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`Paper No. ___
`Filed: May 19, 2021
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`PROGENITY, INC.,
`Petitioner,
`
`v.
`
`NATERA, INC.,
`Patent Owner.
`_____________________________
`
`Case No. IPR2021-00282
`Patent No. 10,266,893
`_____________________________
`
`PETITIONER’S PRE-INSTITUTION REPLY1
`
`
`
`1 Authorization for this reply was given by Board order on May 12,
`
`2021. Paper 7. All emphases in quotes throughout are added unless indicated.
`
`The order did not authorize an update regarding Fintiv arguments. Updates
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`have been provided in related cases (IPR2021-00266, -00267, -00279) and
`
`Petitioner is willing to provide a similar update here.
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`
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`

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`The Quackenbush Declaration (EX2001) relied upon in Natera’s Preliminary
`
`Response (“POPR”) in this proceeding is a copy of the same document submitted in
`
`IPR2021-00266 concerning a different U.S. patent (U.S. Patent No. 9,424,392).
`
`Progenity filed a reply in the -266 IPR addressing, inter alia, the falsity and
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`unreliability of that testimony, as well as the prejudicial nature of such testimony at
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`the pre-institution stage where discovery, rebuttal testimony, etc. are lacking.
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`The same issues remain at play here and are further compounded by the
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`irrelevant nature of Dr. Quackenbush’s testimony vis-à-vis the different ’893 patent
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`presently challenged. Dr. Quackenbush’s testimony is from the wrong timeframe,
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`ignores years of technological development and prior art, is critically divorced from
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`the subject matter and claims presently challenged, and replete with content even
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`Natera acknowledges has no relevance to the present proceeding. See e.g., Paper 7
`
`at 3 (Natera conceding that “many issues raised in IPR2021-00266 are not applicable
`
`to the present proceeding.”). Neither Progenity nor the Board should be expected to
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`play archeologist with the record, sorting through testimony—which addresses a
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`different timeframe and a different patent—in an attempt to discern which of
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`Natera’s many factual contentions may or may not comport with the views of a
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`declarant that has not been, and may never be2, subject to cross-examination.
`
`I.
`
`DR. QUACKENBUSH’S IRRELEVANT TESTIMONY IS ENTITLED NO WEIGHT.
`An obviousness inquiry must consider the state of the art at the time of the
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`invention. Randall Mfg. v. Rea, 733 F.3d 1355, 1362-63 (Fed. Cir. 2013). Because
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`Dr. Quackenbush’s testimony plainly indicates it ignores the state of the art at the
`
`relevant time, it is entitled little, if any, weight here as a threshold matter.
`
`Dr. Quackenbush’s testimony is expressly limited to a timeframe years prior
`
`to the earliest conceivable ’893 patent priority date. In the section titled “Relevant
`
`Timeframe for Determining Obviousness,” Dr. Quackenbush states “[f]or the
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`purposes of this declaration, I will use November 26, 2005 as the time of the
`
`invention. My testimony is directed to the state of the art as of that date.” EX2001,
`
`¶20. As set forth in the petition materials, however, the ’893 patent is not entitled to
`
`a priority date earlier than March 17, 2008. Pet., 14. Natera has never rebutted the
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`Examiner’s findings in this regard and presumably will not seek to do so. Compare
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`with POPR, 55 (“The Patent Office has already spoken”). As a result, Dr.
`
`Quackenbush’s testimony fails to consider several years of prior art, including
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`critical technological developments in the NGS field relevant to the challenged
`
`
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`2 Dr. Quackenbush does not state a willingness to appear for cross-examination.
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`- 2 -
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`claims. Multiple NGS platforms became commercially available and were widely
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`published during the timeframe ignored by Dr. Quackenbush. See e.g., Pet. 19; see
`
`also Pet. 18-21; 29-30 (2007 Manufacturer’s Instructions).
`
`These aspects of the prior art and state of the art at the time are particularly
`
`pertinent in view of the challenged claims, which do little beyond reciting
`
`conventional aspects of NGS sequencing platforms well-known at the time (e.g.,
`
`universal amplification, cluster/clonal amplification, sequencing, quantitating
`
`sequence reads). See e.g., Pet. 1-3, 21, 33-35, 38, 40; EX1005, ¶¶67-69, 86-95, 101-
`
`03, 139, 142-144, 146, 157, 163-64, 201-02. A POSA would not have ignored the
`
`state of the art at the time as Dr. Quackenbush did in his declaration. Instead, the
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`Quackenbush Declaration spends many pages discussing irrelevant material,
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`including isolation of fetal cells, measurement of polymorphic loci, and the Huang
`
`reference. See, e.g, EX2001, ¶¶32-36, 48-58, 84-126.
`
`Further, it is clear from the Declaration that Dr. Quackenbush either ignores
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`or does not subscribe to various claim interpretations and arguments in the POPR.
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`Natera, for example, argues that the claims require “segregating” or “distinguishing”
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`fetal DNA following sequencing (POPR, 3), but neither Natera nor Dr. Quackenbush
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`justify re-writing the claims to replace the recited term “measuring” with new
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`terminology. Dr. Quackenbush provides no testimony how “measuring the amounts
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`of clonally amplified fetal chromosome segments by performing next-generation
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`sequencing” might plausibly exclude the prior art disclosure under any claim
`
`interpretation. See e.g., EX1007, ¶[0096] (distinguishing “the [post-clonal
`
`amplification] sequences mapped to the Y chromosome” as “fetal-specific”); Pet.
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`17, 23, 41; see also, Shimkets 61:11-14 (distinguishing post-clonal amplification
`
`sequence reads). Relevant prior art disclosures are largely or entirely ignored in
`
`Natera’s argument, and lacking discussion entirely in the Quackenbush declaration.
`
`Similarly, Natera assumes without evidence that the prior Examiner
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`accurately assessed Lo’s express disclosure of determining the fetal fraction post-
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`clonal amplification (e.g., Pet., 2, 16-17; EX1007, ¶¶[0092]-[0093] (mapping after
`
`clonal amplification), [0096]3 (post-mapping determination of fetal fraction from
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`fetal-specific sequences)) but “required” that the “fetal DNA be segregated (or
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`distinguished) from the amounts of maternal DNA” in some unexplained, different
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`manner. POPR, 3. Neither the Quackenbush Declaration, nor the prosecution
`
`history, support Natera’s contention that the Examiner meaningfully considered Lo’s
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`post-clonal amplification analysis of fetal fraction when erroneously (and without
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`the benefit of expert testimony) viewing Lo. Curiously, Natera generated newly
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`tailored witness declarations for every Progenity IPR except this case. One may
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`
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`3 The Examiner did not cite paragraph 96 of Lo.
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`reasonably infer a tactical decision was made to submit the Quackenbush ’392 patent
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`Declaration here, rather than a declaration tailored to this case, because Dr.
`
`Quackenbush simply did not support Natera’s positions regarding the ’893 patent.
`
`II. NATERA’S ARGUMENTS NOT COMMENSURATE WITH THE PATENT OR ART.
`Natera and Dr. Quackenbush also argue that fetal DNA concentrations in
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`maternal blood were lower in early pregnancy and increased over time. POPR, 56-
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`57, 61; EX2001, ¶114. No challenged claim limits the sample to being taken early
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`in pregnancy. Moreover, it was known that prenatal diagnosis was not only “helpful
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`for managing the remaining term of the pregnancy,” but remained helpful through
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`the end of pregnancy for the purposes of “planning for possible complications with
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`the birth process, preparing for problems that can occur in the newborn infant, and
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`finding conditions that may affect future pregnancies.” EX1098, [0011].4
`
`
`
`4 Although Natera submitted EX1098 in the ’392 patent IPR as EX2015, Natera
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`omitted the reference from its filing in this case after Progenity pointed out in
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`IPR2021-00266, as it does here, that the reference confirms prenatal diagnosis was
`
`useful throughout the pregnancy. In other words, Natera edited its filing here to
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`exclude literature references that it later learned undermined its argument.
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`- 5 -
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`Moreover, Natera erroneously focuses on the period and types of pregnancy
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`where fetal DNA is least abundant. POPR, 56-57. As just discussed, neither the
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`claims nor the prior art limit the utility of non-invasive prenatal testing to early
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`gestation or so-called “normal” pregnancies. The literature Natera previously
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`submitted in IPR2021-00266 demonstrates that fetal cfDNA concentrations can be
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`much higher than those used by Dr. Quackenbush for his calculations. EX2001,
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`¶¶120-22. For example, Bischoff discloses that mean fetal DNA concentrations later
`
`in pregnancy averaged 292.2 GEq/ml and ranged as high as 769 GEq/ml. EX1099,
`
`60.5 Using Dr. Quackenbush’s own assumptions that “one GE is approximately
`
`0.0036 ng,” these concentrations equate respectively to 1.05 ng and 2.77 ng per mL,
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`or ~4-11 ng for a 4 mL blood sample), higher than the threshold set by Dr.
`
`Quackenbush. As another example, Bianchi discloses that fetal cfDNA levels were
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`enhanced for certain pregnancy types, reporting a mean concentration of 381 GE/mL
`
`in samples obtained from women with symptomatic pre-eclampsia. EX1008, p. S98,
`
`left-hand col., 2nd para. Using Dr. Quackenbush’s own assumptions, this works out
`
`to 1.37 ng/mL, or 5.49 ng for a 4 mL sample. Even Dr. Quackenbush agrees that the
`
`
`
`5 Although Natera submitted EX1099 in the ’392 patent IPR as EX2007, Natera
`
`omitted the reference from its filing in this case.
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`- 6 -
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`typical blood draw would be as large as 10-15 mL. EX2001, ¶120. In other words,
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`Dr. Quackenbush’s own math demonstrates that a single “typical” blood draw
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`generally obtains more than enough fetal cfDNA to perform the proposed analyses.
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`Furthermore, Dr. Quackenbush was operating under multiple assumptions
`
`that systematically understate the amount of fetal cfDNA available in a blood draw.
`
`The 2004 Johnson reference, for example, demonstrates that a maternal blood draw
`
`during pregnancy easily can be larger than supposed by Dr. Quackenbush. EX1100,
`
`Abstract (“20 mL of peripheral blood from 20 pregnant women between 10 and 20
`
`weeks of gestation”); EX1005, ¶55 (volume of maternal blood sample can be
`
`increased to obtain more genetic material). Johnson also showed that fetal cfDNA
`
`concentration in maternal blood early in pregnancy were higher than Dr.
`
`Quackenbush supposed. For example, Johnson asked five different centers to
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`analyze the same blood samples using a standardized protocol and found that fetal
`
`DNA concentration averaged 228 GE/mL when samples were promptly processed
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`and extraction was properly performed. EX1100, Abstract, 519-20 & Table 2.
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`Johnson also discloses that these centers could improve their results by “a more in-
`
`depth standardized DNA extraction procedure, as well as increased experience with
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`the protocol.” Id., 519-20. Using Dr. Quackenbush’s own assumptions that “one GE
`
`is approximately 0.0036 ng,” this equates to 0.82 ng per mL, 3.28 ng for a 4 mL
`
`blood sample, and 16.42 ng for Johnson’s 20 mL blood sample. Johnson thus
`- 7 -
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`confirms that Dr. Quackenbush was given assumptions about blood draw volume
`
`and fetal cfDNA concentration that systematically underestimate the amount of fetal
`
`cfDNA obtained, giving the false impression that maternal blood would provide
`
`insufficient fetal cfDNA for analysis. This was no accident. As Natera’s arguments
`
`and Dr. Quackenbush’s testimony are based on a series of false assumptions, a few
`
`examples of which have been discussed here, their arguments should be rejected.
`
`III. NATERA’S ATTACKS ON SHIMKETS REQUIRE ERRONEOUS ASSUMPTIONS.
`A. All Shimkets Applications Use Quantitative Next-Gen Sequencing.
`Natera argues
`that complex-sample sequencing and sequence-based
`
`karyotyping are fundamentally different, mutually exclusive technologies, the
`
`former allegedly being only suitable for “primitive microorganisms.” See, e.g.,
`
`POPR, 39-40; EX2001, ¶¶57-66. This is incorrect. All Shimkets applications use
`
`the same quantitative next-generation sequencing methodology. See, e.g., EX1010,
`
`3:14-20, 21:10-24. Shimkets compares the sequences from the sample to a known
`
`reference or control. Id., 19:27-20:1. Shimkets teaches it can obtain the “complete
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`nucleotide sequence of an organism” and can determine DNA sequence differences
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`between “different but related” organisms. Id., 18:11-19:1. Natera thus
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`manufactures an artificial distinction between “complex sample sequencing” and
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`“Sequence-based Karyotyping,” but Shimkets discloses its technology detects and
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`identifies sequence differences between samples, regardless of their origin and
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`whether they are mixed or “pure.”
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`- 8 -
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`Natera argues without support that Shimkets’s technology works only for
`
`“primitive microorganisms.” POPR, 39. Dr. Quackenbush does not testify that
`
`Shimkets is limited to “primitive microorganisms.” Besides attacking references
`
`individually, Natera’s argument also is at odds with the reference itself, which
`
`specifically teaches that its technology is appropriate for pre-natal testing. EX1010,
`
`16:21-23. Of course, pre-natal testing is used for mammals (especially humans), not
`
`primitive microorganisms.
`
`B. Natera’s Attacks on Shimkets’s Sensitivity Should Be Rejected.
`Natera’s assertions that Shimkets would be inoperable for mixed sample
`
`analysis due to sensitivity limitations are not appropriate for the pre-trial stage and
`
`are wrong. For example, they argue that Shimkets’s example ratios of greater than
`
`1.5 and less than 0.75 (and failure to diagnose aneuploidy based on deviations as
`
`great 25%) represented the limit of Shimkets’s abilities. See, e.g., POPR, 39-40,
`
`EX2001, ¶¶47, 68. But Shimkets merely provided these ratios and Fig. 1 as
`
`examples; these examples do not limit the sensitivity capacity of the technology.
`
`EX1010, 16:14-17:4, 58:26-59:5. Shimkets discloses that the ratios for a given
`
`analysis should be adjusted based on “the amount of sequencing” employed.
`
`EX1010, 64:24-29. Shimkets also teaches that “resolution” is improved by
`
`increasing the number of sequences assessed and teaches employing a “desired
`
`amount of sequenc[ing]” for a desired sensitivity. EX1006, 1:23-26, 3:14-20, 16:3-
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`- 9 -
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`6, 47:1-2, 60:3-8. Shimkets’s teaching to read up to one million or more sequences
`
`showed how it would have sufficient sensitivity. Pet., 21-23; EX1005, ¶¶107-08.
`
`Natera dismisses prior teachings to enhance sensitivity based on pure conjecture.
`
`EX1010, 54:20-30; EX1005, ¶¶232, 243; Pet. 61.
`
`IV. EX PARTE PROSECUTION ARGUMENT DOES NOT BAR BOARD EVALUATION.
`Natera and Dr. Quackenbush argue that finding Shimkets inoperable for
`
`aneuploidy detection is a foregone conclusion on the basis of argument by different
`
`lawyers during ex parte prosecution of a different case on a different record. POPR,
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`40-43; EX2001, ¶¶54-56, 66-79. Besides mischaracterizing the record and ignoring
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`the evidence in the petition (Pet. 3, 54, 61-62), Natera does not establish, nor could
`
`they, that ex parte prosecution argument is somehow binding on the Board. See
`
`Fromson v. Advance Offset Plate, Inc., 755 F.2d 1549, 1555 (Fed. Cir. 1985)
`
`(examiner’s decision is not binding); Salesforce.com, Inc. v. VirtualAgility, Inc.,
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`CBM2013-0024, Paper 47 at 10–11 (P.T.A.B. Sept. 16, 2014) (post-grant review
`
`necessarily includes patents previously reviewed by an examiner). Natera’s
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`speculative and unfounded attacks against Shimkets should be rejected.
`
`
`
`Dated: May 19, 2021
`
`
`
`
`
`Respectfully submitted,
`
`/ Michael T. Rosato /
`Michael T. Rosato, Lead Counsel
`Reg. No. 52,182
`
`- 10 -
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`

`

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`- 11 -
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`1043
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`1046
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`1047
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`1048
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`1049
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`1050
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`1051
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`
`1053
`
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`1055
`
`1056
`
`1057
`1058
`
`
`
`

`

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`Intentionally left blank
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`- 15 -
`
`1059
`
`1060
`
`1061
`
`1062
`
`1063
`1064
`
`1065
`
`1066
`
`1067
`
`1068
`
`1069
`
`1070
`
`1071
`
`1072
`1073
`
`1074
`
`1075
`
`1076
`
`1077
`
`
`
`

`

`File History for U.S. Patent Application No. 12/178,181 to Lo et al.
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`
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`1080
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`1082
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`1083
`
`1084
`
`1085
`
`1086
`
`1087
`
`1088
`
`1089
`
`1090
`
`1091
`
`1092
`
`1093
`
`1094
`
`
`
`

`

`1095
`
`1096
`
`1097
`
`1098
`
`1099
`
`1100
`
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`
`
`
`
`- 17 -
`
`
`
`

`

`CERTIFICATE OF SERVICE
`
`The undersigned certifies that the foregoing Petitioner’s Pre-Institution
`
`Reply and Exhibits 1098-1100 were served on May 19, 2021, on the Patent Owner
`
`at the following electronic correspondence addresses:
`
`H. Annita Zhong
`Jason Sheasby
`IRELL & MANELLA LLP
`hzhong@irell.com
`jsheasby@irell.com
`NateraIPR@irell.com
`
`
`
`
`
`Dated: May 19, 2021
`
`
`
`
`
`
`
`Respectfully submitted,
`
`/ Michael T. Rosato /
`Michael T. Rosato, Lead Counsel
`Reg. No. 52,182
`
`- 18 -
`
`