Trials@uspto.gov
`571-272-7822
`
`Paper 9
`Entered: July 26, 2024
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`GENEOSCOPY, INC.,
`Petitioner,
`v.
`EXACT SCIENCES CORPORATION,
`Patent Owner.
`
`IPR2024-00459
`Patent 11,634,781 B2
`
`
`
`
`
`
`
`
`
`Before TINA E. HULSE, DAVID COTTA, and JAMIE T. WISZ,
`Administrative Patent Judges.
`HULSE, Administrative Patent Judge.
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`Geneoscopy Exhibit 1033, Page 1
`
`
`571-272-7822
`
`Paper 9
`Entered: July 26, 2024
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`GENEOSCOPY, INC.,
`Petitioner,
`v.
`EXACT SCIENCES CORPORATION,
`Patent Owner.
`
`IPR2024-00459
`Patent 11,634,781 B2
`
`
`
`
`
`
`
`
`
`Before TINA E. HULSE, DAVID COTTA, and JAMIE T. WISZ,
`Administrative Patent Judges.
`HULSE, Administrative Patent Judge.
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`Geneoscopy Exhibit 1033, Page 1
`
`
`
`IPR2024-00459
`Patent 11,634,781 B2
`
`INTRODUCTION
`I.
`Geneoscopy, Inc. (“Petitioner”) filed a Petition requesting an inter
`partes review of claims 1–20 of U.S. Patent No. 11,634,781 B2 (Ex. 1001,
`“the ’781 Patent”). Paper 1 (“Pet.”). Exact Sciences Corporation (“Patent
`Owner”) filed a Preliminary Response to the Petition. Paper 6 (“Prelim.
`Resp.”). We authorized additional briefing for the parties to address
`(1) discretionary denial under 35 U.S.C. § 325(d); and (2) discretionary
`denial under General Plastic Industrial Co. v. Canon Kabushiki Kaisha,
`IPR2016-01357, Paper 19 (PTAB Sept. 6, 2017) (precedential as to
`§ II.B.4.i) (“General Plastic”). Ex. 3001. Petitioner filed a Reply to Patent
`Owner’s Preliminary Response (Paper 7, “Pet. Reply”) and Patent Owner
`filed a Sur-reply (Paper 8, “PO Sur-reply”).
`We have authority under 35 U.S.C. § 314, which provides that an
`inter partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a). Upon considering
`the arguments and evidence presented in the papers, we determine that
`Petitioner has established a reasonable likelihood that it would prevail in
`showing the unpatentability of at least one claim challenged in the Petition
`and we decline to exercise our discretion to deny institution under 35 U.S.C.
`§§ 314(a) and 325(d). Accordingly, we institute an inter partes review of
`the challenged claims of the ’781 Patent.
`Real Parties-in-Interest
`A.
`Petitioner identifies itself as the real party-in-interest. Pet. 2.
`Patent Owner identifies itself as the real party-in-interest. Paper 4, 2.
`
`2
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`Geneoscopy Exhibit 1033, Page 2
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`IPR2024-00459
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`Related Matters
`B.
`The parties identify Exact Sciences Corporation v. Geneoscopy, Inc.,
`No. 23-cv-1319-MN (D. Del.) as involving the ’781 Patent. Pet. 2–3;
`Paper 4, 2.
`
`The ’781 Patent
`C.
`The ’781 Patent, entitled “Fecal Sample Processing and Analysis
`Comprising Detection of Blood,” was filed as U.S. Application No.
`17/936,335 on September 28, 2022, and claims priority to a series of
`continuation applications, including U.S. Application No. 16/634,607 (“the
`’607 Application”), and U.S. Provisional Application No. 61/149,581 (“the
`’581 Provisional”), which was filed on February 3, 2009. Ex. 1001, codes
`(54), (21), (22), (60), (63), 1:8–19. Thus, the earliest possible effective filing
`date of the ’781 Patent is February 3, 2009, which we apply to our analysis
`in this Decision.
`The ’781 Patent relates to methods and kits for analysis of fecal
`samples. Id. at 1:30–31. According to the Specification, colorectal cancer
`(“CRC”) is a leading cause of cancer-related deaths worldwide. Id. at 1:41–
`42. Most colon cancers arise from adenomatous polyps, which are usually
`asymptomatic. Id. at 1:46–52. Because of this, mass screening of
`asymptomatic patients is the cornerstone for detecting and eliminating these
`precursor lesions to reduce the risk of CRC. Id. at 1:52–55.
`Colonoscopy is the primary screening test for CRC because of its high
`sensitivity and specificity and the ability to remove polyps if found. Id. at
`1:65–2:1. The procedure, however, is invasive, costly, and has certain risks,
`such as infection and perforation of the bowel. Id. at 2:1–3. Fecal occult
`blood testing (“FOBT”), which tests for blood in the stool, is commonly
`used and less invasive and less expensive than colonoscopy. Id. at 2:4–12.
`
`3
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`But because occult blood in stool can be indicative of different
`gastrointestinal disorders, further testing is necessary to detect CRC. Id. at
`2:9–12. There are two types of FOBT: guaiac FOBT (“gFOBT”), which
`detects peroxidase activity of hemoglobin in fecal blood, and
`immunochemical FOBT (“iFOBT” or “FIT”), which uses anti-human
`hemoglobin antibodies to detect fecal blood. Id. at 2:13–34. Although the
`immunochemical procedure is more complicated and more expensive,
`iFOBT is more sensitive than gFOBT. Id. at 2:25–40.
`The Specification also explains that recent developments in testing
`look specifically for mutations in DNA characteristic of colorectal neoplasia
`that are detectable in exfoliated epithelial cells in the stool. Id. at 2:44–47.
`The Specification explains that increased DNA methylation is an epigenetic
`alteration that is common in human cancers. Id. at 3:5–7. Aberrantly
`methylated DNA has also been proposed as a potential tumor marker for
`CRC detection. Id. at 3:7–9.
`The ’781 Patent further explains that, although combined assays for
`detecting CRC have been described, their approach targets either multiple
`protein markers or multiple DNA alterations. Id. at 3:41–43. According to
`the Specification, “[t]o date, immunochemical tests and DNA tests for CRC
`detection have been evaluated and compared on a separate basis only.” Id.
`at 3:43–45.
`The ’781 Patent states that the invention “aims to improve the positive
`and negative predictive value and also the sensitivity and specificity of
`detection of colorectal cancer through non-invasive means.” Id. at 6:42–45.
`Accordingly, the invention is based upon a combination of tests for detecting
`proteins and epigenetic modification markers in the same fecal sample. Id.
`at 6:49–53.
`
`4
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`Geneoscopy Exhibit 1033, Page 4
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`Patent 11,634,781 B2
`
`Illustrative Claim
`D.
`Petitioner challenges claims 1–20 of the ’781 Patent, of which claim 1
`is the only independent claim. Claim 1 is illustrative and reproduced below:
`1. A method of processing a freshly-collected fecal sample
`without freezing, the method comprising:
`a) collecting a fecal sample from a human subject, wherein
`the fecal sample is collected at home by the human subject
`by defecation directly into a sealable collection vessel;
`b) removing a portion of the fecal sample to a separate
`sealable container to produce a removed portion and a
`remaining portion of the fecal sample;
`c) combining the removed portion of the fecal sample in the
`separate sealable container with a buffer that prevents
`denaturation or degradation of blood proteins found in a
`fecal sample, and sealing the sealable container; and
`d) combining the remaining portion of the fecal sample in the
`sealable collection vessel with a stabilizing buffer, and
`sealing the sealable collection vessel.
`Ex. 1001, 45:21–38.
`The Asserted Grounds of Unpatentability
`E.
`Petitioner asserts that claims 1–20 would have been unpatentable on
`the following grounds:
`
`5
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`Claim(s) Challenged
`1–9, 11, 14–20
`12, 13
`
`35 U.S.C. §1
`103
`103
`
`Reference(s)/Basis
`Lenhard,2 Vilkin,3 Itzkowitz4
`Lenhard, Vilkin, Itzkowitz,
`Kanaoka5
`Lenhard, Vilkin, Itzkowitz,
`103
`Derks6
`Shuber,7 Vilkin
`103
`Shuber, Vilkin, Kanaoka
`103
`Shuber, Vilkin, Derks
`103
`Petitioner also relies on the Declaration of Duncan Whitney, Ph.D.
`Ex. 1002. Patent Owner relies on the Declaration of Vadim Backman, Ph.D.
`Ex. 2001.
`
`10
`1–9, 11, 14–20
`12, 13
`10
`
`
`1 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125
`Stat. 284, 287–88 (2011), amended 35 U.S.C. § 103, effective March 16,
`2013. Because the ’781 Patent has an effective filing date before March 16,
`2013, the pre-AIA version of § 103 applies. Our decision, however, would
`be the same under either version.
`2 Lenhard et al., Analysis of Promoter Methylation in Stool: A Novel Method
`for the Detection of Colorectal Cancer, 3 CLINICAL GASTROENTEROLOGY
`AND HEPATOLOGY 142–49 (2005) (Ex. 1004, “Lenhard”).
`3 Vilkin et al., Performance Characteristics and Evaluation of an
`Automated-Developed and Quantitative, Immunochemical, Fecal Occult
`Blood Screening Test, 100 AM. J. GASTROENTEROL. 2519–25 (2005)
`(Ex. 1005, “Vilkin”).
`4 Itzkowitz et al., Improved Fecal DNA Test for Colorectal Cancer
`Screening, 5 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 111–17
`(2007) (Ex. 1006, “Itzkowitz”).
`5 S. Kanaoka, US2006/0216714 A1, published Sept. 28, 2006 (Ex. 1007,
`“Kanaoka”).
`6 Derks et al., Promoter methylation precedes chromosomal alterations in
`colorectal cancer development, 28 CELLULAR ONCOLOGY 247–57 (2006)
`(Ex. 1008, “Derks”).
`7 Shuber et al., WO2005/113769 A1, published Dec. 1, 2005 (Ex. 1009,
`“Shuber”).
`
`6
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`II. ANALYSIS
`Person of Ordinary Skill in the Art
`A.
`Petitioner contends that a person of ordinary skill in the art at the time
`of the invention (“POSA”) would have had “a Ph.D. in chemistry,
`biochemistry, biology, or a related field and at least five years of experience
`designing and performing diagnostic assays on fecal samples.” Pet. 12
`(citing Ex. 1002 ¶¶ 9–12).
`Patent Owner disagrees. Prelim. Resp. 46–48. According to Patent
`Owner, a POSA would have had “a doctoral degree in medicine, chemistry,
`biochemistry, biology, or a related field and 1–2 years of experience in the
`processing and analysis of biological samples, including fecal samples.” Id.
`at 47 (citing Ex. 2001 ¶ 43). Patent Owner also indicates that such a person
`could have been an individual or a member of a team of scientists addressing
`fecal sample processing and analysis. Id. Patent Owner notes that
`Petitioner’s proposal in the Petition is significantly different from the
`proposal in its ex parte reexamination request, which merely required a
`bachelor’s degree and several years of experience processing biological
`samples. Id. at 46; Ex. 1021, 7. 8 Patent Owner also contends that the level
`of skill set forth in the Petition requires an extraordinary level of skill within
`an overly narrow focus. Prelim. Resp. 47. Regardless, Patent Owner states
`that its expert, Dr. Backman, is a person of at least ordinary skill and the
`claims of the ’781 Patent would not have been obvious under any of the
`parties’ proposed definitions of the level of ordinary skill in the art.
`
`
`8 We cite to the page numbers of the exhibit for prosecution histories such as
`Exhibit 1021 and Exhibit 2003. Unless stated otherwise, we cite to the page
`numbers of the reference for all other exhibits.
`
`7
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`We do not discern much of a substantive difference between the
`parties’ respective definitions in this proceeding beyond the number of years
`of experience after obtaining a doctoral degree. Compare Pet. 12, with
`Prelim. Resp. 47. For purposes of this Decision, we adopt Patent Owner’s
`definition as it appears to be reasonable and falls between Petitioner’s
`definitions asserted in the reexamination request and in the Petition.
`Ex. 2001 ¶ 43. Moreover, Patent Owner’s definition appears consistent with
`the prior art’s demonstration of the level of ordinary skill in the art at the
`time of the invention. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed.
`Cir. 2001) (explaining that specific findings regarding ordinary skill level
`are not required “where the prior art itself reflects an appropriate level and a
`need for testimony is not shown” (quoting Litton Indus. Prods., Inc. v. Solid
`State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985))). To the extent the
`parties continue to disagree on the level of ordinary skill in the art, they
`should brief the issue further during trial.
`Claim Construction
`B.
`In an inter partes review, the Board applies the same claim
`construction standard that would be used to construe claims in a civil action
`under 35 U.S.C. § 282(b). See 37 C.F.R. § 100(b). Under that standard,
`claim terms “are generally given their ordinary and customary meaning” as
`understood by a person of ordinary skill in the art at the time of the
`invention. Phillips v. AWH Corp., 415 F.3d 1303, 1312–13 (Fed. Cir. 2005)
`(en banc).
`Petitioner does not explicitly address claim construction in the
`Petition. See generally Pet.
`Patent Owner states that it “does not believe that the Board must
`construe any claim terms in order to deny institution” and “reserves the right
`
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`to assert claim construction positions should the Board institute IPR.”
`Prelim. Resp. 46.
`At this stage of the proceeding, we agree with the parties that no
`construction of any claim term is necessary for purposes of our Decision.
`See Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir.
`2011) (“[C]laim terms need only be construed ‘to the extent necessary to
`resolve the controversy.’” (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g,
`Inc., 200 F.3d 795, 803 (Fed. Cir. 1999))).
`Asserted Obviousness Grounds over Lenhard, Itzkowitz, and Vilkin
`C.
`Petitioner contends that claims 1–9, 11, and 14–20 would have been
`unpatentable as obvious over Lenhard, Itzkowitz, and Vilkin (Ground I).
`Pet. 20–43. Petitioner also argues that dependent claims 12 and 13 would
`have been unpatentable over Lenhard, Itzkowitz, Vilkin, and Kanaoka
`(Ground II) (Pet. 43– 46) and that dependent claim 10 would have been
`unpatentable over Lenhard, Itzkowitz, Vilkin, and Derks (Ground III)
`(Pet. 46–47). Patent Owner opposes. Prelim. Resp. 48–54.
`Having considered the arguments and evidence presented by the
`parties, we determine that Petitioner has shown a reasonable likelihood of
`prevailing on its assertion that the challenged claims would have been
`unpatentable as obvious over the cited references.
`Lenhard (Ex. 1004)
`1.
`Lenhard is a journal article entitled “Analysis of Promoter
`Methylation in Stool: A Novel Method for the Detection of Colorectal
`Cancer” that appears to have been published in the journal Clinical
`Gastroenterology and Hepatology in 2005 and is therefore prior art under
`35 U.S.C. § 102(b). Ex. 1004, 142. Patent Owner does not challenge the
`
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`prior art status of Lenhard at this stage of the proceeding. See generally
`Prelim. Resp.
`According to Lenhard, the detection of tumor-derived genetic changes
`in stool is a promising new approach for CRC screening. Id. Lenhard
`describes a study involving the potential use of hypermethylated in cancer 1
`(“HIC1”) promoter methylation as a stool-based DNA marker. Id. at 143.
`According to Lenhard, the promoter of HIC1 frequently is methylated in
`CRC, but not in normal or aging colonic tissue. Id. Lenhard states that it
`has shown that “HIC1 promoter methylation can be detected frequently and
`with high specificity in stool samples from patients with CRCs.” Id.
`Moreover, Lenhard states “[t]he combination of HIC1 methylation analysis
`with FOBT allowed for detection of two thirds of CRCs.” Id. at 147.
`According to Lenhard, “[t]he combination of both assays resulted in
`increased detection rates for CRCs.” Id.; see also id. at 146 (Table 4)
`(providing data for positivity rates of HIC1 assay, FOBT assay, and
`combination of the tests). Lenhard further states that “[a]lthough the
`combined test detected all localized cancers, no increase in sensitivity for
`adenoma was seen.” Id.
`Lenhard states that stool samples were collected preoperatively from
`patients with verified CRCs and before colonoscopy for patients with
`adenomas larger than one centimeter. Id. Samples were received within ten
`hours after defecation at the laboratory, subjected to gFOBT immediately on
`receipt, and then stored at -80oC until analyzed for methylated DNA. Id. at
`143, 145.
`
`Itzkowitz (Ex. 1006)
`2.
`Itzkowitz is a journal article entitled “Improved Fecal DNA Test for
`Colorectal Cancer Screening” that appears to have been published in the
`
`10
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`journal Clinical Gastroenterology and Hepatology in 2007 and is therefore
`prior art under 35 U.S.C. § 102(b). Ex. 1006. Patent Owner does not
`challenge the prior art status of Itzkowitz at this stage of the proceeding. See
`generally Prelim. Resp.
`Itzkowitz explains that several studies have shown the feasibility of
`detecting colon tumor-specific products in stool. Id. at 111. The markers in
`these studies represent alterations of various genes. Id. Itzkowitz teaches
`that pilot studies have shown that several technical and conceptual advances
`could improve fecal DNA testing. Id. For example, adding a DNA-
`stabilizing buffer to the stool immediately on defecation was shown to
`prevent DNA degradation for several days and enhance the performance of a
`DNA integrity assay (“DIA”). Id. Also, promoter methylation has become
`recognized as a key pathway by which colon cancers develop. Id.
`Itzkowitz describes a two-phase study. Id. at 112. Phase 1 involved
`analyzing stool samples from approximately 50 patients with CRC and 200
`patients with normal colonoscopy to define suitable DIA cut-off values and
`to determine optimal markers for the new assay. Id. Phase 2, which is
`ongoing, was designed as a validation set in which an additional 125 patients
`with CRC and 200 patients with normal colonoscopy will be analyzed using
`the optimal marker panel from phase 1. Id.
`Itzkowitz explains that subjects were given a special stool collection
`kit that is mounted on the toilet bowl. Id. Immediately after defecation, the
`subject added 250 ml of a DNA-stabilizing buffer to the stool specimen and
`then shipped the specimen at room temperature overnight to a laboratory for
`processing and analyzing. Id.
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`Vilkin (Ex. 1005)
`3.
`Vilkin is a journal article entitled “Performance Characteristics and
`Evaluation of an Automated-Developed and Quantitative, Immunochemical,
`Fecal Occult Blood Screening Test” that appears to have been published in
`the American Journal of Gastroenterology in 2005 and is therefore prior art
`under 35 U.S.C. § 102(b). Ex. 1005. Patent Owner does not challenge the
`prior art status of Vilkin at this stage of the proceeding. See generally
`Prelim. Resp.
`Vilkin explains that the standard guaiac fecal occult blood test
`(“gFOBT”) is faulted for its low sensitivity for significant colorectal
`neoplasia (i.e., CRC and advanced adenomatous polyps (“AAP”)), and low
`specificity due to nonspecificity for human hemoglobin (“Hb”). Id. at 2519.
`Vilkin explains that the introduction of central laboratory and office-
`developed, immunochemical fecal occult blood tests (“iFOBT”) specific for
`human Hb improved specificity. Id. Vilkin describes a colonoscopy-
`controlled study that allowed for a detailed evaluation of an automated
`desktop instrument for quantitative, immunochemical determination of fecal
`occult blood. Id. at 2523.
`Vilkin describes a fecal test sampling device shaped like a small test
`tube with a fecal probe that is inserted into the stool and then pushed back
`into the tube, through a membrane into a sample cup that includes a Hb
`stabilizing buffer. Id. at 2520. Vilkin explains that the samples are double-
`closed in ziplock bags and kept in the refrigerator until returned to the
`laboratory where they are kept at 4oC until development. Id.
`Analysis of Claim 1
`4.
`Petitioner asserts that the combination of Lenhard, Itzkowitz, and
`Vilkin teaches each limitation of claim 1 and a POSA would have had a
`
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`reason to combine the references with a reasonable expectation of success.
`On this record, we agree.
`A method of processing a freshly-collected fecal sample
`a)
`without freezing, the method comprising
`Petitioner asserts that to the extent the preamble is limiting, both
`Vilkin and Itzkowitz teach processing fecal samples without freezing.
`Pet. 26–27. Vilkin teaches refrigerating the sample and Itzkowitz teaches
`shipping the sample at room temperature. Id. (citing Ex. 1005, 2520;
`Ex. 1006, 112; Ex. 1002 ¶¶ 164–167). Thus, Petitioner asserts that both
`references teach processing freshly collected fecal samples without freezing.
`collecting a fecal sample from a human subject, wherein
`b)
`the fecal sample is collected at home by the human subject by
`defecation directly into a sealable collection vessel
`Petitioner asserts that Itzkowitz describes this limitation, as subjects
`were provided with a “special stool collection kit that is mounted on the
`toilet bowl.” Pet. 27 (citing Ex. 1006, 112). Moreover, because the sample
`was “shipped at room temperature” to the laboratory, Petitioner asserts that a
`POSA would understand that the sample was collected at home in a
`container that must have been sealable. Id. (citing Ex. 1006, 112; Ex. 1002
`¶ 169). Moreover, Petitioner argues that direct defecation into a sealable
`container was a standard method for collecting stool samples before the
`priority date. Id. at 27–28 (citing Ex. 1002 ¶¶ 170–171).
`removing a portion of the fecal sample to a separate
`c)
`sealable container to produce a removed portion and a
`remaining portion of the fecal sample
`combining the removed portion of the fecal sample in the
`separate sealable container with a buffer that prevents
`
`d)
`
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`denaturation or degradation of blood proteins found in a fecal
`sample, and sealing the sealable container
`Petitioner asserts that the combination of Lenhard and Vilkin teaches
`these limitations. Petitioner asserts that Lenhard describes removing a
`portion of a patient’s stool sample to test for blood proteins using gFOBT
`and then testing the remaining portion for tumor-derived DNA. Pet. 28
`(citing Ex. 1004, 143–45). Petitioner further asserts that it would have been
`obvious to replace the gFOBT of Lenhard with the iFOBT of Vilkin given
`the numerous advantages of iFOBT over gFOBT described by Vilkin. Id. at
`29. Moreover, Petitioner asserts that in Vilkin, the patient removes a portion
`of the fecal sample using a fecal test device that seals the sample in the
`sealable container along with an amount of hemoglobin stabilizing buffer.
`Id. at 29–31 (citing Ex. 1005, 2520; Ex. 1002 ¶¶ 173–178).
`combining the remaining portion of the fecal sample in
`e)
`the sealable collection vessel with a stabilizing buffer, and
`sealing the sealable collection vessel
`Petitioner asserts that the combination of Lenhard and Itzkowitz
`teaches this limitation, because a POSA would have been motivated to
`combine the DNA stabilizing buffer of Itzkowitz with the remaining portion
`of the fecal sample of Lenhard to “preserve the integrity of the DNA in that
`portion of the sample when it was shipped to a diagnostic laboratory for
`analysis.” Pet. 31 (citing Ex. 1006, 112). Moreover, according to Petitioner,
`a POSA would have understood that the collection vessel containing the
`remaining portion and buffer would be sealed before shipping. Id. at 31–32
`(citing Ex. 1002 ¶ 181).
`On this record, we find Petitioner has shown sufficiently that the
`combination of Lenhard, Itzkowitz, and Vilkin teaches each limitation of the
`claims for the reasons stated by Petitioner. At this stage of the proceeding,
`
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`we are not persuaded by Patent Owner’s arguments to the contrary. In its
`Preliminary Response, Patent Owner attacks the references individually
`rather than considers them in combination, as is required in an obviousness
`analysis. Bradium Techs. LLC v. Iancu, 923 F.3d 1032, 1050 (Fed. Cir.
`2019) (“A finding of obviousness . . . cannot be overcome by ‘attacking
`references individually where the rejection is based upon the teachings of a
`combination of references.’”) (quoting In re Merck & Co., 800 F.2d 1091,
`1097 (Fed. Cir. 1986)). For example, Patent Owner asserts that Lenhard
`does not describe “at-home collection, or separation into separate sealed
`containers, or the addition of stabilizing buffers, or processing of the
`samples without freezing.” Prelim. Resp. 48 (citing Ex. 1004; Ex. 2001
`¶¶ 47–52). Patent Owner also argues that Vilkin does not suggest “home
`separation of the sample and addition of buffer to each of the removed and
`remaining portions in separate sealable containers.” Id. at 49. And Patent
`Owner argues that Itzkowitz “does not suggest the home collection
`processes of the claims, let alone testing a single sample using both FOBT
`and DNA tests.” Id. at 50. We are not persuaded by Patent Owner’s attacks
`on each reference individually, as Petitioner relies on the combination of
`cited references for those limitations of the claim, as explained above.
`Reason to combine Lenhard, Itzkowitz, and Vilkin with a
`f)
`reasonable likelihood of success
`Petitioner asserts that it would have been obvious for a POSA to use
`the iFOBT of Vilkin and the fecal collection and DNA stabilization process
`of Itzkowitz in the screening method of Lenhard to arrive at the claimed
`method. Pet. 20–21. Specifically, Petitioner argues that Lenhard provides
`the reason to combine the references, because it teaches that “[t]he
`combination of HIC1 methylation analysis with FOBT allowed for the
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`Patent 11,634,781 B2
`detection of two thirds of CRCs” and that combining the tests “increased
`detection rates for CRCs” and “detected all localized cancers.” Id. at 21
`(citing Ex. 1004, 143, 147).
`Although Lenhard does not expressly disclose the use of the claimed
`buffers, Petitioner asserts it would have been obvious to replace the gFOBT
`in Lenhard with the iFOBT of Vilkin, which stabilized the stool sample in a
`buffer to prevent blood protein degradation. Pet. 21–22 (citing Ex. 1005,
`2519–20). According to Petitioner, a POSA would have had a reason to
`modify Lenhard’s assay to use Vilkin’s iFOBT, because Vilkin teaches
`numerous advantages of iFOBT over gFOBT, which were known in the art,
`including iFOBT’s higher sensitivity and its ability to quantify the blood
`proteins so a physician could choose the Hb threshold level for a patient. Id.
`at 22–23 (citing Ex. 1002 ¶¶ 143–147).
`As for combining Itzkowitz, Petitioner asserts that a POSA would
`have had a reason to improve Lenhard’s assay by directly defecating into a
`sealable container, as was done in Itzkowitz and generally well known in the
`art, and by adding a stabilization buffer to the sample so it could be shipped
`to a laboratory without freezing. Pet. 24 (citing Ex. 1002 ¶¶ 148–158).
`Petitioner asserts that a POSA would have had a reasonable
`expectation of successfully combining the references to reach the claimed
`invention because “it amounts to the routine performance, in combination, of
`two well-established prior art tests that already had been shown to work on
`fecal samples.” Id. at 26 (citing Ex. 1002 ¶ 161).
`Patent Owner disagrees, arguing that a POSA would have been
`discouraged from combining iFOBT with nucleic acid-based testing because
`the increased sensitivity came with a reduction in specificity. Prelim. Resp.
`50–51 (citing Ex. 2001 ¶¶ 50, 73). Patent Owner further notes that Lenhard
`
`16
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`IPR2024-00459
`Patent 11,634,781 B2
`concludes that combining HIC1 with a few additional methylation markers
`is preferred as it may be highly sensitive and specific for detection of CRCs
`and adenomas. Id. at 51 (citing Ex. 1004, 7). In other words, Patent Owner
`argues that Lenhard does not suggest combining HIC1 testing with FOBT.
`Id. Moreover, Patent Owner argues that a POSA would have known that the
`combination of gFOBT and nucleic acid-based testing in Lenhard was not as
`sensitive or specific as either iFOBT alone or other fecal nucleic acid-based
`tests and would therefore have had no reason to add to the cost and
`complexity of combining the two different types of tests. Id. at 53 (citing
`Ex. 2001 ¶ 83). Finally, Patent Owner argues that a POSA would have had
`no way to predict without testing whether a combination of different tests
`would result in improved performance. Id. at 54 (citing Ex. 2001 ¶ 84).
`At this stage of the proceeding, we are persuaded that Petitioner has
`shown sufficiently that a POSA would have had a reason to modify the assay
`of Lenhard to combine Vilkin’s iFOBT and Itzkowitz’s collection process
`and DNA stabilization buffer with a reasonable expectation of success.
`Lenhard expressly states that “[t]he combination of [HIC1 methylation
`analysis with gFOBT] resulted in increased detection rates for CRCs” and
`includes data that supports this statement. See Ex. 1004, 147, 146 (Table 4);
`see also id. at 143 (“The combination of HIC1 methylation analysis with
`FOBT allowed for the detection of two thirds of CRCs.”). We find these
`positive statements and supporting data in Lenhard are sufficient to provide
`a “rational underpinning” to combine the gFOBT and DNA test at this stage
`of the proceeding. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418
`(2007). Moreover, we are persuaded on this record that Vilkin’s explanation
`of the benefits of iFOBT over gFOBT provide a reason to replace Lenhard’s
`gFOBT with Vilkin’s iFOBT assay. See Ex. 1005, 2519. And we agree at
`
`17
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`Geneoscopy Exhibit 1033, Page 17
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`IPR2024-00459
`Patent 11,634,781 B2
`this stage of the proceeding that a POSA would have had a reason to
`improve Lenhard’s assay by requiring a patient to directly defecate into a
`sealable container and add a stabilization buffer to the sample so it could be
`shipped to a laboratory without freezing, as described in Itzkowitz. See
`Ex. 1002 ¶¶ 148–158.
`On this record, we are not persuaded by Patent Owner’s arguments to
`the contrary. Although Lenhard concluded that combining different nucleic
`acid tests may allow for more sensitive and specific detection of CRCs and
`adenomas, that does not teach away from combining FOBT and DNA tests.
`The Federal Circuit instructs that the reason to combine need not coincide
`with the preferred or most desirable combination described in the prior art to
`provide motivation for the invention. See Gen. Elec. Co. v. Raytheon Techs.
`Corp., 983 F.3d 1334, 1351 (Fed. Cir. 2020) (holding the Board erred in
`finding no motivation to combine where the art merely suggested a
`preference for a different engine and did not teach away from the claimed
`invention) (citing In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004) (“[O]ur
`case law does not require that a particular combination must be the
`preferred, or the most desirable, combination described in the prior art in
`order to provide motivation for the current invention.”)).
`Moreover, even if the combined tests in Lenhard were not as sensitive
`or specific as either Vilkin’s iFOBT alone or other fecal nucleic acid tests,
`Patent Owner misses the point. First, the claims do not require a particular
`level of sensitivity or specificity. See Ex. 1001, 45:20–47:4. Second, we are
`persuaded on this record that a POSA would have sought to improve the
`combined assay of Lenhard by using Vilkin’s iFOBT given the advantages
`of iFOBT over gFOBT taught by Vilkin, including increased specificity,
`lack of diet restrictions, and Hb quantification. See Ex. 1005, 2519; see also
`
`18
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`Geneoscopy Exhibit 1033, Page 18
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`Patent 11,634,781 B2
`Ex. 1002 ¶¶ 143–147. Regardless, conclusive proof of efficacy is not
`required to show obviousness. See Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326, 1331 (Fed. Cir. 2014) (“Conclusive proof of efficacy is not
`necessary to show obviousness. All that is required is a reasonable
`expectation of success.”).
`Accordingly, having considered the parties’ respective evidence and
`arguments, we find on this record that Petitioner has shown a reasonable
`likelihood of prevailing on its assertion that claim 1 would have been
`unpatentabl
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