Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 1 of 13
`Case 1:17-cv—12194-MLW Document 32-3 Filed 03/01/18 Page 1 of 13
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`EXHIBIT 3
`EXHIBIT 3
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`

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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 2 of 13
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`Attorney Docket No.: 37901-715.305
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`PATENT
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`Confirmation No.: 5406
`
`Inventors: Daniel D. VON HOFF, et al.
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`Group No.:
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`1631
`
`Serial No.: 14/187,015
`
`Examiner:
`
`LIN, JERRY
`
`Filing Date: February 21, 2014
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`Customer No.
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`96600
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`For: MOLECULAR PROFILING OF TUMORS
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`ELECTRONICALLY FILED NOVEMBER 16, 2015
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`RESPONSE TO NON-FINAL OFFICE ACTION
`
`Sir/Madam:
`
`Introductory Comments:
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`This communication is in response to Non-Final Office Action dated June 16, 2015. The
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`shortened statutory period for response expired on September 16, 2015. Therefore, Applicants submit
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`fees for a two-month extension of time herewith.
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`Applicants respectfully request reconsideration of the above-referenced application in view of the
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`following remarks.
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`Amendments to the Claims begin on page 2 of this paper.
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`Remarks begin on page 6 of this paper.
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`Docket No. 37901-715.305
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`

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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 3 of 13
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`U.S. Serial No. 14/187,015
`Response to Non-Final Office Action of June 16, 2015
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`Amendments to the Claims
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`1.
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`(Previously Presented) A system for generating a report identifying a therapeutic agent for an
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`individual with lung cancer comprising:
`
`a.
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`at least one device configured to assay a plurality of molecular targets in a biological sample
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`from the individual with lung cancer to determine molecular profile test values for the
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`plurality of molecular targets, wherein the plurality of molecular targets comprises PTEN,
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`CTNNBI, cKIT, BRAF and PIK3CA;
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`b. at least one computer database comprising:
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`1. a reference value for each of the plurality of molecular targets;
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`11. a listing of available therapeutic agents for the plurality of molecular targets;
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`c. a computer-readable program code comprising instructions to input the molecular profile test
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`values and to compare each of the molecular profile test values with a corresponding
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`reference value from the at least one computer database in (b )(i);
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`d. a computer-readable program code comprising instructions to access the at least one
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`computer database in (b )(ii) and to identify at least one therapeutic agent if present in the at
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`least one computer database for each of the plurality of molecular targets wherein said
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`comparison to the reference values in ( c) indicates a likely benefit of the at least one
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`therapeutic agent; and
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`e. a computer-readable program code comprising instructions to generate a report that
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`comprises a listing of the members of the plurality of molecular targets for which the
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`comparison to the reference value indicated a likely benefit of the at least one therapeutic
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`agent in ( d) and the at least one therapeutic agent identified in ( d).
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`2.
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`(Previously Presented) The system of claim 1, wherein the molecular profile test values are input
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`into the system from a location that is remote from the at least one computer database.
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`3.
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`(Previously Presented) The system of claim 1, wherein the molecular profile test values are input
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`into the system over an internet connection.
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`4.
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`(Original) The system of claim 1, wherein the report is in electronic or paper format.
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`Docket No. 37901-715.305
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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 4 of 13
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`U.S. Serial No. 14/187,015
`Response to Non-Final Office Action of June 16, 2015
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`5.
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`(Previously Presented) The system of claim 1, wherein the at least one computer database further
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`comprises data corresponding to at least one clinical trial of a member of the plurality of
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`molecular targets.
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`6.
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`(Previously Presented) The system of claim 1, wherein the reference value for each of the
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`plurality of molecular targets comprises a sequence, presence and/ or level of a nucleic acid and/ or
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`a protein.
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`7.
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`(Previously Presented) The system of claim 1, wherein the molecular profile test values for the
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`plurality of molecular targets are determined after the individual has received at least one drug
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`therapy for the lung cancer.
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`8.
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`(Previously Presented) The system of claim 1, wherein the molecular profile test values are
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`determined by assessing a cell, a tissue sample, a blood sample or a combination thereof.
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`9.
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`(Previously Presented) The system of claim 1, wherein the molecular profile test values are
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`determined by performing a test for a gene and/or protein.
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`10. (Previously Presented) The system of claim 1, wherein each reference value is obtained from at
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`least one individual without lung cancer.
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`11. (Previously Presented) The system of claim 1, wherein the plurality of molecular targets further
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`comprises KRAS.
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`12. (Previously Presented) The system of claim 1, wherein the report further comprises a listing of at
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`least one additional molecular target for which the comparison to the reference value in ( c)
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`indicates a likely lack of benefit of at least one therapeutic agent and the at least one additional
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`therapeutic agent.
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`13. (Previously Presented) The system of claim 1, further comprising a computer-readable program
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`code comprising instructions to prioritize the list of the at least one therapeutic agent.
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`14. (Previously Presented) The system of claim 1, wherein the report provides a prioritized list of the
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`at least one therapeutic agent.
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`15. (Previously Presented) The system of claim 1, wherein the individual has been treated by and
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`failed to respond to at least one cancer therapeutic.
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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 5 of 13
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`U.S. Serial No. 14/187,015
`Response to Non-Final Office Action of June 16, 2015
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`16. (Original) The system of claim 1, wherein the individual has failed to respond to at least one
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`treatment for the lung cancer.
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`17. (Previously Presented) The system of claim 1, wherein the molecular targets further comprises
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`RRMI.
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`18. (Previously Presented) The system of claim 1, wherein the molecular profile test value for the
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`molecular target PTEN is determined by protein and nucleic acid testing.
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`19. (Previously Presented) The system of claim 17, wherein the molecular profile test value for the
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`molecular target RRMl is determined by immunohistochemistry testing.
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`20. (Previously Presented) The system of claim 1, wherein the molecular profile test values for the
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`molecular targets PTEN, CTNNBl, cKIT, BRAF and PIK3CA is determined by sequencing.
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`21. (Previously Presented) The system of claim 17, wherein the molecular profile test values for the
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`plurality of molecular targets comprises: (i) sequencing of the molecular targets CTNNBl, cKIT,
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`BRAF, PTEN and PIK3CA; and (ii) immunohistochemistry of the molecular targets PTEN and
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`RRMI.
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`22. (Previously Presented) The system of claim 1, wherein the at least one device configured to assay
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`the plurality of molecular targets is configured to perform at least one of polymerase chain
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`reaction (PCR), pyrosequencing, real-time PCR, sequencing, NextGen sequencing, methylation
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`specific PCR (MSPCR), restriction fragment length polymorphism (RFLP) analysis,
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`immunohistochemistry (IHC), an immunoassay, an expression microarray analysis, a comparative
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`genomic hybridization (CGH) microarray analysis, a single nucleotide polymorphism (SNP)
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`microarray analysis, in-situ hybridization (ISH), fluorescent in-situ hybridization (FISH), and a
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`proteomic array analysis.
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`23. (Previously Presented) The system of claim 1, wherein the at least one device configured to assay
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`the plurality of molecular targets is configured to perform at least one of gene expression
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`analysis, nucleic acid sequence analysis, nucleic acid methylation analysis, and proteomic
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`analysis.
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`24. (Previously Presented) The system of claim 1, wherein the at least one device configured to assay
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`the plurality of molecular targets is configured to identify at least one of a mutation,
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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 6 of 13
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`U.S. Serial No. 14/187,015
`Response to Non-Final Office Action of June 16, 2015
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`polymorphism, deletion, insertion, substitution, translocation, fusion, break, duplication,
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`amplification or repeat in a nucleic acid sequence corresponding to at least one member of the
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`plurality of molecular targets.
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`[REMAINDER OF PAGE INTENTIONALLY BLANKJ
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`-5-
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`Docket No. 37901-715.305
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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 7 of 13
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`U.S. Serial No. 14/187,015
`Response to Non-Final Office Action of June 16, 2015
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`REMARKS
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`With this Response, no claim amendments are made. Applicant respectfully requests
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`reconsideration of the pending claims based on the following arguments.
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`I.
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`Information Disclosure Statement
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`Applicant thanks the Examiner for acknowledging the Supplemental IDS statement filed June 11,
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`2014.
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`II. Election
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`Applicant thanks the Examiner for withdrawing the species requirement, thereby rejoining claim
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`11 and considering claims 22-24 in the current prosecution. See Office Action, p. 2.
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`III. Priority
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`The Examiner alleges that the present application does not receive the benefit of its parent
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`applications earlier filing dates on the grounds that "[t]he disclosure of the prior-filed application,
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`Application No. 12/658,770, fails to provide adequate support or enablement in the manner provided by
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`35 U.S.C. l 12(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application."
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`Office Action, pp. 2-3. Specifically, the Examiner alleges that "[t]he instant claims include subject matter
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`that is not present in Application No. 12/658,770. Application No. 12/658,770 does not recite a panel of
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`PTEN, CTNNBl, cKIT, BRAF and PIK3CA. Application No. 12/658,770 does not recite the biomarkers
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`CTNNBl or PIK3CA." Id. at p. 3.
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`Applicant respectfully disagrees. PIK3CA is referred to in parent application 12/658,770 under
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`the alias "PI3K." See, e.g., paragraph [0018] of application no. 12/658, 770 (teaching that PI3K can be
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`assessed according to the methods of the invention). This alias would be understood by one of skill in the
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`art to refer to the same biomarker as PIK3CA. See, e.g., the listing "Aliases for PIK3CA Gene" available
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`online at www.genecards.org/cgi-bin/carddisp.pl?gene=PIK3CA (last checked November 12, 2015).
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`Similarly, CTNNB 1 is referred to in parent application 12/658, 770 under the alias "beta-catenin."
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`See, e.g., paragraph [0195] of application no. 12/658, 770 (teaching that beta-catenin can be assessed
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`according to the methods of the invention). This alias would be understood by one of skill in the art to
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`refer to the same biomarker as CTNNB 1. See, e.g., the listing "Aliases for CTNNB 1 Gene" available at
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`www.genecards.org/cgi-bin/carddisp.pl?gene=CTNNBl (last checked November 12, 2015).
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`-6-
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`Docket No. 37901-715.305
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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 8 of 13
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`U.S. Serial No. 14/187,015
`Response to Non-Final Office Action of June 16, 2015
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`Accordingly, Applicant respectfully requests that the Examiner acknowledge the priority of the
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`instant claims to be at least as early as parent application no. 12/658,770, which was filed February 12,
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`2010.
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`Applicant notes that the claims were written to recite PIK3CA and CTNNB 1 as these have
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`become the preferred names for these biomarkers in the relevant fields, as evidenced by references to the
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`links to the Genecard database references above. However, Applicant will amend the claims to recite the
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`aliases PI3K and beta-catenin, respectively, if the Examiner requires such amendment in order to restore
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`priority.
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`IV. Claim Rejections under 35 U.S.C. § 101
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`The Examiner rejected claims 1-24 under 35 U.S.C. § 101 as allegedly "directed to a judicial
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`exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more."
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`Office Action, p. 3. The Examiner alleges that the claims comprises "computational steps[, which] are an
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`abstract idea. Thus, the instant claims are drawn to a judicial exception of an abstract idea." Id. at p. 4.
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`The Examiner reasons that "[t]he device and different assays, recited in the instant claims, are routine,
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`conventional and well-known data gathering steps" and that "[s]uch routine, conventional, and well(cid:173)
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`known data gathering steps are not sufficient to transform an abstract idea into patent eligible subject
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`matter." Id. The Examiner also states that "generic computer system is also not sufficient to transform the
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`claimed abstract idea into patent eligible subject matter." Id. Applicant respectfully traverses the rejection.
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`On December 16, 2014, the USPTO guidance issued updated guidelines for determining subject
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`matter eligibility under 35 U.S.C. 101 in view ofrecent decisions by the U.S. Supreme Court (the
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`"Guidance"). The Guidance provides "a number of considerations [identified by the Supreme Court] for
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`determining whether a claim with additional elements amounts to significantly more than the judicial
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`exception itself." Guidance, p. 21. In the instant application, the claims provide "[i]mprovements to
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`another technology or technical field" and thus recite eligible subject matter. See id. at p. 21 (citation
`
`removed).
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`Applicant submits herewith a Declaration under 37 CFR § 1.132 from medical oncologist
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`Sandeep K. Reddy, M.D. (the "Reddy Declaration"). In the declaration, Dr. Reddy states that the system
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`of the invention has been implemented in the real world and used to assist treating physicians in the care
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`of lung cancer patients by suggesting therapeutic agents as having likely benefit for those patients. See
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`-7-
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`Docket No. 37901-715.305
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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 9 of 13
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`U.S. Serial No. 14/187,015
`Response to Non-Final Office Action of June 16, 2015
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`Reddy Declaration, iii! 5-6. The Reddy Declaration provides evidence that the claimed invention effects
`an improvement in the treatment of lung cancer victims. See id.
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`Accordingly, Applicant submits evidence herewith that the claimed system provides an
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`improvement in another technology or technical field, namely in the medical field and specifically in the
`treatment oflung cancer victims. See Reddy Declaration, if 7. Accordingly, the claims recite
`"significantly more" than any alleged judicial exception. See Guidance, p. 21. Applicant respectfully
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`requests that the Examiner reconsider and withdraw this rejection.
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`V. Claim Rejections under 35 U.S.C. § 103(a)
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`The Examiner rejected claims 1-22 as allegedly unpatentable under pre-AIA 35 U.S.C. 103(a)
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`over Lancaster et al. (US 200710172844 Al) in view of Fritz et al. (US 2011/0118298 Al) in view of
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`Halbert et al. (US 2013/0287772 Al). Office Action, p. 5. Applicant respectfully traverses the rejection.
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`The Examiner alleges that the primary reference Lancaster recites various components of a
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`system such as recited by the claimed invention but admits that Lancaster et al. fail to disclose "where the
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`molecular targets are PTEN, CTNNBl, cKIT, BRAF, PIK3CA, KRAS, or RRMl." Office Action, pp. 5-
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`6. However, the Examiner alleges that Fritz et al. supplies "a method that uses lung cancer biomarkers
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`that include PTEN, CTNNBl, BRAF, PIK3CA, and KRAS (paragraphs 0036 and 0047)" and other assay
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`components. Id. at p. 6. The Examiner further admits that "neither Fritz et al. nor Lancaster et al. teach
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`where the lung cancer biomarkers include cKIT, RRMl or KRAS. Id. However, the Examiner alleges that
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`"Halbert et al. teach a method that uses lung cancer biomarkers that includes PTEN, KRAS, BRAF,
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`PIK3CA, cKIT, and RRMl (paragraphs 0031, 0403, 0404, and 0935)." Id. at p. 7. The Examiner
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`concludes that "one of ordinary skill in the art would have used the markers of Fritz et al. and Halbert et
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`al. in the method of Lancaster et al. to determine if a lung cancer patient would respond to a particular
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`therapy." Id.
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`As noted above, the priority of the instant claims is at least as early as parent application no.
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`12/658,770, which was filed February 12, 2010. Fritz et al. was filed November 12, 2010 and is therefore
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`not prior art to the instant application. Fritz et al. claims the benefit of priority to several U.S. provisional
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`patent applications, two of which were filed before February 12, 2010: U.S. Provisional Patent
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`Applications 61/261,064, filed November 13, 2009; and 61/283,150, filed November 30, 2009.
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`Examination of these priority documents reveals that neither recites any of PTEN, CTNNBl, BRAF or
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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 10 of 13
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`U.S. Serial No. 14/187,015
`Response to Non-Final Office Action of June 16, 2015
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`PIK3CA, and KRAS is only mentioned in passing on p. 101 of application no. 61/283, 150. Accordingly,
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`Fritz et al. is not prior art for that for which it is cited.
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`Halbert et al. was filed March 1, 2011 and has an earliest priority date of March 1, 2010.
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`Accordingly, Halbert et al. is not prior art to the claimed invention.
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`As the Examiner admits that Lancaster et al. fail to disclose "where the molecular targets are
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`PTEN, CTNNBl, cKIT, BRAF, PIK3CA, KRAS, or RRMl" and neither Fritz et al. nor Halbert et al. are
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`prior art, Applicant respectfully requests that the Examiner withdraw this rejection and issue all claims to
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`allowance.
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`CONCLUSION
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`Applicant submits that this Response fully addresses the Non-Final Office Action dated June 16,
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`2015. Applicant believes that the pending claims are under condition for allowance. Applicant
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`respectfully solicits the Examiner to expedite the prosecution of this patent application to issuance.
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`FEE AUTHORIZATION
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`The Commissioner is authorized to charge any additional fees which may be required, including
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`petition fees and extension of time fees, to Deposit Account No. 50-4961 (Docket No. 37901-715.305).
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`Respectfully submitted,
`
`CARIS MPI, INC.
`
`/Ramin Akhavan/
`Ramin Akhavan
`Registration No. 58,120
`
`Date: November 16 2015
`
`Caris MPI, Inc.
`6655 N. MacArthur Blvd.
`Irving, TX 75039
`Customer No. 96600
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`-9-
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`Docket No. 37901-715.305
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`

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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 11 of 13
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`Confirmation No.: 5406
`
`Inventors: Daniel D. VON HOFF et al.
`
`Group Art Unit: 1631
`
`Serial No.: 14/187,015
`
`Examiner: LIN, JERRY
`
`Filed: February 21, 2014
`
`Customer No. 96600
`
`For: MOLECULAR PROFILING OF TUMORS
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-14 5 0
`
`DECLARATION OF SANDEEP K. REDDY, M.D., UNDER 37 CFR § 1.132
`
`I, Sandeep K. Reddy, M.D., declare and state that:
`
`1. I am a Medical Oncologist and am board certified in Medical Oncology by the American
`
`Board oflnternal Medicine. I have practiced in this field for over 12 years and have
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`prescribed chemotherapeutic treatment for hundreds of patients. I recently left my personal
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`practice to serve as Senior Vice President and Chief Medical Officer of Caris MPI, Inc.
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`("Caris"), the Assignee of the above referenced patent application.
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`2. Prior to my current position at Caris, I was Chief of Staff at Los Alamitos Medical Center
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`and actively practiced clinical hematology and oncology. I hold an adjunct faculty position at
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`the Geffen/UCLA School of Medicine as a clinical instructor at Harbor-UCLA Medical
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`Center, where I was awarded the distinguished teaching award for clinical faculty in 2006. I
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`am a member of the Los Angeles Biomedical Institute, American Society of Clinical
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`Oncology (ASCO), and International Association for the Study of Lung Cancer (IASLC). My
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`medical training includes a fellowship in hematology and medical oncology and therapeutics
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`research at the City of Hope National Medical Center, and Internal Medicine residency at
`Attorney Docket No. 37901-715.305
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`

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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 12 of 13
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`U.S. Serial No. 14/187,015
`Response to Non-Final Office Action dated June 16, 2015
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`Harbor-UCLA Medical Center. I received my M.D. from the Geffen/UCLA School of
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`Medicine after receiving my B.S. in biomedical sciences at the University of California,
`
`Riverside.
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`3. I have reviewed the pending claims and Office Action mailed on June 16, 2015 (the "Office
`
`Action"). The invention is directed to a system for generating a report identifying a
`
`therapeutic agent for an individual with lung cancer. The system includes a device configured
`
`to assay the biomarkers PTEN, CTNNBl, cKIT, BRAF and PIK3CA and computer
`
`instructions to identify at least one therapeutic agent based on the assay results. The system
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`also includes computer instructions to generate a report identifying the therapeutic agent of
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`likely benefit.
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`4. It is my understanding that the claimed invention was rejected in part as abstract. Office
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`Action, pp. 3-4. However, I believe that the claimed invention provides a concrete
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`improvement in the practice of medicine by identifying therapeutic agents that are of likely
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`benefit to an individual with lung cancer.
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`5. Caris provides a tumor molecular profiling service known as Caris Molecular Intelligence TM
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`("CMI"). The CMI service includes devices to assay the biomarkers PTEN, CTNNBl, cKIT,
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`BRAF and PIK3CA in a sample from an individual with lung cancer, and computer
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`technology to identify therapeutic agents of likely benefit for the lung cancer based on the
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`assay results and to generate a report identifying such therapeutic agents. Thus, this system
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`includes the components in the claimed invention.
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`6. To date, Caris has performed the CMI service on over 75,000 cancer patient samples,
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`including thousands of lung cancer samples. We have assayed PTEN, CTNNBl, cKIT,
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`BRAF and PIK3CA in lung cancers, and have used these results in providing reports to
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`treating physicians that recommend therapeutic agents as having likely benefit or lack of
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`benefit for the patients. Indeed, treating physicians have used these reports in the real world
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`to assist in the treatment of their cancer patients.
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`-2-
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`Attorney Docket No. 37901-715.305
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`Case 1:17-cv-12194-MLW Document 32-3 Filed 03/01/18 Page 13 of 13
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`U.S. Serial No. 14/187,015
`Response to Non-Final Office Action dated June 16, 2015
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`7. In sum, it is my expert medical opinion that the system of the claimed invention provides
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`improvements in the practice of medicine by identifying therapeutic agents that are of likely
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`benefit to an individual with lung cancer. This result cannot be determined by mere
`
`phenotypic parameters and can only be determined using the specific analytes and
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`informatics contained within the invention.
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`8. I declare that all statements made herein of my own knowledge are true and that all
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`statements were made on information and belief are believed to be true; and further that these
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`statements were made with the knowledge that willful false statements and the like to made
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`are punishable by fine or imprisonment, or both, under 18 U.S.C. § 1001 and that willful
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`false statements may jeopardize the validity of this application and any patent issuing
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`therefrom.
`
`Sandeep K. Reddy, M.D.
`
`Signed this day 13 ofNovember, 2015
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`-3-
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`Attorney Docket No. 37901-715.305
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