Caris MPI, Inc.Download PDFPatent Trials and Appeals BoardMay 13, 2020IPR2019-00203 (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. ____________ IPR2019-00203 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 17, 19–21, and 24 to be Unpatentable 35 U.S.C. § 318(a) IPR2019-00203 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 17, 19–21, and 24 of U.S. Patent No. 9,292,660 B2 (Ex. 1101, “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 17, 19–21, and 24 of the ’660 patent are unpatentable under 35 U.S.C. § 103. IPR2019-00203 Patent 9,292,660 B2 3 B. Related Proceedings Along with the current Petition, Petitioner has filed another Petition challenging additional claims of the ’660 patent not challenged here. See IPR2019-00166 (claims 1–16, 18, 22, and 23). We issue our final written decision in IPR2019-00166 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. 1101) 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. 1101, 2:31–33. According to the patent, treatment therapies or regimens are typically selected according to what particular disease a patient has been diagnosed with, although some regimens have been determined using molecular profiling and clinical characterization of a patient. Id. at 1:29–48. IPR2019-00203 Patent 9,292,660 B2 4 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 included in the FISH mutation profile, and have no mutations or one or more IPR2019-00203 Patent 9,292,660 B2 5 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. IPR2019-00203 Patent 9,292,660 B2 6 D. Illustrative Claims Petitioner challenges claims 17, 19–21, and 24 of the ’660 patent. These claims all depend directly or indirectly from independent claim 1, which is reproduced below to provide context: 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). IPR2019-00203 Patent 9,292,660 B2 7 Claim 17 depends from claim 1 and specifies that “the molecular targets further comprises RRM1.†Claims 19 and 21 further depend from claim 17, and specify that the “the molecular profile test value for the molecular target RRM1 is determined by immunohistochemistry testing†(claim 19) and that “the molecular profile test values for the plurality of molecular targets comprises: (i) sequencing of the molecular targets CTNNB 1, cKIT, BRAF, PTEN and PIK3CA; and (ii) immunohistochemistry of the molecular targets PTEN and RRM1†(claim 21). Claim 20 depends from claim 1, and specifies that “the molecular profile test values for the molecular targets PTEN, CTNNB 1, cKIT, BRAF and PIK3CA is determined by sequencing.†Claim 24 depends from claim 1, and specifies that “at least one device configured to assay the plurality of molecular targets is configured to identify at least one of a mutation, polymorphism, deletion, insertion, substitution, translocation, fusion, break, duplication, amplification or repeat in a nucleic acid sequence corresponding to at least one member of the plurality of molecular targets.†E. The Asserted Grounds of Unpatentability We instituted inter partes review in this proceeding based on the following ground as presented in the Petition: IPR2019-00203 Patent 9,292,660 B2 8 Claim(s) challenged 35 U.S.C. § Reference(s) 17, 19 103(a) Von Hoff,1 Bibikova,2 Illumina,3 Gautam4 20, 24 103(a) Von Hoff, Bibikova, Illumina, Gnirke5 21 103(a) Von Hoff, Bibikova, Illumina, Gautam, Gnirke In support of its arguments, Petitioner relies upon the expert declarations of Paul Spellman, Ph.D. (Ex. 1102 and Ex. 1120). Patent Owner relies upon the expert declaration of Joyce O’Shaughnessy, M.D. (Ex. 2116). 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. 1101, code (63). Additionally, the ’660 patent claims priority to provisional applications dating back to May 18, 2006. Id., code (60). Among this chain 1 Von Hoff et al., US 2008/0014146 A1, published Jan. 17, 2008 (Ex. 1174) (“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. 1147) (“Bibikovaâ€). 3 Illumina® Gene Expression Profiling, Technical Bulletin, RNA Profiling with the DASL® Assay (2005) (Ex. 1105) (“Illuminaâ€). 4 Ashish Gautam et al., RRM1-induced metastasis suppression through PTEN-regulated pathways, 22 Oncogene 2135 (2003) (Ex1173) (“Gautamâ€). 5 Andreas Gnirke et al., Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing, 27 Nature Biotechnology 182 (2009) (Ex. 1169) (“Gnirkeâ€). IPR2019-00203 Patent 9,292,660 B2 9 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 CTNNB1) as part of a long list of “[g]enes and gene products.†Pet. 18; see Ex. 1179, 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. 1101, 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. Pet. 18–19 (citing Ex. 1102 ¶¶ 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 19–20.6 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. 6 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. 19 (citing Ex. 1102 ¶ 115). IPR2019-00203 Patent 9,292,660 B2 10 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, including at least two to three years of research experience in the field of cancer genomics.†Pet. 16 (citing Ex. 1102 ¶ 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. 4. 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 4–5 (citing Ex. 2116 ¶ 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. 2115, 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 7 (citing Ex. 2116 ¶¶ 5–11, 46; Ex. 2115, 16:10–12). IPR2019-00203 Patent 9,292,660 B2 11 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. 7–8. 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 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. 1218, 118:5–13; Ex. 1220 ¶ 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 IPR2019-00203 Patent 9,292,660 B2 12 treatment options for cancer patients. See, e.g., Ex. 1101, 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 effective treatment regimen may be overlooked for a particular individual†(emphasis added)); Ex. 1174 ¶ 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. 1219, 398:13–20 (Dr. O’Shaughnessy testifying that as an oncologist, she IPR2019-00203 Patent 9,292,660 B2 13 was not “qualified†to speak to “computerized decision support system and databases†or the “construct of the infrastructureâ€); Ex. 1220 ¶ 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 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). IPR2019-00203 Patent 9,292,660 B2 14 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).7 Under the broadest reasonable construction standard, 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 one claim construction issue: whether claim 1 (and by 7 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 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. IPR2019-00203 Patent 9,292,660 B2 15 extension all the challenged dependent claims) require the claimed system to test for contraindications.8 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. 36–42. 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. 2116 ¶ 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 8 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 1013, 1017 (Fed. Cir. 2017) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)). IPR2019-00203 Patent 9,292,660 B2 16 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. 1101, 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 otherwise be recommended is contraindicated as a result of the presence of the BRAF mutation.†Id. (citing Ex. 2116 ¶ 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; Reply 9– 17. 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. 37 (citing Ex. 1102 ¶ 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 IPR2019-00203 Patent 9,292,660 B2 17 least one therapeutic agent’ from the ‘listing of available therapeutic agents for the plurality of molecular targets.’†Id. (citing Ex. 1102 ¶ 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 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. 1101, 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 IPR2019-00203 Patent 9,292,660 B2 18 relevant computer database.†Inst. Dec., 10. 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 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. 1101, 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. 1220 ¶ 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. 1101, 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 IPR2019-00203 Patent 9,292,660 B2 19 acknowledged that those skilled in the art were working towards developing potential new therapies based on the BRAF target. See Ex. 2116 ¶ 58; Ex. 1220 ¶ 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 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. 1101, 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. 1222, 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 18–19. Patent Owner plainly knew how to describe and claim a system that tested for contraindications, and it could have expressly recited identifying or testing IPR2019-00203 Patent 9,292,660 B2 20 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 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. C. Patentability Analysis 2. Prior Art Petitioner relies primarily upon the following prior art teachings in its challenge. a. Von Hoff (Ex. 1174) Von Hoff is a U.S. patent application published January 17, 2008. Von Hoff is listed as an inventor of the ’660 patent. Ex. 1101, 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. IPR2019-00203 Patent 9,292,660 B2 21 Von Hoff describes a system and method for determining individualized medical intervention for a particular disease state. Ex. 1174 ¶ 8. Figure 2 of Von Hoff is reproduced below. 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. IPR2019-00203 Patent 9,292,660 B2 22 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, 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. IPR2019-00203 Patent 9,292,660 B2 23 b. Bibikova (Ex. 1147) 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 Clinical Chemistry in 2004 (vol. 5, no. 12). Ex. 1147, 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. 1105) Illumina is a technical bulletin prepared by Illumina, Inc. regarding RNA profiling with the DASL assay. Ex. 1105. 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 IPR2019-00203 Patent 9,292,660 B2 24 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 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. 1124, 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. 1147, 2384 (Bibikova describing Illumina’s DASL assay); Ex. 1101, 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 IPR2019-00203 Patent 9,292,660 B2 25 could have looked to Illumina’s website, where technical bulletins such as the Illumina reference could be accessed. 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. d. Gautam (Ex. 1173) Gautam regards a study of the expression of the RRM1 gene and lung cancer. Ex. 1173, 1235, Abstract. Gautam states that studies had shown a relationship between chromosome 11 allele loss, including loss of the RRM1 gene, and metastasis formation and poor survival in patients with lung cancer. Id. at 2138. Gautam investigated whether RRM1 overexpression influences spontaneous metastasis formation and, based on the study, concluded that RRM1 overexpression is capable of suppressing spontaneous in vivo metastasis formation in the lung for an animal model. Id. Gautam further teaches that a reported decrease in invasiveness for an RRM1- transfected human oropharyngeal carcinoma cell line and genetic complementation of human lung cancer cell lines with whole chromosome 11 or fragments thereof containing RRM1, which resulted in suppression of xenograft formation, “suggested a role for RRM1 in the phenotypic behavior of malignant cells.†Id. at 2139. IPR2019-00203 Patent 9,292,660 B2 26 e. Gnirke (Ex. 1169) Gnirke discloses that sequencing the entire human genome has important applications but research and diagnostic goals can be achieved by sequencing a specific subset of the genome in large numbers of samples. Ex. 1169, 182. According to Gnirke, one method of accomplishing this is via microarray capture, which “uses hybridization to arrays containing synthetic oligonucleotides that match the target sequence to capture templates from randomly sheared, adaptor-ligated genomic DNA.†Id. Gnirke discloses a method that “combines the simplicity and robust performance of oligonucleotide hybridization with the advantages of amplifying array-synthesized oligonucleotides and performing the selection reaction in solution†that, in principle, “can target any arbitrary sequence.†Id. at 183, 186. Gnirke also teaches that its method can detect single- nucleotide polymorphism (SNP). Id. at 186. 3. Obviousness Analysis As the grounds of unpatentability in its Petition for this proceeding, Petitioner contends that a) claims 17 and 19 are rendered obvious by the combined teachings of Von Hoff, Bibikova, Illumina, and Gautam; b) claims 20 and 24 are rendered obvious by the combined teachings of Von Hoff, Bibikova, Illumina, and Gnirke; and c) claim 21 is rendered obvious by the combined teachings of Von Hoff, Bibikova, Illumina, Gautam, and Gnirke. Pet. 27–66. As set forth below, we determine that Petitioner has demonstrated by a preponderance of the evidence that claims 17, 19–21 and 24 are unpatentable. Because these claims all depend on claim 1, it is necessary to first consider the parties’ contentions and evidence with respect to the independent claim limitations. Petitioner and Patent Owner rely upon IPR2019-00203 Patent 9,292,660 B2 27 the same arguments considered in the related proceeding, IPR2019-00166, for these independent claim limitations. See Pet. 27–40; PO Resp. 42–59 (arguing that Von Hoff, Bibikova, and Illumina do not teach testing for contraindicated therapies). For the reasons stated in our Final Written Decision in IPR2019-00166, we have determined that Petitioner has demonstrated that claim 1 would have been obvious based on the combination of Von Hoff, Bibikova, and Illumina. We incorporate our analysis for the independent claim limitations into our decision in this proceeding. a. Ground 1 – Obviousness of Claims 17 and 19 Based on Von Hoff, Bibikova, Illumina, and Gautam Petitioner contends that dependent claims 17 and 19 are rendered obvious by the combined teachings of Von Hoff, Bibikova, Illumina, and Gautam. Pet. 40–42. These claims recite RRM1 as an additional molecular target that is assayed by the claimed system. As discussed in our Final Written Decision in IPR2019-00166, Petitioner has demonstrated that the independent claim limitations are taught or suggested by the combination of Von Hoff, Bibikova, and Illumina. Petitioner and its declarant, Dr. Spellman, further rely upon Gautam as disclosing that RRM1 is a molecular target to be screened in lung cancers. See, e.g., Ex. 1173 Abstract (“overexpression of RRM1 in human [] lung cancer cell lines induced PTEN expression, reduced phosphorylation of focal adhesion kinase (FAK), suppressed migration, invasion, and metastasis formation, and increased survivalâ€); id. at 2137-38, Fig. 1; Ex. 1102 ¶¶ 248–256. Petitioner contends that a POSA would have been motivated with a reasonable expectation of success to include RRM1 because applying IHC analysis to determine IPR2019-00203 Patent 9,292,660 B2 28 RRM1’s protein expression level in a lung had been done before, and thus it would have been no more than applying a known technology in a known way to achieve a predictable result. Id. 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 17 and 19 would have been obvious based on Von Hoff, Illumina, Bibikova, and Gautam. b. Ground 2 – Obviousness of Claims 20 and 24 Based on Von Hoff, Bibikova, Illumina, and Gnirke Petitioner contends that dependent claims 20 and 24 are rendered obvious by the combined teachings of Von Hoff, Bibikova, Illumina, and Gnirke. Pet. 54–65. Claim 20 recites that the molecular profile test values are determined by sequencing. Ex. 1101, cl. 20. Claim 24 recites that the device “is configured to identify at least one of a mutation, polymorphism, deletion, insertion, substitution, translocation, fusion, break, duplication, amplification or repeat in a nucleic acid sequence corresponding to at least one member of the plurality of molecular targets. Id., cl. 24. As discussed in our final written decision in IPR2019-00166, Petitioner has demonstrated that the independent claim limitations are taught or suggested by the combination of Von Hoff, Bibikova, and Illumina. Petitioner and its declarant contend that the additional limitations of these dependent claims are taught or suggested by the disclosure in Gnirke of using an Illumina platform sequencer to provide test values for molecular targets, such as the identification of single nucleotide polymorphisms IPR2019-00203 Patent 9,292,660 B2 29 (SNPs), insertions, deletions, and translocations of the sequences, and that the test sequencing values derived from a tumor sample can be compared to reference values from a normal tissue sample. Pet. 54–65; Ex. 1102 ¶¶ 257– 278. Petitioner contends that a POSA would have been motivated to use sequencing technology in such a manner because it would have provided additional molecular profile information, because there were technical commonalities with expression microarrays, such as the DASL assay, and because Gnirke teaches that the disclosed approach “enable[s] efficient, cost-effective, and routine deep resequencing of important targets and help identify biologically and medically relevant mutations.†Pet. 59–61. Petitioner contends that a POSA would have had a reasonable expectation of success because POSA would only have had to rely upon routine and conventional technology known to those skilled in the art prior to February 2010. Id. at 61–65. 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 20 and 24 would have been obvious based on Von Hoff, Illumina, Bibikova, and Gnirke. c. Ground 3 – Obviousness of Claims 21 Based on Von Hoff, Bibikova, Illumina, Gautam, and Gnirke Petitioner contends that dependent claim 21 is rendered obvious by the combined teachings of Von Hoff, Bibikova, Illumina, Gautam, and Gnirke. Pet. 65–70. Claim 21 further depends from claim 17 and specifies determining the molecular profile by (i) sequencing of the molecular targets IPR2019-00203 Patent 9,292,660 B2 30 CTNNB1, cKIT, BRAF, PTEN and PIK3CA, and (ii) immunohistochemistry of the molecular targets PTEN and PIK3CA. Ex. 1101, cl. 21. Petitioner and its expert contend that Von Hoff discloses using IHC analysis and microarray in combination with other devices to analyze molecular targets of interest, and further rely upon Gautam’s teachings with respect to including RRM1 as a molecular target when profiling lung cancer (as discussed with respect to Ground 1) and Gnirke’s teachings with respect to using sequencing technology to identify certain other molecular targets (as discussed with respect to Ground 2). Pet. 65–70; Ex. 1102 ¶¶ 279–293. 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 claim 21 would have been obvious based on Von Hoff, Illumina, Bibikova, Gautam, and Gnirke. III. CONCLUSION9 Petitioner has demonstrated by a preponderance of the evidence that claims 17, 19–21, and 24 of the ’660 patent would have been obvious for the reasons discussed above. 9 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 IPR2019-00203 Patent 9,292,660 B2 31 In summary: IV. ORDER Accordingly, it is hereby: ORDERED that Petitioner has demonstrated by a preponderance of the evidence that claims 17, 19–21, and 24 of the ’660 patent are 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; 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 17, 19 103(a) Von Hoff, Illumina, Bibikova, Gautam 17, 19 20, 24 103(a) Von Hoff, Illumina, Bibikova, Gnirke 20, 24 21 103(a) Von Hoff, Illumina, Bibikova, Gautam, Gnirke 21 Overall Outcome 17, 19–21, 24 IPR2019-00203 Patent 9,292,660 B2 32 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