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. 9,540,445
`Issue Date: January 10, 2017
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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. 9,540,445
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`Table of Contents
`INTRODUCTION ........................................................................................... 9
`I.
`II. MANDATORY NOTICES ...........................................................................11
` Notice of Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) .................. 11
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) ............................ 11
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`Designation of Lead and Back-Counsel (37 C.F.R. § 42.8(b)(3)) ...... 11
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`Service Information (37 C.F.R. § 42.8(b)(4)) ..................................... 12
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`Power of Attorney ............................................................................... 12
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`PAYMENT OF FEES (37 C.F.R. § 42.103) .................................................12
`III.
`IV. REQUIREMENTS UNDER §§ 42.104 AND 42.108 ...................................12
` Grounds for Standing (§ 42.104(a)) .................................................... 12
`Grounds of Challenge (§ 42.104(b)) ................................................... 13
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`Requirements for IPR (§ 42.108(c)) .................................................... 13
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`PRIORITY DATE .........................................................................................13
`V.
`VI. TECHNOLOGY BACKGROUND ...............................................................14
`T Cells ................................................................................................. 15
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`CAR T Cells ........................................................................................ 15
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`Engineering CAR T Cells ................................................................... 16
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`VII. PERSON OF ORDINARY SKILL IN THE ART ........................................18
`VIII. THE ’445 PATENT .......................................................................................19
`IX. CLAIM CONSTRUCTION ..........................................................................19
`“Anti-tumor effective amount” ........................................................... 19
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`PRIOR ART ...................................................................................................21
`Campana .............................................................................................. 21
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`Sequence Art ....................................................................................... 23
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` Milone.................................................................................................. 24
`CART-19 ClinicalTrials.gov ............................................................... 25
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`Porter ................................................................................................... 26
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`Select Art Teaching Pharmaceutical Compositions of T-Cell
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`Therapy ................................................................................................ 27
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`X.
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`Honsik ....................................................................................... 27
`1.
`Riddell ....................................................................................... 27
`2.
`XI. GROUND 1: INDEPENDENT CLAIM 1 AND DEPENDENT
`CLAIMS 2, 4, 6, 8-9, 11, 16, 21-22, AND 27-30 ARE RENDERED
`OBVIOUS BY CAMPANA IN VIEW OF NICHOLSON, HONSIK,
`AND CART-19 CLINICALTRIALS.GOV ..................................................28
`Independent Claim 1 ........................................................................... 28
`
`1.
`Claim Limitations Directed to the Structure of the
`Claimed CAR T Cell ................................................................. 30
`a.
`“[c] wherein T cells comprise a nucleic acid
`sequence encoding a chimeric antigen receptor
`(CAR)” ............................................................................30
`“[d] 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” ........31
`“[e] wherein the CAR further comprises a
`transmembrane domain, a 4-1BB costimulatory
`signaling region, and a CD3 zeta signaling
`domain” ...........................................................................35
`“[f] wherein the T cells are from a human having
`cancer” ............................................................................36
`Claim Limitations Directed to a Pharmaceutical
`Composition Compromising … an Anti-tumor Effective
`Amount ...................................................................................... 37
`a.
`Preamble of “[a] pharmaceutical composition…” .........37
`b.
`“anti-tumor effective amount” ........................................38
`Dependent Claims ............................................................................... 46
`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” .......................................................................................... 46
`Claim 4: “wherein said antigen binding fragment is a
`scFv” ......................................................................................... 46
`Claim 6: “wherein the transmembrane domain is CD8α
`transmembrane domain” ........................................................... 46
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`3.
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`2.
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`2.
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`b.
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`c.
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`d.
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`4.
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`5.
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`6.
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`7.
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`Claims 8 and 9: “wherein the CAR further comprises a
`hinge domain” and “wherein the hinge domain is a CD8α
`hinge domain” ........................................................................... 46
`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” ....................................................................... 47
`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” ............................................................... 47
`Claims 27, 28, and 29: “wherein the pharmaceutical
`composition further comprises a pharmaceutically
`acceptable carrier, diluent or excipient,” “wherein the
`pharmaceutical composition comprises a buffer,” or
`“wherein the buffer is a neutral buffer saline or phosphate
`buffered saline” ......................................................................... 48
`XII. GROUND 2: INDEPENDENT CLAIM 1 AND DEPENDENT
`CLAIMS 2-6, 8-9, 11, 13, 16, 21-22, AND 27-30 ARE RENDERED
`OBVIOUS BY CAMPANA IN VIEW OF JENSEN, HONSIK, AND
`CART-19 CLINICALTRIALS.GOV ............................................................48
`Independent Claim 1 ........................................................................... 49
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`1.
`([a]) “A pharmaceutical composition comprising” ................... 49
`2.
`([b]) “an anti-tumor effective amount of a population of
`human T cells,” ......................................................................... 49
`([c]) “wherein the T cells comprise a nucleic acid
`sequence encoding a chimeric antigen receptor (CAR),” ......... 50
`([d]) “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” ...................... 51
`([e]) “wherein the CAR further comprises a
`transmembrane domain, a 4-1BB costimulatory signaling
`region, and a CD3 zeta signaling domain,” .............................. 53
`([f]) “wherein the T cells are from a human having
`cancer.”...................................................................................... 53
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`6.
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`3.
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`4.
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`5.
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`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” ............................................................................................ 54
`Dependent Claims 5 and 13: “wherein the scFv comprises the
`amino acid sequence of SEQ ID NO: 20” and “wherein the
`CD19 antigen binding domain is encoded by a nucleic acid
`sequence comprising SEQ ID NO: 14” ............................................... 56
` Dependent Claims 2, 4, 6, 8-9, 11, 16, 21-22, 27-29 .......................... 57
`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), HONSIK, AND RIDDELL ...............58
`Claim 1 ................................................................................................ 58
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`Dependent Sequence Claims ............................................................... 60
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`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 ............................................................................... 60
`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” ....................................................................... 62
`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”........ 64
`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” ............... 66
`Dependent Vector/Promoter Claims ................................................... 67
`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” ................................................ 67
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`2.
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`3.
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`4.
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`2.
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`Claims 25 and 26: “wherein the vector further comprises
`a promoter” or “wherein the promoter is an EF-1α
`promoter” .................................................................................. 68
` Dependent Pharmaceutical Composition Claim ................................. 69
`1.
`Claim 30: “wherein the pharmaceutical composition
`further comprises a carbohydrate” ............................................ 69
`Remaining Challenged Claims ............................................................ 70
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`XIV. GROUND 4: ALL CHALLENGED CLAIMS ARE RENDERED
`OBVIOUS BY CAMPANA, PORTER, SEQUENCE ART, HONSIK,
`AND RIDDELL .............................................................................................70
`Porter is Prior Art ................................................................................ 70
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`1.
`Provisional Applications Do Not Provide Adequate
`Support for the Claims .............................................................. 70
`No Disclosure of SEQ NO: 20 in the Provisional
`Applications .............................................................................. 72
`All Challenged Claims are Rendered Obvious by Campana,
`Sequence Art, and Porter ..................................................................... 74
`XV. 35 U.S.C. § 325(D) SHOULD NOT BAR THE PETITION ........................78
`XVI. CONCLUSION ..............................................................................................80
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`2.
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`TABLE OF AUTHORITIES
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` Page(s)
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`Cases
`Alcon Rsch. v. Apotex,
`687 F.3d 1362 (Fed. Cir. 2012) ................................................................ 20, 40, 8
`Ariad Pharm. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) .......................................................................... 70
`Boehringer Ingelheim Pharms. v. Mylan Pharms.,
`803 F. App’x 397 (Fed. Cir. 2020) ..................................................................... 55
`Fiers v. Revel,
`984 F.2d 1164 (Fed. Cir. 1993) .................................................................... 73, 74
`Genentech v. Chiron,
`112 F.3d 495 (Fed. Cir. 1997) ............................................................................ 34
`Genzyme Therapeutic Prods. v. Biomarin Pharm.,
`825 F.3d 1360 (Fed. Cir. 2016) .................................................................... 44, 45
`Grünenthal GmbH v. Antecip Bioventures II LLC,
`PGR2017-00022, Paper 60, 49-56 (P.T.A.B. Nov. 14, 2018) ............................ 55
`Husky Injection Molding Sys. v. Athena Automation,
`838 F.3d 1236 (Fed. Cir. 2016) .......................................................................... 33
`KSR Int’l v. Teleflex,
`550 U.S. 398 (2007) ............................................................................................ 65
`Regents of the Univ. of Cal. v. Eli Lilly & Co.,
`119 F.3d 1559 (Fed. Cir. 1997) .......................................................................... 74
`Trend Micro v. CUPP Computing AS,
`IPR2021-00813, Paper 7 (P.T.A.B. Oct. 25, 2021) ............................................ 79
`Valeant Pharms. v. Mylan Pharms.,
`955 F.3d 25 (Fed. Cir. 2020) ........................................................................ 54, 55
`Vitronics v. Conceptronic,
`90F.3d 1576, 1582 (Fed. Cir. 1996) ................................................................... 21
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`Statutes
`35 U.S.C. § 103 ........................................................................................................ 14
`35 U.S.C. § 314(a) ................................................................................................... 13
`35 U.S.C. § 325(d) ....................................................................................... 78, 79, 80
`Other Authorities
`37 C.F.R. § 42.8 ................................................................................................. 11, 12
`37 C.F.R. § 42.103 ............................................................................................. 12, 13
`37 C.F.R. § 42.104 ............................................................................................. 12, 13
`37 C.F.R. § 42.108 ............................................................................................. 12, 13
`37 C.F.R. § 42.15(a) ................................................................................................. 13
`45 C.F.R. § 46.111(a)(2) .......................................................................................... 44
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`I.
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`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 21-30 (“Challenged Claims”) of U.S. Patent 9,540,445
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`(“the ’445 patent,” Ex.1001). The ’445 patent is owned by The Trustees of the
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`University of Pennsylvania (“Patent Owner”). The Challenged Claims of the ’445
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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 an “anti-tumor effective amount” of
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`chimeric antigen receptor (“CAR”) T cells. Patent Owner did not invent the claimed
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`CAR—a CAR with a CD19 antigen binding domain, a transmembrane domain, a
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`4-1BB costimulatory signaling region, and CD3-zeta(ζ) signaling domain. This
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`CAR was fully disclosed many years before—as “anti-CD19-BB-ζ”—in U.S. Patent
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`Application Publication No. US 2005/0113564 (“Campana”) (Ex.1003). Indeed, the
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`’445 patent specification credits prior-art authors for the claimed CAR.
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`The only information in the ’445 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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`claims for “an anti-tumor effective amount” of a prior-art CAR. An “anti-tumor
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`effective amount” is defined broadly in the specification as any amount providing
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`one of several possible biological effects, including “a decrease in the number of
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`tumor cells.” Ex.1001, 12:28–37. Here, the §102(b) prior art already showed that the
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`claimed CAR (1) killed human tumor cell lines in vitro; (2) decreased the number of
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`tumor cells in vivo in mouse xenograft studies (i.e., mice with human tumor cells);
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`and (3) was administered in an ongoing clinical trial at a dose, 2.5×107 to 6.1×108
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`cells per kg, that falls within the range of the ’445 patent’s own exemplar “anti-
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`tumor effective amounts.” These prior art disclosures demonstrate that a person of
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`ordinary skill in the art (“POSA”) would reasonably expect the prior-art CAR to at
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`least produce “a decrease in the number of tumor cells” at a dose taught in the prior
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`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 ’445 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 ’445
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`patent, it renders all Challenged Claims obvious.
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`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 ’445 patent.
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`Petitioner is not aware of any related matters involving the ’445 patent. Along with
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`the instant Petition, Petitioner is filing petitions against related U.S. Pat. Nos.
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`9,518,123 and 9,464,140.
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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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`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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`the agent of record for the ’445 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
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`C.F.R. § 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 ’445 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 ’445 patent are not patentable on the following grounds:
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`Ground Claims
`1-4, 6, 8-9, 11,
`1
`16, 21-22, 27-30
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`1-6, 8-9, 11, 13,
`16, 21-22, 27-30
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`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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`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), Honsik, and Riddell
`Obvious under §103 over Campana in view of
`Porter, Sequence Art (Nicholson, Jensen,
`Littman, Sadelain), Honsik, and Riddell
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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.
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`See 35 U.S.C. § 314(a).
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`V.
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`PRIORITY DATE
`The ’445 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 ’445 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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`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, 402.1,2
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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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`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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` 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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`(“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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`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 CAR construct is then inserted into a plasmid along with other gene
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`sequences (e.g., green, blue, and orange, below) necessary for transduction into the
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`T cells and expression of the CAR protein. Id., ¶37. The viral vector with the CAR-
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`encoding plasmid infects, also known as transduces, the T cells with the CAR
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`sequence. Id., ¶36.
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`
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`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
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`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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`VII. PERSON OF ORDINARY SKILL IN THE ART
`A POSA is a person skilled in the art of administering CAR T-cell therapies.
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`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.
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`VIII. THE ’445 PATENT
`The ’445 patent is directed to a pharmaceutical composition comprising an
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`anti-tumor effective amount of a population of T cells from a human having cancer,
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`where the T cells contain a CAR with specific domains. See Ex.1001, claim 1. Some
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`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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`IX. CLAIM CONSTRUCTION
`“Anti-tumor effective amount”
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`Claim 1 requires “[a] pharmaceutical composition comprising an anti-tumor
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`effective amount of a population of human T cells.” Ex. 1001, claim 1.3 The
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`specification describes exemplary “anti-tumor effective amount[s]”: “It can
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`generally be stated that a pharmaceutical composition comprising the T cells
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`described herein may be administered at a dosage of 104 to 109 cells/kg body weight,
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`preferably 105 to 106 cells/kg body weight, including all integer values within those
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`ranges.” Id., 37:60–64. The broader range quoted is also expressly claimed in
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`dependent claim 2 to be an “anti-tumor effective amount.” While claim 1 does not
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`expressly state a numerical range for an “anti-tumor effective amount,” claim 1
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`3 Bold italics in quotes and highlighting denotes emphasis added.
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`necessarily encompasses at least the numerical range stated in dependent claim 2.
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`See Alcon Rsch. v. Apotex, 687 F.3d 1362, 1367 (Fed. Cir. 2012) (explaining that an
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`independent claim directed to a “therapeutically effective amount” must incorporate
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`the concentration range in a dependent claim). Therefore, the term “anti-tumor
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`effective amount” at least encompasses a dosage of 104 to 109 cells per kg.
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`A POSA would also understand that doses outside the range of 104 to 109 cells
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`per kg can satisfy the claim limitation of “anti-tumor effective amount” if the CAR
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`T cells provide an “anti-tumor effect,” which is defined in the specification as
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`follows:
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`The term “anti-tumor effect” as used herein, refers to a
`biological effect which can be manifested by [(i)] a
`decrease in tumor volume, [(ii)] a decrease in the number
`of tumor cells, [(iii)] a decrease in the number of
`metastases, [(iv)] an increase in life expectancy, or [(v)]
`amelioration of various physiological
`symptoms
`associated with the cancerous condition. An “anti-tumor
`effect” can also be manifested by [(vi)] the ability of the
`peptides, polynucleotides, cells and antibodies of the
`invention in prevention of the occurrence of tumor in the
`first place.
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`Ex.1001, 12:28–37; Junghans, ¶¶54-58. Because the definition is disjunctive, “a
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`decrease in the number of tumor cells” meets the requirement of an “anti-tumor
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`effect.” It follows that an “anti-tumor effective amount” comprises any amount of
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`CAR T cells that would have an “anti-tumor effect” in a patient with cancer cells.
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`Accordingly, the patent defines an “anti-tumor effective amount” of CAR T cells as
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`an amount that causes any of the biological effects described above, including “a
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`decrease in the number of tumor cells.” See Vitronics v. Conceptronic, 90F.3d 1576,
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`1582 (Fed. Cir. 1996) (“The specification acts as a dictionary when it expressly
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`defines terms used in the claims[.]”).
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`In sum, the term “anti-tumor effective amount” should be understood to
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`encompass at least “104 to 109 cells/kg body weight,” and any other amount of CAR
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`T cells that would have at least one of the biological effects specifically described in
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`the specification, including “a decrease in the number of tumor cells.” Ex.1001,
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`37:60–64, 12:28–37. Junghans, ¶59.
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`X.
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`PRIOR ART
` Campana
`The CAR that is claimed by the ’445 patent was disclosed in the prior art by
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`2005, many years before the priority date. Specifically, two researchers at St. Jude
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`Children’s Research Hospital—Drs. Dario Campana and Chihaya Imai—submitted
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`a patent application, which later published as Campana, disclosing the structure of
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`the CAR and claiming use of the CAR to treat cancer patients. Ex.1003, [0013],
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`Figure 1, claims 17–21. Campana is §102(b) prior art.
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`Campana discloses an exemplary CAR, called anti-CD19-BB-ζ (or “Campana
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`CAR”), which contains a CD8α signaling peptide (i.e., the leader peptide), an
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`anti-CD19 binding domain, a CD8α hinge and transmembrane domain, a 4-1BB
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`signaling domain, and a CD3-zeta signaling domain, as illustrated below:
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`
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`Id., Figure 1. With one exception, Campana does not provide amino acid or nucleic
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`acid sequences for these structural components. That is unsurprising because such
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`sequences were well known in the art, as discussed in Section X.B.
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`Campana discloses results from in vitro studies using T cells “transduced with
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`the anti-CD19-BB-ζ receptor.” Id., [0050]–[0054]. The results found that “T-cells
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`transduced with the anti-CD19-BB-ζ receptor exhibit cytotoxic activity in an
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`environment critical for B-lineage leukemic cell growth,” id., [0053], and “provide
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`compelling justification for clinical trials using T cells expressing anti-CD19-BB-
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`ζ,” id., [0118].
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`Campana also claims “[a] method for treating an individual suffering from
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`cancer” with the CAR T cells. Id., claims 17–21. Campana states that “[m]ethods of
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`re-introducing cellular components are known in the art and include procedures such
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`as those exemplified in U.S. Pat. Nos. 4,844, 893 and 4