FIVE3 GENOMICS, LLC

Patent Trials and Appeals Board

Mar 22, 2022

2021002398 (P.T.A.B. Mar. 22, 2022)

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. 14/893,403 11/23/2015 Stephen Charles Benz 102039.0016US 9402 149345 7590 03/22/2022 Umberg Zipser, LLP 1920 Main Street, Suite 750 Irvine, CA 92614 EXAMINER WHALEY, PABLO S ART UNIT PAPER NUMBER 3619 NOTIFICATION DATE DELIVERY MODE 03/22/2022 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): ipsupport@umbergzipser.com patents@umbergzipser.com rdean@umbergzipser.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte STEPHEN CHARLES BENZ and CHRISTOPHER SZETO ____________ Appeal 2021-002398 Application 14/893,403 Technology Center 3600 ____________ Before DONALD E. ADAMS, ERIC B. GRIMES, and RACHEL H. TOWNSEND, 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 1-13 and 18-20 (Final Act.2 2).3 We have jurisdiction under 35 U.S.C. § 6(b). 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 “Five3 Genomics, LLC” (Appellant’s September 22, 2020, Appeal Brief (Appeal Br.) 2). 2 Examiner’s July 20, 2020, Final Office Action. 3 Pending claims 14-17 and 21-23 stand withdrawn from consideration. Appeal 2021-002398 Application 14/893,403 2 STATEMENT OF THE CASE Appellant’s disclosure relates to “computational modeling and use of pathway models, especially as it relates to in silico modulation of pathway models to identify pathway elements useful for development of treatment recommendations” (Spec. ¶ 2). Appellant’s independent claims 1 and 18 are reproduced below: 1. A method of treating a patient having a neoplastic disease by identifying a drug combination using an in silico analysis system comprising a pathway model system and data sets derived from omics data of cells, wherein the pathway model system is capable of simulating an intervention, the method comprising: a. receiving a plurality of distinct data sets derived from omics data of a plurality of distinct diseased cells, respectively, wherein each data set comprises a plurality of pathway element data, wherein the pathway element data comprises gene copy number data, gene mutation data, gene expression data, protein expression data, or protein activity data wherein at least one of the distinct data sets is generated from a tumor sample of the patient; b. identifying a determinant pathway element in the plurality of distinct data sets, wherein the determinant pathway element is associated with a drug resistance to a first drug of the diseased cells; c. modulating, using the in silico analysis, at least one of the gene expression data, the protein expression data, or the protein activity data for the determinant pathway element in one data set of one of the distinct diseased cells that are resistant to the first drug to produce a modified data set and to simulate an anticipated effect on the drug resistance to the first drug; d. identifying, using the in silico analysis, a change of the at least one of the gene expression data, the protein expression level, or the protein activity in the determinant Appeal 2021-002398 Application 14/893,403 3 pathway element as being effective to decrease the drug resistance toward drug sensitivity in the diseased cell when a level of the decrease of the drug resistance toward drug sensitivity for the first drug exceeds a predetermined threshold; e. identifying, using the in silico analysis, a drug combination comprising the first drug and a second drug that is a more effective treatment for the diseased cell than use of the first drug alone, wherein the second drug targets the determinant pathway element; and f. treating the patient having the neoplastic disease with the drug combination. (Appeal Br. 13-14.) 18. A non-transient computer readable medium containing program instructions for causing a computer system coupled with a pathway model system and a pathway model database to perform a method of identifying a drug combination for treatment of a patient having a neoplastic disease, wherein the pathway model system is capable of simulating an intervention, the method comprising the steps of: a. transferring from the pathway model database a plurality of distinct data sets derived from omics data of a plurality of distinct diseased cells, respectively, wherein each data set comprises a plurality of pathway element data, and wherein the pathway element data comprises gene copy number data, gene mutation data, gene expression data, protein expression data, or protein activity data wherein at least one of the distinct data sets is generated from a tumor sample of the patient; b. identifying, using the computer system, a determinant pathway element in the plurality of distinct data sets, wherein the determinant pathway element is associated with a drug resistance to a first drug of the diseased cells; c. modulating, using the computer system, at least one of the gene expression data, the protein expression data, or the Appeal 2021-002398 Application 14/893,403 4 protein activity data for the determinant pathway element in one data set of one of the distinct diseased cells that are resistant to the first drug to produce a modified data set and to simulate an anticipated effect on the drug resistance to the first drug; d. identifying, using the computer system, a change of the at least one of the gene expression data, the protein expression level, or the protein activity in the determinant pathway element as being effective to decrease the drug resistance toward drug sensitivity for the first drug in the diseased cell when a level of the decrease of the drug resistance toward drug sensitivity for the first drug exceeds a predetermined threshold; and e. identifying, using the computer system, a drug combination comprising the first drug and a second drug that is a more effective treatment for the diseased cell than use of the first drug alone, wherein the second drug targets the determinant pathway element. (Id. at 17-18.) Grounds of rejection before this Panel for review: Claims 1-13 and 18-20 stand rejected under the written description provision of 35 U.S.C. § 112(a). Claims 1-13 and 18-20 stand rejected under 35 U.S.C. § 101. FACTUAL FINDINGS (FF) FF 1. Appellant discloses: Various systems and methods of computational modeling of pathways are known in the art. For example, some algorithms (e.g., GSEA, SPIA, and PathOlogist) are capable of successfully identifying altered pathways of interest using pathways curated from literature. Still further tools have constructed causal graphs from curated interactions in literature Appeal 2021-002398 Application 14/893,403 5 and used these graphs to explain expression profiles. Algorithms such as ARACNE, MINDy and CONEXIC take in gene transcriptional information (and copy-number, in the case of CONEXIC) to so identify likely transcriptional drivers across a set of cancer samples. However, these tools do not attempt to group different drivers into functional networks identifying singular targets of interest. Some newer pathway algorithms such as NetBox and Mutual Exclusivity Modules in Cancer (MEMo) attempt to solve the problem of data integration in cancer to thereby identify networks across multiple data types that are key to the oncogenic potential of samples. . . . More recently, various improved systems and methods have been described to obtain in silico pathway models of in vivo pathways, and exemplary systems and methods are described in WO 2011/139345 and WO 2013/062505. Further refinement of such models was provided in WO 2014/059036 (collectively referred to herein as “PARADIGM”) disclosing methods to help identify cross-correlations among different pathway elements and pathways. While such models provide valuable insights, for example, into interconnectivities of various signaling pathways and flow of signals through various pathways, numerous aspects of using such modeling have not been appreciated or even recognized. (Spec. ¶¶ 4, 6.) FF 2. Appellant discloses: With respect to omics data, all known omics data are considered suitable and preferred omics data especially include gene copy number data, gene mutation data, gene methylation data, gene expression data, RNA splice information data, siRNA data, RNA translation data, and/or protein activity data. Likewise, numerous data formats are deemed appropriate for use herein, however, particularly preferred data formats are PARADIGM datasets. Determinant pathway element[s] may vary considerably, however, especially preferred determinant Appeal 2021-002398 Application 14/893,403 6 pathway elements include the expression state of a gene, the protein level of a protein, and/or protein activity of a protein. Therefore, the inventors also contemplate a system for in silico analysis of data sets derived from omics data of cells that will include a pathway model database that is informationally coupled to a machine learning system and a pathway analysis engine. Most typically, the pathway model database will be programmed to store a plurality of distinct data sets derived from omics data of a plurality of distinct diseased cells, respectively, and each data set will comprise a plurality of pathway element data. The machine learning system is then programmed to receive from the pathway model database the plurality of distinct data sets, and further programmed to identify a determinant pathway element in the plurality of distinct data sets that is associated with a status of a treatment parameter of the diseased cells. Most typically, the pathway analysis engine is programmed to receive at least one of the distinct data sets from the diseased cells and further programmed to modulate the determinant pathway element in the at least one distinct data set to produce a modified data set from the diseased cell, and the machine learning system is programmed to identify a change in the status of the treatment parameter for the diseased cell using the modified data set. Typically, the system is further programmed to generate output data that comprise a treatment recommendation for the patient. (Spec. ¶¶ 13-14; see also id. ¶ 17 (Appellant discloses that “the omics data may include gene copy number data, gene mutation data, gene methylation data, gene expression data, RNA splice information data, siRNA data, RNA translation data, and/or protein activity data, and it is especially contemplated that the distinct data sets are PARADIGM datasets.”).) FF 3. Appellant discloses: [P]athway analysis and pathway model modifications can be used in silico to identify drug treatment options and/or simulate drug treatment targeting pathway elements that are a determinant of or associated with a treatment relevant Appeal 2021-002398 Application 14/893,403 7 parameter (e.g., drug resistance and/or sensitivity to a particular treatment) of a condition, and especially a neoplastic disease. (Spec. ¶ 30.) FF 4. Appellant discloses: [T]hat various omics data from diseased cells and/or tissue of a patient can be used in a computational approach to determine a sensitivity profile for the cells and/or tissue, wherein the profile is based on a priori identification of pathways and/or pathway elements in a variety of similarly diseased cells (e.g., breast cancer cells)[, wherein] . . . [o]nce the sensitivity profile is established, treatment can be directly predicted from the a priori identified pathway(s) and/or pathway element(s), or identified pathways and/or pathway elements can be modulated in silico using known pathway modeling system and methods to so help predict likely outcomes for the pharmaceutical intervention and/or treatment regimen. (Spec. ¶ 32.) FF 5. Appellant discloses: [A]ny language directed to a computer should be read to include any suitable combination of computing devices, including servers, interfaces, systems, databases, agents, peers, engines, controllers, or other types of computing devices operating individually or collectively. One should appreciate the computing devices comprise a processor configured to execute software instructions stored on a tangible, non- transitory computer readable storage medium (e.g., hard drive, solid state drive, RAM, flash, ROM, etc.). The software instructions preferably configure the computing device to provide the roles, responsibilities, or other functionality as discussed below with respect to the disclosed apparatus. In especially preferred embodiments, the various servers, systems, databases, or interfaces exchange data using standardized protocols or algorithms, possibly based on HTTP, HTTPS, AES, public-private key exchanges, web service APIs, known financial transaction protocols, or other electronic information exchanging methods. Data exchanges preferably are conducted Appeal 2021-002398 Application 14/893,403 8 over a packet-switched network, the Internet, LAN, WAN, VPN, or other type of packet switched network. (Spec. ¶ 33.) FF 6. Appellant discloses: Most cancer patients are rarely subject to monotherapy, however, accurate prediction of a response to particular drug combinations is one of the most profound challenges in cancer therapy. As the number of potential drug combinations is large, there is currently little statistically significant data to support any given combination for a specific cancer. Instead, most of the current combination therapies are hand-selected to target independent pathways. Unfortunately, while current methods to design combination therapies are somewhat pragmatic, they tend to be perfunctory as there is no accurate statistical approach to identify candidate drugs for synergistic dual therapy. Moreover, numerically combining monotherapy predictions will not accurately predict the results of combinations, as the mechanisms of drug response are not necessarily independent. (Spec. ¶ 34 (emphasis added); see also id. ¶ 11 (Appellant discloses that “[w]hile not limiting to the inventive subject matter, it is generally preferred that output data are generated that comprise a treatment recommendation for the patient,” wherein “contemplated methods will also include a step of identifying a drug that targets the determinant pathway element when the change in status exceeds a predetermined threshold”).) FF 7. Appellant discloses: [T]he inventors have demonstrated the feasibility of such systems and methods using known breast cancer cell line data and a large panel of monotherapy drug response profiles for these cells. In order to simulate the effect of dual therapies, the inventors used the highly accurate drug response models trained upon pathway modeling system data as further described below, and inspected these pathway modeling system-based models for gene candidates that were putatively associated with resistance. Appeal 2021-002398 Application 14/893,403 9 These resistance-associated features were silenced in silico in the pathway modeling system as a proxy for simulating the effect of a targeted drug intervention against the action of those genes. The so obtained models were then used to reassess the post-intervention dataset for a shift towards sensitivity. If a shift is observed, the inference is that the drug response that the model predicted in silico will likely be enhanced in vivo by combining a first drug with a second, rationale-based targeted drug therapy against the candidate gene. (Spec. ¶ 36). FF 8. Appellant additionally contemplates “systems and methods [that] will also be suitable to identify secondary drugs (e.g., known chemotherapeutic drugs) that may increase efficacy of the new therapeutic compound” (Spec. ¶ 51). FF 9. Appellant discloses: [I]t should also be recognized that new targets for an existing drug may be identified for which no pharmaceutical compound exists. For example, where the systems and methods presented herein indicate a particular pathway element as a determinant pathway element for a successful treatment for which no current drug exists, rational drug design may be employed to develop leads and even active pharmaceutical compounds (e.g., antibodies, enzymatic inhibitors, etc.) that specifically target these so identified determinant pathway elements. (Spec. ¶ 52 (emphasis added).) FF 10. Appellant discloses: As is well known, different cell lines of a diseased tissue (e.g., of breast cancer) have very different expression and regulatory environment in response to treatment with a particular drug. For example, while some types of breast cancer (e.g., basal, not basal) will have distinct sensitivity towards cisplatin . . ., other types of breast cancer (ERBB2AMP, not ERBB2AMP) will have distinct sensitivity towards Geldanamycin. (Spec. ¶ 54.) Appeal 2021-002398 Application 14/893,403 10 FF 11. Appellant discloses: [E]xpression and gene regulation is substantially different from cell line to cell line, with no apparent pattern associated with sensitivity towards or resistance against cisplatin. Therefore, while a wealth of genomic information is available, the skilled artisan lacks effective or even informative guidance from these data to identify a suitable treatment strategy or recommendation. (Spec. ¶ 55.) Written Description: ISSUE Does the preponderance of evidence on this record support Examiner’s finding that Appellant’s Specification fails to provide written descriptive support for the claimed invention? ANALYSIS “The ‘written description’ requirement serves a teaching function, . . . in which the public is given ‘meaningful disclosure in exchange for being excluded from practicing the invention for a limited period of time.”’ University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 922 (Fed. Cir. 2004) (citation omitted). Another “purpose of the ‘written description’ requirement is . . . [to] convey with reasonable clarity to those skilled in the art that, as of the filing date [], [the applicant] was in possession of the invention.” Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir. 1991); see also Enzo Biochem Inc. v. GenProbe Inc., 296 F.3d 1316, 1329 (Fed. Cir. 2002). The written description requirement is satisfied when the specification “set[s] forth enough detail to allow a person of ordinary skill in the art to Appeal 2021-002398 Application 14/893,403 11 understand what is claimed and to recognize that the inventor invented what is claimed.” Rochester, 358 F.3d at 928. “[A]pplicants have some flexibility in the ‘mode selected for compliance’ with the written description requirement” (id.), and it is well settled that actual reduction to practice is not necessary to satisfy the requirement (id. at 926). Whether or not a specification satisfies the requirement is a question of fact, which must be resolved on a case-by-case basis (Vas-Cath, 935 F.2d at 1562-63), and it is Examiner’s “initial burden [to] present[ ] evidence or reasons why persons skilled in the art would not recognize in the disclosure a description of the invention defined by the claims” (In re Wertheim, 541 F.2d 257, 263 (CCPA 1976)). “The written description requirement is not met if the specification merely describes a “desired result.”' Vasudevan Software, Inc. v. MicroStrategy, Inc., 782 F.3d 671, 682 (Fed. Cir. 2015) (citing Ariad Pharm. Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349 (Fed. Cir. 2010)). On this record, Examiner finds Appellant’s “claimed modulating and identifying steps are not limited to comprise any specific computational or mathematical techniques showing how these functions are actually achieved, i.e. they generically read on doing analysis and encompass all means or methods of resolving the problem” (Ans.4 5-6). In addition, Examiner finds that although Appellant’s “[S]pecification generally discloses ‘pathway models’ . . . none of these models are required by the instantly claimed invention nor are they defined in terms of structural limitations and/or mathematical parameters that would necessarily achieve the claimed results” 4 Examiner’s December 23, 2020, Answer. Appeal 2021-002398 Application 14/893,403 12 (Final Act. 9 (citing Spec. ¶¶ 0006-0010, 0030, 0035); see also id. (Examiner finds that Appellant’s “modulating and identifying steps are all generically recited functional limitations that are not limited to comprise any specific computational or mathematical techniques for achieving the claimed functions, i.e. they generically encompass critical thinking and doing math.”)). Examiner finds, “[a]t best, . . . [Appellant’s Specification] exemplifies [a] specific PARADIGM model (for inferring pathway-specific activities),” but “does not explain in sufficient detail how this model is used for achieving the intended result of identifying drug combinations” (Ans. 6 (citing Spec. ¶¶ 0006, 0035, 0059)). For the foregoing reasons, Examiner finds that Appellant’s Specification fails to provide written descriptive support for “a ‘broad genus claim that covers all ways of performing the claimed functions when the specification provides only one method and there is no evidence that a more generic way is contemplated’” and for “a ‘claim that defines the invention in functional language specifying a desired result when the specification does not sufficiently identify how the invention achieves the claimed function’” (Ans. 6). In addition, with regard to the treating step of Appellant’s claim 1 and the step of identifying a drug combination comprising a first drug and a second drug that is a more effective treatment for a diseased cell than the first drug alone, set forth in Appellant’s claims 1 and 18, Examiner finds that Appellant’s Specification lacks written descriptive support for “the requisite gene expression/drug combination correlations (necessary for identifying drugs that are ‘more effective’ treatments) for the full scope of drug combinations being claimed” (Ans. 7; see also Final Act. 10). See AbbVie Appeal 2021-002398 Application 14/893,403 13 Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1299 (Fed. Cir. 2014) (quoting Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568-69 (Fed. Cir. 1997) (“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus” (alteration original)). On this record, Examiner finds that although Appellant’s Specification “generically mention[s] the use of a predetermined threshold for identifying a drug,” it “does not clarify the scope of the operations encompassed by the claimed ‘identifying’ step” (Final Act. 9 (citing Spec. ¶ 11)). In addition, Examiner finds that Appellant’s Specification discloses that because “the number of potential drug combinations is large, there is currently little statistically significant data to support any given combination for a specific cancer” (Final Act. 9 (citing Spec. ¶ 34)). Examiner finds that Appellant’s Specification, “[a]t best, provides a limited embodiment for treating a patient using two selected drugs [cisplatin and geldanamycin] . . ., but not necessarily in combination” (Final Act. 10). Therefore, Examiner finds that Appellant’s Specification “does not provide a sufficient disclosure as to the full scope of drug combinations being claimed as well as how the inventor devised to identify these drug combinations” (id.). In sum, Examiner finds that Appellant’s Specification “does ‘little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.’” (id. (citing In re Wilder, 736 F.2d 1516, 1521 (Fed. Cir. 1984)); see also Ans. 7-8). Appeal 2021-002398 Application 14/893,403 14 For the foregoing reasons, we are not persuaded by Appellant’s contention that its Specification “discloses specifically recite[d] pathway models, specific types of cancer, and specific drugs” and, thus, “provides a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can visualize or recognize the members of the claimed genus” (Appeal Br. 9; cf. FF 6 (Appellant discloses that “numerically combining monotherapy predictions will not accurately predict the results of combinations, as the mechanisms of drug response are not necessarily independent”); id. (Appellant discloses that “[a]s the number of potential drug combinations is large, there is currently little statistically significant data to support any given combination for a specific cancer”); FF 9 (Appellant discloses that rational drug design may be necessary “to develop leads and even active pharmaceutical compounds” for use in the “successful treatment . . . [of diseases] for which no current drug exists”)). Further, as Appellant recognizes: [E]xpression and gene regulation is substantially different from cell line to cell line, with no apparent pattern associated with sensitivity towards or resistance against cisplatin. Therefore, while a wealth of genomic information is available, the skilled artisan lacks effective or even informative guidance from these data to identify a suitable treatment strategy or recommendation. (FF 11.) As Examiner explains, although Appellant’s Specification “exemplifies [a] specific PARADIGM model (for inferring pathway-specific activities,” Appellant’s Specification “does not explain in sufficient detail how this model is used for achieving the intended result of identifying drug Appeal 2021-002398 Application 14/893,403 15 combinations” (Ans. 6). Therefore, we are not persuaded by Appellant’s contentions that because the PARADIGM model was well known to those of ordinary skill in this art, at the time of Appellant’s claimed invention, and this model is able “to infer the activities of genetic pathways from integrated patient data,” its Specification provides written descriptive support for the full scope of their claimed invention (Appeal Br. 9-10; see also Reply Br.5 3 (Appellant contends that “[t]he [S]pecification describes the PARADIGM pathway model system to manipulate the expression/activity of genes/proteins to test an effect on the pathway is sufficiently described in the instant [S]pecification”); Reply Br. 3 (Appellant contends that “it is understood that these pathway modeling systems incorporate omics data, and by manipulating genes or proteins in these pathways, an effect (simulated intervention) can be tested in silico”)). Simply stated, Appellant’s Specification fails to adequately describe how a pathway model system, within the scope of Appellant’s claimed invention, which includes various identification and manipulations of data sets, correlates with the selection of specific combinations of known and/or unknown drugs, within the scope of Appellant’s claimed invention, that result in a more effective treatment than any single drug alone, as required by Appellant’s claimed invention. See Vasudevan, 782 F.3d at 682 (“The written description requirement is not met if the specification merely describes a ‘desired result.’”). 5 Appellant’s February 18, 2021, Reply Brief. Appeal 2021-002398 Application 14/893,403 16 CONCLUSION The preponderance of evidence on this record supports Examiner’s finding that Appellant’s Specification fails to provide written descriptive support for the claimed invention. The rejection of claim 1 under the written description provision of 35 U.S.C. § 112(a) is affirmed. Claims 2-13 and 18-20 are not separately argued and fall with claim 1. Subject Matter Eligibility: 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. 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 Appeal 2021-002398 Application 14/893,403 17 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))). 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 Appeal 2021-002398 Application 14/893,403 18 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 Subject Matter Eligibility Guidance, 84 Fed. Reg. 50 (Jan. 7, 2019) (“Guidance”).6 “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. 6 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). Appeal 2021-002398 Application 14/893,403 19 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”).7 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 (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 Appellant’s independent claims 1 and 18 are reproduced above. Appellant’s claims 2-13, 19, and 20 depend directly or indirectly from Appellant’s claims 1 and 18, respectively. 7 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 2021-002398 Application 14/893,403 20 (Step 1) We first consider whether the claimed subject matter falls within the four statutory categories set forth in § 101, namely “[p]rocess, machine, manufacture, or composition of matter.” Guidance, 84 Fed. Reg. at 53-54; see 35 U.S.C. § 101. Appellant’s claims 1-13 and 18-20 are directed to a method, i.e., a process. Appellant’s claims 18-20 are directed to a non- transient computer readable medium, i.e., a manufacture. Thus, Appellant’s claimed invention is directed to statutory subject matter (see Final Act. 3). Therefore, we proceed to the next steps of the analysis. (Step 2A, Prong 1) The method of Appellant’s claim 1 comprises, inter alia, the steps of: b. identifying a determinant pathway element in the plurality of distinct data sets, wherein the determinant pathway element is associated with a drug resistance to a first drug of the diseased cells; c. modulating, using the in silico analysis, at least one of the gene expression data, the protein expression data, or the protein activity data for the determinant pathway element in one data set of one of the distinct diseased cells that are resistant to the first drug to produce a modified data set and to simulate an anticipated effect on the drug resistance to the first drug; d. identifying, using the in silico analysis, a change of the at least one of the gene expression data, the protein expression level, or the protein activity in the determinant pathway element as being effective to decrease the drug resistance toward drug sensitivity in the diseased cell when a level of the decrease of the drug resistance toward drug sensitivity for the first drug exceeds a predetermined threshold; and e. identifying, using the in silico analysis, a drug combination comprising the first drug and a second drug that is a more Appeal 2021-002398 Application 14/893,403 21 effective treatment for the diseased cell than use of the first drug alone, wherein the second drug targets the determinant pathway element. The non-transient computer readable medium of Appellant’s claim 18, contains program instructions for causing a computer system coupled with a pathway model system and a pathway model database to perform a method of identifying a drug combination for treatment of a patient having a neoplastic disease, wherein the pathway model system is capable of simulating an intervention, the method comprising, inter alia, the steps of: b. identifying, using the computer system, a determinant pathway element in the plurality of distinct data sets, wherein the determinant pathway element is associated with a drug resistance to a first drug of the diseased cells; c. modulating, using the computer system, at least one of the gene expression data, the protein expression data, or the protein activity data for the determinant pathway element in one data set of one of the distinct diseased cells that are resistant to the first drug to produce a modified data set and to simulate an anticipated effect on the drug resistance to the first drug; d. identifying, using the computer system, a change of the at least one of the gene expression data, the protein expression level, or the protein activity in the determinant pathway element as being effective to decrease the drug resistance toward drug sensitivity for the first drug in the diseased cell when a level of the decrease of the drug resistance toward drug sensitivity for the first drug exceeds a predetermined threshold; and e. identifying, using the computer system, a drug combination comprising the first drug and a second drug that is a more effective treatment for the diseased cell than use of the first drug alone, wherein the second drug targets the determinant pathway element. Appeal 2021-002398 Application 14/893,403 22 We agree with Examiner’s finding that the foregoing steps recite a judicial exception, specifically mental processes, which is an abstract idea. Specifically, Examiner finds that the steps are all akin to mental steps of relating information and/or analyzing data. Even if a computer was used to perform these steps . . . they are still mental equivalents because one can look at numerical and/or graphical representations of data (e.g. by eye or mentally) and come to a conclusion using one’s mind. (Final Act. 4; see also Ans. 3 (Examiner finds that Appellant’s “claimed modulating and identifying steps are reasonably interpreted as mental processes”)).) “[A]n invention directed to collection, manipulation, and display of data [recites] . . . an abstract process.” Intellectual Ventures I LLC v. Capital One Fin. Corp., 850 F.3d 1332, 1340 (Fed. Cir. 2017); see also Digitech Image Techs., LLC v. Elecs. for Imaging, Inc., 758 F.3d 1344, 1351 (Fed. Cir. 2014) (“Without additional limitations, a process that employs mathematical algorithms to manipulate existing information to generate additional information is not patent eligible”); CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1375 (Fed. Cir. 2011) (“The mere manipulation or reorganization of data . . . does not satisfy the transformation prong”); Alice, 573 U.S. at 221 (“[M]erely requir[ing] generic computer implementation[] fail[s] to transform that abstract idea into a patent-eligible invention.”); Guidance, 84 Fed. Reg. at 52. Thus, we find no error in Examiner’s finding that Appellant’s claimed method and manufacture recite judicial exceptions. (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 Appeal 2021-002398 Application 14/893,403 23 integrates the recited judicial exception into a practical application of the exception. See Guidance, 84 Fed. Reg. at 54. Considering each claim as a whole, we find that Appellant’s independent claims 1 and 18 comprise the following additional steps: Claim 1: a. receiving a plurality of distinct data sets derived from omics data of a plurality of distinct diseased cells, respectively, wherein each data set comprises a plurality of pathway element data, wherein the pathway element data comprises gene copy number data, gene mutation data, gene expression data, protein expression data, or protein activity data wherein at least one of the distinct data sets is generated from a tumor sample of the patient; and f. treating the patient having the neoplastic disease with the drug combination. Claim 18: a. transferring from the pathway model database a plurality of distinct data sets derived from omics data of a plurality of distinct diseased cells, respectively, wherein each data set comprises a plurality of pathway element data, and wherein the pathway element data comprises gene copy number data, gene mutation data, gene expression data, protein expression data, or protein activity data wherein at least one of the distinct data sets is generated from a tumor sample of the patient As Examiner explains, the foregoing receiving and transferring steps represent “insignificant extra-solution activity,” specifically, mere data gathering steps (Ans. 4). See CyberSource, 654 F.3d at 1370 (quoting In re Grams, 888 F.2d 835, 840 (Fed. Cir. 1989)) (Our reviewing court has “held that mere ‘[data-gathering] step[s] cannot make an otherwise nonstatutory Appeal 2021-002398 Application 14/893,403 24 claim statutory.’” (alteration original)); see also Guidance, 84 Fed. Reg. at 55; see also MPEP § 2106.05(g). As Examiner further explains, the treatment step of Appellant’s claim 1, “is not a particular treatment,” because it “is generically recited and since the intended uses or effects of the first and second drugs has no limiting effect on the method as claimed” (Ans. 4). We agree with Examiner’s reasoning. See, e.g., October 2019 Update 14 § III(C)(i) (When an “administration step is not particular, and is instead merely instructions to ‘apply’ the exception in a generic way . . . the administration step does not integrate the mental analysis step into a practical application”). (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 industry, specified at a high level of generality, to the judicial exception. Guidance, 84 Fed. Reg. at 52-56. As Examiner explains, the additional limitations recited in Appellant’s claims relating to “‘computer readable medium,’ ‘database’, and ‘computer system’” are “nothing more than an attempt to generally link the use of the judicial exception to the technological environment of a computer” (Ans. 4- 5 (citing MPEP § 2106.05(h)). We agree. We further find that “merely requir[ing] generic computer implementation[] fail[s] to transform that abstract idea into a patent-eligible invention.” Alice, 573 U.S. at 221; see Appeal 2021-002398 Application 14/893,403 25 also FF 5 (Appellant discloses a variety of generic computer components that may be utilized to practice Appellant’s claimed invention). Thus, we find that Appellant’s claims do not add a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in this field as required by the Guidance. For the foregoing reasons, we are not persuaded by Appellant’s contention that “[i]ndependent claims 1 and 18 recite a limitation of a practical application,” wherein “claim 1 is directed to a method of treating a patient having a neoplastic disease by identifying a drug combination using computer analysis to analyze omics data from cells including tumor cells from the patient” and “claim 18 is directed towards the practical application of identifying a drug for treatment of a patient having a neoplastic disease using a computer system coupled with a pathway model system and a pathway model database” (Appeal Br. 7-8). Cf. SAP Am. Inc. v. InvestPic, LLC, 898 F.3d 1161, 1163 (Fed. Cir. 2018) (“No matter how much of an advance in the finance field the claims recite, the advance lies entirely in the realm of abstract ideas, with no plausibly alleged innovation in the non- abstract application realm. An advance of that nature is ineligible for patenting.”); BSG Tech, 899 F.3d at 1290 (“It has been clear since Alice that a claimed invention’s use of the ineligible concept to which it is directed cannot supply the inventive concept that renders the invention ‘significantly more’ than that ineligible concept.”). We are not persuaded by Appellant’s contention that its generically recited treatment step is “similar to the claims in [Vanda],” which were “directed to a specific method of treatment for specific patients using a Appeal 2021-002398 Application 14/893,403 26 specific compound at specific doses to achieve a specific outcome.” See Appeal Br. 8-9; cf. Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd, 887 F.3d 1117, 1136 (Fed. Cir. 2018) (emphasis added). For the foregoing reasons, we are not persuaded by Appellant’s contention that its claims are directed to “a specific treatment that does not encompass all applications of the judicial exception” (Reply Br. 2). We are not persuaded by Appellant’s unsupported contention that “[t]he features of the instant application are too complex to be performed in the mind of a human or by using a pencil and paper” (Reply Br. 1-2). Initially, we note that argument by counsel cannot take the place of evidence. In re Cole, 326 F.2d 769, 773 (CCPA 1964); In re Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997); In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take the place of evidence.”). Further, even if Counsel’s contention is correct “[w]ithout additional limitations, a process that employs mathematical algorithms to manipulate existing information to generate additional information is not patent eligible.” Digitech Image Techs., LLC v. Elecs. for Imaging, Inc., 758 F.3d 1344, 1351 (Fed. Cir. 2014). We are not persuaded by Appellant’s contention that its claimed invention “does not encompass all applications of the judicial exception” (Reply Br. 2). Although “preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility.” Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1379 (Fed. Cir. 2015). Appeal 2021-002398 Application 14/893,403 27 CONCLUSION The preponderance of evidence of record supports Examiner’s finding that Appellant’s claimed invention is directed to patent-ineligible subject matter. The rejection of claims 1 and 18 under 35 U.S.C. § 101 is affirmed. Claims 2-13, 19, and 20 are not separately argued and fall with claims 1 and 18 respectively. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1-13, 18-20 112(a) Written Description 1-13, 18-20 1-13, 18-20 101 Eligibility 1-13, 18-20 Overall Outcome 1-13, 18-20 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) (2019). AFFIRMED