunderstanding of specific experiments in
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`Wang, testifying that the "Analysis of Deletions" and "Analysis of Amplification"
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`sections used a single window rather than plural sliding windows. Ex. 1090,
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`87:21-90:9, 98:7-99:5. In both of these experiments, Wang explicitly states that
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`they utilized sliding windows. Ex. 1005, p. 16160, Fig. 3B legend; p. 16159, right
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`col., 1st full ¶. Given these inaccuracies, Detter's testimony regarding Wang
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`carries little weight.
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`Patent Owner goes on make the same assertion regarding the windows of
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`Wang that they made regarding the windows of Lo II, namely that they are "a
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`region being analyzed for abnormal distribution" rather than a subset of that region.
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`However, this assertion is without merit. First, as discussed above, a window may
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`be a region being analyzed for abnormal distribution. Second, the sliding windows
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`used by Wang measure chromosomal sequence tag density which allows the
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`determination of over and under representation of chromosomes.
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`Patent Owner asserts that one of ordinary skill in the art would not have
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`combined Hillier or Smith with Wang because Wang specifically teaches
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`discounting sequence tags with single nucleotide mismatches. This argument is
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`without merit. The exclusion of mismatches in Wang was a function of its use of
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`"first generation" Sanger sequencing, which had a low error rate at the time Wang
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`was published in 2002. One of ordinary skill in the art reading Wang in 2008
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`would have recognized that this prohibition would not extend to massively parallel
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`sequencing methods, which had relatively high error rates at that time — a point
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`noted by both Hillier and Smith. Ex. 1009, p. 2, right col, 1st ¶; Ex. 1006, p. 185,
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`Fig. 2; Ex. 1010, 141-142. Due to these higher error rates, the alignment of
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`sequence reads with one or more mismatches was well known and routine in the
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`art in 2008. Ex. 1010, ¶¶141-143. Patent Owner's own witnesses have testified
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`that the alignment program ELAND, which was used in the '415 Patent to align
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`sequence tags to a reference genome, could align sequences with one mismatch.
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`Ex. 1089, 51:23-55:18; Ex. 1090, 117:23-119:19. Other alignment programs
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`available at the time likewise allowed for mismatches. Ex. 1095, p. 1852, left col.,
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`4th full ¶. Thus, the teachings of Wang would have been insufficient to teach
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`away from the use of aligned sequence tags with a single mismatch in 2008.
`III. CONCLUSION
`For all of the reasons set forth above and in Paper 1, claims 1-17 of the '415
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`Patent should be found unpatentable over the prior art and canceled.
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`Dated: July 7, 2014
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`Respectfully submitted,
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`Perkins Coie LLP
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`By: /Michael J. Wise/
`Michael J. Wise, Reg. No. 34,047
`Patrick D. Morris, Reg. No. 53,351
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`CERTIFICATE OF SERVICE
`I certify that a true and correct copy of the foregoing SEQUENOM REPLY
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`TO PATENT OWNER RESPONSE was served electronically via email on the
`Patent Owner through its attorneys of record on this 7th day of July, 2014 as
`follows:
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`R. Danny Huntington, Esq. (dhuntington@rfem.com)
`Sharon E. Crane, Ph.D., Esq. (scrane@rfem.com)
`Rothwell, Figg, Ernst & Manbeck, PC
`607 14th Street, NW, Suite 800
`Washington, DC 20005
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`/Patrick D. Morris/
`Patrick D. Morris
`Registration No. 53,351
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