Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MILTENYI BIOMEDICINE GmbH and MILTENYI BIOTEC INC.
`Petitioner
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`v.
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`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`Patent Owner
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`IPR Trial No. IPR2022 -
`U.S. Patent No. 9,464,140
`Issue Date: October 11, 2016
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`Title: Compositions and Methods for Treatment of Cancer
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`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,464,140
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`

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`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
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`Table of Contents
`INTRODUCTION ........................................................................................... 1
`I.
`II. MANDATORY NOTICES ............................................................................. 3
` Notice of Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) .................... 3
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) .............................. 3
`
`Designation of Lead and Back-Counsel (37 C.F.R. § 42.8(b)(3)) ........ 3
`
`Service Information (37 C.F.R. § 42.8(b)(4)) ....................................... 3
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`Power of Attorney ................................................................................. 4
`
`PAYMENT OF FEES (37 C.F.R. § 42.103) ................................................... 4
`III.
`IV. REQUIREMENTS UNDER §§ 42.104 AND 42.108 ..................................... 4
` Grounds for Standing (§ 42.104(a)) ...................................................... 4
`Grounds of Challenge (§ 42.104(b)) ..................................................... 4
`
`Requirements for IPR (§ 42.108(c)) ...................................................... 5
`
`PRIORITY DATE ........................................................................................... 5
`V.
`VI. TECHNOLOGY BACKGROUND ................................................................. 6
`T Cells ................................................................................................... 6
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`CAR T Cells .......................................................................................... 7
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`Engineering CAR T Cells ..................................................................... 8
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`VII. PERSON OF ORDINARY SKILL IN THE ART ........................................10
`VIII. THE ’140 PATENT .......................................................................................10
`IX. CLAIM CONSTRUCTION ..........................................................................11
`Preamble – “treating cancer” ............................................................... 11
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`“Anti-tumor effective amount” ........................................................... 13
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`PRIOR ART ...................................................................................................15
`Campana .............................................................................................. 15
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`Sequence Art ....................................................................................... 17
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` Milone.................................................................................................. 18
`CART-19 ClinicalTrials.gov ............................................................... 19
`
`Porter ................................................................................................... 19
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`X.
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`- i -
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`

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`b.
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`XI. GROUND 1: INDEPENDENT CLAIM 1 AND DEPENDENT
`CLAIMS 2, 6, 8-9, 11, 16, 21-22, AND 27-28 ARE RENDERED
`OBVIOUS BY CAMPANA IN VIEW OF NICHOLSON, HONSIK,
`AND CART-19 CLINICALTRIALS.GOV ..................................................20
`Independent Claim 1 ........................................................................... 20
`
`1.
`Claim Limitations Directed to the Structure of the
`Claimed CAR T Cell ................................................................. 22
`a.
`“[d] wherein T cells comprise a nucleic acid
`sequence encoding a chimeric antigen receptor
`(CAR)” ............................................................................22
`“[e] wherein the CAR comprises a CD19 antigen
`binding domain comprising, from the amino to the
`carboxy terminus, a light chain variable region and
`a heavy chain variable region of SEQ ID NO: 20” ........23
`“[f] wherein the CAR further comprises a
`transmembrane domain, a 4-1BB costimulatory
`signaling region, and a CD3 zeta signaling
`domain” ...........................................................................27
`Claim Limitations Directed to a Method of Treating
`Cancer Comprising Administering a Pharmaceutical
`Composition Compromising an Anti-tumor Effective
`Amount of a Population of Human T cells ............................... 28
`a.
`Preamble of “[a] method of treating cancer in a
`human patient” ................................................................28
`“[b] administering to the human patient a
`pharmaceutical composition…” .....................................29
`“[c] anti-tumor effective amount of a population of
`human T cells” ................................................................30
`Dependent Claims ............................................................................... 38
`1.
`Claim 2: “anti-tumor effective amount of T cells is 104 to
`109 cells per kg body weight of a human in need of such
`cells” .......................................................................................... 38
`Claim 6: “wherein the transmembrane domain is CD8α
`transmembrane domain” ........................................................... 38
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`2.
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`2.
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`c.
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`b.
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`c.
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`- ii -
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`4.
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`5.
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`6.
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`3.
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`Claims 8 and 9: “wherein the CAR further comprises a
`hinge domain” and “wherein the hinge domain is a CD8α
`hinge domain” ........................................................................... 38
`Claims 11 and 16: “wherein the 4-1BB costimulatory
`signaling region comprises the amino acid sequence of
`SEQ ID NO: 23” and “wherein the 4-1BB costimulatory
`signaling region comprises the nucleic acid sequence of
`SEQ ID NO: 17” ....................................................................... 39
`Claims 21 and 22: “wherein the T cells are T cells of a
`human having a cancer” and “wherein the cancer is a
`hematological cancer” ............................................................... 39
`Claims 27 and 28: “wherein the pharmaceutical
`composition further comprises a pharmaceutically
`acceptable carrier, diluent or excipient” and “wherein the
`pharmaceutical composition comprises a buffer” ..................... 40
`XII. GROUND 2: INDEPENDENT CLAIM 1 AND DEPENDENT
`CLAIMS 2, 3, 6, 8-9, 11, 13, 16, 21-22, AND 27-28 ARE
`RENDERED OBVIOUS BY CAMPANA IN VIEW OF JENSEN,
`HONSIK, AND CART-19 CLINICALTRIALS.GOV .................................40
`Independent Claim 1 ........................................................................... 41
`
`1.
`([a]) “A method of treating cancer in a human patient” ........... 41
`2.
`([b]) “administering to the human patient a
`pharmaceutical composition” .................................................... 41
`([c]) “an anti-tumor effective amount of a population of
`human T cells,” ......................................................................... 42
`([d]) “wherein the T cells comprise a nucleic acid
`sequence encoding a chimeric antigen receptor (CAR),” ......... 43
`([e]) “wherein the CAR comprises a CD19 antigen
`binding domain comprising, from the amino to the
`carboxy terminus, a light chain variable region and a
`heavy chain variable region of SEQ ID NO:20” ...................... 43
`([f]) “wherein the CAR further comprises a
`transmembrane domain, a 4-1BB costimulatory signaling
`region, and a CD3 zeta signaling domain,” .............................. 46
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`3.
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`4.
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`5.
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`6.
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`- iii -
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`Dependent Claim 3: an “anti-tumor effective amount of T cells
`is 105 to 106 cells per kg body weight of a human in need of
`such cells” ............................................................................................ 46
`Dependent Claim 13: “wherein the CD19 antigen binding
`domain is encoded by a nucleic acid sequence comprising SEQ
`ID NO:14” ........................................................................................... 47
` Dependent Claims 2, 6, 8-9, 11, 16, 21-22, and 27-28 ....................... 49
`XIII. GROUND 3: ALL CHALLENGED CLAIMS ARE RENDERED
`OBVIOUS BY CAMPANA IN VIEW OF MILONE, CART-19
`CLINICALTRIALS.GOV, SEQUENCE ART (NICHOLSON,
`JENSEN, LITTMAN, SADELAIN), AND HONSIK ..................................49
`Claim 1 ................................................................................................ 50
`
`Dependent Sequence Claims ............................................................... 51
`
`1.
`Claims 7 and 14: “wherein the CD8α transmembrane
`domain comprises the amino acid sequence of SEQ ID
`NO: 22” and “wherein the CD8α transmembrane domain
`comprises the nucleic acid sequence of SEQ ID NO: 16,”
`respectively ............................................................................... 51
`Claim 10 and 15: “wherein the CD8α hinge comprises
`the amino acid sequence of SEQ ID NO: 21” or “wherein
`the CD8α hinge comprises the nucleic acid sequence of
`SEQ ID NO: 15” ....................................................................... 53
`Claims 12 and 17: “wherein the CD3 zeta signaling
`domain comprises the amino acid sequence of SEQ ID
`NO: 24” or “wherein the CD3 zeta signaling domain
`comprises the nucleic acid sequence of SEQ ID NO: 18”........ 56
`Claims 18 and 19: “wherein the CAR comprises amino
`acid sequence of SEQ ID NO: 12” or “wherein the CAR
`comprises nucleic acid sequence of SEQ ID NO: 8” ............... 57
`Dependent Vector/Promoter Claims ................................................... 58
`1.
`Claims 23 and 24: “wherein the T cells comprise a vector
`that comprises the nucleic acid sequence” or “wherein
`the vector is a lentiviral vector” ................................................ 58
`Claims 25 and 26: “wherein the vector further comprises
`a promoter” or “wherein the promoter is an EF-1α
`promoter” .................................................................................. 59
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`2.
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`2.
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`3.
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`4.
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`- iv -
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`2.
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`Remaining Challenged Claims ............................................................ 60
`
`XIV. GROUND 4: ALL CHALLENGED CLAIMS ARE RENDERED
`OBVIOUS BY CAMPANA, PORTER, SEQUENCE ART, AND
`HONSIK ........................................................................................................60
`Porter is Prior Art ................................................................................ 60
`
`1.
`Provisional Applications Do Not Provide Adequate
`Support for the Claims .............................................................. 61
`No Disclosure of SEQ NO: 20 in the Provisional
`Applications .............................................................................. 62
`All Challenged Claims are Rendered Obvious by Campana,
`Porter, Sequence Art, and Honsik ....................................................... 65
`1.
`Claims 4 and 5: “wherein the T cells are administered to
`the human patient in a single dose divided over three
`days where 10% of the cells are administered on the first
`day, 30% of the cells are administered on the second day
`and 60% of the cells are administered on the third day”
`and “[t]he method of claim 4, further comprising
`administration of a second dose of the cells to the human
`patient on the tenth day.” .......................................................... 68
`XV. 35 U.S.C. § 325(D) SHOULD NOT BAR THE PETITION ........................69
`XVI. CONCLUSION ..............................................................................................71
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Alcon Rsch. v. Apotex,
`687 F.3d 1362 (Fed. Cir. 2012) .................................................................... 14, 32
`Ariad Pharm. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) .......................................................................... 61
`Aspex Eyewear v. Marchon Eyewear,
`672 F.3d 1335 (Fed. Cir. 2012) .......................................................................... 11
`Catalina Mktg. v. Coolsavings.com,
`289 F.3d 801 (Fed. Cir. 2002) ................................................................ 11, 12, 13
`Fiers v. Revel,
`984 F.2d 1164 (Fed. Cir. 1993) .................................................................... 64, 65
`Genentech v. Chiron,
`112 F.3d 495 (Fed. Cir. 1997) ............................................................................ 26
`Genzyme Therapeutic Prods. v. Biomarin Pharm,
`825 F.3d 1360 (Fed. Cir. 2016) .......................................................................... 37
`Husky Injection Molding Sys. v. Athena Automation,
`838 F.3d 1236 (Fed. Cir. 2016) .......................................................................... 25
`KSR Int’l v. Teleflex,
`550 U.S. 398 (2007) ............................................................................................ 57
`Regents of the Univ. of Cal. v. Eli Lilly & Co.,
`119 F.3d 1559 (Fed. Cir. 1997) .......................................................................... 64
`TomTom v. Adolph,
`790 F.3d 1315 (Fed. Cir. 2015) .......................................................................... 12
`Trend Micro v. CUPP Computing AS,
`IPR2021- 00813 .................................................................................................. 70
`
`- vi -
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`
`Valeant Pharms. v. Mylan Pharms.,
`955 F.3d 25 (Fed. Cir. 2020) .............................................................................. 47
`Statutes
`35 U.S.C. § 103 ...................................................................................................... 1, 5
`35 U.S.C. § 314(a) ..................................................................................................... 5
`35 U.S.C. § 325(d) ....................................................................................... 70, 71, 72
`Other Authorities
`37 C.F.R. § 42.8 ..................................................................................................... 3, 4
`37 C.F.R. § 42.103 ................................................................................................. 4, 5
`37 C.F.R. § 42.104 ................................................................................................. 4, 5
`37 C.F.R. § 42.108 ................................................................................................. 4, 5
`37 C.F.R. § 42.15(a) ................................................................................................... 5
`45 C.F.R. § 46.111(a)(2) .......................................................................................... 36
`
`- vii -
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`
`I.
`
`INTRODUCTION
`Miltenyi Biomedicine GmbH and Miltenyi Biotec Inc. (collectively,
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`“Petitioner”) respectfully requests that the Board institute inter partes review (“IPR”)
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`and cancel claims 1-19 and 21-28 (“Challenged Claims”) of U.S. Patent 9,464,140
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`(“the ’140 patent,” Ex.1001). The ’140 patent is owned by The Trustees of the
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`University of Pennsylvania (“Patent Owner”). The Challenged Claims of the ’140
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`patent should be found unpatentable as obvious under pre-AIA 35 U.S.C. § 103.
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`All Challenged Claims are directed to a method of treating cancer comprising
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`administering an “anti-tumor effective amount” of chimeric antigen receptor
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`(“CAR”) T cells. Patent Owner did not invent the claimed CAR—a CAR with a
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`CD19 antigen binding domain, a transmembrane domain, a 4-1BB costimulatory
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`signaling region, and CD3-zeta (ζ) signaling domain. This CAR was fully disclosed
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`many years before—as “anti-CD19-BB-ζ”—in U.S. Patent Application Publication
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`No. US 2005/0113564
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`(“Campana”)
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`(Ex.1003).
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`Indeed,
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`the ’140 patent
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`specification credits prior-art authors for the claimed CAR.
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`The only information in the ’140 patent specification not expressly disclosed
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`by §102(b) prior art is initial results from a few patients in a clinical trial using the
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`aforementioned CAR. But this disclosure is insufficient to render non-obvious
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`method claims using an “an anti-tumor effective amount” of a prior-art CAR. An
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`“anti-tumor effective amount” is defined broadly in the specification as any amount
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`providing one of several possible biological effects, including “a decrease in the
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`number of tumor cells.” Ex.1001, 12:28–37. Here, the §102(b) prior art already
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`showed that the claimed CAR (1) killed human tumor cell lines in vitro;
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`(2) decreased the number of tumor cells in vivo in mouse xenograft studies (i.e., mice
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`with human tumor cells); and (3) was administered in an ongoing clinical trial at a
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`dose, 2.5×107 to 6.1×108 cells per kg, that falls within the range of the ’140 patent’s
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`own exemplar “anti-tumor effective amounts.” These prior art disclosures
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`demonstrate that a person of ordinary skill in the art (“POSA”) would reasonably
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`expect the prior-art CAR to at least produce “a decrease in the number of tumor
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`cells” at a dose taught in the prior art.
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`Alternatively, intervening prior art published by the inventors—David L.
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`Porter et al, Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid
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`Leukemia, 365 N. ENGL J. MED. 725 (2011) (“Porter”) (Ex.1012)—renders all
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`Challenged Claims obvious because the ’140 patent is not entitled to the priority
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`benefit of two provisional applications. Neither provisional application discloses the
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`amino acid sequence required by the sole independent claim. For this reason, the
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`Examiner found that the provisional applications “fail to provide adequate support
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`or enablement” and that the earliest possible priority date was December 9, 2011.
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`Petitioner agrees. Because Porter discloses the clinical use claimed in the ’140
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`patent, it renders all Challenged Claims obvious.
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`- 2 -
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`
`II. MANDATORY NOTICES
` Notice of Real Party-In-Interest (37 C.F.R. § 42.8(b)(1))
`Miltenyi Biomedicine GmbH and Miltenyi Biotec Inc. are real-parties-in-
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`interest.
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` Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`Petitioner is not aware of any related matters involving the ’140 patent. Along
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`with the instant Petition, Petitioner is filing petitions against related U.S. Pat. Nos.
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`9,540,445 and 9,518,123.
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` Designation of Lead and Back-Counsel (37 C.F.R. § 42.8(b)(3))
`LEAD COUNSEL
`BACKUP COUNSEL
`Yite John Lu (Reg. No. 63158)
`Gary N. Frischling (Reg. No. 35515)
`Milbank LLP, 2029 Century Park East,
`Milbank LLP, 2029 Century Park East,
`33rd Floor, Los Angeles, CA 90067
`33rd Floor, Los Angeles, CA 90067
`Tel. (424) 386-4318
`Tel. (424) 386-4316
`Fax. (213) 629-5063
`Fax. (213) 629-5063
`jlu@milbank.com
`gfrischling@milbank.com
`
`
`David I. Gindler (to be pro hac vice)
`Milbank LLP, 2029 Century Park East,
`33rd Floor, Los Angeles, CA 90067
`Tel. (424) 386-4313
`Fax. (213) 629-5063
`dgindler@milbank.com
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`
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`Service Information (37 C.F.R. § 42.8(b)(4))
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`A copy of this Petition, in its entirety, including all Exhibits and a Power of
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`Attorney, is being served by Priority Mail Express, costs prepaid, to the address of
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`- 3 -
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`the agent of record for the ’140 patent: Kathryn Doyle & Patent Docket Clerk, Saul
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`Ewing Arnstein & Lehr LLP, Centre Square West, 1500 Market Street, 38th Floor,
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`Philadelphia PA 19102-2186. Petitioner may be served at the addresses provided
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`above in Section II.C for lead and back-up counsel, and Petitioner consents to
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`electronic service at the above email addresses.
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`Power of Attorney
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`The Power of Attorney is filed concurrently with this petition per 37 C.F.R.
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`§ 42.10(b).
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`III. PAYMENT OF FEES (37 C.F.R. § 42.103)
`The required fees are submitted herewith in accordance with 37 C.F.R. §§
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`42.103(a) and 42.15(a). The Office is authorized to charge any additional fee that
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`might be due or required to Deposit Account No. 13-3250.
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`IV. REQUIREMENTS UNDER §§ 42.104 AND 42.108
` Grounds for Standing (§ 42.104(a))
`Petitioner certifies that the ’140 patent is available for inter partes review and
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`that Petitioner is not barred or otherwise estopped.
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` Grounds of Challenge (§ 42.104(b))
`Petitioner requests institution of IPR and a finding that the identified claims
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`of the ’140 patent are not patentable on the following grounds:
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`- 4 -
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`
`Ground Claims
`1-2, 6, 8-9, 11,
`1
`16, 21-22, 27-28
`
`1-2, 6, 8-9, 11,
`13, 16, 21-22,
`27-28
`All Challenged
`Claims
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`All Challenged
`Claims
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`2
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`3
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`4
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`
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`Basis
`Obvious under §103 over Campana in view of
`Nicholson, Honsik, and CART-19
`ClinicalTrials.gov
`Obvious under §103 over Campana in view of
`Jensen, Honsik, and CART-19
`ClinicalTrials.gov
`Obvious under §103 over Campana in view of
`Milone, CART-19 ClinicalTrials.gov,
`Sequence Art (Nicholson, Jensen, Littman,
`Sadelain), and Honsik
`Obvious under §103 over Campana in view of
`Porter, Sequence Art (Nicholson, Jensen,
`Littman, Sadelain), and Honsik
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`This Petition is supported by the Declaration of Dr. Richard Paul Junghans
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`(Ex.1002) (“Junghans”), an expert in the field of CAR T-cell therapy.
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` Requirements for IPR (§ 42.108(c))
`The Board should institute inter partes review because this Petition establishes
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`a reasonable likelihood of prevailing with respect to at least one Challenged Claim.
`
`See 35 U.S.C. § 314(a).
`
`V.
`
`PRIORITY DATE
`The ’140 patent
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`is a continuation of Nonprovisional Application
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`No. 13/992,622, which was
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`filed as PCT/US2011/064191
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`(Ex.1018) on
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`December 9, 2011. The ’140 patent claims priority to two provisional applications:
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`61/502,649 (“’649 application”) (Ex.1019), filed on June 29, 2011, and 61/421,470
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`(“’470 application”) (Ex.1020), filed on December 9, 2010. As discussed in
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`- 5 -
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`

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`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`Section XIV.A, the Examiner found, and Patent Owner did not disagree, that the
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`earliest priority date is December 9, 2011 because the two provisional applications
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`do not adequately support the claimed invention. Ex.1021, 224.1,2
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`VI. TECHNOLOGY BACKGROUND
`In the early 2000’s, scientists developed cancer treatments that involved
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`drawing out patients’ own T cells, engineering those cells to target tumors, and then
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`re-infusing those engineered cells back into the patients. This engineering process
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`involved inserting foreign DNA into the patients’ T cells so that these cells would
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`express a surface receptor that targeted an “antigen” found on cancer tumor cells.
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`Junghans, ¶¶36-38. This engineered receptor became known as a “chimeric antigen
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`receptor,” or CAR. Id., ¶¶31-32. And this type of therapy became known as CAR
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`T-cell therapy. Id., ¶35.
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` T Cells
`T cells are a type of lymphocyte and play a role in a person’s natural immune
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`response by attacking foreign threats, such as pathogens. Id., ¶¶23-25. They are able
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`to recognize and destroy pathogens through interactions between receptors on their
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`surface and antigens on the pathogen’s surface. Id., ¶¶25-26. These T-cell receptors
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`1 Pre-AIA versions of §102 and §103 apply.
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`2 Citations refer to original pagination unless absent.
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`(“TCR”) bind to the antigen, which in turn activates the T cell to secrete certain
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`chemicals that participate in the destruction of the pathogen. Id., ¶¶26-30.
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` CAR T Cells
`A chimeric antigen receptor, or CAR, is an engineered receptor on the surface
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`of a T cell that can bind to and destroy cancerous cells. Id., ¶¶31-32. The CAR
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`includes three basic components: (1) an antigen-binding domain on the extracellular
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`surface, e.g., a single-chain variable-fragment antibody (“scFv”) specific to a
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`tumor-associated antigen; (2) intracellular (also known as cytoplasmic) signaling
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`domains, such as CD3-zeta and 4-1BB signaling domains; and (3) a transmembrane
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`domain that connects the scFv to the intracellular domain. Id., ¶¶32-33. An
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`illustration of how a CAR is positioned on a T-cell surface is shown below:
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`
`Id., ¶51.
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`CAR T-cell therapies have been developed for hematological cancers such as
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`lymphoma and leukemia. Id., ¶34. Lymphoma and leukemia usually involve
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`cancerous B cells, which have on their surface an antigen known as CD19. Id. CAR
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`T-cell therapies directed at these cancers therefore involve modifying the patient’s
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`T cells to become CAR T cells that bind CD19 (a.k.a., anti-CD19 CAR) to destroy
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`cancerous B cells. Id.
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` Engineering CAR T Cells
`The first step in CAR T-cell therapy is to isolate natural T cells from the
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`patient through a process called leukapheresis (or apheresis). Id., ¶35. Next, nucleic
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`acid (DNA) sequences that encode each section of the CAR (e.g., anti-CD19 binding
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`domain, transmembrane domain, and signaling domains) are “stitched” together to
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`form one continuous DNA sequence and packaged into a viral vector. Id., ¶¶35-37.
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`A viral vector is a virus, like a retrovirus or lentivirus, that contains DNA in the form
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`of a plasmid, which is a circular DNA molecule, intended to be introduced into cells.
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`Id., ¶37. The viral vector with the CAR-encoding plasmid infects, also known as
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`transduces, the T cells with the CAR sequence. Id., ¶36.
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`
`
`
`Cellular machinery in the T cell transcribes the DNA into mRNA and then
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`translates the mRNA into the amino acids that form the CAR. This process is
`
`depicted below:
`
`
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`Id., ¶¶38-39. The CAR is a chain of amino acids that begins with the amino group
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`(the NH2) of the first amino acid and ends with the carboxyl group (the COOH) of
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`the last amino acid. Id., ¶¶38-41.
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`The CAR-transduced T cells are then allowed to multiply in the laboratory
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`before they are reintroduced into the cancer patient, where they can target and kill
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`cancer cells that they have been engineered to destroy. Id., ¶¶42-47.
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`
`VII. PERSON OF ORDINARY SKILL IN THE ART
`A POSA is a person skilled in the art of administering CAR T-cell therapies.
`
`The person would possess a relatively high level of skill and have at least an MD,
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`together with several years of experience in administering CAR T-cell therapies. The
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`person would also have experience designing CARs. The POSA would have
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`knowledge of the scientific literature pertaining to immunology, including CARs
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`and methods for utilizing CARs before the priority date. A POSA would also be
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`knowledgeable about laboratory techniques related to engineering and testing the
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`function of CAR T cells. A POSA would also be knowledgeable about designing
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`clinical trials, including selecting dose ranges, that evaluate CAR T-cell therapies.
`
`VIII. THE ’140 PATENT
`The ’140 patent is directed to a method of treating cancer with a
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`pharmaceutical composition comprising an anti-tumor effective amount of a
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`population of human T cells, where the T cells contain a CAR with specific domains.
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`Some dependent claims specify particular amino acid and nucleic acid sequences for
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`domains of the claimed CAR. Other dependent claims specify anti-tumor effective
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`dosing ranges, components used in DNA cloning, and particular components for the
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`pharmaceutical composition.
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`- 10 -
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`
`IX. CLAIM CONSTRUCTION
`Preamble – “treating cancer”
`
`The sole independent claim of the ’140 patent, claim 1, requires “[a] method
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`of treating cancer in a human patient comprising administering to the human patient
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`a pharmaceutical composition[.]” Ex.1001, claim 1.3 The phrase “treating cancer” in
`
`the preamble is not limiting.
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`“[A]s a general rule preamble language is not treated as limiting.” Aspex
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`Eyewear v. Marchon Eyewear, 672 F.3d 1335, 1347 (Fed. Cir. 2012). “[A] preamble
`
`is not limiting ‘where a patentee defines a structurally complete invention in the
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`claim body and uses the preamble only to state a purpose or intended use for the
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`invention.’” Catalina Mktg. v. Coolsavings.com, 289 F.3d 801, 808 (Fed. Cir. 2002).
`
`That is the situation here.
`
`The preamble language of “treating cancer” only states a purpose for the steps
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`articulated in the body of the claim. The body of the claim has an “administering to
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`the human patient a pharmaceutical composition” step, an “anti-tumor effective
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`amount” limitation, and a description of the CAR T cells to be administered.
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`Ex.1001, claim 1. This body of the claim provides a structurally complete invention.
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`This is consistent with the specification, which describes the steps of administering
`
`
`3 Bold italics in quotes and highlighting in figures denotes emphasis added.
`
`- 11 -
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`an effective amount of a CAR T cell, without more, as “thereby treating the
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`mammal”:
`
`Id., 3:7-13.
`
`In one embodiment, the method comprises administering
`to a mammal an effective amount of a cell genetically
`modified to express a CAR wherein the CAR comprises
`an antigen binding domain, a costimulatory signaling
`region, and a CD3 zeta signaling domain comprising the
`amino acid sequence of SEQ ID NO: 24, thereby treating
`the mammal.
`
`The preamble language of “treating cancer” does not recite any essential
`
`structure or steps, nor is it necessary to understanding the remaining limitations or
`
`terms in the claim body. None of the claims depends on the “treating cancer”
`
`preamble language for an antecedent basis. Therefore, the “treating cancer”
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`preamble language is not limiting.
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`Even if another part of the preamble, e.g., “a human patient,” is limiting
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`because it provides an antecedent basis, this does not indicate that the “treating
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`cancer” preamble language is limiting. See TomTom v. Adolph, 790 F.3d 1315,
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`1323–24 (Fed. Cir. 2015) (“That the phrase in the preamble ‘destination tracking
`
`system of at least one mobile unit’ provides a necessary structure for claim 1 does
`
`not necessarily convert the entire preamble into a limitation[.]”). That said, even this
`
`remaining part of the preamble, “a human patient,” does not add any patentable
`
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`

`

`Petition for Inter Partes Review of
`U.S. Patent No. 9,464,140
`weight because the claim body is fully understandable without the preamble. See
`
`Catalina Mktg. Int’l, 289 F.3d, 808.
`
`If the Board disagrees and finds that “treating cancer” is limiting, the term
`
`should be construed as requiring no greater efficacy than what is provided by the
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`claim body’s limitation of administering an “anti-tumor effective amount.” The
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`specification defines “to ‘treat’” as “to reduce the frequency or severity of at least
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`one sign or symptom of a disease or disorder.” Ex.1001, 18:18–20. A POSA would
`
`understand that in cancer patients, providing an “anti-tumor effect” is reducing the
`
`frequency or severity of a sign or symptom of cancer. Junghans, ¶¶54-55. Tumors
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`are a sign and symptom of cancer, and an “anti-tumor effect” is necessarily reducing
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`the frequency or severity of cancer. Id. Therefore, if found to be limiting, a method
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`of “treating cancer” does not require any greater efficacy than administering an
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`“anti-tumor effective amount” of T cells.
`
`“Anti-tumor effective amount”
`
`Claim 1 requires “a pharmaceutical composition comprising an anti-tumor
`
`effective amount of a population of human T cells.” The specification describes
`
`exemplary “anti-tumor effective amount[s]”: “It can generally be stated that a
`
`pharmaceutical composition comprising the T cells described herein m