`
`UNITED STATES PATENT AND TRADEMARK OFFIGE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`!
`OX.
`Address: COMMISSIONER FOR PATENTS
`Alexandria, Virginia 22313-1450
`www.uspto.gov
`
`APPLICATION
`NUMBER
`
`FILING or
`371(c) DATE
`
`GRP ART
`UNIT
`
`
`
`
`
`FIL
`
`62/169,112
`
`06/01/2015
`
`FEE REC'D
`
`130
`
`72960
`
`9978DEMINGWAY, SUITE 310
`
`MIDDLETON, WI 53562
`
`ATTY.DOCKET.NO
`
`ITOT CLAIMSJIND CLAIMS
`
`UCHI-34458/US-1/PRO
`
`CONFIRMATION NO. 3728
`FILING RECEIPT
`
`NDAO.40
`
`Date Mailed: 06/11/2015
`
`It will not be examined for patentability and will
`Receipt is acknowledged of this provisional patent application.
`become abandonednotlater than twelve monthsafter its filing date. Any correspondence concerning the application
`mustinclude the following identification information: the U.S. APPLICATION NUMBER, FILING DATE, NAME OF
`APPLICANT, and TITLE OF INVENTION. Feestransmitted by checkor draft are subject to collection. Please verify
`the accuracy of the data presented on this receipt. If an error is noted on this Filing Receipt, please submit
`a written request for a Filing Receipt Correction. Please provide a copy of this Filing Receipt with the
`changes noted thereon. If you received a "Notice to File Missing Parts" for this application, please submit
`any corrections to this Filing Receipt with your reply to the Notice. When the USPTO processesthe reply
`to the Notice, the USPTO will generate another Filing Receipt incorporating the requested corrections
`
`Inventor(s)
`
`Applicant(s)
`
`Thomas F. Gajewski, Chicago, IL;
`Ayelet Sivan, Chicago, IL;
`Leticia Corrales, Chicago, IL;
`
`The University of Chicago, Chicago, IL
`Powerof Attorney:
`David Staple--65903
`
`Permission to Access - A proper Authorization to Permit Access to Application by Participating Offices
`(PTO/SB/39 or its equivalent) has been received by the USPTO.
`
`If Required, Foreign Filing License Granted: 06/10/2015
`
`The country code and number of your priority application, to be usedfor filing abroad under the Paris Convention,
`is US 62/169,112
`
`Projected Publication Date: None, application is not eligible for pre-grant publication
`
`Non-Publication Request: No
`
`Early Publication Request: No
`** SMALL ENTITY **
`Title
`
`TREATMENT OF CANCER BY MANIPULATION OF COMMENSAL MICROFLORA
`
`Statement under 37 CFR 1.55 or 1.78 for AIA (First Inventor to File) Transition Applications: No
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`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
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`Since the rights granted by a U.S. patent extend only throughout the territory of the United States and have no
`effect in a foreign country, an inventor who wishes patent protection in another country must apply for a patent
`in a specific country or in regional patent offices. Applicants may wish to consider thefiling of an international
`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
`of patent applications on the same invention in member countries, but does notresult in a grantof "an international
`patent" and doesnoteliminate the needof applicantsto file additional documents and fees in countries where patent
`protection is desired.
`
`Almost every country has its own patent law, and a person desiring a patent in a particular country must make an
`application for patent in that country in accordancewith its particular laws. Since the laws of many countries differ
`in various respects from the patent law of the United States, applicants are advised to seek guidance from specific
`foreign countries to ensure that patent rights are not lost prematurely.
`
`Applicants also are advised that in the case of inventions madein the United States, the Director of the USPTO must
`issue a license before applicants can apply for a patent in a foreign country. Thefiling of a U.S. patent application
`serves as a request for a foreign filing license. The application's filing receipt contains further information and
`guidance asto the status of applicant's license for foreign filing.
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`Applicants may wish to consult the USPTO booklet, "General Information Concerning Patents”(specifically, the
`section entitled "Treaties and Foreign Patents") for more information on timeframes and deadlinesfor filing foreign
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`For information on preventing theft of your intellectual property (patents, trademarks and copyrights), you may wish
`to consult the U.S. Government website, http:/Avww.stopfakes.gov. Part of a Department of Commerceinitiative,
`this website includes self-help "toolkits" giving innovators guidance on how to protectintellectual property in specific
`countries such as China, Korea and Mexico. For questions regarding patent enforcementissues, applicants may
`call the U.S. Governmenthotline at 1-866-999-HALT (1-866-999-4258).
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`LICENSE FOR FOREIGN FILING UNDER
`
`Title 35, United States Code, Section 184
`
`Title 37, Code of Federal Regulations, 5.11 & 5.15
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`GRANTED
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`The applicant has been granted a license under 35 U.S.C. 184,
`LICENSE GRANTED"followed by a date appears on this form. Such licenses are issuedin all applications where
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`set forth in 37 CFR 5.15. The scope andlimitations of this license are set forth in 37 CFR 5.15(a) unless an earlier
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`This licenseis to be retained by the licensee and maybe usedat any time onor after the effective date thereof unless
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`The grantof a license doesnot in any way lessen the responsibility of a licensee for the security of the subject matter
`as imposed by any Governmentcontract or the provisions of existing laws relating to espionage and the national
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`respect to certain countries, of other agencies, particularly the Office of Defense Trade Controls, Department of
`State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Bureau of Industry and
`Security, Department of Commerce (15 CFR parts 730-774); the Office of Foreign AssetsControl, Department of
`Treasury (31 CFR Parts 500+) and the Department of Energy.
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`NOT GRANTED
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`No license under 35 U.S.C. 184 has been granted at this time, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" DOESNOTappear on this form. Applicant maystill petition for a license under 37 CFR 5.12,
`if a license is desired before the expiration of 6 months from thefiling date of the application. If 6 months has lapsed
`from thefiling date of this application and the licensee has not received any indication of a secrecy order under 35
`U.S.C. 181, the licensee mayforeign file the application pursuant to 37 CFR 5.15(b).
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`
`SelectUSA
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`The United States represents the largest, most dynamic marketplace in the world and is an unparalleled location for
`businessinvestment, innovation, and commercialization of new technologies. The U.S. offers tremendous resources
`and advantages for those who invest and manufacture goods here. Through SelectUSA, our nation works to
`promote andfacilitate business investment. SelectUSAprovides information assistance to the international investor
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`PTO/AIA/14 (07-14)
`Approved for use through 04/30/2017. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection ofinformation unless it contains a valid OMB control number.
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` .
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`. Attorney Docket Number|UCHI-34458/US-1/PRG
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`Application Data Sheet 37 CFR 1.76
`
`Application Number
`
`
`
`
`
`
`
`Title of Invention|TREATMENT OF CANCER BY MANIPULATION OF COMMENSAL MICROFLORA
`
`The application data sheetis part of the provisional or nonprovisional application for whichit is being submitted. The following form contains the
`bibliographic data arranged in a format specified by the United States Patent and Trademark Office as outlined in 37 CFR 1.76.
`This document may be completed electronically and submitted to the Office in electronic format using the Electronic Filing System (EFS) or the
`document may be printed and included in a paper filed application.
`
`Secrecy Order 37 CFR 5.2
`Oo Portions or all of the application associated with this Application Data Sheet may fall under a Secrecy Order pursuantto
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`Inventor Information:
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`Inventor
`Legal Name
`
`Prefix) Given Name
`Middle Name
`Family Name
`Suffix
`
`1
`
`
`Residence Information (Select One)
`(e) US Residency
`©) NonUS Residency
`() Active US Military Service
`
`Mailing Addressof Inventor:
`
`Address 1
`
`Address 2
`
`5801 S. Ellis Avenue
`
`Postal Code
`
`60637
`
`US
`
`2
`Inventor
`
`Legal Name
`
`
`
` Ayelet Sivan
`Residence Information (Select One)
`(@} US Residency
`©) NonUS Residency
`() Active US Military Service
`
`
`City|Chicago State/Province|IL Country of Residence i|US
`
`
`
`Mailing Address of Inventor:
`
`
`
` 5801 S. Ellis Avenue
`Address 1
`
`Address 2
`
`
`Postal Code
`
`60637
`
`Inventor
`Legal Name
`
`3
`
`Middle Name Family NamePrefix) Given Name Suffix
`
`
`Leticia
`Corrales
`Residence Information (Select One)
`©) NonUSResidency
`EFS Web 2.2.12
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`
`(@) US Residency
`
`() Active USMilitary Service 1012)
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`PTO/AIA/14 (07-14)
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`Underthe Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
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`
`Application Data Sheet 37 CFR 1.76
`
`
`
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`
`TREATMENT OF CANCER BY MANIPULATION OF COMMENSAL MICROFLORA
`Title of Invention
`
`
`
`
`
`City | Country of Residencei|US Chicago | State/Province | IL
`
`Application Number
`
`Mailing Address of Inventor:
`Address 1
`5801 S. Ellis Avenue
`
`
`
`Address 2
`
`Postal Code
`
`60637
`
`
`
`
`
`
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`Inventor Information blocks may be
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`For further information see 37 CFR 1.33(a}.
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`[|]An Addressis being provided for the correspondence Information of this application.
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`72960
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`Email Address
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`docketing@casimirjones.com
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`Application Information:
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`Title of the Invention
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`TREATMENT OF CANCER BY MANIPULATION OF COMMENSAL MICROFLORA
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`Attorney Docket Number| UCHI-34458/US-1/PRO
`
`Small Entity Status Claimed
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`Application Type
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`Provisional
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`Subject Matter
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`Utility
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`7Total Numberof Drawing Sheets (if any) Suggested Figure for Publication {if any)
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`provided in the appropriate section(s) below (i.e., "Domestic Benefit/National Stage Information” and “Foreign Priority Information’).
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`For the purposesof a filing date under 37 CFR 1.53(b), the description and any drawings of the present application are replaced by this
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`[_] Request Early Publication (Fee required at time of Request 37 CFR 1.219)
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`35U.S.C. 122(b) and certify that the invention disclosed in the attached application has not and will not be the
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`Application Data Sheet 37 CFR 1.76
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`— Title of Invention|TREATMENT OF CANCER BY MANIPULATION OF COMMENSAL MICROFLORA
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`Representative Information:
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`Representative information should be provided for all practitioners having a power of attorney in the application. Providing
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`72960
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`Application Data Sheet 37 CFR 1.76
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`— Title of Invention|TREATMENT OF CANCER BY MANIPULATION OF COMMENSAL MICROFLORA
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`Statement under 37 CFR 1.55 or 1.78 for AIA (First Inventor to File) Transition
`Applications
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`This application (1) claims priority to or the benefit of an application filed before March 16, 2013 and (2) also
`contains, or contained at any time, a claim to a claimed invention that has an effective filing date on or after March
`[] 16, 2013.
`NOTE: Byproviding this statement under 37 CFR 1.55 or 1.78, this application, with a filing date on or after March
`16, 2013, will be examined underthefirst inventorto file provisions of the AIA.
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`Authorization to Permit Access:
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`If checked, the undersigned hereby grants the USPTO authority to provide the European Patent Office (EPO),
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`is filed access to the instant patent application. See 37 CFR 1.14(c) and (h). This box should not be checkedif the applicant
`does not wish the EPO, JPO, KIPO, WIPO, or otherintellectual property office in which a foreign application claiming priority
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`In accordance with 37 CFR 1.14(h)(3), access will be provided to a copy of the instant patent application with respect
`to: 1) the instant patent application-as-filed; 2) any foreign application to which the instant patent application
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`©)_Joint Inventor OQ Assignee
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`PTO/AIA/14 (07-14)
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`Underthe Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
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`Application Data Sheet 37 CFR 1.76
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` The Privacy Act of 1974 (P.L. 93-579) requires that you be given certain information in connection with your submission of the attached form related toGenomeEx. 1012
`
`EFS Web 2.2.12
`
`Page 10 of 68
`
`Genome Ex. 1012
`Page 10 of 68
`
`
`
`FIG. 1
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`th. ame
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`1/7
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`GenomeEx. 1012
`Page 11 of 68
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`Genome Ex. 1012
`Page 11 of 68
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`
`
`FIG.2
`
`2ez<
`
`ChIAN toc
`
`%
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`ae
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`8
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`Day Pow
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`BEARAAGR
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`2/7
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`GenomeEx. 1012
`Page 12 of 68
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`Genome Ex. 1012
`Page 12 of 68
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`GenomeEx. 1012
`Page 13 of 68
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`Genome Ex. 1012
`Page 13 of 68
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`
`
`FIG. 4
`
`2ODLYcatyeccccccceencesece
`
`PRR
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`AMM
`
`pW
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`Jeevel
`
`4/7
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`GenomeEx. 1012
`Page 14 of 68
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`Genome Ex. 1012
`Page 14 of 68
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`
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`
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`
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`
`
`FIG. 5
`
`
`
`a = RWWAX
` BI6.SIY
`
`
` Day 7
`Day24
`IFN-y ELISPOT SIY Pentarner
`SY Pentarner
`
`fewwwwwwes TUM! Grawth ~owwrrre}
`
`Cc
`
`2%SIY*ofCD8*Tcelis
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`
`
`
`
`TumorVolume(mm)
`
`he TAC feces
`
`te JAX feces 7
`
`21
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`14
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`DayPost Injection
`
`;
`35
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`30
`
` SEEREEREEE
`%SIY*ofCD&"*Tcells
`EEEEEEEEEEEEEEEEEEEEEEEEEE! XN
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`5/7
`
`GenomeEx. 1012
`Page 15 of 68
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`Genome Ex. 1012
`Page 15 of 68
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`
`
`FIG.6
`
`Cc
`
`80
`a0
`
`20
`
`40
`8
`
`
`
`
`2000-4}Untreated
`OBIF
`MR ie oe OE
`
`JAX feces
`Heatinactvated
`= 15004}
`M® Heat killed BIF
`2
`5S
`2
`500
`5
`
`31000
`one
`
`;
`
`/
`
`r
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`Day postinjection
`
`10%
`
`107
`
`Tati
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`Serial Dilution
`
`F
`
`S000 gy Untreated
`
`seek
`
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`AD
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`Day postinjection
`
`A
`
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`Daypostinjection
`
`6/7
`
`GenomeEx. 1012
`Page 16 of 68
`
`B
`
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`mR
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`
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`TumorValume(mm) fe
`
`aK
`0.020q Ey py
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`0.060
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`
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`} JAX feces
`40004
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`3000
`
`2000:
`
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`A 2 ey
`Day postinjection
`
`on Qo
`
`
`
`Relativeabundance
`
`%SIY*ofCD8*Tcells
`
`
`
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`
`TumorVolume(mm?)
`
`80009 4 Untreated
`<>BIF
`DQ3S2
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`Genome Ex. 1012
`Page 16 of 68
`
`
`
`FIG. 7
`
`0
`Adoptive transfer of
`1x10°CFSE-abeled
`CD8'CD45.1:CD45.2'
`2C T cells into CD45.2>
`B6 mise
`
`1
`Subcutaneos
`engraftment of
`1x10" BI6.SIY
`calls
`
`7
`Stimulation of whole
`spleen and TdLN cells
`ex vive with SIY
`peptide; measurement
`of IFN-y
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`
`
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`
`
`7/7
`
`GenomeEx. 1012
`Page 17 of 68
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`Genome Ex. 1012
`Page 17 of 68
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`
`
`Attorney Docket No. UCHI-34458/US-1/PRO
`
`TREATMENT OF CANCER BY MANIPULATION OF COMMENSAL MICROFLORA
`
`FIELD
`
`Provided herein are methodsof treatment and/or prevention of cancer by manipulation of
`
`commensal microflora. In particular, the amount, identity, presence, and/or ratio of microflora
`
`(e.g., gut microflora) in a subject is manipulated to facilitate one or more co-treatments.
`
`BACKGROUND
`
`Harnessing the host immunesystem constitutes a promising approach for the treatment of
`
`10
`
`cancer becauseofits potential to specifically target tumor cells while limiting harm to normal
`
`tissue, with durability of benefit associated with immunologic memory. Enthusiasm has been
`
`fueled by recent clinical success, particularly with antibodies that block immuneinhibitory
`
`pathways, specifically CTLA-4 and the PD-1/PD-L1 axis (Hodi et al. The New England journal
`
`of medicine 363, 711-723 (2010).; Hamid et al. The New England journal of medicine 369, 134-
`
`15
`
`144 (2013).; herein incorporated by referencein their entireties). Early data have indicated that
`
`clinical responses to these immunotherapies are more frequent in patients who show evidence of
`
`an endogenous T cell response ongoing in the tumor microenvironmentat baseline (Tumehetal.
`
`Nature 515, 568-571 (2014).; Spranger et al. Science translational medicine 5, 200ral116 (2013).;
`
`Ji et al. Cancer immunology, immunotherapy : CI 61, 1019-1031 (2012).; Gajewskietal.
`
`20
`
`Cancer journal 16, 399-403 (2010).; herein incorporated by referencein their entireties). Despite
`
`the functional and clinical importance ofthis T cell-inflamed tumor microenvironment, the
`
`mechanismsthat govern the presence or absenceof this phenotype have not been well
`
`understood. Theoretical sources of inter-patient heterogeneity include germline genetic
`
`differencesat the level of the host, variability in patterns of somatic alterations in tumorcells,
`
`25
`
`and environmental differences with the potential to impact on systemic i