Caris MPI, Inc.Download PDFPatent Trials and Appeals BoardMay 13, 2020IPR2019-00166 (P.T.A.B. May. 13, 2020) Copy Citation Trials@uspto.gov Paper No. 53 571-272-7822 Date: May 13, 2020 UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ FOUNDATION MEDICINE, INC., Petitioner, v. CARIS MPI, INC., Patent Owner. ____________ IPR2019-00166 Patent 9,292,660 B2 ____________ Before CHRISTOPHER G. PAULRAJ, KRISTI L. R. SAWERT, and DAVID COTTA, Administrative Patent Judges. PAULRAJ, Administrative Patent Judge. JUDGEMENT Final Written Decision Determining Claims 1–11, 13–16, 18, 22, and 23 to be Unpatentable Determining Claim 12 Not Proven Unpatentable 35 U.S.C. § 318(a) IPR2019-00166 Patent 9,292,660 B2 2 I. INTRODUCTION A. Background and Summary This is our Final Written Decision entered pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73. Foundation Medicine, Inc., (“Petitionerâ€) filed a Petition (Paper 3, “Pet.â€), requesting institution of an inter partes review of claims 1–16, 18, 22, and 23 of U.S. Patent No. 9,292,660 B2 (Ex. 1001, “the ’660 patentâ€). Caris MPI, Inc., (“Patent Ownerâ€) timely filed a Preliminary Response (Paper 7, “Prelim. Resp.â€). Pursuant to our authorization (Paper 8), Petitioner filed a preliminary Reply to Patent Owner’s Preliminary Response (Paper 9) and Patent Owner filed a preliminary Sur-Reply to Petitioner’s Reply (Paper 10). In our Institution Decision, we determined that there was a reasonable likelihood that Petitioner would prevail with respect to at least one challenged claim and, accordingly, instituted an inter partes review pursuant to 35 U.S.C. § 314 based on all challenges presented in the Petition. Paper 12 (“Inst. Dec.â€). Following institution, Patent Owner filed its post- institution Patent Owner Response (Paper 29, “PO Resp.â€), Petitioner filed its post-institution Reply to Patent Owner’s Response (Paper 41, “Replyâ€)), and Patent Owner filed its post-institution Sur-Reply (Paper 45, “Sur- Replyâ€). No Motion to Amend was filed in this proceeding. An oral hearing was held on February 12, 2020, and a transcript of that hearing has been entered into the record. Paper 52 (“Tr.â€). For the reasons set forth below, we determine that Petitioner has shown by a preponderance of the evidence that claims 1–11, 13–16, 18, 22, and 23 of the ’660 patent are unpatentable under 35 U.S.C. § 103. We also IPR2019-00166 Patent 9,292,660 B2 3 determine that Petitioner has not shown by a preponderance of the evidence that claim 12 of the ’660 patent is unpatentable. B. Related Proceedings Along with the current Petition, Petitioner has filed another Petition challenging additional claims of the ’660 patent not challenged here. See IPR2019-00203 (challenging claims 17, 19, 21, and 24). We issue our final written decision in IPR2019-00203 concurrently with this Decision. The following proceedings, before the Board, also involve the same parties and related patents: IPR2019-00164 (U.S. Patent No. 8,880,350 B2), IPR2019-00165 (U.S. Patent No. 9,092,392 B2), IPR2019-00170 (U.S. Patent No. 9,372,193 B2), and IPR2019-00171 (U.S. Patent No. 9,383,365 B2). Institution of an inter partes review in IPR2019-00165 was denied. IPR2019-00165, Paper 7. In addition, Patent Owner has asserted the ’660 patent along with the other related patents against Petitioner in litigation in the United States District Court for the District of Massachusetts: Caris MPI, Inc. v. Foundation Medicine, Inc., No. 1:17-cv-12194 (D. Mass.). Pet. 2; Paper 5. That litigation has been stayed pending resolution of these inter partes review proceedings. C. The ’660 Patent (Ex. 1001) The ’660 patent issued on March 22, 2016, to Von Hoff et al., and relates generally to the field of personalized medicine, which uses “the results from molecular profiling to identify treatments for individuals.†Ex. 1001, 2:31–33. According to the patent, treatment therapies or regimens are typically selected according to the particular disease a patient has been IPR2019-00166 Patent 9,292,660 B2 4 diagnosed with, although some regimens have been determined using molecular profiling and clinical characterization of a patient. Id. at 1:29–48. The ’660 patent discloses that molecular profiling analysis can provide “more informed and effective personalized treatment options, which can result in improved patient care and enhanced treatment outcomes.†Id. at 2:21–24. The ’660 patent discloses a method of identifying a candidate treatment for a subject that includes, among other things, analyzing a sample from the subject. Id. at 2:36–46. The patent discloses that the analysis (i.e., molecular profiling) can be performed by “any known means for detecting a molecule in a biological sample.†Id. at 8:43–44. The types of analysis include: immunohistochemistry (IHC) analysis to determine an IHC expression profile for at least five proteins, a microarray analysis to determine a microarray expression profile of at least ten genes, a fluorescent in-situ hybridization (FISH) analysis to determine a FISH mutation profile on at least one gene, and DNA sequencing to determine a sequencing mutation profile of at least one gene. Id. at 2:36–44, 8:44–62. According to the ’660 patent, the results for the analysis are compared against a “rules database.†Id. at 2:46–49. The ’660 patent discloses that the rules can be generated from abstracts of peer reviewed clinical oncology literature, expert opinions, and clinical citations that have been assessed for relevance. Id. at 51:23–32, 57:20–23. For instance, the rules database can indicate which treatment has a known biological activity against cancer cells that overexpress or underexpress one or more proteins in the IHC expression profile, overexpress or underexpress one or more genes in the microarray expression profile, have no mutations or one or more mutations of the genes IPR2019-00166 Patent 9,292,660 B2 5 included in the FISH mutation profile, and have no mutations or one or more mutations of the genes included in the sequencing mutation profile. Id. at 2:49–58. A candidate treatment is identified if the comparison step indicates a biological activity against the cancer for the treatment and the comparison step does not contraindicate the treatment for treating the cancer. Id. at 2:58–61. Such a comparison may be conducted by using a database that maps treatments and molecular profiling results. Id. at 53:35–36. Such maps may be created, for example, by reviewing literature for links between biological agents and therapeutic agents. Id. at 53:46–49. In a particular example, a rules database may show that overexpression of the ADA gene or protein indicates pentostatin as a possible treatment whereas underexpression of the ADA gene or protein indicates resistance to cytarabine and that the latter is not an optimal treatment. Id. at 54:63–67. The ’660 patent further discloses a system that uses molecular profiling of a patient’s biological specimen to determine individualized medical intervention. Id. at 143:56–59. The system includes, among other things, an application program stored in a memory that is accessible by a processor, internal databases, and external databases. Id. at 143:59–65. The internal databases can include information about the patient biological sample, patient test results from molecular profiling, clinical data, and study protocols. Id. at 144:10–14. The external databases can include drug libraries, gene libraries, disease libraries, and public and private databases. Id. at 144:14–18. IPR2019-00166 Patent 9,292,660 B2 6 D. Illustrative Claim Petitioner challenges claims 1–16, 18, 22, and 23 of the ’660 patent. Independent claim 1 is illustrative, and is reproduced below: 1. A system for generating a report identifying a therapeutic agent for an individual with lung cancer comprising: a. at least one device configured to assay a plurality of molecular targets in a biological sample from the individual with lung cancer to determine molecular profile test values for the plurality of molecular targets, wherein the plurality of molecular targets comprises PTEN, CTNNBl, cKIT, BRAF and PIK3CA; b. at least one computer database comprising: i. a reference value for each of the plurality of molecular targets; ii. a listing of available therapeutic agents for the plurality of molecular targets; c. a computer-readable program code comprising instructions to input the molecular profile test values and to compare each of the molecular profile test values with a corresponding reference value from the at least one computer database in (b)(i); d. a computer-readable program code comprising instructions to access the at least one computer database in (b)(ii) and to identify at least one therapeutic agent if present in the at least one computer database for each of the plurality of molecular targets wherein said comparison to the reference values in (c) indicates a likely benefit of the at least one therapeutic agent; and e. a computer-readable program code comprising instructions to generate a report that comprises a listing of the members of the plurality of molecular targets for which the comparison to the reference value indicated a likely benefit of the at least one therapeutic agent in (d) and the at least one therapeutic agent identified in (d). IPR2019-00166 Patent 9,292,660 B2 7 E. The Asserted Ground of Unpatentability We instituted inter partes review in this proceeding based on the following ground as presented in the Petition: Claim(s) challenged 35 U.S.C. § Reference(s) 1–16, 18, 22, 23 § 103(a) Von Hoff,1 Bibikova,2 Illumina3 In support of its arguments, Petitioner relies upon the expert declarations of Paul Spellman, Ph.D. (Ex. 1002 and Ex. 1120). Patent Owner relies upon the expert declaration of Joyce O’Shaughnessy, M.D. (Ex. 2016). F. Priority Date The ’660 patent is a continuation of Application No. 12/658,770 (“the ’770 applicationâ€), filed February 12, 2010, which in turn is a continuation- in-part of a series of non-provisional applications dating back to Application No. 11/750,721 (“the ’721 application), filed May 18, 2007. Ex. 1001, code (63). Additionally, the ’660 patent claims priority to provisional applications dating back to May 18, 2006. Id., code (60). Among this chain of priority applications, Petitioner contends that the first possible support for “CTNNB1,†a molecular target recited in claim 1, is found in the ’770 application, which recites “BETA-CATENIN†(an alternate name for 1 Von Hoff et al., US 2008/0014146 A1, published Jan. 17, 2008 (Ex. 1074) (“Von Hoffâ€). 2 Marina Bibikova et al., Gene Expression Profiles in Formalin-Fixed, Paraffin-Embedded Tissues Obtained with a Novel Assay for Microarray Analysis, 50 Clinical Chemistry (2004) 2384. (Ex. 1047) (“Bibikovaâ€). 3 Illumina® Gene Expression Profiling, Technical Bulletin, RNA Profiling with the DASL® Assay (2005) (Ex. 1005) (“Illuminaâ€). IPR2019-00166 Patent 9,292,660 B2 8 CTNNB1) as part of a long list of “[g]enes and gene products.†Pet. 18; see Ex. 1079, 44:14–46:45 (U.S. Patent No. 8,768,629 issued from the ’770 application). That same disclosure is found in the ’660 patent. Ex. 1001, 45:5–47:44. Because the challenged claims all require CTNNB1 to be included on any panel to be assayed, Petitioner contends that none of those claims can have a priority date earlier than February 12, 2010. Id. at 18–19 (citing Ex. 1002 ¶¶ 106–107). As such, Petitioner contends that the Von Hoff reference, which is a publication of the ’721 application, qualifies as prior art under pre-AIA 35 U.S.C. § 102(b) even though it is in the chain of priority for the ’660 patent. Id. at 19–20.4 Patent Owner does not dispute Petitioner’s contention that the effective filing date for the claims of the ’660 patent is February 12, 2010, and thus Von Hoff qualifies as prior art. PO Resp. 29 n.78; Tr. 41:7–11. As Petitioner’s position that the claims can have a priority date no earlier than February 12, 2010 is supported by the record and not disputed by Patent Owner, we consider February 12, 2010 as the relevant date for our patentability analysis in this proceeding. II. ANALYSIS A. Level of Skill in the Art Petitioner contends that a person of ordinary skill in the art (“skilled artisan†or “POSAâ€) for the ’660 patent “would have had a Ph.D. in genetics, molecular biology, bioinformatics, or a related field, and at least five years of research experience in an academic or industry setting, 4 Petitioner also contends Von Hoff lists only two inventors of the ’660 patent and thus is prior art by “another†under pre-AIA § 102(a). Pet. 20 (citing Ex. 1002 ¶ 115). IPR2019-00166 Patent 9,292,660 B2 9 including at least two to three years of research experience in the field of cancer genomics.†Pet. 16 (citing Ex. 1002 ¶ 31). Patent Owner contends that the POSA “is an oncologist having a medical degree, at least 10 years of experience treating cancer patients at a medical research facility or hospital, and experience with clinical trials involving anti-cancer therapeutic agents.†PO Resp. 3. Patent Owner asserts that “the claimed invention is directed towards an oncologist because oncologists are the people who treat cancer patients and therefore need to understand which anticancer therapies are more or less likely to be of therapeutic benefit to their patient.†Id. at 4 (citing Ex. 2016 ¶ 14). Patent Owner disputes Petitioner’s proposed definition requiring research rather than clinical experience for the POSA because “[s]uch researchers do not treat or select therapy options for cancer patients, and their research findings are not allowed to contribute to the medical record or form the basis for clinical decision-making.†Id. at 5 (citing Ex. 2015, 126:5–127:8). Patent Owner further contends that its declarant, Dr. O’Shaughnessy, meets the correct definition of a POSA, whereas Petitioner’s declarant, Dr. Spellman, does not meet this definition. Id. at 6–7 (citing Ex. 2016 ¶¶ 5–11, 46; Ex. 2015, 16:10–12). In our Institution Decision, we adopted Petitioner’s definition of the POSA as it was undisputed at the time and consistent with the evidence of record. Inst. Dec. 7. Based on our consideration of the full record, we maintain our determination that someone with a Ph.D. in genetics, molecular biology, bioinformatics, or a related field, and at least five years of research experience in an academic or industry setting, including at least two to three years of research experience in the field of cancer genomics, would satisfy IPR2019-00166 Patent 9,292,660 B2 10 the definition of a POSA. Although the POSA may have an M.D. instead of or in addition to a Ph.D., we find that the POSA need not be an oncologist with experience treating cancer patients as asserted by Patent Owner. Factors influencing the proper POSA definition include: “(1) the educational level of the inventor; (2) type of problems encountered in the art; (3) prior art solutions to those problems; (4) rapidity with which innovations are made; (5) sophistication of the technology; and (6) educational level of active workers in the field.†Daiichi Sankyo Co. v. Apotex, Inc., 501 F.3d 1254, 1256 (Fed. Cir. 2007). All of these factors either support Petitioner’s definition of a POSA or are neutral. With respect to the educational level of the inventor (factor 1), Dr. O’Shaughnessy acknowledged that at least half of the named inventors for the ’660 patent would not have met Patent Owner’s definition of a POSA. Ex. 1118, 118:5–13; Ex. 1120 ¶ 17. This supports Petitioner’s definition. With respect to the type of problems encountered in the art and the prior art solutions to those problems (factors 2 and 3), we find that the “problem†identified and purportedly solved by the invention described in the ’660 patent as well as the prior art of record relates generally to computerized methods and systems using molecular profiling to identify treatment options for cancer patients. See, e.g., Ex. 1001, 2:24–27 (“The present invention provides methods and systems for identifying treatments for these individuals by molecular profiling a sample from the individual.â€); id. at 1:29–55 (criticizing the use of “molecular profiling in combination with clinical characterization of a patient such as observations made by a physician,†because the use of “medical information typically relied upon by a physician to make a diagnosis in a specific disease†“presents a risk that an IPR2019-00166 Patent 9,292,660 B2 11 effective treatment regimen may be overlooked for a particular individual†(emphasis added)); Ex. 1074 ¶ 7 (prior art von Hoff reference describing “a need for a system and method for determining an individualized medical intervention for a disease state based on molecular profiling that is used to target specific genes and/or gene expressed proteins with specific drugs or agents that is independent of disease lineage diagnosisâ€). Although the claimed system could be used by an oncologist to help guide treatment decisions, we are not persuaded that the POSA would necessarily have to be an oncologist who treats patients. Indeed, the claim language does not require treating patients. Instead, the claim language recites “at least one device configured to assay a plurality of molecular targets,†a “computer database,†and “computer-readable program code†with instructions to perform various functions of the system. Insofar as the development of the claimed system requires knowledge of molecular mechanisms, computer systems, and databases, we find that the experience and education level of an oncologist would be less relevant than a Ph.D. researcher for assessing patentability issues for the ’660 patent. See Ex. 1119, 398:13–20 (Dr. O’Shaughnessy testifying that as an oncologist, she was not “qualified†to speak to “computerized decision support system and databases†or the “construct of the infrastructureâ€); Ex. 1120 ¶ 16. Finally, we note that the educational levels and years of experience for both parties’ proposed definitions are high. Thus, we find that the outcome of this case would be the same regardless of which definition is used. That is, although we agree with and have adopted Petitioner’s definition for the POSA, our analysis and conclusions herein would not change even under IPR2019-00166 Patent 9,292,660 B2 12 Patent Owner’s definition. Patent Owner does not identify any arguments that depend specifically upon its definition of a POSA. We further find that both parties’ experts are qualified to provide opinions about the ’660 patent from the perspective of the POSA even if they personally do not qualify as a POSA. As recognized in the Office’s Trial Practice Guide: An expert witness must be qualified as an expert by knowledge, skill, experience, training, or education to testify in the form of an opinion. Fed. R. Evid. 702. There is, however, no requirement of a perfect match between the expert’s experience and the relevant field. SEB S.A. v. Montgomery Ward & Co., 594 F.3d 1360, 1373 (Fed. Cir. 2010). A person may not need to be a person of ordinary skill in the art in order to testify as an expert under Rule 702, but rather must be “qualified in the pertinent art.†Sundance, Inc. v. DeMonte Fabricating Ltd., 550 F.3d 1356, 1363–64 (Fed. Cir. 2008). See Notice of Update to Office Patent Trial Practice Guide, 83 Fed. Reg. 156, (Aug. 13, 2018) (available at https://www.uspto.gov/sites/default/files/documents/2018_Revised_Trial_Pr actice_Guide.pdf). B. Claim Construction Based on the filing date of the Petition (November 6, 2018), the Board interprets claim terms in the ’660 patent according to the broadest reasonable construction in light of the specification of the patent in which they appear. 37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2142–46 (2016).5 Under the broadest reasonable construction standard, 5 On October 11, 2018, the USPTO revised its rules to harmonize the Board’s claim construction standard for interpreting claims in trial proceedings before the Patent Trial and Appeal Board with the standard used IPR2019-00166 Patent 9,292,660 B2 13 claim terms are generally given their ordinary and customary meaning, as would have been understood by one of ordinary skill in the art at the time of the invention. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). “Absent claim language carrying a narrow meaning, the PTO should only limit the claim based on the specification . . . when [it] expressly disclaim[s] the broader definition.†In re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004). “Although an inventor is indeed free to define the specific terms used to describe his or her invention, this must be done with reasonable clarity, deliberateness, and precision.†In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). Based on the parties’ arguments in this proceeding, we find it necessary to resolve two claim construction issues. First, we must determine whether claim 1 (and by extension all the challenged dependent claims) require the claimed system to test for contraindications. Second, with respect to dependent claim 12, we must determine the scope and meaning of “a likely lack of benefit of at least one therapeutic agent and the at least one additional therapeutic agent†as recited in that claim.6 in federal district court. CHANGES TO THE CLAIM CONSTRUCTION STANDARD FOR INTERPRETING CLAIMS IN TRIAL PROCEEDINGS BEFORE THE PATENT TRIAL AND APPEAL BOARD, 83 Fed. Reg. 51,340 (Oct. 11, 2018) (codified at 37 C.F.R. § 42.100(b)). This rule change, however, applies to petitions filed on or after November 13, 2018, and, therefore, does not apply to this proceeding. Id. 6 Patent Owner also argues that the claims should be construed to require “cancer lineage independence.†PO Resp. 31–36. However, we determine that it is not necessary to address this claim construction issue to resolve the disputed issues in this proceeding. “[W]e need only construe terms ‘that are in controversy, and only to the extent necessary to resolve the controversy.’†Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. Ltd., 868 F.3d IPR2019-00166 Patent 9,292,660 B2 14 1. Contraindication Testing Patent Owner argues that the claimed system must test for contraindications based on the language of sections (a) and (d) of claim 1. PO Resp. 36–46. Patent Owner equates testing for “contraindications†in its proposed construction with a requirement that the claimed system determine whether any of the molecular targets assayed in accordance with section (a) indicate a likely lack of benefit for therapeutic agents that might be otherwise identified in accordance with section (d). Id. As support for this construction, Patent Owner points out that “[t]he group of molecular targets claimed in section (a) includes both targets to identify therapies of likely benefit (PTEN, CTNNB1, and cKIT) and contraindications against therapies with a likely lack of benefit (BRAF and PIK3CA).†Id. at 36 (citing Ex. 2016 ¶ 58). According to Patent Owner, the ’660 patent specification provides no available therapeutic agents for the BRAF and PIK3CA targets, and recommends changes to the therapy if the tumor indicates a BRAF mutation. Id. at 37. Patent Owner points to entries from Table 2 of the Specification stating that “BRAF mutations are associated with resistance to EGFR-targeted antibody therapies and associated decreased survival,†while “[w]ild-type BRAF is associated with potential response to EGFR-targeted antibody therapies and associated with increased survival.†Id. (citing Ex. 1001, cols. 59–60). Patent Owner interprets these entries as indicating that “no therapeutic agent is identified for patients with a BRAF mutation but an EGFR-targeted therapy that might 1013, 1017 (Fed. Cir. 2017) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)). IPR2019-00166 Patent 9,292,660 B2 15 otherwise be recommended is contraindicated as a result of the presence of the BRAF mutation.†Id. (citing Ex. 2016 ¶ 58). Additionally, Patent Owner contends that: [t]he “if present†language in section (d) reflects the inventors’ discovery that some targets (e.g., BRAF and PIK3CA) were not associated with therapeutic agents at that time, yet testing for those markers could still provide valuable information regarding the potential efficacy—or lack thereof—of therapeutic agents associated with different targets found in the patient’s lung tumor. PO Resp. 38–39. Patent Owner contends that “it would make no sense for the claim to require the testing and comparison of the BRAF or PIK3CA targets and then ignore those results when identifying therapeutic agents that are a ‘likely benefit.’†Id. at 39. Petitioner contends that the claim language requires no explicit construction, and disagrees with Patent Owner’s proposed construction requiring that the system must test for contraindications. Pet. 16–17; Reply 9–18. However, in its analysis for section (d) of claim 1, Petitioner contends that “the broadest reasonable interpretation of ‘likely benefit of the at least one therapeutic agent’ is any therapeutic agent with potential efficacy.†Pet. 35 (citing Ex. 1002 ¶ 177). Additionally, Petitioner contends that “a POSA would understand claim element (d) to not require a therapeutic agent for any particular molecular target because claim element (d) only requires ‘at least one therapeutic agent’ from the ‘listing of available therapeutic agents for the plurality of molecular targets.’†Id. (citing Ex. 1002 ¶ 178). We determine that the claimed system does not require contraindication testing. We recognize that, at several points, the Specification teaches that “[t]he candidate treatment is identified if: 1) the IPR2019-00166 Patent 9,292,660 B2 16 comparison step indicates that the treatment should have biological activity against the cancer; and 2) the comparison step does not contraindicate the treatment for treating the cancer.†See, e.g., Ex. 1001, 2:58–61 (emphasis added); see also id. at 3:53–57, 4:33–63, 43:29–33, 49:35–39, 50:24–29. This disclosure regarding determining contraindications when identifying the candidate treatment was first added as part of the ’770 application filed February 12, 2010. Additionally, as discussed further below, we recognize that dependent claim 12 recites that the report generated by the claimed system “indicates a likely lack of benefit of at least one therapeutic agent and the at least one additional therapeutic agent.†Id., cl. 12. But we find nothing in the language of claim 1 that requires the claimed system to specifically test for any contraindications or otherwise determine whether any therapeutic agents have a likely lack of benefit. Simply put, there is no textual basis in the claim language that supports Patent Owner’s construction. To the contrary, limitation 1(d) only requires the claimed system to perform a comparison that “indicates a likely benefit of the at least one therapeutic agent.†Id., cl. 1(d). As we noted in our Institution Decision, the language of limitation 1(d), “on its face, appears to require the system to be capable of identifying a therapeutic agent correlating to each of the five molecular targets recited in the claims (PTEN, CTNNBl, cKIT, BRAF and PIK3CA) as long as such a therapeutic agent is present in the relevant computer database.†Inst. Dec., 9. Patent Owner does not dispute this statement. PO Resp. 38. We are unpersuaded by Patent Owner’s arguments that the claims require testing for contraindications because the ’660 patent provides no available therapeutic agents for the BRAF and PIK3CA targets, and further IPR2019-00166 Patent 9,292,660 B2 17 because the “if present†language in limitation 1(d) “reflects the inventors’ discovery that some targets (e.g., BRAF and PIK3CA) were not associated with therapeutic agents at that time.†PO Resp. 36–39. The entries regarding BRAF from Table 2 cited by Patent Owner do not necessarily support a construction requiring contraindication testing. Those entries identify EGFR-targeted antibody therapies (Cetuximab and Panitumumab) as “Recommended Agents†for wild-type BRAF genotype. Ex. 1001, cols. 59–60. Although those same therapies are indicated as “Resistant Agents†for a mutated BRAF genotype, claim 1 on its face is not limited to assays that perform a mutational analysis. See Ex. 1020 ¶ 23 (Dr. Spellman testifying that scope of claims include assays that would not typically be used to perform a “‘Mutational Analysis’ on BRAF, such as IHC and expression microarrays assayâ€) Ex. 1001, 4:40–43 (“In some embodiments, any one of the microarray analysis, the FISH mutational analysis or the sequencing mutation analysis is not performed.â€). To the extent that the assay performed in accordance with limitation 1(a) identifies wild-type BRAF in the patient, the system may indicate that certain antibody therapies provide a “likely benefit†in accordance with limitation 1(d). Nothing in the claim language or the specification suggests that the system must necessarily test for whether those same therapies are contraindicated due to a mutated BRAF genotype. Moreover, both parties’ declarants acknowledged that those skilled in the art were working towards developing potential new therapies based on the BRAF target. See Ex. 2016 ¶ 58; Ex. 1120 ¶ 25. Nothing in the claim language or the specification suggests that the therapeutic targets identified by the claimed system should be limited to those that were commercially available as of the filing date of the ’660 IPR2019-00166 Patent 9,292,660 B2 18 patent. To the contrary, the ’660 patent contemplates that the therapeutic agent database would be “continuously updated†as new agents and associations are discovered. Ex. 1001, 57:33–35 (“The set of rules in the database can be updated as new treatments and new treatment data become available.â€). Petitioner argues that the prosecution history of related patents also undermines Patent Owner’s claim construction arguments. Reply 13, 15. We agree. During prosecution of the ’770 application (the parent application of the ’660 patent), Patent Owner initially sought claims reciting a system that identified a candidate treatment if the comparison step “does not contraindicate the treatment for treating the cancer.†Ex. 1122, 142 (limitation 1(f)). Prior to allowance, however, Patent Owner removed this limitation, and the final claim recited a limitation like that found in the ’660 patent: “producing a computer generat[ed] report . . . wherein the report identifies the one or more candidate treatment.†Id. at 172. We are not persuaded by Patent Owner’s rationale that the arguments made during prosecution confirm that the claims require the concept of “contraindicated†treatments “without using the exact phrase.†PO Sur-Reply 21–23. Patent Owner plainly knew how to describe and claim a system that tested for contraindications, and it could have expressly recited identifying or testing for “contraindicated†therapies or those with a “likely lack of benefit†if that was intended to be a claim requirement. In sum, we do not construe the claims to require contraindication testing as argued for by Patent Owner. Despite any support that might be otherwise present for such a requirement in the specification, there is no textual support in the claim language for Patent Owner’s construction. In IPR2019-00166 Patent 9,292,660 B2 19 determining the scope of the invention, “the name of the game is the claim.†In re Hiniker Co., 150 F.3d 1362, 1369 (Fed. Cir. 1998). Thus, consistent with the plain language of the claims, we construe the claim language to only require the system be capable of identifying a therapeutic agent correlating to each of the five molecular targets recited in the claims (PTEN, CTNNBl, cKIT, BRAF and PIK3CA) as long as such a therapeutic agent is present in the relevant computer database. 2. Claim 12 – “Likely Lack of Benefit of At Least One Therapeutic Agent†Dependent claim 12 recites that the report generated by the claimed system “comprises a listing of at least one additional molecular target for which the comparison to the reference value in (c) indicates a likely lack of benefit of at least one therapeutic agent and the at least one additional therapeutic agent.†Ex. 1001, cl. 12 (emphasis added). Related to its argument that the independent claim requires contraindication testing, Patent Owner further argues that, when dependent claim 12 is read in context, “a POSA would understand ‘lack of likely benefit’ to mean the report further comprises a listing of a least one additional molecular target for which the comparison to the reference value in (c) indicates a contraindication for at least one therapeutic agent and at least one additional therapeutic agent.†PO Resp. 42. According to Patent Owner, claim 12 requires the report to contain two additional components: “a listing of (1) at least one additional molecular target (i.e., the contraindication target) for which the comparison to the reference value in (c) indicates a likely lack of benefit of at least one therapeutic agent and (2) the at least one additional therapeutic agent (i.e., the contraindicated agent).†PO Sur-Reply 10. IPR2019-00166 Patent 9,292,660 B2 20 In support, Patent Owner points to Figure 40B of the ’660 patent as showing an excerpt of a sample patient report that includes as part of the summary a list of biomarkers, results and the associated “Agents Associated With LACK OF CLINICAL BENEFIT.†PO Resp. 42–43. That Figure is part of a series of illustrations (40A-40J) of an exemplary patient report based on molecular profiling. Ex. 1001, 8:23–24. Figures 40A and 40B illustrate a Summary listing of biomarkers identified as differentially expressed by microarray or IHC analysis with treatment options corresponding to each differentially expressed biomarker presented. Id. at 164:10–14. Patent Owner further relies upon an example in the specification indicating that both monoclonal antibody and small molecule kinase inhibitors are identified as a possible treatment, but cautioning that “molecular profiling may also reveal that some or all of these treatments are likely to be less effective,†and thus “the presence of a drug resistance mutation would contraindicate selection of the small molecule kinase inhibitors.†PO Sur-Reply 10–11 (citing Ex. 1001, 51:47–65). Patent Owner points to the specification’s teaching of identifying candidate treatments based on differentially expressed (overexpressed or underexpressed) biological markers as teaching “both the positive and negative mappings between treatments and molecular profiling results (i.e., agents likely to benefit and agents likely not to benefit).†Id. at 11 (citing Ex. 1001, 8:63–9:31, 7:49–65, 54:47–49 (Table 1), 145:16–146:35, 148:33– 48, 152:14–154:5, Figs. 2, 4, 26-31). Patent Owner argues that Petitioner incorrectly understands Claim 12 to require a listing of at least one molecular target “in situations where there is no change in expression for a target gene between normal and disease IPR2019-00166 Patent 9,292,660 B2 21 samples.†PO Resp. 42 (citing Ex. 1002 ¶ 210). Petitioner, however, responds that claim 12 does not require any construction. Reply 17. Based on Dr. O’Shaughnessy’s testimony that “the word ‘contraindicated’ in medicine . . . means you really shouldn’t use it,†Petitioner contends that Patent Owner and its expert “seek to import a limitation that is inconsistent with the plain meaning of the claim text.†Id. at 18 (citing Ex. 1119, 352:17–22). Although Petitioner has not proposed its own construction, the dispute over claim 12 focuses on whether the requirement that the report indicate a “likely lack of benefit†is satisfied by the prior art’s disclosure indicating only that the values for markers fall within a “normal†range (e.g., the marker is neither overexpressed or underexpressed) as compared to a reference. Compare PO Resp. 44–45 (contending that Petitioner and its expert “mistakenly conclude that the phrase ‘no likely benefit of at least one therapeutic agent’ appearing in claim 12 means values for markers that fall within normal range for reference based on FIGS. 3A–3D of the Von Hoff referenceâ€), with Reply 18 (contending that example from prior art “showing no change from a reference value could convey that certain therapeutic agents would not be effective (i.e., a likely lack of benefit)â€). Based on our consideration of the record, we agree with Patent Owner that claim 12 should be construed to require that the report lists at least one additional molecular target (the contraindication target) for which the comparison to the reference value indicates a likely lack of benefit (contraindication) of at least one therapeutic agent as well as the additional therapeutic agent (the contraindicated agent). Under this construction, the report generated according to claim 12 must do more than simply indicate IPR2019-00166 Patent 9,292,660 B2 22 that expression of the additional molecular target falls within a “normal†range or that there is no change from the reference value for expression of that molecular target. This interpretation is supported by both the claim language and the specification. Unlike independent claim 1, the plain language of claim 12 recites that the report specifically identify a therapeutic agent for which there is a “likely lack of benefit.†Ex. 1001, cl. 12. We find that this claim requirement is exemplified in Figure 40B, which shows a report identifying “Agents Associated with LACK OF CLINICAL BENEFIT†for certain biomarkers. Id., Fig. 40B. Additionally, the specification equates identifying contraindications with a determination that certain treatments are likely to be less effective. Id. at 51:58–65. In this regard, we are unpersuaded by Petitioner’s contention that Patent Owner seeks to import a limitation that is inconsistent with the plain meaning of the claim text because Dr. O’Shaughnessy testified that “the word ‘contraindicated’ in medicine … means you really shouldn’t use it. It’s a pretty strong terminology, ‘contraindicated.’ We rarely have that kind of black-and-white certainty.†Reply 18 (citing Ex. 1119, 352:17–22). Although we agree that the term “contraindicated†in the abstract might normally be understood to prohibit administration of the therapeutic agent, the ’660 patent does not appear to take such an absolute approach when describing contraindicated therapies. On cross-examination, Dr. O’Shaughnessy affirmed her position that the term “contraindication†in the context of the ’660 patent means that there is “less likely chance of benefiting from a particular therapy if a patient’s cancer has a negative predictive marker.†Ex. 1119, 347:14– 350:16. We credit Dr. O’Shaughnessy’s testimony on this point and apply IPR2019-00166 Patent 9,292,660 B2 23 the term “contraindicate†in our claim construction consistent with this testimony. C. Patentability Analysis 3. Prior Art Petitioner relies primarily upon the following prior art teachings in its challenge. a. Von Hoff (Ex. 1074) Von Hoff is a U.S. patent application published January 17, 2008. Von Hoff is listed as an inventor of the ’660 patent. Ex. 1001, codes (43), (76). As noted above, Patent Owner does not dispute Von Hoff’s status as § 102(b) prior art based on the February 12, 2010, priority date attributed to the ’660 patent. Von Hoff describes a system and method for determining individualized medical intervention for a particular disease state. Ex. 1074 ¶ 8. Figure 2 of Von Hoff is reproduced below. IPR2019-00166 Patent 9,292,660 B2 24 Id., Fig. 2. Figure 2 of Von Hoff is a flowchart of “a method for determining individualized medical intervention for a particular disease state that utilizes molecular profiling of a patient’s biological specimen that is non-disease specific.†Id. ¶ 17. Von Hoff discloses performing at least one test for at least one target from a biological sample of a patient (i.e., step 52 in Figure 2). Id. ¶ 53. The target may be one or more genes, one or more gene expressed proteins, IPR2019-00166 Patent 9,292,660 B2 25 one or more molecular mechanisms, and/or combinations thereof. Id. Von Hoff teaches that the test can include IHC analysis, micro array analysis, and other molecular tests. Id. The gene can be, among others, PTEN and KIT, and the gene expressed protein can be, among others, c-kit. Id. ¶¶ 9–10. Von Hoff’s method further includes determining whether one or more targets exhibit a change in expression compared to a normal reference for the particular target (i.e., step 60 in Fig. 2). Id. ¶ 55. Subsequently, a non- disease specific agent that interacts with each target having a changed expression is identified (i.e., step 70 in Fig. 2). Id. ¶ 56, Table 1. The agent may be a therapeutic drug or compound capable of interacting with the sample target that has exhibited a change in expression. Id. Von Hoff discloses that identification of the drug therapy to be administered may be conducted via an automated review of an extensive literature database and/or database generated from clinical trials. Id. ¶¶ 8, 52. Such a database may have stored data, such as patient data, biological sample data, prior treatment and protocol data, patient clinical data, molecular profiling data of biological samples, data on therapeutic drug agents and/or investigative drugs, a gene library, a disease library, a drug library, and other types of data stored within the database. Id. ¶¶ 24, 59. Von Hoff further teaches that a patient profile report can be provided that includes test results for various targets and any proposed therapies based on the results (i.e., step 80 in Fig. 2). Id. ¶ 57. b. Bibikova (Ex. 1047) Bibikova is an article entitled “Gene Expression Profiles in Formalin- Fixed, Paraffin-Embedded Tissues Obtained with a Novel Assay For Microarray Analysis†that appears to have been published in the journal IPR2019-00166 Patent 9,292,660 B2 26 Clinical Chemistry in 2004 (vol. 5, no. 12). Ex. 1047, 2384. Specifically, Bibikova teaches the use of the cDNA-mediated annealing, selection, extension, and ligation (DASL) assay developed at Illumina, Inc. as a gene expression method. Id. Bibikova discloses that 16 formalin-fixed, paraffin- embedded (FFPE) tissue samples of four types (i.e., prostrate, colon, breast, and lung) from both nondiseased and cancer tissues were profiled. Id. Bibikova states that the DASL assay provided highly reproducible intensity measurements for the FFPE samples and the results showed “increased expression of tumor- and stroma-specific markers,†which demonstrated the feasibility of using heterogeneous FFPE tissues for biomarker discovery. Id. at 2384–85. c. Illumina (Ex. 1005) Illumina is a technical bulletin prepared by Illumina, Inc. regarding RNA profiling with the DASL assay. Ex. 1005. Illumina teaches that microarray analysis of gene expression has proven to be a remarkable tool but has faced challenges because high quality cryopreserved RNA samples are limited in availability and must be collected over the course of a disease and because FFPE tissue samples provide RNA of poor integrity. Id. at 1, Introduction. In view of this, Illumina discloses a gene expression assay for microarrays capable of using partially degraded RNA. Id. Specifically, Illumina discloses its DASL assay can monitor RNA expression of up to 1536 sequence targets derived from RNA in FFPE samples. Id. The cancer panel for the DASL assay is a pool of selected probe groups that targets 502 genes from ten publicly available gene lists. Id. at 4. The cancer panel genes include, among others, BRAF, CTNNB1, KIT, KRAS2, PIK3CA, and IPR2019-00166 Patent 9,292,660 B2 27 PTEN. Id. at Table 1. Illumina discloses that the DASL can assay RNA from normal samples and from cancer tissues. Id. at 7–8. In our Institution Decision, we found that Petitioner made a sufficient showing for purposes of institution that the Illumina reference qualified as a prior art printed publication. Inst. Dec. 14–18. As we noted, the Illumina reference itself bears indicia that it was likely published, including a publication date (November 16, 2005) and a publication number (470-2005- 003). Id. at 15. Moreover, Illumina is identified as a “technical bulletin,†akin to a product catalog, which “is the type of document intended for public dissemination, and it bears no designations, such as ‘draft’ or ‘confidential,’ that might suggest that it was not intended for public distribution.†See Nobel Biocare Servs. AG v. Instradent USA, Inc., 903 F.3d 1365, 1377 (Fed. Cir. 2018). In addition to the dates and markings on the document itself, Petitioner submitted the declaration of the Internet Archive’s Office Manager, Christopher Butler, attesting that the Illumina publication was archived by the Wayback Machine on December 27, 2005, thereby confirming that it was publicly available on Illumina’s website. Ex. 1024, 5. The evidence of record indicates that the relevant public, including those skilled in the art, would have been generally aware that Illumina, Inc. offered research tools used for gene expression assays. See Ex. 1047, 2384 (Bibikova describing Illumina’s DASL assay); Ex. 1001, 21:55–60 (’660 patent noting the “Illumina Whole Genome DASL assay†was used for some embodiments). As such, we find that anyone interested in the DASL assay could have looked to Illumina’s website, where technical bulletins such as the Illumina reference could be accessed. IPR2019-00166 Patent 9,292,660 B2 28 Although the issue was contested in Patent Owner’s Preliminary Response, Patent Owner did not contest Illumina’s status as prior art after institution. Thus, any prior arguments by Patent Owner questioning Illumina’s prior art status in support of its patentability contentions are hereby waived. See Paper 13, 8 (“Patent Owner is cautioned that any arguments for patentability not raised in the response may be deemed waived.â€). We determine, based on the full record, that Petitioner has shown by a preponderance of the evidence that Illumina qualifies as a prior art printed publication for the reasons discussed in our Institution Decision. 4. Obviousness of Claim 1–16, 18, 22, and 23 Based on Von Hoff, Bibikova, and Illumina As the only ground of unpatentability in its Petition for this proceeding, Petitioner contends that claims 1–16, 18, 22, and 23 are rendered obvious by the combined teachings of Von Hoff, Bibikova, and Illumina. Pet. 26–38. As set forth below, we determine that Petitioner has demonstrated by a preponderance of the evidence that claims 1–11, 13–16, 18, 22, and 23 are unpatentable. However, we determine that Petitioner has not demonstrated by a preponderance of the evidence that claim 12 is unpatentable. a. Claim 1 The preamble of claim 1 recites “[a] system for generating a report identifying a therapeutic agent for an individual with lung cancer.†Ex. 1001, 164:39–40. Petitioner contends that the recitations of the preamble are taught because Von Hoff discloses a system that determines medical intervention for a disease state, particularly cancer, by providing a patient profile report and identifying a proposed drug therapy, and further because IPR2019-00166 Patent 9,292,660 B2 29 Bibikova discloses profiling lung cancer tissue samples. Pet. 26–27 (citing Ex. 1074 Abstract, ¶ 11, Fig. 2; Ex. 1047, 2384, 2386). Claim 1 further recites: “a. at least one device configured to assay a plurality of molecular targets in a biological sample from the individual with lung cancer to determine molecular profile test values for the plurality of molecular targets, wherein the plurality of molecular targets comprises PTEN, CTNNB1, cKIT, BRAF, and PIK3CA.†Ex. 1001, 164:41–46. Petitioner asserts Von Hoff teaches various devices to assay molecular targets in a biological sample to obtain test results, such as an expression microarray. Pet. 27 (citing Ex. 1074 ¶¶ 9, 53–54). Petitioner argues Illumina discloses the DASL Assay, which allows determining expression values for nucleic acid sequence targets that correspond to 502 cancer- related genes, including PTEN, CTNNB1, cKIT, BRAF, and PIK3CA. Id. at 27–29 (citing Ex. 1005 1, 3–4, 7, Table 1). Petitioner also asserts that Bibikova discloses that the DASL Assay may be used to provide a molecular profile for a lung cancer sample. Id. at 28 (citing Ex. 1047, 2384, 2386). Claim 1 further recites: “b. at least one computer database comprising: i. a reference value for each of the plurality of molecular targets; ii. a listing of available therapeutic agents for the plurality of molecular targets.†Ex. 1001, 164:47–51. Petitioner argues Von Hoff discloses a computer database with biological profile data that includes reference values for molecular targets and a listing of therapeutic agents for the molecular targets. Pet. 30– 31 (citing Ex. 1074 ¶¶ 13, 24). Petitioner also contends Illumina discloses comparing test expression values derived from a cancerous sample to reference values from a normal sample. Id. at 31–32 (citing Ex. 1005, 7, Fig. 7; Ex. 1002 ¶¶ 169–170). IPR2019-00166 Patent 9,292,660 B2 30 Claim 1 further recites: “c. a computer-readable program code comprising instructions to input the molecular profile test values and to compare each of the molecular profile test values with a corresponding reference value from the at least one computer database in (b)(i).†Ex. 1001, 164:52–56. Petitioner argues that Von Hoff discloses a system comprising instructions for determining whether a gene, a gene expressed protein, a molecular mechanism, and other molecular findings of a molecular profile exhibit a change in expression in comparison to a normal reference. Pet. 32– 33 (citing Ex. 1074 claim 12, ¶ 45, Fig. 2). Petitioner argues Illumina also discloses comparing a molecular profile test with a corresponding reference value. Id. at 34 (citing Ex. 1005, 7). Claim 1 further recites: d. a computer-readable program code comprising instructions to access the at least one computer database in (b)(ii) and to identify at least one therapeutic agent if present in the at least one computer database for each of the plurality of molecular targets wherein said comparison to the reference values in (c) indicates a likely benefit of the at least one therapeutic agent. Ex. 1001, 164:57–63. Under its broadest reasonable interpretation, discussed above, Petitioner contends Von Hoff discloses limitation (d) of claim 1 because Von Hoff teaches a system having computer program instructions that compares genes with changes in expression to a normal reference and accesses a drug therapy database to identify one or more drug therapies for genes exhibiting a change in expression. Id. at 36–37 (citing Ex. 1074 ¶¶ 17, 45, 56, claim 12, Fig. 2). Petitioner further contends “[t]o the extent that claim element (d) requires at least one therapeutic agent with ‘likely benefit’ to be associated with at least one of the recited genes in the claims, there were already therapeutic agent(s) with potential efficacy IPR2019-00166 Patent 9,292,660 B2 31 associated with each recited gene prior to February 12, 2010.†Id. at 36 n.8. (citing Ex. 1002 ¶ 178). Claim 1 finally recites: e. a computer-readable program code comprising instructions to generate a report that comprises a listing of the members of the plurality of molecular targets for which the comparison to the reference value indicated a likely benefit of the at least one therapeutic agent in (d) and the at least one therapeutic agent identified in (d). Ex. 1001, 164:64 to 165:2. Petitioner asserts that this limitation is not entitled to patentable weight because it is directed to the content of information and lacks a requisite functional relationship (i.e., is non- functional descriptive material). Pet. 37 (citing Praxair Distribution, Inc. v. Mallinckrodt Hospital Prods. IP Ltd., 890 F.3d 1024, 1032 (Fed. Cir. 2018)). Petitioner contends nonetheless that, in the event limitation (e) is given patentable weight, Von Hoff discloses the creation of a patient profile report including test results for various targets and proposed therapies that meet this claim limitation. Id. at 37–38 (citing Ex. 1074 ¶ 57 Figs. 3A–3D). Based on the foregoing cited prior art teachings and evidence, we determine that Petitioner has demonstrated that a POSA would have been motivated to combine the teachings of von Hoff with Illumina and Bibikova to arrive at the claimed system with a reasonable expectation of success. Von Hoff teaches most of the limitations of claim 1 except that it does not specifically mention lung cancer or identify the molecular targets CTNNB1, BRAF, and PIK3CA. We find that a POSA would have been motivated to modify or substitute Von Hoff’s micro array analysis with the DASL Assay as taught by Illumina and Bibikova in order to provide a more IPR2019-00166 Patent 9,292,660 B2 32 comprehensive molecular profile that could be used to identify potential therapeutic agents for an individual with lung cancer. For these points, we credit the testimony of Petitioner’s declarant Dr. Spellman, who explains with citations to supporting evidence that such a motivation would have been based on both the general recognition by POSAs of the problem to be solved in the art (i.e., the need to provide more effective diagnostic and therapeutic options for patients by using molecular profiling), as well as the specific teachings of the references themselves. Ex. 1002 ¶¶ 139–152 (citing Ex. 1050; Ex. 1051). Dr. Spellman further testifies, and we agree, that a POSA would have “recognized no conflict in combining Von Hoff and Illumina†because both references are directed to molecular profiling of cancer using known assay techniques, with overlapping molecular targets identified in both references, and both use established technologies that were capable of simultaneously screening hundreds of targets each. Id. ¶ 153. As Dr. Spellman attests, and we agree, “as early as 2004, it was regular practice to assay many or most of the molecular targets available,†and a POSA “would not have felt arbitrarily limited in capacity to select only a handful of targets to assay.†Ex. 1002 ¶ 154 (citing Ex. 1007; Ex. 1047). This testimony of Dr. Spellman sufficiently supports our conclusion that a POSA would have been motivated to combine the teachings of the references as it merely constitutes the combination of prior art elements according to known methods to yield predictable results. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.â€). IPR2019-00166 Patent 9,292,660 B2 33 We have considered, but are not persuaded by, Patent Owner’s arguments and evidence in support of patentability. Patent Owner’s arguments are primarily dependent upon its claim construction requiring testing for contraindications. As we have construed claim 1 to not require testing for contraindications, we are not persuaded by Patent Owner’s contentions that the prior art does not teach or suggest all the claim limitations because it does not disclose testing for contraindications. For instance, Patent Owner argues that Von Hoff does not teach or suggest identifying contraindicated therapeutic agents. PO Resp. 47–54. According to Patent Owner, “Von Hoff describes a system that identifies cancer-lineage independent therapeutic agents for treating a patient based upon molecular markers, and provides a report that lists options for physicians.†Id. at 48. Patent Owner recognizes that “[i]n Von Hoff’s system, if a patient’s tumor exhibits a value for a certain molecular marker that differs from a reference value, the system will generate a report listing therapeutic agents for that marker independent of cancer lineage.†Id. Patent Owner likewise argues that neither Illumina nor Bibikova teaches or suggests identifying contraindicated therapeutic agents. Id. at 54– 57. More generally, Patent Owner contends that the DASL Cancer panel described in Illumina and Bibikova does not connect the genes with any cancer therapies. Id. at 54–55. Patent Owner points out that the Illumina reference explicitly acknowledges that any clinical applications are tied to tissue-specific and cancer specific-markers. Id. at 55. Patent Owner argues that Bibikova is largely redundant of Illumina and does not identify treatment options for a particular lung cancer patient, let alone cancer lineage-independent options for the patient. Id. at 56–57. Patent Owner IPR2019-00166 Patent 9,292,660 B2 34 contends that Petitioner and Dr. Spellman “mischaracterize Bibikova when they state that Bibikova provides ‘treatment recommendations based on such molecular profile information across a variety of cancers, including lung cancer’†because Bibikova actually states that the DASL assay can “provide sufficient expression information to monitor multiple stages in disease progression as well as response to treatment . . . accelerate the identification of potential biomarkers as prognostic indicators . . . [and] permit rapid analysis of expression patterns in hundreds of clinical samples.†Id. (citing Ex. 1047, 2386). We are unpersuaded by these arguments because, regardless of whether Illumina or Bibikova independently teach recommending treatments based on the DASL assay, Von Hoff teaches the identification of a “non disease specific†therapeutic agent that is of likely benefit for a particular molecular target. See, e.g., Ex. 1074 ¶ 2 (teaching that the method includes “identifying a drug therapy capable of interacting with the genes, gene expressed proteins, molecular mechanisms, or combinations of such molecular findings that exhibited a change in expressionâ€); id. ¶ 56 (“[a]fter determining which targets exhibit a change in expression . . . , at least one non-disease specific agent is identified that interacts with each target having a changed expressionâ€). Since we do not interpret the claims to require identification of contraindicated therapies, we agree with Petitioner and Dr. Spellman that the teachings in Von Hoff are sufficient to satisfy the requirement to identify at least one therapeutic agent that is recited in limitation 1(d). Pet. 34–37; Ex. 1002 ¶¶ 179–181. Additionally, we are not persuaded by Patent Owner’s contention that a POSA would not have been motivated to combine the Von Hoff system IPR2019-00166 Patent 9,292,660 B2 35 with Illumina and Bibikova because “Illumina discloses the testing those targets only for RNA expression, but Dr. Spellman does not identify any therapies associated with CTNNB1, BRAF, PIK3CA, or KRAS[7] gene expression that would be indicated by RNA gene expression testing.†PO Resp. 58. With regard to the BRAF and KRAS targets, Patent Owner contends that only the identification of active mutations, and not RNA gene expression, would predict the lack of benefit from anti-EGFR antibody therapy, and “[b]ecause RNA expression testing of these molecular targets had no associated therapies and would not identify the activating mutations of interest, the POSA would have had no reason to add testing of those markers by the Illumina DASL assay to the system disclosed by Von Hoff.†Id. (citing Ex. 2016 ¶ 79). As discussed above, the claim language only requires identification of a therapeutic agent correlating to each of the recited molecular targets as long as such a therapeutic agent is present in the relevant computer database. As such, there is no requirement for the claimed system to identify a therapeutic agent for those targets that are tested only based on RNA expression. Moreover, Von Hoff encourages the testing of a “large number of targets†regardless of whether those targets are associated with known therapies, noting that such testing may lead one to “find additional targets or molecular findings that can be exploited by using specific therapeutic agents.†Ex. 1074 ¶ 6. We find that a POSA would not have been constrained to only assay those molecular targets included as part of the DASL assay for which there were known associated therapeutic agents. To 7 KRAS is identified as an additional molecular target that is assayed in dependent claim 11. Ex. 1001, cl. 11. IPR2019-00166 Patent 9,292,660 B2 36 the contrary, a POSA would have been motivated to incorporate the entirety of Illumina’s assay into Von Hoff’s system because it provided a more comprehensive approach for identifying potential lung cancer therapeutics. Ex. 1120 ¶ 38. Patent Owner also argues that objective evidence of non-obviousness in the form of industry praise supports the patentability of the challenged claims. PO Resp. 59–60. In particular, Patent Owner contends that Petitioner itself praised the claimed invention by touting the benefits of providing a report that identified contraindicated therapies. Id. (citing Ex. Ex. 2051; Ex. 2052; Ex. 2053). We are unpersuaded that this evidence demonstrates non-obviousness. Patent Owner has not shown how the statements it relies upon from Petitioner’s marketing documents have any nexus to the claimed system or Patent Owner’s system covered by the claims. See S. Alabama Med. Sci. Found. v. Gnosis S.P.A., 808 F.3d 823, 827 (Fed. Cir. 2015) (affirming a finding of no nexus where the patent owner “failed to connect the evidence of industry praise to the novel elements of the claims,†given that “the praise was particularly directed to ... an element already known in the prior artâ€). Even if this could be considered praise directed to the claimed system, we are not persuaded that this relatively weak evidence outweighs the strong evidence in favor of a determination of obviousness discussed above. We determine that Petitioner has demonstrated by a preponderance of the evidence that claim 1would have been obvious based on Von Hoff, Illumina, and Bibikova. IPR2019-00166 Patent 9,292,660 B2 37 b. Claims 2–11, 13–16, 18, 22, and 23 Petitioner also contends that claims 2–11, 13–16, 18, 22, and 23 would have been obvious based on the same combination of prior art. Petitioner identifies teachings in the prior art references that teach or suggest the limitations of these dependent claims. Pet. 38–46, 48–53. Petitioner also supports its contentions for these claims with the testimony of Dr. Spellman. Ex. 1002 ¶¶ 185–208, 212–230. Patent Owner does not present any arguments for these dependent claims other than what we have already considered with respect to independent claim 1. We have considered the evidence and arguments of record and determine that Petitioner has demonstrated by a preponderance of the evidence that claims 2–11, 13–16, 18, 22, and 23 would have been obvious based on Von Hoff, Illumina, and Bibikova for the reasons discussed in the Petition as supported by the testimony of Dr. Spellman. Pet. 38–46, 48–53; Ex. 1002 ¶¶ 185–208, 212–230. c. Claim 12 Claim 12 depends from claim 1 and recites “wherein the report further comprises a list of at least one additional molecular target for which the comparison to the reference value in (c) indicates a likely lack of benefit of at least one therapeutic agent and the at least one additional therapeutic agent.†Ex. 1001, cl. 12. Petitioner contends that Von Hoff discloses or renders obvious the additional limitation of claim 12 based on its teaching with respect to Figures 2 and 3A–3D. Pet. 46–47. In particular, Petitioner points to steps 70 and 80 of Figure 2 of Von Hoff, which respectively teach “identify[ing] at least one non-disease specific agent that interacts with one or more targets IPR2019-00166 Patent 9,292,660 B2 38 exhibiting a change in expression†and “provid[ing a] patient profile report containing test and proposed therapy/agent.†Pet. 46–47; Ex. 1002 ¶ 210; Ex. 1074, Fig. 2. Figure 3A–3D illustrate an exemplary patient profile report in accordance with step 80 of Figure 2. Ex. 1074 ¶ 18. Figure 3B of Von Hoff reproduces a portion of the report indicating a conclusion of “NEGATIVE†for certain molecular targets based on advanced IHC analysis. Id., Fig. 3B. Figure 3C reproduces a portion of the report showing microarray analysis results with an indication of “NO CHANGE†for certain gene targets. Id., Fig. 3C. Figure 3D reproduces a portion of the conclusion of the report cautioning that “[t]he finding of a target does not necessarily indicate pharmacologic effectiveness.†Id., Fig. 3D. Petitioner contends that Von Hoff’s report indicates a likely lack of benefit of at least one therapeutic agent and the at least one additional therapeutic agent based on the notation of “negative†or “no change†for various targets (“i.e., in situations where there is no change in expression for a target gene between normal and disease samplesâ€). Pet. 46–47. Alternatively, Petition contends that claim 12 would have been obvious to a POSA because “the one additional target†that needs to be identified according to this claim “can be any molecular target besides the targets explicitly recited in the claim†and “[i]t was well known in the art as of February 2010 that some mutations in genes result in resistance to target- specific drugs.†Id. at 47. As support, Petitioner points to a 2005 review article by Xie and Frueh describing certain mutations that can cause clinical resistance to small molecule inhibitors targeting oncogenic tyrosine kinases as a “common cause of cancer therapy failure.†Id. (citing Ex. 1068, 329– 330). IPR2019-00166 Patent 9,292,660 B2 39 We determine that Petitioner has not met its burden with respect to claim 12. As discussed above, we construe claim 12 such that the report that is generated must do more than simply indicate that expression of the additional molecular target falls within a “normal†range or that there is “no change†from the reference value for expression of that molecular target. We construe this claim language, consistent with Patent Owner’s arguments, to require that the report list at least one additional molecular target (the contraindication target) for which the comparison to the reference value indicates a likely lack of benefit (contraindication) of at least one therapeutic agent as well as the additional therapeutic agent (the contraindicated agent). The mere fact that the report in Von Hoff identifies situations where there is no change in expression for a target gene is insufficient to satisfy the requirement of claim 12. Furthermore, we are unpersuaded that Petitioner has made a sufficient showing that a POSA would have found it obvious to include “one additional target†in the report generated according to Von Hoff’s system based on the knowledge in the art that certain gene mutations can result in resistance to target-specific drugs. For instance, Petitioner does not identify any particular benefit that would be gained by including information about such an additional molecular target that would have motivated a POSA to further modify Von Hoff’s teachings to obtain the claimed subject matter. A determination of obviousness “cannot be sustained by mere conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.†In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). IPR2019-00166 Patent 9,292,660 B2 40 We determine that Petitioner has not demonstrated by a preponderance of the evidence that claim 12 would have been obvious over Von Hoff, Illumina, and Bibikova. III. CONCLUSION8 Petitioner has demonstrated by a preponderance of the evidence that claims 1–11, 13–16, 18, 22, and 23 of the ’660 patent would have been obvious based on Von Hoff, Illumina, and Bibikova, as discussed above. Petitioner has not demonstrated by a preponderance of the evidence that claim 12 would have been obvious. In summary: 8 Should Patent Owner wish to pursue amendment of the challenged claims in a reissue or reexamination proceeding subsequent to the issuance of this decision, we draw Patent Owner’s attention to the April 2019 Notice Regarding Options for Amendments by Patent Owner Through Reissue or Reexamination During a Pending AIA Trial Proceeding. See 84 Fed. Reg. 16,654 (Apr. 22, 2019). If Patent Owner chooses to file a reissue application or a request for reexamination of the challenged patent, we remind Patent Owner of its continuing obligation to notify the Board of any such related matters in updated mandatory notices. See 37 C.F.R. § 42.8(a)(3), (b)(2). Claims 35 U.S.C. § References Claims Shown Unpatentable Claims Not shown Unpatentable 1–16, 18, 22, 23 103(a) Von Hoff, Illumina, Bibikova 1–11, 13–16, 18, 22, 23 12 Overall Outcome 1–11, 13–16, 18, 22, 23 12 IPR2019-00166 Patent 9,292,660 B2 41 IV. ORDER Accordingly, it is hereby: ORDERED that Petitioner has demonstrated by a preponderance of the evidence that claims 1–11, 13–16, 18, 22, and 23 of the ’660 patent are unpatentable; FURTHER ORDERED that Petitioner has not demonstrated by a preponderance of the evidence that claim 12 is unpatentable; and FURTHER ORDERED that, because this is a Final Written Decision, any party to the proceeding seeking judicial review of the decision must comply with the notice and service requirements of 37 C.F.R. § 90.2. IPR2019-00166 Patent 9,292,660 B2 42 PETITIONER: David Cavanaugh David.cavanaugh@wilmerhale.com William Kim William.kim@wilmerhale.com Kevin Yurkerwich Kevin.yurkerwich@wilmerhale.com Eric Ross Cohen Ross.cohen@wilmerhale.com PATENT OWNER: Dorothy Whelan whelan@fr.com Mike Kane kane@fr.com Martina Hufnal hufnal@fr.com Copy with citationCopy as parenthetical citation