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Guardant Health, Inc. v. Foundation Medicine, Inc.

United States District Court, D. Delaware

November 1, 2019

GUARDANT HEALTH, INC., Plaintiff,
v.
FOUNDATION MEDICINE, INC., Defendant. GUARDANT HEALTH, INC., Plaintiff,
v.
PERSONAL GENOME DIAGNOSTICS, INC., Defendant.

          REPORT AND RECOMMENDATION

          CHRISTOPHER J. BURKE UNITED STATES MAGISTRATE JUDGE

         In these two related actions filed by Plaintiff Guardant Health, Inc. ("Guardant" or "Plaintiff) against Defendants Foundation Medicine, Inc. ("FMI") and Personal Genome Diagnostics, Inc. ("PGDx" and collectively with FMI, "Defendants"), Guardant alleges infringement of United States Patent Nos. 9, 598, 731 (the "731 patent"), 9, 834, 822 (the '"822 patent"), 9, 840, 743 (the "743 patent") and 9, 902, 992 (the "'992 patent" and collectively with the other patents, "the asserted patents"). Presently before the Court is the matter of claim construction. The Court recommends that the District Court adopt the constructions as set forth below.

         I. BACKGROUND AND STANDARD OF REVIEW

         The Court hereby incorporates by reference the summary of the background of this matter set out in its September 6, 2019 Report and Recommendation ("September 6 R&R"). (D.I. 354 at 2-3)[1] It additionally incorporates by reference the legal principles regarding claim construction set out in the September 6 R&R. (Id. at 3-5)

         II. DISCUSSION

         The parties had claim construction disputes regarding 13 terms or sets of terms (hereinafter, "terms" or "term sets"). The Court has addressed seven of these terms/term sets in previously-issued Reports and Recommendations. (D.I. 354; D.I. 359; D.I. 389) The Court addresses four of the remaining six terms/term sets herein; it will not construe the remaining two terms at this stage of the case.[2]

         A. "attaching tags ... to said cell free DNA obtained from said bodily sample" / "attaching tags ... to the cfDNA molecules" / "ligating ... to both ends of the cfDNA molecules" (the "attaching/ligating" terms)

         The attaching/ligating terms are found in claim 1 of the 731 patent and claim 1 of the '992 patent. Accordingly, these claims are reproduced below, with the disputed terms highlighted:

1. A method for quantifying single nucleotide variant tumor markers in cell-free DNA from a subject, comprising:
(a) providing at least 10 ng of cell-free DNA obtained from a bodily sample of the subject;
(b) attaching tags comprising barcodes having from 5 to 1000 distinct barcode sequences to said cell-free DNA obtained from said bodily sample of the subject, to generate non-uniquely tagged parent polynucleotides, wherein each barcode sequence is at least 5 nucleotides in length;
(c) amplifying the non-uniquely tagged parent polynucleotides to produce amplified non-uniquely tagged progeny polynucleotides;
(d) sequencing the amplified non-uniquely tagged progeny polynucleotides to produce a plurality of sequence reads from each parent polynucleotide, wherein each sequence read comprises a barcode sequence and a sequence derived from cell-free DNA;
(e) grouping the plurality of sequence reads produced from each non-uniquely tagged parent polynucleotide into families based on i) the barcode sequence and ii) at least one of: sequence information at a beginning of the sequence derived from cell-free DNA, sequence information at an end of the sequence derived from cell-free DNA, and length of the sequence read, whereby each family comprises sequence reads of non-uniquely tagged progeny polynucleotides amplified from a unique polynucleotide among the non-uniquely tagged parent polynucleotides;
(f) comparing the sequence reads grouped within each family to each other to determine consensus sequences for each family, wherein each of the consensus sequences corresponds to a unique polynucleotide among the non-uniquely tagged parent polynucleotides;
(g) providing one or more reference sequences from a human genome, said one or more reference sequences comprising one or more loci of reported tumor markers, wherein each of the reported tumor markers is a single nucleotide variant;
(h) identifying consensus sequences that map to a given locus of said one or more loci of reported tumor markers; and
(i) calculating a number of consensus sequences that map to the given locus that include the single nucleotide variant thereby quantifying single nucleotide variant tumor markers in said cell-free DNA from said subject.

(731 patent, col. 62:8-54 (emphasis added))

1. A method for detecting genetic aberrations in cell-free DNA ("cfDNA") molecules from a subject, comprising:
a) providing cfDNA molecules obtained from a bodily sample of the subject;
b) attaching tags comprising barcodes having a plurality of different barcode sequences to the cfDNA molecules to tag at least 20% of the cfDNA molecules, which attaching comprises ligating adaptors comprising the barcodes to both ends of the cfDNA molecules, wherein ligating comprises using more than 10x molar excess of the adaptors as compared to the cfDNA molecules, thereby generating tagged parent polynucleotides;
c) amplifying the tagged parent polynucleotides to produce amplified tagged progeny polynucleotides;
d) sequencing the amplified tagged progeny polynucleotides to produce a plurality of sequence reads from each of the tagged parent polynucleotides, wherein each sequence read of the plurality of sequence reads comprises a barcode sequence and a sequence derived from a cfDNA molecule of the cfDNA molecules;
e) mapping sequence reads of the plurality of sequence reads to one or more reference sequences from a human genome;
f) grouping the sequence reads mapped in e) into families based at least on barcode sequences of the sequence reads, each of the families comprising sequence reads comprising the same barcode sequence, whereby each of the families comprises sequence reads amplified from the same tagged parent polynucleotide;
g) at each of a plurality of genetic loci in the one or more reference sequences, collapsing sequence reads in each family to yield a base call for each family at the genetic locus; and
h) detecting, at one or more genetic loci, a plurality of genetic aberrations, wherein the plurality of genetic aberrations comprises two or more different members selected from the group of members consisting of a single base substitution, a copy number variation (CNV), an insertion or deletion (indel), and a gene fusion.

('992 patent, col. 64:2-41 (emphasis added)) The parties' competing proposed constructions for the attaching/ligating terms are set out in the chart below:

Term

Plaintiffs Proposed Construction

Defendants' Proposed Construction

"attaching tags ... to said cell free DNA obtained from said bodily sample" / "attaching tags ... to the cfDNA molecules" / "ligating ... to both ends of the cfDNA molecules"

No construction necessary.

"attaching/ligating tags to the unmodified cell-free DNA from step (a) without end repair and/or A-tailing"

         (D.I. 59 at 4) As reflected by the claim language, claim 1 of the 731 patent and claim 1 of the '992 patent require attaching/ligating tags to cell free DNA (or "cfDNA"). The parties have agreed that the terms "cell-free DNA" and "cfDNA" shall be construed to mean "DNA that exist(s) within a bodily fluid within the body outside of a cell and in solution, including in blood, plasma, serum, urine, saliva, mucosal excretions, sputum, stool or tears." (D.I. 53, ex. A at 1) The parties' dispute with regard to the attaching/ligating terms is whether tags may be attached to cell free DNA that has undergone the processes of end repair and/or A-tailing (Plaintiff says yes, Defendants say no). (D.I. 59 at 4; D.I. 68 at 3-4; Tr. at 100)

         As a preliminary matter, the parties' briefing (and their technology tutorials) did not make clear what end repair and A-tailing actually are. During the Markman hearing, Guardant's counsel explained that end repair and A-tailing are intermediate steps in the process of attaching adaptors to DNA. (Tr. at 95) When DNA comes out of cells, the ends of the DNA are "messed up" and "jagged." (Id.; see also D.I. 286, ex. A at 67) End repair is a process for repairing the ends of the DNA in which something is stuck to one of the ends, or the ends are made blunt so that there is no overhang. (Tr. at 95-96; D.I. 286, ex. A at 67-68) A-tailing entails attaching a series of As to the end of the DNA that can be used as a site ligation. (Tr. at 96; D.I. 286, ex. A at 68) Defendants assert that "[t]here is no dispute that end repair and A-tailing modify and add chemical moieties" to the DNA. (D.I. 74 at 4; see also Guardant's Markman Presentation, Slide 55) Moreover, the specification makes specific mention of end repair and A-tailing in the following discussion regarding isolation and extraction of "[c]ell free polynucleotides":

One method of increasing conversion efficiency involves using a ligase engineered for optimal reactivity on single-stranded DNA, such as a ThermoPhage ssDNA ligase derivative. Such ligases bypass traditional steps in library preparation of end-repair and A-tailing that can have poor efficiencies and/or accumulated losses due to intermediate cleanup steps, and allows for twice the probability that either the sense or anti-sense starting polynucleotide will be converted into an appropriately tagged polynucleotide. It also converts double-stranded polynucleotides that may possess overhangs that may not be sufficiently blunt-ended by the typical end-repair reaction.

(731 patent, cols. 35:42, 54, 36:42-53 (emphasis added))

         With both claims at issue requiring the attachment of tags "to said cell free DNA" or "to the cfDNA molecules[, ]" Defendants assert that the parties' agreed-upon construction for cell free DNA/cfDNA (whereby it "exist(s) within a bodily fluid within the body outside of a cell and in solution") compels their proposed construction. (D.I. 68 at 4; D.I. 74 at 4; Tr. at 100, 105) Because the processes of end repair and A-tailing result in DNA that has been modified, Defendants argue that such DNA "is not cell-free DNA because it never existed within the body." (D.I. 68 at 4; see also D.I. 74 at 4; Tr. at 103) Accordingly, Defendants propose that the attaching/ligating terms should be construed to require the attaching of tags to cell free DNA that has not been modified by end repair and/or A-tailing. (D.I. 291 at 2 ("Tags must be attached to the unmodified cfDNA obtained from the bodily sample of the subject-not some other altered molecule.")) For the following three reasons, however, the Court is not persuaded by Defendants' argument.

         First, attaching barcodes to DNA modified by end repair and/or A-tailing is a "traditional way" of attaching barcodes to DNA molecules. (Tr. at 99, 107; D.I. 136 at 2; D.I. 157 at 1; D.I. 173 at 1) The specification describes the processes of end-repair and A-tailing themselves as "traditional steps" in preparing samples of DNA. (731 patent, col. 36:45) Importantly, it does so in a section of the specification that is all about the preparation of cell free polynucleotide samples. (Id., cols. 35:54, 65, 36:4-6, 13, 32, 38) And the claims at issue simply recite "attaching" and "ligating"-without any indication that these terms should be given special meaning or be construed to exclude such "traditional" processes for attaching and ligating. (See D.I. 59 at 5; D.I. 72 at 4; Tr. at 99, 107)[3]

         Second, certain dependent claims of the patents help to demonstrate that the attaching/ligating terms are broad enough to encompass DNA that has gone through end repair and A-tailing. Dependent claim 8 of the 731 patent recites "[t]he method of claim 1, wherein the attaching comprises blunt-end ligation or sticky end ligation." (731 patent, col. 63:12-13)[4]During the Markman hearing, Guardant's counsel asserted that claim 8 is evidence that "attaching" in claim 1 of the 731 patent does not exclude cell free DNA that has undergone end repair and/or A-tailing. (Tr. at 97, 107) According to Guardant's counsel, "blunt-end ligation" and "sticky end ligation" are techniques used in the repair of DNA and can include end repair and A-tailing. (Id. at 95-96, 98; see also D.I. 173 at 1; D.I. 286 at 2) Defendants' response to this line of argument was that blunt-end ligation or sticky-end ligation may not necessarily "involve[] end repair or A-tailing." (Tr. at 110) But Guardant points to certain deposition testimony indicating that these processes are indeed related. For example, FMI's scientist Travis Clark, Ph.D. testified that FMI's ligation process involves "repair[ing] the ends" of the cell free DNA "which makes them blunt" and then "add[ing] 1A to the 3 prime end of each side"-i.e., A-tailing-and that the process is a "form of sticky-end ligation[.]" (D.I. 173, ex. 1 at 57-58 (cited in D.I. 173 at 1)) Similarly, PGDx's scientist Andrew Georgiadis testified that "end repair fixes [] overhangs [on pieces of DNA ends] and [] blunt-ends them" and that he thought that ligation using end-repair and A-tailing is a "form of sticky end ligation." (D.I. 286, ex. A at 67- 70 (cited in D.I. 286 at 2))[5] With dependent claim 8 of the 731 patent and dependent claim 9 of the '992 patent reciting "attaching tags comprising barcodes ... to said cell-free DNA" wherein "the attaching comprises blunt-end ligation or sticky end ligation[, ]" and with the evidence demonstrating that end repair and A-tailing are, at minimum, forms of sticky end ligation, the record supports Guardant's position that the attaching/ligating terms should not be construed to exclude end repair and A-tailing.[6]

         Third, various testimony in the record demonstrates that a person of ordinary skill in the art would understand that attaching tags to cell free DNA encompasses DNA that has undergone end repair and A-tailing. (See D.I. 88 at 2) For example, FMI's expert Dr. Stacey Gabriel testified "the cell-free DNA is .. . end repaired and A-tailed and used and amplified, and then those fragments are what are actually being analyzed here in" step (e) of claim 1 of the 731 patent. (D.I. 88, ex. 2 at 78; see also Id. at 85 (Dr. Gabriel testifying that cell-free DNA that has been end-repaired or A-tailed is "a modified version of a cell-free DNA fragment. . . it contains the cell-free DNA, but it's also been modified")) And FMI's scientist Dr. Clark testified in describing FMI's ligation process that "the cell-free DNA" undergoes steps to "repair[] the ends" and then "there is an enzymatic step that adds 1A to the 3 prime end of each side." (D.I. 173, ex. 1 at 57) Thus, this testimony seems to cut against Defendants' position that "the use of end-repair and A-tailing modifies cell-free DNA such that a skilled artisan would not believe the claim term 'attaching tags ... to said cell free DNA' encompasses the use of end repair and A-tailing." (D.I. 173 at 1; see also D.I. 286 at 1)[7]

         Having clearly resolved the dispute regarding this term set in Plaintiffs favor, and seeing no other dispute regarding this term set's meaning, the Court recommends that the terms "attaching tags ... to said cell free DNA obtained from said bodily sample" / "attaching tags . . . to the cfDNA molecules" / "ligating ... to both ends of the cfDNA molecules" be afforded their plain and ordinary meaning. See Spectrum Pharms., Inc. v. InnoPharma, Inc., Civil Action No. 12-260-RGA-CJB, 2014 WL 3365684, at *9 (D. Del. July 3, 2014).

         B. "sequencing extracellular polynucleotides from a bodily sample from [a/the] subject"

         The claim term "sequencing extracellular polynucleotides from a bodily sample from [a/the] subject" appears in claims 1 and 10 of the 743 patent. Accordingly, these claims are reproduced below, with the disputed term highlighted:

1. A method for detecting copy number variation, comprising:
a) sequencing extracellular polynucleotides from a bodily sample from a subject, wherein each of the extracellular polynucleotides generates a plurality of sequence reads;
b) filtering out reads that fail to meet a set accuracy, quality score, or mapping score threshold;
c) mapping the plurality of sequence reads to a reference sequence;
d) quantifying mapped reads or unique sequence reads in a plurality of predefined regions of the reference sequence; and
e) determining copy number variation in one or more of the plurality of predefined regions by:
i) normalizing a number of reads in the plurality of predefined regions to each other, or a number of unique sequence reads in the plurality of predefined regions to each other; and/or
ii) processing a number of reads in the plurality of predefined regions or a number of unique sequence reads in the plurality of predefined regions with ...

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