BIOMÉRIEUX et al.Download PDFPatent Trials and Appeals BoardFeb 22, 20222021002512 (P.T.A.B. Feb. 22, 2022) 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. 14/649,803 06/04/2015 Marie-Angelique CAZALIS 166535 5461 25944 7590 02/22/2022 OLIFF PLC P.O. BOX 320850 ALEXANDRIA, VA 22320-4850 EXAMINER POHNERT, STEVEN C ART UNIT PAPER NUMBER 1634 NOTIFICATION DATE DELIVERY MODE 02/22/2022 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): OfficeAction25944@oliff.com jarmstrong@oliff.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte MARIE-ANGELIQUE CAZALIS, MAUD TOURNOUD, FABIENNE VENET, ALAIN LEPAPE, and GUILLAUME MONNERET ____________ Appeal 2021-002512 Application 14/649,803 Technology Center 1600 ____________ Before DONALD E. ADAMS, ULRIKE W. JENKS, and JOHN G. NEW, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims 32-35, 38-40, 42, 43, 46-50, 53-55, 57, 58, 61-64, and 66-68 (see Final Act.2 2). We have jurisdiction under 35 U.S.C. § 6(b). 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 “bioMérieux and Hospices Civils de Lyon” (Appellant’s October 26, 2020, Appeal Brief (Appeal Br.) 1). 2 Examiner’s April 22, 2020 Final Office Action. We further note, that although Examiner identified claims 41, 56, and 65 as rejected (Final Act. 2), we find no rejection of these claims on this record. Therefore, claims 41, 56, and 65 were excluded from the listing of claims under rejection and remain free from rejection on this record. Appeal 2021-002512 Application 14/649,803 2 We REVERSE. STATEMENT OF THE CASE Appellant’s disclosure “relates to a method and a kit for making an in vitro prognosis of severity for a patient in septic Shock” (Spec. 1:4-6). Claims 32-34, 39, 46, and 66 are reproduced below: 32. A method of measuring gene expression for a patient in septic shock, comprising: obtaining a biological sample taken from the patient in septic shock within 12 hours from start of vasopressive treatment; and assaying the biological sample to measure an expression level of an expression product expressed from any of (i) a [H]omo sapiens leukocyte immunoglobulin-like receptor, subfamily B with transmembrane domain (TM) and immunoreceptor tyrosine-based inhibition motif (ITIM) domains, member 2 (lilrb2) gene, or (ii) a [H]omo sapiens leukocyte immunoglobulin-like receptor, subfamily B with TM and ITIM domains, member 1 (lilrb1) gene, wherein the expression level of the expression product is measured without hybridization on a biochip. (Appeal Br. A-1.) 33. The method of claim 32, wherein the vasopressive treatment is catecholamine treatment. (Id.) 34. The method of claim 32, wherein the biological sample is assayed to measure whether there is overexpression of the expression product relative to a control level from either a healthy subject or non-surviving septic-shock patient. (Id.) Appeal 2021-002512 Application 14/649,803 3 39. The method of claim 32, wherein the expression product is mRNA and the mRNA is measured using at least one hybridization probe. (Id.) 46. A method of measuring gene expression for a patient in septic shock, comprising: obtaining a biological sample taken from the patient in septic shock within 12 hours from onset of septic shock, which is characterized at least by sepsis, dysfunction of at least one organ, and hypotension despite volume-expander treatment; and assaying the biological sample to measure an expression level of an expression product expressed from any of (i) a [H]omo sapiens leukocyte immunoglobulin-like receptor, subfamily B with transmembrane domain (TM) and immunoreceptor tyrosine-based inhibition motif (ITIM) domains, member 2 (lilrb2) gene, or (ii) a [H]omo sapiens leukocyte immunoglobulin-like receptor, subfamily B with TM and ITIM domains, member 1 (lilrb1) gene, wherein the expression level of the expression product is measured without hybridization on a biochip. (Id. at A-2) 66. A method of measuring gene expression for a patient in septic shock, comprising: obtaining a biological sample taken from the patient in septic shock; and assaying the biological sample to measure whether there is overexpression relative to a control level from either a healthy subject or non- surviving septic-shock patient of an expression product expressed from any of (i) a [H]omo sapiens leukocyte immunoglobulin-like receptor, subfamily B with transmembrane domain (TM) and immunoreceptor tyrosine- based inhibition motif (ITIM) domains, member 2 (lilrb2) gene, or (ii) a [H]omo sapiens leukocyte immunoglobulin-like Appeal 2021-002512 Application 14/649,803 4 receptor, subfamily B with TM and ITIM domains, member 1 (lilrb1) gene, wherein an expression level of the expression product is measured without hybridization on a biochip. (Id. at A-4-A-5.) In response to Examiner’s July 20, 2016, Restriction Requirement, Appellant elected “the lilrb2 gene” (Appellant’s September 20, 2016, Amendment and Response to Restriction and Election of Species Requirement 5). We limit the scope of our review to Appellant’s elected invention. See Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (BPAI 1987). Grounds of rejection before this Panel for review: I. Claim 66 stands rejected under 35 U.S.C. § 102(b) as anticipated by Pachot3 as evidenced by Details.4 II. Claims 32-35, 39, 42, 43, 46-50, 54, 57, 58, and 66 stand rejected under 35 U.S.C. § 103 as unpatentable over the combination of Pachot, Details, and Venet.5 III. Claims 32, 34, 35, 38, 40, 42, 43, 46, 47, 49, 50, 53, 55, 57, 58, 61-64, 66, and 67 stand rejected under 35 U.S.C. § 103 as 3 Pachot et al., Systemic transcriptional analysis in survivor and non- survivor septic shock patients: A preliminary study, 106 Immunology Letters 63-71 (2006). 4 Affymetrix, Details for HG-U133A:210146-X-AT, available at https://www.affymetrix.com/analysis/netaffx/fu11record.affx?pk=HG- U133A:2 l 0146 X AT, last accessed Aug. 21, 2019. 5 Venet et al., Early Assessment of Leukocyte Alterations at Diagnosis of Septic Shock, 34 SHOCK 358-363 (2010). Appeal 2021-002512 Application 14/649,803 5 unpatentable over the combination of Venet, Brown,6 and Kamishikiryo.7 IV. Claims 39 and 54 stand rejected under 35 U.S.C. § 103 as unpatentable over the combination of Venet, Brown, Kamishikiryo, and McIntire.8 V. Claims 33 and 48 stand rejected under 35 U.S.C. § 103 as unpatentable over the combination of Venet, Brown, Kamishikiryo, and McIntire. VI. Claims 33 and 48 stand rejected under 35 U.S.C. § 103 as unpatentable over the combination of Venet, Brown, Kamishikiryo, and Pachot. VII. Claims 34, 49, and 66-68 stand rejected under 35 U.S.C. § 101. Rejection I: ISSUE Does the preponderance of evidence on this record support Examiner’s finding that Pachot, as evidenced by Details, teaches Appellant’s claimed invention? 6 Brown et al., The inhibitory receptor LILRB4 (IL T3) modulates antigen presenting cell phenotype and, along with LILRB2 (IL T4), is upregulated in response to Salmonella infection, 10 BMC Immunology 1-9 (2009). 7 Kamishikiryo et al., HLA-G Molecule, 15 Current Pharmaceutical Design 3318-3324 (2009). 8 McIntire et al., Novel HLA-G-Binding Leukocyte Immunoglobulin-Like Receptor (LILR) Expression Patterns in Human Placentas and Umbilical Cords, 29 Placenta 631-638 (2008). Appeal 2021-002512 Application 14/649,803 6 ANALYSIS The method of measuring gene expression for a patient in septic shock, set forth in Appellant’s claim 66, reproduced above, comprises, inter alia, that the expression level of the expression product is measured without hybridization on a biochip. Examiner finds that Appellant’s Specification does not provide a definition or standard that differentiates “a biochip from any other assay method” (Ans. 7). Thus, Examiner asserts that the “broadest reasonable interpretation of what is encompassed by excluding a biochip is anything that is not identified as a biochip” (id.). Stated differently, Examiner considers only those articles that specifically include the term “biochip” in their name to represent biochips (see id. at 22 (Examiner finds that Appellant’s “claim excludes biochips and not chips in general”). We are not persuaded by Examiner’s unreasonably limited interpretation of the art- recognized term biochip. The scope of the claims in patent applications is determined not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction in light of the specification as it would be interpreted by one of ordinary skill in the art. In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004). Stated differently, [T]he PTO applies to the verbiage of the proposed claims the broadest reasonable meaning of the words in their ordinary usage as they would be understood by one of ordinary skill in the art, taking into account whatever enlightenment by way of definitions or otherwise that may be afforded by the written description contained in the applicant’s specification. In re Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997) (emphasis added). Appeal 2021-002512 Application 14/649,803 7 In contrast to Examiner’s interpretation of the term biochip, those of ordinary skill in this art would understand that the term biochip refers to: 1. An array of miniaturized chemical or biological test sites that is arranged on a substrate so that many tests can be performed simultaneously and that is used to sequence genes, analyze proteins, and identify toxins. 2. A microchip made from organic molecules rather than semiconductors. (Freedictionary;9 see id. (Defining the term “biochip” as “a small glass or silicon plate containing an array of biochemical molecules or structures, use as a biosensor or in gene sequencing. Also called: microarray”.) As Appellant explains: As a factual matter, “biochip” is a term of art that is well understood by those skilled in the art and this term of art includes Pachot’s Affymetrix GeneChip Human Genome U133A microarray (among other microarrays). In general, a “biochip” is understood by those skilled in the art to include microarrays that, for example, measure gene expression (e.g., DNA microarrays, protein microarrays, etc.). See Merriam- Webster Dictionary’s “biochip” definition at www.merriam- webster.com/dictionary/biochip (defining “biochip” as a “microarray”); see also Wikipedia entries for “biochip,” “microarray,” and “DNA microarray” (parenthetically noting that a “DNA microarray” is “also commonly known as [a] DNA chip or biochip”). (Reply Br. 4; see also id. at 2-6.) Because Examiner’s interpretation of the term “biochip” is unreasonable, we are not persuaded by Examiner’s interpretation of Pachot’s disclosure of “chip hybridization” using “HG-U133A oligonucleotide arrays (Affymetrix), containing 22,283 probe sets representing more than 14,500 9 https://www.thefreedictionary.com/biochip, last accessed Feb. 7, 2021. Appeal 2021-002512 Application 14/649,803 8 well-substantiated human genes” as something other than hybridization on a biochip (see Pachot § 2.3; see also Appeal Br. 5 (Appellant contends that “Pachot is non-anticipatory as it requires biochip hybridization”); Reply Br. 4 (Appellant contends that those of ordinary skill in this art would understand that “Pachot’s Affymetrix GeneChip Human Genome U133A microarray is a biochip”); cf. Ans. 6-8). Examiner’s reliance on Details for a description of Affymetrix’s HG-U133A:210146_X_AT GeneChip Array fails to overcome the deficiencies in Pachot discussed above (see Ans. 8). Thus, taken as a whole, Examiner failed to establish an evidentiary basis on this record to support a finding that Pachot, as evidenced by Details, anticipates Appellant’s claimed invention. CONCLUSION The preponderance of evidence on this record fails to support Examiner’s finding that Pachot, as evidenced by Details, teaches Appellant’s claimed invention. Rejection I: The rejection of claim 66 under 35 U.S.C. § 102(b) as being anticipated by Pachot, as evidenced by Details, is reversed. Rejections II-VI: ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? ANALYSIS Rejection II: The method of measuring gene expression for a patient in septic shock, set forth in Appellant’s claim 32, reproduced above, comprises, inter Appeal 2021-002512 Application 14/649,803 9 alia, that the expression level of the expression product is measured without hybridization on a biochip. Examiner asserts that the “broadest reasonable interpretation of what is encompassed by excluding a biochip is anything that is not identified as a biochip” (Ans. 8). For the reasons set forth above, we are not persuaded by Examiner’s interpretation of the term biochip. Because Examiner’s interpretation of the term “biochip” is unreasonable, we are not persuaded by Examiner’s interpretation of Pachot’s disclosure of “chip hybridization” using “HG-U133A oligonucleotide arrays (Affymetrix), containing 22,283 probe sets representing more than 14,500 well-substantiated human genes” as something other than hybridization on a biochip (see Pachot § 2.3; see also Appeal Br. 9 (Appellant contends that “Pachot fails to provide any reason to measure lilrb2 expression without biochip hybridization”); Reply Br. 6 (Appellant contends that “Pachot would not have rendered obvious the claimed methods because it fails to provide any reason to otherwise measure lilrb2 expression in a septic-shock patient in the absence of biochip hybridization”); cf. Ans. 8-12). Examiner’s reliance on Details for a description of Affymetrix’s HG- U133A:210146_X_AT GeneChip Array fails to overcome the deficiencies in Pachot discussed above (see Ans. 9). In addition, Examiner’s reliance on Venet to disclose a sample obtained within 12 hours of vassopressive treatment fails to overcome the deficiencies in the combination of Pachot and Details (see id. at 9-12). Thus, taken as a whole, Examiner failed to establish an evidentiary basis on this record to support a conclusion that the combination of Pachot, Details, and Venet makes obvious Appellant’s claimed invention. Appeal 2021-002512 Application 14/649,803 10 Rejection III: Appellant’s claim 32 is reproduced and discussed above. Venet discloses that “[d]espite marked improvement in critical care medicine and almost 20 years of anti-inflammatory clinical trials, septic syndromes (association of a systemic inflammatory reaction to an infection) are the leading cause of death in noncoronary intensive care units (ICUs) and a major health care problem worldwide” (Venet 358). Venet discloses: Sepsis initiates a complex immunologic response that varies over time, with the concomitant occurrence of both proinflammatory and anti-inflammatory mechanisms alternatively predominating. After a short proinflammatory phase, septic patients enter a stage of protracted immunosuppression illustrated by reactivation of dormant viruses (cytomegalovirus or herpes simplex virus) or infections due to germs normally pathogenic solely in immune- compromised host. Importantly, the intensity and duration of this phase of immunosuppression seem to be closely correlated with mortality and the development of nosocomial infections. (Id. (endnotes omitted).) Venet discloses a study “designed to perform a systematic monitoring of the different circulating leukocyte subpopulations measured in septic shock patients from the time of diagnosis of shock and every 6 h during the first 48 h” (Venet 358). Venet discloses: To minimize heterogeneity, patients were included [in Venet’s study] only if they present with no comorbidity. Septic shock was defined, according to classic definition, by an identifiable site of infection, hypotension persisting despite fluid resuscitation and requiring vasopressor therapy, and evidence of a systemic inflammatory response manifested by at least two of the following criteria: (a) temperature greater than 38°C or less than 36°C, (b) heart rate greater than 90 beats/min, (c) respiratory rate greater than 20 breaths/min, and (d) white blood cell count of more than 12,000/µL or less than 4,000/µL. Appeal 2021-002512 Application 14/649,803 11 Severity was assessed by the Simplified Acute Physiology Scale II. (Venet 359 (emphasis added).) Venet does not, however, disclose “the detection of [an expression product expressed from the] lilrb2” gene (Ans. 14 (emphasis added); see also Appeal Br. 9 (Appellant contends that “Venet does not measure lilrb2 expression” or “mention lilrb2”)). Examiner, therefore, looks to Brown and Kamishikiryo. Brown discloses that “[l]eukocyte Ig-like receptors (LILR) are a family of innate immune receptors with immunomodulatory functions,” wherein “there may be a role for lower level expression and activity of LILRB2 and LILRB4 in response to . . . [Toll-like receptors (TLR)] signaling during an immune response to bacterial infection” (Brown, Abstr.). Brown discloses that “[r]eal-time PCR analysis showed upregulation of both LILRB2 and LILRB4 in Salmonella-infected macrophages” and that “[a] similar result was observed when macrophages were treated with heat-killed bacteria” (Brown 2). Brown discloses that LILRB2 and LILRB4 “receptors play a role in limiting the inflammatory response during infection” (Brown 6). Kamishikiryo discloses that “[h]uman leukocyte antigen-G (HLA-G) is a non-classical HLA class I molecule,” that “binds inhibitory receptors such as leukocyte immunoglobulin-like receptors B1 (LILRB1/ILT2/CD85j) and LILRB2 (ILT4/CD85d), which are widely expressed on immune cells, to suppress a broad range of immune responses” (Kamishikiryo, Abstr.; see also id. at 3323 (Kamishikiryo discloses that “HLA-G interacts with the inhibitory receptors LILRB1 and LILRB2 to regulate immune responses” and “[t]hus, HLA-G has a distinct site of action for immune suppression.”). Appeal 2021-002512 Application 14/649,803 12 Kamishikiryo, therefore, “highlight[s] the molecular basis for the tolerogenic ability of the HLA-G molecule, especially by LILR recognition of various forms of HLA-G” and “discuss[es] the potential clinical applications of HLA-G molecules” (id. at Abstr.). Based on the combination of Venet, Brown, and Kamishikiryo, Examiner reasons that an “artisan would [have been] . . . motivated to determine how septic shock regulates lilrb2 expression and/or determine if lilrb2 expression is a prognostic marker or correlated with outcome. The artisan would be motivated to identify gene expression profiles correlated with survival or non-survival” (Ans. 15-16). Examiner, therefore, concludes that, before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious, in view of the combination of Venet, Brown, and Kamishikiryo to examine expression lilrb2 [in] septic shock patients and non- survivors at time of diagnosis and every 6 hours after diagnosis, wherein septic shock is defined as according to classic definition, by an identifiable site of infection, hypotension persisting despite fluid resuscitation and requiring vasopressor therapy, and evidence of a systemic inflammatory response manifested by at least two of the following criteria: (a) temperature greater than 38ºC or less than 36ºC, (b) heart rate greater than 90 beats/min, (c) respiratory rate greater than 20 breaths/min, and (d) white blood cell count of more than 12,000/2L or less than 4,000/2L. Severity was assessed by the Simplified Acute Physiology Scale II. (Ans. 15-16.) We are not persuaded. As Appellant explains, “Venet does not measure lilrb2 expression for the circulating leukocyte subpopulations as it does not mention lilrb2 Appeal 2021-002512 Application 14/649,803 13 expression in the first place. Thus, Venet fails to provide any reason to measure lilrb2 expression in septic-shock patients” (Appeal Br. 9-10). Appellant similarly contends that “Brown fails to provide any reason to measure lilrb2 expression by assaying a biological sample taken from a septic-shock patient” (id. at 10). We agree. Examiner failed to establish an evidentiary basis on this record to support a finding that salmonella infection is associated with septic shock and would not be recognized, by those of ordinary skill in this art, as a comorbidity in sepsis patients (see id. (Appellant contends that “Salmonella infection is not associated with septic shock in immunocompetent patients such as Venet’s septic-shock patients ‘with no comorbidity.’”); Reply Br. 9 (Appellant contends that “Brown itself does not disclose that Salmonella infections are related to septic shock” and “Examiner provides no evidence of Salmonella infections being understood by those skilled in the art as causing septic shock”); cf. Venet 359 (Venet discloses that “[t]o minimize heterogeneity, patients were included [in Venet’s study] only if they present with no comorbidity.”)). For the foregoing reasons, we agree with Appellant’s contention that “Brown fails to cure the . . . deficiencies” in Venet (Appeal Br. 11). Examiner further fails to establish a nexus between septic shock and Kamishikiryo’s disclosure of “the molecular basis for the tolerogenic ability of the HLA-G molecule, especially by LILR recognition of various forms of HLA-G” and “discuss[es] the potential clinical applications of HLA-G molecules” (see Kamishikiryo, Abstr.; cf. Appeal Br. 11 (Appellant contends that “Kamishikiryo fails to provide any reason to measure lilrb2 expression by assaying a biological sample taken from a septic-shock patient because it is not directed to septic-shock patients but to the HLA-G molecule”)). As Appeal 2021-002512 Application 14/649,803 14 Appellant explains, “Kamishikiryo does not disclose that the HLA-G molecule is relevant to septic shock” (Appeal Br. 11). We are not persuaded by Examiner’s assertion that “Kamishikiryo demonstrate[s] a link to septic shock which is an infection or result of an infection” (Ans. 25-26 (citing Kamishikiryo 3323)). As Appellant explains, “not all infections are relevant to septic shock” and Examiner failed to establish an evidentiary basis to the contrary (Reply Br. 10). Rejections IV-V: Rejection IV: The method of Appellant’s claim 39, reproduced above, depends from and further limits Appellant’s claim 32 to require that the expression product is mRNA and the mRNA is measured using at least one hybridization probe. Rejection V: Appellant’s claim 33 is reproduced and discussed above. Examiner relies on the combination of Venet, Brown, and Kamishikiryo as discussed above (Ans. 17; see id. at 18). For the reasons discussed above, we are not persuaded by Examiner’s assertion that the combination of Venet, Brown, and Kamishikiryo suggests “methods of [detecting] expression of lilrb2 in samples within 12 hours of diagnosis or treatment for septic shock and suggest vassopressive treatment” (Ans. 17; see id. at 18). Examiner recognizes that the combination of Venet, Brown, and Kamishikiryo “does not specifically teach detection of lilbr2 by real time PCR using a probe” or “detection of libr2 by quantitative ELISA” and relies Appeal 2021-002512 Application 14/649,803 15 on McIntire to make up for these deficiencies (id. at 17 (citing McIntire § 2.2); see also id. at 19 (citing McIntire, Fig. 4)). Rejection IV: Based on the combination of Venet, Brown, Kamishikiryo, and McIntire, Examiner concludes that, before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious “to detect LILRB2 mRNA by use of a Taqman probe,” because the use of McIntire’s methodology is nothing more than the substitution of “one art accepted method of mRNA detection for another” (Ans. 17). Rejection V: Based on the combination of Venet, Brown, Kamishikiryo, and McIntire, Examiner concludes that, before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious “to detect LILRB2 protein expression by ELISA . . . to determine if the mRNA expression is correlated with the level of LILRB2 protein,” which would be nothing more than “using known methods to detect a known protein” (Ans. 19). We are not persuaded. McIntire discloses a “study to determine whether cells in the placenta or umbilical cord might be targeted by HLA-G via binding to LILRB1 or LILRB2. The results indicate that in the villous placenta, LILRB1 expression is restricted to stromal cells, which are composed primarily of fibroblasts and macrophages” (McIntire § 1). As Appellant explains, “McIntire fails to provide any reason to measure lilrb2 expression by assaying a biological sample taken from a septic-shock patient because it is not directed to patients in septic shock in the first place” (Appeal Br. 11). For the foregoing reasons, we find that McIntire fails to overcome the deficiencies in the combination of Venet, Brown, and Kamishikiryo (see Appeal 2021-002512 Application 14/649,803 16 Reply Br. 10 (Appellant contends that McIntire “fails to cure [the] deficiencies of the other applied references”). Rejection VI: The method of Appellant’s claim 33, reproduced above, depends from and further limits Appellant’s claim 32 to require that the vasopressive treatment is a catecholamine treatment. Examiner relies on the combination of Venet, Brown, and Kamishikiryo as discussed above (Ans. 18). Examiner further finds that although the combination of Venet, Brown, and Kamishikiryo “suggest treatment with vasopressin,” the combination “does not [disclose the use of] catecholamines as [vasopressive] treatments” (id.). Examiner, therefore, relies on Pachot to disclose vasopressor therapy with “more than 5 g/kg of body weight of epinephrine and/or norepinephrine” (id. (citing Pachot 64)). Based on the combination of Venet, Brown, Kamishikiryo, and Pachot, Examiner concludes that, before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious “to look to the art to determine what is encompassed by vasopressive treatments” and “use epinephrine and/or norepinephrine as vasospressive agents . . . to properly treat septic shock” (Ans. 18). We are not persuaded that Pachot makes up for the deficiencies in the combination of Venet, Brown, and Kamishikiryo discussed above. CONCLUSION The preponderance of evidence relied upon by Examiner fails to support a conclusion of obviousness. Appeal 2021-002512 Application 14/649,803 17 Rejection II: The rejection of claims 32-35, 39, 42, 43, 46-50, 54, 57, 58, and 66 under 35 U.S.C. § 103(a) as unpatentable over the combination of Pachot, Details, and Venet is reversed. Rejection III: The rejection of claims 32, 34, 35, 38, 40, 42, 43, 46, 47, 49, 50, 53, 55, 57, 58, 61-64, 66, and 67 under 35 U.S.C. § 103(a) as unpatentable over the combination of Venet, Brown, and Kamishikiryo is reversed. Rejection IV: The rejection of claims 39 and 54 under 35 U.S.C. § 103(a) as unpatentable over the combination of Venet, Brown, Kamishikiryo, and McIntire is reversed. Rejection V: The rejection of claims 33 and 48 under 35 U.S.C. § 103(a) as unpatentable over the combination of Venet, Brown, Kamishikiryo, and McIntire is reversed. Rejection VI: The rejection of claims 33 and 48 under 35 U.S.C. § 103(a) as unpatentable over the combination of Venet, Brown, Kamishikiryo, and Pachot is reversed. Rejection VII: ISSUE Does the preponderance of evidence of record support Examiner’s finding that Appellant’s claimed invention is directed to patent-ineligible subject matter? PRINCIPLES OF LAW A. Section 101 An invention is patent-eligible if it claims a “new and useful process, machine, manufacture, or composition of matter.” 35 U.S.C. § 101. Appeal 2021-002512 Application 14/649,803 18 However, the U.S. Supreme Court has long interpreted 35 U.S.C. § 101 to include implicit exceptions: “Laws of nature, natural phenomena, and abstract ideas” are not patentable. E.g., Alice Corp. v. CLS Bank Int’l, 573 U.S. 208, 216 (2014). In determining whether a claim falls within an excluded category, we are guided by the Court’s two-part framework, described in Mayo and Alice. Alice, 573 U.S. at 217-18 (citing Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 75-77 (2012)). In accordance with that framework, we first determine what concept the claim is “directed to.” See Alice, 573 U.S. at 219 (“On their face, the claims before us are drawn to the concept of intermediated settlement, i.e., the use of a third party to mitigate settlement risk.”); see also Bilski v. Kappos, 561 U.S. 593, 611 (2010) (“Claims 1 and 4 in petitioners’ application explain the basic concept of hedging, or protecting against risk.”). Concepts determined to be abstract ideas, and thus patent ineligible, include certain methods of organizing human activity, such as fundamental economic practices (Alice, 573 U.S. at 219-20; Bilski, 561 U.S. at 611); mathematical formulas (Parker v. Flook, 437 U.S. 584, 594-95 (1978)); and mental processes (Gottschalk v. Benson, 409 U.S. 63, 67 (1972)). Concepts determined to be patent eligible include physical and chemical processes, such as “molding rubber products” (Diamond v. Diehr, 450 U.S. 175, 191 (1981)); “tanning, dyeing, making water-proof cloth, vulcanizing India rubber, smelting ores” (id. at 182 n.7 (quoting Corning v. Burden, 56 U.S. 252, 267-68 (1854))); and manufacturing flour (Benson, 409 U.S. at 69 (citing Cochrane v. Deener, 94 U.S. 780, 785 (1876))). Appeal 2021-002512 Application 14/649,803 19 In Diehr, the claim at issue recited a mathematical formula, but the Court held that “a claim drawn to subject matter otherwise statutory does not become nonstatutory simply because it uses a mathematical formula.” Diehr, 450 U.S. at 187; see also id. at 191 (“We view respondents’ claims as nothing more than a process for molding rubber products and not as an attempt to patent a mathematical formula.”). Having said that, the Court also indicated that a claim “seeking patent protection for that formula in the abstract . . . is not accorded the protection of our patent laws, and this principle cannot be circumvented by attempting to limit the use of the formula to a particular technological environment.” Id. (citation omitted) (citing Benson and Flook); see, e.g., id. at 187 (“It is now commonplace that an application of a law of nature or mathematical formula to a known structure or process may well be deserving of patent protection.”). If the claim is “directed to” an abstract idea, we turn to the second step of the Alice and Mayo framework, where “we must examine the elements of the claim to determine whether it contains an ‘inventive concept’ sufficient to ‘transform’ the claimed abstract idea into a patent- eligible application.” Alice, 573 U.S. at 221 (internal quotation marks omitted). “A claim that recites an abstract idea must include ‘additional features’ to ensure ‘that the [claim] is more than a drafting effort designed to monopolize the [abstract idea].’” Id. (alterations in original) (quoting Mayo, 566 U.S. at 77). “[M]erely requir[ing] generic computer implementation[] fail[s] to transform that abstract idea into a patent-eligible invention.” Id. B. USPTO Section 101 Guidance In January 2019, the U.S. Patent and Trademark Office (USPTO) published revised guidance on the application of § 101. 2019 Revised Patent Appeal 2021-002512 Application 14/649,803 20 Subject Matter Eligibility Guidance, 84 Fed. Reg. 50 (Jan. 7, 2019) (“Guidance”).10 “All USPTO personnel are, as a matter of internal agency management, expected to follow the guidance.” Id. at 51; see also October 2019 Update at 1. Under the Guidance and the October 2019 Update, we first look to whether the claim recites: (1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes) (“Step 2A, Prong One”); and (2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h) (9th ed. Rev. 08.2017, Jan. 2018)) (“Step 2A, Prong Two”).11 Guidance, 84 Fed. Reg. at 52-55. Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look, under Step 2B, to whether the claim: (3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or 10 In response to received public comments, the Office issued further guidance on October 17, 2019, clarifying the 2019 Revised Guidance. USPTO, October 2019 Update: Subject Matter Eligibility (the “October 2019 Update”) (available at https://www.uspto.gov/sites/default/files/ documents/peg_oct_2019_update.pdf). 11 This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. See Guidance - Section III(A)(2), 84 Fed. Reg. at 54-55. Appeal 2021-002512 Application 14/649,803 21 (4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception. Guidance, 84 Fed. Reg. at 52-56. ANALYSIS The method of Appellant’s claim 34, reproduced above, depends from and further limits Appellant’s claim 32 to require that the biological sample is assayed to measure whether there is overexpression of the expression product relative to a control level from either a healthy subject or non- surviving septic-shock patient. Appellant’s claim 49, depends from and further limits Appellant’s claim 46, reproduced above, to require that the biological sample is assayed to measure whether there is overexpression of the expression product relative to a control level from either a healthy subject or non-surviving septic-shock patient. The method of Appellant’s claim 66, reproduced above and, in view of the Restriction Requirement on this record comprises the steps of (a) obtaining a biological sample taken from a patient in septic shock and (b) assaying the biological sample to measure whether there is overexpression relative to a control level from either a healthy subject or non-surviving septic-shock patient of an expression product expressed from the lilrb2 gene, wherein an expression level of the expression product is measured without hybridization on a biochip. Appellant’s claims 67-68 depend from Appellant’s claim 66. Appeal 2021-002512 Application 14/649,803 22 (Step 1) Appellant claims methods, i.e. a process, which is a statutory category of invention (see Ans. 4). Therefore, we proceed to the next steps of the analysis. (Step 2A, Prong 1) In BRCA1, our reviewing court held that a claimed method for screening a germline of a human subject for an alteration of the BRCA1 gene by comparing a sample BRCA1 gene sequence with a reference, wild-type germline sequence of BRCA1 gene was directed to an abstract idea -- a “mental process of ‘comparing’ and “analyzing' two gene sequences.” In re BRCA1-and BRCA2-Based Hereditary Cancer Test Patent Litigation, 774 F.3d 755, 763-64 (2014) (“allowing a patent on the comparison step could impede a great swath of research relating to the BRCA genes, and it is antithetical to the patent laws to allow these basic building blocks of scientific research to be monopolized.”) Applying the guidance set out in BRCA1, we find no error in Examiner’s finding that the step of measuring whether there is overexpression of the expression product relative to a control level from either a healthy subject or non-surviving septic-shock patient, as set forth in Appellant’s claims 34, 49, and 66, is an abstract idea. A step of measuring x relative to y is a comparison step (see Ans. 20). Therefore, we are not persuaded by Appellant’s contention that its “claims do not actually recite a ‘comparing’ or ‘determining’ step in the first place” and, thus, “Examiner mischaracterizes the claim language for purposes of alleging that the claims recite an abstract idea” (Appeal Br. 14; see also Reply Br. 12; cf. Ans. 20). Appeal 2021-002512 Application 14/649,803 23 Appellant fails to identify an evidentiary basis on this record to support a finding that the foregoing comparison step “cannot be performed in the human mind (even if aided with a computer)” and, thus, cannot be an abstract idea (Reply Br. 12-13). Therefore, Appellant’s contention is not persuasive. (Step 2A, Prong 2) Having determined that Appellant’s claims recite a judicial exception, the Guidance requires an evaluation as to whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. See Guidance, 84 Fed. Reg. at 54-55. Obtaining a biological sample and performing assays using conventional techniques with or without a biochip are insignificant extra- solution activities, i.e. mere data gathering steps, which are insufficient to confer patent eligibility. See generally Ans. 5-6, 21; Guidance, 84 Fed. Reg. at 55; see also CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1370 (2011) (holding that mere “[data-gathering] step[s] cannot make an otherwise nonstatutory claim statutory” (quoting In re Grams, 888 F.2d 835, 840 (Fed.Cir.1989))). (Step 2B) Having determined that Appellant’s claims: (1) recite a judicial exception and (2) do not integrate that exception into a practical application, the Guidance requires that we evaluate whether Appellant’s claims: (a) add a specific limitation beyond the judicial exception that is not “well- understood, routine, conventional” in the field or (b) simply appends well- understood, routine, conventional activities previously known to the Appeal 2021-002512 Application 14/649,803 24 industry, specified at a high level of generality, to the judicial exception. Guidance, 84 Fed. Reg. at 52−56. “Whether something is well-understood, routine, and conventional to a skilled artisan at the time of the patent is a factual determination.” Berkheimer v. HP Inc., 881 F.3d 1360, 1369 (Fed. Cir. 2018). Appellant’s claimed method of measuring gene expression for a patient in septic shock requires a comparison of whether there is overexpression, relative to a control level, from either a healthy subject or non-surviving septic-shock patient of an expression product expressed from the lilrb1 gene. As discussed above, with respect to the prior art rejections, Examiner failed to establish an evidentiary basis to support a finding that a nexus between septic shock and an expression product expressed from the lilrb1 gene existed prior to Appellant’s claimed invention (cf. Ans. 6 (citing Venet, Brown, Kamishikiryo, Pachot, and McIntire)). Thus, on this record, Examiner failed to establish an evidentiary basis to support a conclusion that elements of Appellant’s claimed invention were well-understood, routine, and conventional in this field prior to Appellant’s claimed invention (Appeal Br. 16-17; Reply Br. 14). CONCLUSION The preponderance of evidence of record does not support Examiner’s finding that Appellant’s claimed invention is directed to patent-ineligible subject matter. Rejection VII: The rejection of claims 34, 49, and 66-68 stand rejected under 35 U.S.C. § 101 is reversed. Appeal 2021-002512 Application 14/649,803 25 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 66 102(b) Pachot, Details 66 32-35, 39, 42, 43, 46-50, 54, 57, 58, 66 103 Pachot, Details, Venet 32-35, 39, 42, 43, 46-50, 54, 57, 58, 66 32, 34, 35, 38, 40, 42, 43, 46, 47, 49, 50, 53, 55, 57, 58, 61-64, 66, 67 103 Venet, Brown, Kamishikiryo 32, 34, 35, 38, 40, 42, 43, 46, 47, 49, 50, 53, 55, 57, 58, 61-64, 66, 67 39, 54 103 Venet, Brown, Kamishikiryo, McIntire 39, 54 33, 48 103 Venet, Brown, Kamishikiryo, McIntire 33, 48 33, 48 103 Venet, Brown, Kamishikiryo, Pachot 33, 48 34, 49, 66-68 101 Eligibility 34, 49, 66-68 Overall Outcome 32-35, 38-40, 42, 43, 46-50, 53-55, 57, 58, 61-64, 66-68 REVERSED Copy with citationCopy as parenthetical citation