DiscernDx, Inc.Download PDFPatent Trials and Appeals BoardNov 18, 20202020000640 (P.T.A.B. Nov. 18, 2020) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/414,456 01/24/2017 John Blume 53897-747.201 7289 21971 7590 11/18/2020 WILSON SONSINI GOODRICH & ROSATI 650 PAGE MILL ROAD PALO ALTO, CA 94304-1050 EXAMINER AEDER, SEAN E ART UNIT PAPER NUMBER 1642 NOTIFICATION DATE DELIVERY MODE 11/18/2020 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): patentdocket@wsgr.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte JOHN BLUME, ATHIT KAO, ROSLYN DILLON, LISA CRONER, and BRUCE WILCOX Appeal 2020-000640 Application 15/414,456 Technology Center 1600 Before FRANCISCO C. PRATS, TAWEN CHANG, and CYNTHIA M. HARDMAN, Administrative Patent Judges. CHANG, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 1, 3, 4, 6, 7, and 18–37. We have jurisdiction under 35 U.S.C. § 6(b).2 We AFFIRM. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as DiscernDx, Inc. Appeal Br. 4. 2 We heard oral argument relating to this appeal on October 1, 2020. Appeal 2020-000640 Application 15/414,456 2 STATEMENT OF THE CASE “Colorectal cancer [(CRC)] is a leading cause of cancer-related deaths in the United States.” Spec. ¶ 2. The Specification states that colonoscopy and sigmoidoscopy, “the gold standard for detecting colon cancer,” have low patient acceptance due in part to their expense and highly invasive nature, and also may “expose subjects to risk of complications such as infection.” Id. ¶ 8. The Specification further states that fecal occult blood test (FOBT), the most common non-invasive test for colorectal cancer, has a high false- positive rate and a sensitivity of only around 50%, and also may be less sensitive for detecting early stage CRC. Id. ¶ 9. The Specification also states that numerous serum markers that have been investigated in connection with colon cancer have exhibited low sensitivity. Id. ¶ 9. According to the Specification, the invention relates to methods of assessing CRC status in an individual by determining blood levels for a panel of biomarkers comprising the proteins C9, CEA, DPP4, MIF, ORM1, PKM, SAA, and TFRC, as well as the individual’s age and gender.3 Id. ¶ 12. CLAIMED SUBJECT MATTER The claims are directed to a method of assessing colorectal health of an individual. Claim 1 is illustrative: 1. A method of assessing colorectal health of an individual, comprising: obtaining a circulating blood sample from said individual; 3 C9 and CO9 both refer to the protein complement C9. Spec. 13, Table 1. Likewise, DPP4 is synonymous with DPPIV, which refers to the protein dipeptidyl peptidase 4. Id. Appeal 2020-000640 Application 15/414,456 3 detecting protein levels for each member of a list of proteins in sample, said list of proteins comprising DPPIV, CO9, TFRC, ORM1, MIF, PKM, SAA, and CEA; and obtaining age information and gender information for said individual. Appeal Br. 30 (Claims App.). REJECTIONS A. Claims 1, 3, 4, 25–29, 32, and 35–37 are rejected under 35 U.S.C. § 103 as being unpatentable over Cordero,4 Brock,5 Chen,6 Thorsen,7 Meng,8 Etzioni,9 and Mercer.10 Ans. 3. 4 OJ Cordero et al., Preoperative Serum CD26 Levels: Diagnostic Efficiency and Predictive Value for Colorectal Cancer, 83 BRITISH J. CANCER 1139 (2000). 5 Randall Brock et al., A Multiplex Serum Protein Assay for Determining the Probability of Colorectal Cancer, 2 AM. J. CANCER RES. 598 (2012). 6 William Tzu-Liang Chen et al., Identification of Biomarkers to Improve Diagnostic Sensitivity of Sporadic Colorectal Cancer in Patients with Low Preoperative Serum Carcinoembryonic Antigen by Clinical Proteomic Analysis, 412 CLINICA CHIMICA ACTA 636 (2011). 7 Stine Buch Thorsen et al., Detection of Serological Biomarkers by Proximity Extension Assay for Detection of Colorectal Neoplasias in Symptomatic Individuals, 11:253 J. TRANSLATIONAL MED. (2013), available at http://www.translational-medicine.com/content/11/1/253. 8 Wen Meng et al., Serum M2-Pyruvate Kinase: A Promising Non-Invasive Biomarker for Colorectal Cancer Mass Screening, 4 WORLD J. GASTROINTESTINAL ONCOLOGY 145 (2012). 9 Ruth Etzioni et al, The Case for Early Detection, 3 NATURE REVIEWS CANCER 243 (2003), available at https://www.nature.com/articles/nrc1041. References in the opinion to page numbers in Etzioni refer to the online version of the article, which is numbered consecutively beginning with page 1 on the first page. 10 Donald W. Mercer, Use of Multiple Markers to Enhance Clinical Utility, in IMMUNODIAGNOSIS OF CANCER 39 (Ronald B. Herberman & Donald W. Mercer eds., 2nd ed. 1990). Appeal 2020-000640 Application 15/414,456 4 B. Claims 1, 3, 4, 6, 7, and 18–37 are rejected under 35 U.S.C. § 103 as being unpatentable over Cordero, Brock, Chen, Thorsen, Meng, Etzioni, Mercer, and Vokes.11 Ans. 7. OPINION A. Issues The same issues are dispositive for both of the rejections on appeal.12 We therefore consider the rejections together. The Examiner concludes that the claims are drawn to methods comprising detecting levels in blood of known colorectal cancer biomarkers, i.e., DPPIV, CO9, TFRC, ORM1, MIF, PKM, SAA, and CEA. Ans. 3. In particular, the Examiner finds that Cordero, Brock, Chen, Thorsen, and Meng teach using, respectively, (1) DPPIV or CEA levels, (2) CO9, ORM1, and SAA levels, (3) a combination of CEA and MIF levels, (4) CEA, TFRC, and MIF levels, and (5) PKM or CEA levels in a blood sample to detect an individual’s colorectal cancer risk. Ans. 3–5. The Examiner finds that Cordero, Brock, Thorsen, and Meng also teach the relevance of age and/or gender to detecting colorectal cancer risk. Id. at 3, 4. Finally, the Examiner finds that Meng, Etzioni, and Mercer suggest the advantages of 11 Everett E. Vokes & Ralph R. Weichselbaum, Concomitant Chemoradiotherapy: Rationale and Clinical Experience in Patients with Solid Tumors, 8 J. CLINICAL ONCOLOGY 911 (1990). 12 In the Answer, the Examiner withdrew the nonstatutory double patenting rejection over claims 1–21 of US 9,689,874 B2 in view of Cordero, Etzioni, and Mercer and the provisional nonstatutory double patenting rejection over claims 31–36 of copending application No. 15/629,593 in view of Cordero, Etzioni, and Mercer. Ans. 8. Appeal 2020-000640 Application 15/414,456 5 using multiple tumor markers to diagnose cancer, namely early diagnosis and/or increased sensitivity and specificity, and that Mercer teaches that “incorporating CEA into a colorectal cancer detection panel . . . increase[s] sensitivity.” Id. at 5–6. The Examiner concludes that a skilled artisan “would have been motivated with an expectation of success” to combine the teachings of the cited references to arrive at the claimed invention, because all the proteins recited in the claims are known colorectal cancer biomarkers in circulating blood, and using multiple markers for diagnosis has the advantages of early diagnosis, increased sensitivity and specificity, and greater acceptability to patients as compared to an invasive procedure such as colonoscopy. Ans. 6. The Examiner further concludes that the claims would have been obvious because they recite combinations that are “merely a ‘predictable use of prior art elements according to their established functions.’” Id. In a second rejection, the Examiner additionally cites Vokes as rendering obvious the chemotherapy or radiation treatment recited in certain dependent claims. Ans. 7. Appellant contends that the Examiner fails to show that a skilled artisan would have had reason to combine the cited references to arrive at the claimed invention, with a reasonable expectation of success. Appeal Br. 11–19. Appellant further contends that the claimed subject matter exhibits unexpected results. Id. at 19–24; see also Reply Br. 7–8. Finally, with respect to claims 25, 26, 36, and 37, Appellant contends that the cited references do not disclose the additional dependent limitations regarding “wherein said list of proteins comprises no more than 15 [or 8] proteins.” Appeal Br. 17–18. Appeal 2020-000640 Application 15/414,456 6 The issues with respect to these rejections are (1) whether a preponderance of evidence supports the Examiner’s conclusion that a skilled artisan would have had a reason to combine the cited references to arrive at the claimed invention, with a reasonable expectation of success; (2) whether a preponderance of evidence supports the Examiner’s conclusion that the cited prior art combination teaches or suggests the additional limitations in dependent claims 25, 26, 36, and 37; and (3) whether Appellant has presented evidence of unexpected results that, when considered together with evidence of obviousness, shows the claims to be nonobvious. B. Analysis Claims 1, 3, 4, 6, 7, 18–24, and 27–35 With the exception of claims 25, 26, 36, and 37, Appellant does not separately argue the claims.13 We therefore focus our analysis on claim 1 as representative of the remaining claims. Unless otherwise noted, we adopt the Examiner’s findings of fact and reasoning on scope and content of the prior art with respect to claim 1 (Non-Final Act.14 7–19; Ans. 3–7, 9–24) and agree that claim 1 is obvious over Cordero, Brock, Chen, Thorsen, Meng, 13 Appellant also refers to claim 27, the other independent claim on appeal, in the Appeal Brief. However, to present separate argument regarding appealed claims, “[u]nder each heading identifying the ground of rejection being contested, any claim(s) argued separately or as a subgroup shall be argued under a separate subheading that identifies the claim(s) by number.” 37 C.F.R. 41.37(c)(1)(iv). Appellant has not provided a separate subheading for claim 27; accordingly, we understand that Appellant is not separately arguing claim 27. In any event, even if Appellant properly argued claim 27 separately, our analysis for claim 1 set forth below would apply to claim 27 as well. 14 Office Action mailed July 6, 2018. Appeal 2020-000640 Application 15/414,456 7 Etzioni, and Mercer. We respond to Appellant’s arguments below. Only those arguments timely made by Appellant in the briefs have been considered; arguments not so presented are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015); see also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) (“Any bases for asserting error, whether factual or legal, that are not raised in the principal brief are waived.”). Appellant contends that, “[w]hile elements of claims 1 and 27 may be found scattered throughout some of [the cited prior art] references, there is no context or disclosure which would lead a person of skill in the art to select these particular elements.” Appeal Br. 17. In particular, Appellant contends that Cordero is limited to a DPPIV diagnostic, and Brock teaches CO9 only in the context of a particular 7-marker panel. Chen teaches CEA in combination with MIF or alpha-enolase. Thorsen describes CRC risk detection using CEA, TFRC, and MIF only within the context of a 5-marker panel that also includes OPN and CA242. Meng teaches only the use of PKM as a single marker for CRC detection in place of CEA. Etzioni and Mercer fail to provide guidance to arrive at the combination of markers of claims 1 and 27. Id.; see also id. at 11–15. We are not persuaded. As the Examiner points out, whether taught individually or as part of a biomarker panel, each of the proteins recited in claim 1 is known in the art to be useful in assessing the colorectal health of an individual. Ans. 6–7. Based on the disclosures in Etzioni and Mercer that combining sensitive biomarkers may achieve greater diagnostic accuracy, a skilled artisan would have had reason to combine these biomarkers in a method to assess colorectal health. Id. at 5–6; see also, e.g., Appeal 2020-000640 Application 15/414,456 8 Chen 638–639, bridging paragraph (“[c]ombining the determinations of serum CEA . . . with Alpha-enolase or MIF levels to diagnose primary CRC increased the number of diagnoses”); Thorsen 2, left column (stating that “a number of studies . . . demonstrated that higher discrimination power could be obtained by combining biomarkers”). We further agree with the Examiner that a skilled artisan would have additional reason to combine the cited references to arrive at the claimed invention, because the “combination is merely a ‘predictable use of prior art elements according to their established functions.’” Ans. 6 (quoting KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 417 (2007)); cf. In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980) (“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose.”). We are not persuaded by Appellant’s arguments that a skilled artisan, in view of the prior art, would have understood the recited biomarkers to be useful only in the specific context or combinations in which the biomarkers are discussed in each of the references. Appeal Br. 11–15. A reference is prior art for all that it teaches to a person of ordinary skill in the art, who is also “a person of ordinary creativity, not an automaton.” Beckman Instruments, Inc. v. LKB Produkter AB, 892 F.2d 1547, 1551 (Fed. Cir. 1989); KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). Furthermore, “[n]on-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references. . . . [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a Appeal 2020-000640 Application 15/414,456 9 whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Thus, we agree with the Examiner that a skilled artisan reading the combination of cited references would have understood that each of the biomarkers recited in claim 1 is useful in assessing colorectal health of an individual in combination with other sensitive biomarkers for, e.g., detecting CRC, even if the other biomarkers are not disclosed in the same reference. Appellant contends that, “[w]hile elements of claims 1 and 27 may be found scattered throughout some of these various references, there is no context or disclosure which would lead a person of skill in the art to select these particular elements and expect their combination to be successful.” Appeal Br. 17. Appellant contends that, thus, “to arrive at the combination of markers recited . . . , one skilled in the art must ‘vary all parameters or try each of the numerous possible choices’ of the references without ‘direction as to which of the many choices is likely to be successful,’” which “courts have held not to be a reasonable expectation of success.” Id. (quoting Medichem, S.A. v. Rolabo, 437 F.3d 1157, 1165 (Fed. Cir. 2006)). More particularly, Appellant contends that Brock, Chen, and Thorsen highlight how a combination of promising markers cherry-picked from the art is likely to be found ineffective upon further evaluation. The Office fails to offer any explanation for how the low success rate demonstrated by the references of record (e.g. ⁓6.8% success rate in Thorsen) could suggest a particular panel of markers out of countless possible panels would have a reasonable expectation of success. By arbitrarily picking markers in isolation from disparate references to arrive at the claimed panel of markers that has been experimentally validated only in the pending application, the Office is engaging in impermissible hindsight analysis. Appeal 2020-000640 Application 15/414,456 10 Id. at 18–19; see also id. at 13–14. We are not persuaded. As the Examiner notes, claim 1 does not require the claimed method of assessing colorectal health to achieve any particular level of sensitivity, specificity, or efficiency. Ans. 16. As the Examiner also notes, all of the recited biomarkers in claim 1 have been validated in the prior art as blood biomarkers for assessing colorectal health (e.g., by detecting colorectal cancer). Id. at 20. Nothing cited by Appellant suggests that biomarkers known to be useful in assessing colorectal health of an individual would become ineffective when combined with other known sensitive biomarkers, even if there may be variations in sensitivity and specificity based on the composition of a particular panel. Thus, contrary to Appellant’s assertion, to arrive at the combination of claim 1 does not require “‘vary[ing] all parameters or try each of the numerous possible choices’ of the references without ‘direction as to which of the many choices is likely to be successful.’” Finally, we note that “the expectation of success need only be reasonable, not absolute.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). Brock, Chen, and Thorsen do not suggest the contrary. Appellant contends that Brock taught that an initial list of 14 promising candidate proteins identified by mass spectrometry had to be culled to arrive at a 7-marker panel to improve its diagnostic effectiveness. Brock demonstrates that a panel is not necessarily improved by having more biomarkers and, in fact, is diminished by having the wrong combination of markers — thus highlighting the unpredictability of assembling biomarker panels. Appeal Br. 18. Appeal 2020-000640 Application 15/414,456 11 We are not persuaded. As the Examiner points out and as discussed above, claim 1 does not require the method to have any particular degree of sensitivity, specificity, or efficiency. Ans. 20. Brock teaches that the peptides reported in its final panel of 6 biomarkers “provide the model with the best sensitivity, specificity and negative predictive value.” Brock 599, left column (emphasis added). However, Appellant has not pointed us to any portion of Brock that persuasively suggests that the other 46 peptides from the 14 proteins identified in its biomarker discovery project would not have been useful in methods to assess colorectal health. Moreover, the biomarkers recited in claim 1 were not merely identified in the prior art as differentially expressed in normal versus CRC serum samples, as were the initial 46 peptides from 14 proteins identified in Brock’s biomarker discovery project. Brock 598–599, bridging paragraph. Instead, they were specifically mentioned in their respective reference as useful in assessing colorectal health (e.g., in diagnosing CRC) either individually or as part of a panel. With respect to Chen, Appellant contends that “Chen initially investigated HSP27 as a potential marker for colon cancer” but that, “despite being identified as being overexpressed an average of 4.2-fold in CRC tissue using mass spectrometry analysis . . . , HSP27 ultimately failed to demonstrate predictive efficacy during validation experiments.” Appeal Br. 18. We are not persuaded. As the Examiner points out, unlike HSP27, which was known to be overexpressed in tumor tissue but is not significantly overexpressed in serum levels of the CRC patients examined, each of the biomarkers recited in claim 1 was known to be a serum biomarker. Ans. 20; Chen Abstract. Thus, the fact that “HSP27 did not appear to be a suitable Appeal 2020-000640 Application 15/414,456 12 candidate serum biomarker” in Chen does not suggest that a skilled artisan would not have found it obvious to use known serum biomarkers, such as those recited in claim 1, in a method for assessing colorectal health of an individual that comprises detecting protein levels in a circulating blood sample of the individual. Chen 640, left column. Finally, as discussed above and as the Examiner points out, each of the recited biomarkers in claim 1 have been “experimentally validated as colorectal cancer blood biomarkers by cited prior art related to colorectal cancer diagnosis.” Ans. 20. In contrast, the initial pool of 74 potential CRC biomarkers screened in Thorsen were selected from literature using the more general criteria of “proteins present in the pathways involved in CRC, proteins involved in inflammation and cancer, proteins found in biomarker screening studies of CRC tumor tissue and general cancer markers.” Thorsen 3, left column. Thus, we are not persuaded by Appellant’s argument that the alleged “low success rate demonstrated by the references of record (e.g., ~6.8% success rate in Thorsen)” shows that a skilled artisan would not have had a reasonable expectation that a particular biomarker, such as those claimed in claim 1, would be successful in a method for assessing colorectal health. Appeal Br. 13–14, 19. Appellant also contends that, with respect to the limitation regarding “obtaining age . . . and gender information for said individual,” none of Cordero, Thorsen, and Meng suggests that age and gender are useful for diagnosing colorectal cancer risk, that Meng found that gender and age did Appeal 2020-000640 Application 15/414,456 13 not affect PKM levels,15 and that Cordero in fact “teaches that age and gender are not useful for assessing colorectal health . . . and discourages combining these elements into a panel with DPPIV.” Appeal Br. 12, 14. We are not persuaded. As the Examiner noted, claim 1 does not recite any limitations regarding how age and gender information should be used in the claimed method. Ans. 14. Appellant does not dispute that Cordero, Thorsen, and Meng all disclose obtaining age and gender information from the subjects in their study. In addition, the Examiner cites in the Answer evidence that relationships between age/gender and colorectal cancer are known in the art. Id. at 14–15; see also, e.g., Brock 598, left column (describing a recommendation that screening for CRC begin at age 50 and continue until age 75). Appellant has not persuasively disputed such evidence in the Reply Brief. We agree with the Examiner that the cited prior art does not suggest that age and gender are irrelevant to assessing colorectal health of an individual. As the Examiner points out, Cordero in fact teaches that “[t]here were no significant differences between the two sex- and age-groups for both donor and patient samples” in terms of serum CD26 concentration. Ans. 15; Cordero 1140, right column; 1141, Table 1. In short, Cordero and Meng merely teach that there may not be a significant relationship between gender/age and levels of particular biomarkers, not that gender and age is irrelevant to assessing colorectal health. 15 We note that Meng appears to teach that “[a]mong the normal group, there was no significant difference in serum M2-PK between men and women . . . or between different age groups.” Meng 147, right column (emphasis added). Appeal 2020-000640 Application 15/414,456 14 Finally, citing to Figure 7 of the Specification and the Wilcox Declaration,16 Appellant contends that the particular biomarker panels recited in claims 1 and 27 exhibit unexpected results. Appeal Br. 19. To facilitate our discussion, Exhibit A to the Wilcox Declaration is reproduced below: Wilcox Decl. Ex. A. Exhibit A to the Wilcox Declaration depicts a modified version of Figure 7 of the Specification, which plots, for 1,000 biomarker panels, the frequency of panels having a given area under the curve (AUC) 16 Declaration of Bruce Wilcox, Ph.D. under 37 C.F.R. § 1.132 (Aug. 16, 2017). Appeal 2020-000640 Application 15/414,456 15 value as a function of the AUC value.17 Wilcox Decl. ¶¶ 14–17; Spec. ¶ 225. Exhibit A of the Wilcox Declaration further indicates the subset of biomarker panels comprising DPPIV, CEA, and CO9 (i.e., the biomarkers recited in claim 27) by solid black shading. Wilcox Decl. ¶ 20. Our reviewing court has explained that “[m]ere improvement in properties does not always suffice to show unexpected results,” but “when an applicant demonstrates substantially improved results . . . and states that the results were unexpected, this should suffice to establish unexpected results in the absence of evidence to the contrary.” In re Soni, 54 F.3d 746, 751, 34 USPQ2d 1684, 1688 (Fed. Cir. 1995) (emphasis in original). Moreover, “when unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art” and “be commensurate in scope with the claims.” In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991); In re Dill, 604 F.2d 1356, 1361 (CCPA 1979). In this case, we agree with the Examiner that Appellant has not demonstrated that the claimed combination of biomarkers exhibits 17 We understand that the area under a receiver operating characteristic (ROC) curve is one way to measure the performance of a biomarker panel in assessing a health condition. Spec. ¶ 14 (describing “a Validation Area Under curve (AUC)” as “a parameter of panel test success”), ¶ 97 (stating that “[t]he overall performance of a classifier is assessed in some cases via the AUC of the ROC”). More specifically, we understand that an ROC curves may be used to represent “[t]he quantitative relationship between sensitivity and specificity,” wherein “[t]he x-axis of a ROC curve shows the false-positive rate of an assay” and “[t]he y-axis of ROC curve reports the sensitivity for an assay.” Spec. ¶ 256. “This allows one to . . . determine a sensitivity of an assay for a given specificity, and vice versa.” Id. Appeal 2020-000640 Application 15/414,456 16 substantially improved results that were unexpected as compared to the closest prior art. Ans. 21. As an initial matter, we acknowledge Appellant’s argument that the comparison of biomarker panels comprising DPPIV, CEA, and CO9 to other panels in Figure 7 is a comparison to the prior art because the panels are generated by reference to the art, and further acknowledge Appellant’s argument that Figure 7 in fact overestimates AUC values that may be generated from a random selection of markers in the art because “the pool from which the panels of Figure 7 draws is already enriched for higher- performing markers.” Appeal Br. 20–21; Wilcox Decl. ¶ 18. We similarly acknowledge Dr. Wilcox’s statements that “[p]anels comprising DPPIV, CEA, and CO9 substantially outperform other panels in the set” and that “[n]othing in the art as [he] understands it suggests that panels comprising DPPIV, CEA and CO9 would out-perform other panels for the assessment of colorectal health.” Wilcox Decl. ¶¶ 22, 25. Nevertheless, as the Examiner points out, neither the Specification nor the Wilcox Declaration provides sufficient evidence as to the composition of the randomly generated panels (or, for that matter, how the panels used in Figure 7 were “enriched for higher-performing markers”). Ans. 21. Thus, we are not persuaded that Appellant has shown that any improved results were unexpected. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007) (“[I]n order to properly evaluate whether a superior property was unexpected, the [fact-finder] should have considered what properties were expected. Here, Pfizer’s evidence must fail because the record is devoid of any evidence of what the skilled artisan would have expected.”). In this regard, we also note that Appeal 2020-000640 Application 15/414,456 17 [t]he Board has broad discretion as to the weight to give to declarations offered in the course of prosecution. See Velander v. Garner, 348 F.3d 1359, 1371 (Fed. Cir. 2003) (‘[A]ccord[ing] little weight to broad conclusory statements [in expert testimony before the Board] that it determined were unsupported by corroborating references [was] within the discretion of the trier of fact to give each item of evidence such weight as it feels appropriate.’). In re American Acad. of Science Tech Ctr., 367 F.3d 1359, 1368 (Fed. Cir. 2004) (alterations in original); see also Perreira v. Secretary of the Dept. of HHS, 33 F.3d 1375, 1377 (Fed. Cir. 1994) (“An expert opinion is no better than the soundness of the reasons supporting it.”).18 In its Reply Brief, Appellant contends that, with respect to the data in Figure 7, the Specification describes that “a 187 member original candidate pool was first selected from the literature,” that “[t]his 187 marker pool was 18 According to Dr. Wilcox, the majority – although not all – of the panels comprising DPPIV, CEA, and CO9 have AUC values of at least 0.80, while for the complete randomized panel the most frequent AUCs were 0.77 to 0.79. Wilcox Decl. ¶ 22. While we need not and do not rely on the below in order to affirm the Examiner’s rejection, we note that Dr. Wilcox provides no explanation why an alleged improvement of 0.03 to 0.01 in the AUC would be considered substantial, particularly given that some panels that do not comprise DPPIV, CEA, and CO9 also appear to have AUCs of 0.80 or above. Wilcox Decl. Ex. A. Similarly, even though evidence of unexpected results must be commensurate with the scope of the claims (and claims 1, 3, 4, 6, 7, 18–24, and 27–35 are not limited as to the size of the panel), all of the panels tested in Figure 7 had the same size – i.e., contained the same number (10) of classifiers/markers. Although Dr. Wilcox states that “we understand that the results can be generalized to panels of other sizes” and “expect that, independent of classifier number, panels comprising DPPIV, CEA and CO9 will be disproportionately represented among the higher- performing classes,” Wilcox Decl. ¶ 23, no evidence or explanation was provided to support this understanding or expectation. As discussed above, “[a]n expert opinion is no better than the soundness of the reasons supporting it.” See Perreira, 33 F.3d at 1377. Appeal 2020-000640 Application 15/414,456 18 then analyzed for efficacy in determining health status to identify a much smaller pool of 31 biomarkers,” that “[t]his narrowed list of 31 biomarkers was then further narrowed to 27, and then to a set of 25 biomarkers, from which random panels were generated that performed ‘much better than those generated from the unenriched parent 187 marker set.’” Reply Br. 7. Appellant thus argues that, contrary to the Office’s suggestion that the claimed panel may not exhibit superlative performance on grounds that the members of the 25 marker set may be ineffective blood biomarkers, this shortened set of 25 biomarkers was experimentally validated for the claimed methodology, having been identified by culling the 187 marker pool and yielding superior performance. Id. We are not persuaded. Although the Specification describes the 25 biomarkers used in Figure 7 as being culled from a pool of 187 markers, Appellant points to only the most general description of how such culling was accomplished. “[T]he burden of showing unexpected results rests on he who asserts them.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984). We agree with the Examiner that the cursory description in the Specification and the Wilcox Declaration regarding Figure 7 does not suffice to show that the claimed panels exhibits unexpected results as compared to the closest prior art.19 19 In the Reply Brief, Appellant cites for the first time an article that Appellant contends to be “[a] corresponding scientific publication” of the experiment described in Figure 7 of the Specification, in order to provide additional details regarding the 25 markers used in that figure. Reply Br. 8. Appeal 2020-000640 Application 15/414,456 19 We are further unpersuaded by Appellant’s unexpected results arguments because, as the Examiner points out, Meng, Brock, and Thornsen each teach biomarker or biomarker panels with AUC values that appear to be higher than the AUC values of the panels in Figure 7. Ans. 24. For example, Brock reported that the ROC curve of its model relative to the test data had an AUC of 0.8989. Brock 602, left column. Likewise, Thorsen noted that “when applying the indicators to identify early-stage CRC a combination of CEA, TFRC and CA242 resulted in a ROC curve with an area under the curve of 0.861.” Thorsen Abstract. Finally, Meng reported that the AUC for serum M2-PK (i.e., PKM) was 0.89 for CRC stages I–III. Meng 145, right column. In response, Appellant argues in its Reply Brief that the Office’s comparison is made across different samples (e.g., different cancer stages) obtained using different methods (e.g., different methods of collection, storage, sample processing, etc) by different research groups (e.g., variation in protocols and other factors between groups that may not even be accounted for) and evaluated using different experimental techniques (e.g., various types of mass spectrometry analysis, ELISA, etc), and as such, any direct comparison using performance metrics such as AUC is meaningless. Instead, the available data includes In particular, Appellant cites to the publication to show that the 25 markers used were blood plasma markers rather than, for instance, tissue markers. Id. No showing of good cause was made by Appellant to explain why the article and any accompanying arguments were not presented earlier during prosecution, thereby denying the Board the benefit of the Examiner’s response. Accordingly, we decline to consider the article and arguments related thereto, which are waived. See 37 C.F.R. § 41.41(b)(2); cf. Optivus Tech., Inc. v. Ion Beam Applications S.A., 469 F.3d 978, 989 (Fed. Cir. 2006). Appeal 2020-000640 Application 15/414,456 20 Figure 7 and the Wilcox Declaration, dated August 17, 2017, which show that the specific biomarkers recited in the instant claims outperformed other panels selected from the 25 blood biomarkers. Reply Br. 8. We are not persuaded. Even if comparisons of AUCs disclosed in the prior art and in Figure 7 are inapposite, Appellant’s attorney arguments do not suffice to show that the comparative panels of Figure 7 are, in fact, the closest prior art as compared to, for example, Brock, Thorsen, or Meng. Baxter, 952 F.2d at 392 (unexpected results must be shown to be unexpected compared with the closest prior art); Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989) (“Attorneys’ argument is no substitute for evidence.”). Accordingly, for the reasons above, we affirm the Examiner’s rejection of claim 1 as obvious over Cordero, Brock, Chen, Thorsen, Meng, Etzioni, and Mercer. Claims 3, 4, 6, 7, 18–24, and 27–35, which are not separately argued, fall with claim 1. Claims 25, 26, 36, and 37 Appellant contends that claims 25, 26, 36, and 37 “recite an upper limit of no more than 15 or no more than 8 proteins, respectively.” Appeal Br. 17. Appellant contends that “[t]he cited art does not specifically teach or suggest the recited upper limit to the number of proteins of any particular panel.” Id. at 17. Appellant contends that Etzioni “teaches away from the limits on the number of proteins in a given panel,” because it teaches that “larger panels are uniformly better at colorectal health assessments.” Id. We are not persuaded. Claims 25 and 26 depend from claim 1 and further recite “wherein said list of proteins comprises no more than 15 Appeal 2020-000640 Application 15/414,456 21 proteins” or 8 proteins, respectively. Appeal Br. 31. Claims 36 and 37 depend from claim 27 and similarly recite “wherein said list of proteins comprises no more than 15 proteins” or 8 proteins, respectively. As the Examiner points out (Ans. 19), however, these claims recite methods “comprising” detecting protein levels from a list of proteins. While the claims recite that the “list” comprises no more than 15 or 8 proteins, the transition term “comprising” encompasses methods of detecting any number of additional proteins that are not on the recited list. CIAS, Inc. v. Alliance Gaming Corp., 504 F.3d 1356, 1360 (Fed. Cir. 2007) (“In the patent claim context, the term ‘comprising’ is well understood to mean ‘including but not limited to.’”). Accordingly, under the broadest reasonable interpretation of the claims, claims 25, 26, 36, and 37 do not “recite an upper limit” of proteins as Appellant alleges and are invalid as obvious for the same reasons discussed above with respect to claim 1.20 20 Although we affirm the Examiner’s rejection based on the broadest reasonable interpretation of the claims, we note that, even assuming that claims 25/36 and 26/37 in fact recite biomarker panels having no more than 15 or 8 proteins, respectively, the claims would be obvious in light of cited prior art. Cordero, Brock, Chen, Thorsen, Meng, and Mercer all teach methods of assessing colorectal health using less than 8 or 15 proteins. More, the prior art teaches that the number of biomarkers used in a panel is a result effective variable – for instance, Mercer teaches that measuring several markers simultaneously increases sensitivity but may, at the same time, decrease specificity. Mercer 40–41. “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276 (CCPA 1980). Appeal 2020-000640 Application 15/414,456 22 CONCLUSION In summary: Claims Rejected 35 U.S.C. § Reference(s)/Ba sis Affirmed Reversed 1, 3, 4, 25–29, 32, 35–37 103 Cordero, Brock, Chen, Thorsen, Meng, Etzioni, Mercer 1, 3, 4, 25– 29, 32, 35– 37 1, 3, 4, 6, 7, 18–37 103 Cordero, Brock, Chen, Thorsen, Meng, Etzioni, Mercer, Vokes 1, 3, 4, 6, 7, 18–37 Overall Outcome 1, 3, 4, 6, 7, 18–37 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED Copy with citationCopy as parenthetical citation