UNITED STATES PATENT AND TRADEMARK OFFICE
`
`______________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`______________________
`
`
`
`MILTENYI BIOMEDICINE GmbH and MILTENYI BIOTEC INC.
`Petitioner
`
`v.
`
`FRED HUTCHINSON CANCER CENTER
`Patent Owner
`
`______________________
`
`
`IPR Trial No. IPR2023-
`U.S. Patent No. 9,987,308
`Issue Date: June 5, 2018
`
`Title: Method and Compositions for Cellular Immunotherapy
`
`
`______________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,987,308
`
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`
`Page
`INTRODUCTION .......................................................................................... 1
`I.
`II. MANDATORY NOTICES ............................................................................ 4
`A. Notice of Real Party-In-Interest (37 C.F.R. §42.8(b)(1)) .................... 4
`B. Notice of Related Matters (37 C.F.R. §42.8(b)(2)) .............................. 4
`C. Designation of Lead and Back-up Counsel (37 C.F.R.
`§42.8(b)(3)) .......................................................................................... 4
`Service Information (37 C.F.R. §42.8(b)(4)) ....................................... 5
`D.
`Power of Attorney ................................................................................ 5
`E.
`III. PAYMENT OF FEES (37 C.F.R. §42.103) ................................................... 5
`IV. REQUIREMENTS UNDER §§42.104 AND 42.108 ..................................... 5
`A. Grounds for Standing (§42.104(a)) ...................................................... 5
`B. Grounds of Challenge (§42.104(b)) ..................................................... 6
`C.
`Requirements for IPR (§42.108(c)) ...................................................... 6
`PRIORITY DATE .......................................................................................... 6
`V.
`VI. TECHNOLOGY BACKGROUND ................................................................ 7
`A.
`T Cells .................................................................................................. 7
`B.
`T-Cell Subpopulations .......................................................................... 7
`C.
`T-Cell Markers ..................................................................................... 8
`D.
`Fluorescence-Activated Cell Sorting (“FACS”) .................................. 9
`E.
`Adoptive Immunotherapy .................................................................. 13
`F.
`Chimeric Antigen Receptors .............................................................. 14
`VII. PERSON OF ORDINARY SKILL IN THE ART ....................................... 15
`VIII. THE ’308 PATENT ...................................................................................... 15
`IX. CLAIM CONSTRUCTION ......................................................................... 17
`A.
`“adoptive cellular immunotherapy composition” .............................. 17
`B.
`“and/or” .............................................................................................. 20
`PRIOR ART .................................................................................................. 21
`
`X.
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`i
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`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`B.
`
`C.
`
`A. Adoptive Cellular Immunotherapy Compositions With
`CD45RA+, CD45RO+, and/or CD62L+ Immunophenotypes
`Were Known ....................................................................................... 21
`1.
`Singh ........................................................................................ 21
`2. Mitsuyasu ................................................................................. 22
`The Modularity of Chimeric Antigen Receptors Was Known .......... 24
`1.
`Cooper ...................................................................................... 24
`CARs Targeting CD19, CD20, CD22, ROR1, CEA, Her2, L1-
`CAM, and Mesothelin Were Known ................................................. 24
`1.
`Hudecek I ................................................................................. 24
`2.
`Hudecek II ................................................................................ 25
`3.
`Abken ....................................................................................... 25
`4.
`Reckamp ................................................................................... 26
`5.
`Carpenito .................................................................................. 26
`D. Using Equivalent Numbers of CD4+ and CD8+ T Cells in
`Adoptive Cellular Immunotherapy Compositions Was Known ........ 27
`1. Moeller ..................................................................................... 27
`Benefits of TCM, which are CD62L+ T Cells, Was Known ................ 28
`1. Wang ........................................................................................ 28
`2.
`Yang I & II ............................................................................... 29
`3.
`Sallusto ..................................................................................... 29
`4.
`Sun............................................................................................ 30
`Formulations for Adoptive Cellular Immunotherapy
`Compositions Were Known ............................................................... 30
`1.
`Jensen ....................................................................................... 30
`XI. GROUND 1: INDEPENDENT CLAIM 1 AND DEPENDENT
`CLAIMS 2-7, 14, 16, 21, AND 26-28 ARE ANTICIPATED BY
`SINGH .......................................................................................................... 31
`A.
`Independent Claim 1 .......................................................................... 31
`
`E.
`
`F.
`
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`ii
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`

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`TABLE OF CONTENTS
`(continued)
`
`Page
`
`1.
`
`2.
`
`b.
`
`c.
`
`Limitations Directed to Components of the Claimed
`Composition ............................................................................. 32
`a.
`[a] “[a]n adoptive cellular immunotherapy
`composition” .................................................................. 32
`[b] “containing chimeric antigen receptor-modified
`CD4+ T lymphocytes and chimeric antigen
`receptor-modified CD8+ T lymphocytes,” .................... 34
`[c] & [e] “wherein: (a) the chimeric antigen
`receptor-modified CD4+ T lymphocytes [and (b)
`the chimeric antigen receptor-modified CD8+ T
`lymphocytes] contain a chimeric antigen receptor
`that specifically binds to an antigen” ............................. 35
`Limitations Directed to Phenotypic Marker Surface
`Positivity .................................................................................. 35
`a.
`[d] & [f] “at least 50% of the chimeric antigen
`receptor-modified CD4+ helper T lymphocytes in
`the composition are surface positive for CD62L
`and/or CD45RA,” and “at least 50% of CD8+
`cytotoxic T lymphocytes in the composition are
`surface positive for CD62L and/or CD45RO” .............. 36
`B. Dependent Antigen Claims ................................................................ 42
`1.
`Claims 2 and 26-28: “wherein the antigen is associated
`with a disease or disorder” ....................................................... 42
`Claims 3 and 21: “wherein the antigen is selected from
`ROR1, tEGFR, Her2, L1-CAM, CD19, CD20, CD22,
`mesothelin, and CEA” ............................................................. 44
`C. Dependent CAR Component Claims ................................................. 44
`1.
`Claims 4 and 5: “extracellular antibody variable domain
`or single-chain antibody fragment and an intracellular
`signaling module” .................................................................... 44
`Claims 7 and 16: Claims Related to Whether the CAR is
`the Same in the CD4+ and CD8+ T Cells ................................. 46
`
`2.
`
`2.
`
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`iii
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`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`D. Dependent Claims Related to Percentage Surface Positivity of
`T-Cell Markers ................................................................................... 46
`Dependent Ratio Claim ...................................................................... 47
`E.
`XII. GROUND 2: INDEPENDENT CLAIM 1 AND DEPENDENT
`CLAIMS 2-7, 14, 16, 21, AND 26-28 ARE RENDERED OBVIOUS
`BY SINGH IN VIEW OF JENSEN ............................................................. 48
`A.
`Independent Claim 1 .......................................................................... 48
`B.
`Claims 2-7, 14, 16, 21, and 26-28 ...................................................... 50
`XIII. GROUND 3: ALL CHALLENGED CLAIMS ARE RENDERED
`OBVIOUS BY SINGH IN VIEW OF JENSEN, MITSUYASU,
`COOPER, HUDECEK I & II, ABKEN, RECKAMP, CARPENITO,
`MOELLER, WANG, YANG I & II, SALLUSTO, AND SUN ................... 50
`A.
`Independent Claim 1 .......................................................................... 52
`B. Dependent Antigen Claims ................................................................ 52
`1.
`Claims 3 and 18-25 .................................................................. 52
`Claims to Marker Positivity Percentages ........................................... 55
`1.
`Claims 1, 6 and 9-13 ................................................................ 55
`D. Dependent Ratio Claims ..................................................................... 60
`E.
`Dependent Claims Requiring Comparison to Other Populations ...... 61
`1.
`Claim 8 ..................................................................................... 61
`2.
`Claim 29 ................................................................................... 63
`3.
`Claim 30 ................................................................................... 64
`4.
`Claim 31 ................................................................................... 65
`Remaining Challenged Claims ........................................................... 66
`F.
`XIV. GROUND 4: INDEPENDENT CLAIM 1 AND DEPENDENT
`CLAIMS 6 AND 9-16 ARE RENDERED OBVIOUS BY
`MITSUYASU IN VIEW OF SINGH AND COOPER ................................ 66
`A.
`Independent Claim 1 and Dependent Claims 6 and 9-13................... 66
`1.
`Claim Limitations Directed to Components of the
`Claimed Composition .............................................................. 66
`
`C.
`
`
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`iv
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`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`a.
`
`b.
`
`c.
`
`2.
`
`[a] “[a]n adoptive cellular immunotherapy
`composition” .................................................................. 67
`[b] “containing chimeric antigen receptor-modified
`CD4+ T lymphocytes and chimeric antigen
`receptor-modified CD8+ T lymphocytes,”..................... 68
`[c] & [e] “wherein: (a) the chimeric antigen
`receptor-modified CD4+ T lymphocytes [and (b)
`the chimeric antigen receptor-modified CD8+ T
`lymphocytes] contain a chimeric antigen receptor
`that specifically binds to an antigen” ............................. 70
`Claim Limitations Directed to Phenotypic Marker
`Surface Positivity ..................................................................... 71
`B. Dependent Ratio Claims ..................................................................... 76
`C. Dependent CAR Component Claim ................................................... 77
`XV. 35 U.S.C. §325(D) SHOULD NOT BAR THE PETITION ........................ 77
`XVI. CONCLUSION ............................................................................................. 80
`
`
`
`
`v
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`

`

`
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte
`GmbH,
`IPR2019-01469, Paper 6, 8 (P.T.A.B. 2020) ...................................................... 78
`Arctic Cat v. GEP Power Prods.,
`919 F.3d 1320 (Fed. Cir. 2019) .................................................................... 17, 18
`Becton, Dickinson v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8, 17-18 (P.T.A.B. Dec. 15, 2017) ................................ 79
`Catalina Mktg. Int’l v. Coolsavings.com,
`289 F.3d 801 (Fed. Cir. 2002) ............................................................................ 19
`Cochlear Bone Anchored Sols. AB v. Oticon Med. AB,
`958 F.3d 1348 (Fed. Cir. 2020) .......................................................................... 20
`E.I. DuPont de Nemours v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) ............................................................................ 59
`Fresenius USA, v. Baxter Int'l,
`582 F.3d 1288 (Fed. Cir. 2009) .......................................................................... 43
`Trend Micro v. CUPP Computing AS,
`IPR2021-00813, Paper 7, 23 (P.T.A.B. Oct. 25, 2021) ...................................... 79
`In re Vivint,
`14 F.4th 1342 (Fed. Cir. 2021) ........................................................................... 79
`Statutes
`35 U.S.C. §§102 and 103 ........................................................................................... 1
`35 U.S.C. §325(D) ............................................................................................. 77, 78
`Other Authorities
`37 C.F.R. §42.8(b)(1) ................................................................................................. 4
`
`
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`vi
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`37 C.F.R. §42.8(b)(2) ................................................................................................. 4
`37 COF.R. §42.8(b)(2)scecscccsssssecssccsssssccsscesssssessccessssessecessssssseccesssusesseesrsnsesseeessneesseeesen 4
`37 C.F.R. §42.8(b)(3) ................................................................................................. 4
`37 CFR. §42.8(b)(3)ccecscccsssssecseccessssccsscesssssessccessssessecessesssseccesssusesseesrsnsssceersneesseeenen 4
`37 C.F.R. §42.8(b)(4) ................................................................................................. 5
`37 CFR. §42.8(b)(4) scecscccsssssecssccsssssccsscesrsssessecessssessecessessssscsesssnsesseesrsnseseceersneesseeenen 5
`37 C.F.R. §42.103 ...................................................................................................... 5
`37 COF.R. §42.103 .ccscccessccsssssscseccessssscsssssssssessecessssessecessessesecsesssneessessrsnsessesersneesseeesen 5
`37 C.F.R. §42.103(a) .................................................................................................. 5
`37 CFR. §42.103(a)scccessccsssssecssccessssccsscessssscssecessssessecessesssseccesssneeseeesrsnsesseeessneesseeenen 5
`37 C.F.R. § 42.15(a) ................................................................................................... 5
`37 COFLR. § 42.15 (a) sccccssccssscsscssccessssscsscesssssessecessssesseceesssssseccesssusesseesrsnsessesersneesseeesen 5
`
`
`
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`vii
`Vii
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`

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`
`
`I.
`
`INTRODUCTION
`Miltenyi Biomedicine GmbH and Miltenyi Biotec Inc. (collectively,
`
`“Petitioner”) respectfully request that the Board institute inter partes review (“IPR”)
`
`and cancel claims 1-16 and 18-31 (“Challenged Claims”) of U.S. Patent 9,987,308
`
`(the “’308 patent,” Ex.1001). The ’308 patent is owned by Fred Hutchinson Cancer
`
`Center (“Patent Owner”). The Challenged Claims should be found unpatentable as
`
`anticipated and obvious under pre-AIA 35 U.S.C. §§102 and 103.
`
`Claim 1 of the ’308 patent—the only independent claim—describes a
`
`composition of chimeric antigen receptor (“CAR”) T cells wherein (1) at least half
`
`of the helper-T cells have a “CD62L and/or CD45RA” surface marker and (2) at
`
`least half of the cytotoxic-T cells have a “CD62L and/or CD45RO” surface marker.
`
`The dependent claims narrow the specified percentages of surface markers and add
`
`insignificant limitations that do not change the conclusion of anticipation or
`
`obviousness.
`
`The claims are much broader than what is taught by the specification. The
`
`specification focuses making a composition enriched for two T-cell subpopulations:
`
`naïve helper T cells (TN) and central-memory cytotoxic T cells (TCM). A “naïve”
`
`T cell is one “that expresses CD62L and CD45RA”1 surface markers, while a
`
`
`1 In quotes, all emphasis added unless otherwise noted.
`
`
`
`

`

`
`
`“central-memory” T cell is one “that expresses CD62L and CD45RO” surface
`
`markers. Ex.1001, 7:13-20, 7:31-37, 15:25-31. The ’308 patent claims, however, are
`
`much broader because they cover T cells with “CD62L and/or CD45RA” and
`
`“CD62L and/or CD45RO” surface markers. The Challenged Claims are, therefore,
`
`not limited to a composition with majority helper TN cells and majority cytotoxic
`
`TCM cells. Instead, most claims cover compositions with a majority of other T-cell
`
`subpopulations, such as effector-memory-T cells (TEM) and effector-T cells (TE)—
`
`which are CD62L-negative according to the patent. Most claims also cover
`
`compositions where all cells are either TN or TCM (as opposed to mix of both), since
`
`both subpopulations are CD62L-positive.
`
`Because the Challenged Claims were drafted so broadly, many are
`
`anticipated. A journal article (Singh) published years before the priority date teaches
`
`CAR-T-cell composition surface-marker percentages that fall squarely within the
`
`scope of many Challenged Claims. Singh teaches CAR-T-cell compositions for
`
`treating blood cancers by targeting the CD19 antigen. During prosecution, Singh
`
`was not submitted in an information disclosure statement (“IDS”) nor evaluated by
`
`the Examiner. Ground 1 explains that Singh is anticipatory. In the alternative,
`
`Ground 2 explains that Singh in combination with another reference (Jensen) renders
`
`obvious the same subset of Challenged Claims.
`
`
`
`2
`
`

`

`
`
`Ground 3 combines Singh with no more than a few other references for each
`
`Challenged Claim to render them all obvious. The dependent claims not addressed
`
`in Grounds 1 and 2 add trivial limitations well known in the prior art. For example,
`
`numerous dependent claims simply specify the antigen targeted by the claimed CAR.
`
`These claims recite well-known CAR-T-cell targets. Other dependent claims specify
`
`the disease associated with the target. These associations between antigen target and
`
`disease state likewise were well-known. Still other dependent claims narrow the
`
`surface-marker percentages. But these percentages too are taught in prior-art
`
`references. The remaining dependent claims recite that claim 1’s T-cell composition
`
`proliferates or otherwise performs better than a reference population of T cells.
`
`These claims, too, are obvious. It was well known that enrichment of some
`
`subpopulations, such as TCM, in a CAR-T-cell composition resulted in better
`
`performance.
`
`Ground 4 relies on another article, Mitsuyasu, instead of Singh as the primary
`
`reference. Mitsuyasu discloses a clinical study where twenty-four HIV-positive
`
`patients had their T cells drawn, which were then genetically modified to target the
`
`HIV virus, cultured to grow, and injected back into the patients. Of the twenty-four
`
`genetically engineered T-cell compositions, all but one had a majority of T cells that
`
`were surface-positive for CD62L and therefore fall within claim 1’s scope.
`
`All Challenged Claims should be found anticipated and/or obvious.
`
`
`
`3
`
`

`

`
`
`II. MANDATORY NOTICES
`A. 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-interest.
`
`B. Notice of Related Matters (37 C.F.R. §42.8(b)(2))
`Petitioner is not aware of any related matters involving the ’308 patent.
`
`C. Designation of Lead and Back-up Counsel (37 C.F.R. §42.8(b)(3))
`Lead Counsel
`Back-Up Counsel
`Yite John Lu (Reg. No. 63158)
`Gary N. Frischling (Reg. No. 35515)
`Orrick, Herrington & Sutcliffe LLP
`Orrick, Herrington & Sutcliffe LLP
`355 S. Grand Ave., Ste. 2700
`631 Wilshire Boulevard, Suite 2-C
`Los Angeles, CA 90071
`Santa Monica, CA 90401
`Tel. (213) 612-2374
`Tel. (310) 633 2841
`Fax. (213) 612-2499
`Fax. (213) 612-2499
`PTABDocketL2Y7@orrick.com
`PTABDocketG2F1@orrick.com
`
`Christopher D. Lynch (Reg. No. 68915)
`Orrick, Herrington & Sutcliffe LLP
`355 S. Grand Ave., Ste. 2700
`Los Angeles, CA 90071
`Tel. (213) 612-2318
`Fax. (213) 612-2499
`PTABDocketC3L8@orrick.com
`
`Sarah M. Goodman (Reg. No. 71630)
`Orrick, Herrington & Sutcliffe LLP
`2050 Main St. #1100
`Irvine, CA 92614
`Tel. (949) 852-7748
`Fax. (949) 567-6710
`PTABDocketG3S7@orrick.com
`
`David I. Gindler (to be pro hac vice)
`Orrick, Herrington & Sutcliffe LLP
`
`
`
`4
`
`

`

`
`
`Lead Counsel
`
`Back-Up Counsel
`355 S. Grand Ave., Ste. 2700
`Los Angeles, CA 90071
`Tel. (213) 612-2370
`Fax. (213) 612-2499
`PTABDocketG3D7@orrick.com
`D.
`Service Information (37 C.F.R. §42.8(b)(4))
`A copy of this Petition, in its entirety, including all Exhibits and a Power of
`
`Attorney, is being served by Priority Mail Express, costs prepaid, to the address of
`
`the agent of record for the ’308 patent: David Carlson, John A. Morgan, and Patent
`
`Docket Clerk, Seed IP Law Group LLP, 701 Fifth Ave., Suite 5400, Seattle, WA
`
`98104. Petitioner may be served at the addresses provided above in Section II.C for
`
`lead and back-up counsel, and Petitioner consents to electronic service at the above
`
`e-mail addresses.
`
`E.
`Power of Attorney
`Power of Attorney is filed concurrently with this petition.
`
`III. PAYMENT OF FEES (37 C.F.R. §42.103)
`The required fees are submitted per 37 C.F.R. §§42.103(a) and 42.15(a). The
`
`Office is authorized to charge any additional fee due or required to the deposit
`
`account of Orrick, Herrington & Sutcliffe LLP: 15-0665.
`
`IV. REQUIREMENTS UNDER §§42.104 AND 42.108
`A. Grounds for Standing (§42.104(a))
`Petitioner certifies that the ’308 patent is available for IPR by Petitioner.
`
`
`
`5
`
`

`

`
`
`B. Grounds of Challenge (§42.104(b))
`Petitioner requests institution and a holding that the identified claims are not
`
`patentable:
`
`Ground
`1
`2
`
`Claims
`1-7, 14, 16, 21, 26-28
`1-7, 14, 16, 21, 26-28
`
`3
`
`1-16, 18-31
`
`4
`
`1, 6, 9-16
`
`
`
`Basis
`Anticipated under §102 by Singh
`Obvious under §103 over Singh in view
`of Jensen
`Obvious under §103 over Singh in view
`of Jensen, Mitsuyasu, Cooper, Hudecek I
`& II, Abken, Reckamp, Carpenito,
`Moeller, Wang, Yang I & II, Sallusto,
`and Sun (not all references are necessary
`for each claim)
`Obvious under §103 over Mitsuyasu in
`view of Singh and Cooper
`
`This Petition is supported by the Declaration of Dr. Jonathan Bramson
`
`(Ex.1002)(“Bramson”), an expert in the field of CAR-T-cell therapy.
`
`C. Requirements for IPR (§42.108(c))
`The Board should institute IPR because this Petition establishes a reasonable
`
`likelihood of prevailing with respect to at least one Challenged Claim.
`
`V.
`
`PRIORITY DATE
`The ’308 patent is a national stage entry of PCT/US2012/030388 (Ex.1005),
`
`filed on March 23, 2012. The patent claims priority from U.S. Provisional Patent
`
`Application No. 61/466,552 (Ex.1006), filed on March 23, 2011. Although this
`
`Petition assumes that the ’308 patent’s priority date is March 23, 2011 (the “Priority
`
`Date”), Petitioner reserves the right to challenge the patent’s priority claims.
`
`
`
`6
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`

`
`
`VI. TECHNOLOGY BACKGROUND
`A. T Cells
`T cells are a type of lymphocyte. T cells detect foreign invaders and secrete
`
`helpful cytokines (protein-based molecules). Bramson, ¶19.
`
`T cells include helper-T cells which express the CD4 membrane glycoprotein
`
`(“CD4”), and cytotoxic-T cells which express the CD8 membrane glycoprotein
`
`(“CD8”). A glycoprotein is a protein with an attached carbohydrate group. Id., ¶20.
`
`Cells that express a high level of a membrane protein can be described with a
`
`“+” sign. Immunologists use a “-” sign if a cell expresses a low level of a protein or
`
`complete absence thereof. Id.
`
`B.
`T-Cell Subpopulations
`T cells include several categories of T-cell subpopulations. Id., ¶21. TN have
`
`not encountered the antigen to which they can bind. Id., ¶22. Once stimulated by
`
`their respective antigenic material, TN cells activate, proliferate, and produce
`
`cytokines. Id. Upon activation, TN cells may differentiate into antigen-specific TCM,
`
`TEM, or TE cells. Id., ¶23. TE cells are primarily responsible for eliminating infected
`
`cells from the body. Id., ¶24. Whereas TE cells typically die after their target antigen
`
`clears from the body, TCM and TEM cells linger, and can respond upon re-exposure to
`
`the antigen. Id. One way TCM and TEM respond to antigen re-exposure is to
`
`differentiate into TE cells. Id. T cells derived from TCM are more capable of persisting
`
`long term than those from TEM. Id., ¶¶24-25.
`
`
`
`7
`
`

`

`
`
`A T cell’s persistence refers to its ability to survive. Greater persistence allows
`
`a T cell to continue to perform immune system functions and proliferate (i.e.,
`
`multiply) continually for a longer period. For example, TCM cells persist longer than
`
`TE cells. Id., ¶25.
`
`C. T-Cell Markers
`The ’308 patent claims recite T-cell subpopulations by their expression of cell
`
`surface proteins. Id., ¶26. These proteins, called “T-cell markers,” are used to
`
`understand which T-cell subpopulations comprise a given composition. Id. A
`
`T cell’s collection of markers is referred to as the T cell’s immunophenotype. Id.
`
`The claims recite three T-cell markers relevant to this petition: CD45RA,
`
`CD45RO, and CD62L. Id., ¶27. As of March 23, 2011, researchers understood those
`
`markers could be used to identify T-cell subpopulations: “CD45RA+ CD62L+ naïve
`
`(TN), CD45RO+ CD62L+ central memory (TCM), and CD62L- effector memory
`
`(TEM).” Bramson, ¶¶27-28, citing Ex.1007, 227. Researchers knew CD45RA+
`
`CD62L+ indicated a TN cell, CD45RO+ CD62L+ indicated a TCM cell, and CD62L-
`
`indicated a TEM or TE cell, as depicted below:
`
`
`
`8
`
`

`

`
`
`
`
`Ex.1007, 228; Bramson, ¶¶29-30.
`
`D.
`Fluorescence-Activated Cell Sorting (“FACS”)
`Fluorescence-activated cell sorting (“FACS”) is a technique for sorting cells
`
`into subpopulations using fluorescent tags that bind to cell surface markers. Id.,
`
`¶¶31-32.
`
`To analyze the number of CD62L+ cells, for example, a scientist would
`
`combine the T-cell population with a tag that binds to CD62L. Id., ¶33. A flow
`
`cytometer would use a laser to detect T cells with the tag attached. Id. Those T cells
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`would be counted and separated from T cells that do not express CD62L. Id.
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`Scientists routinely use flow cytometry to quantify T cell subpopulations. Id., ¶¶34-
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`35,104.
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`9
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`A typical two-dimensional plot of flow cytometry data is shown below. The
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`x- and y-axes each represent expression of a cell surface molecule; here, Surface
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`Molecules #1 and #2:
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`
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`Id., ¶36. In this plot, each dot represents a cell. Id., ¶37.The dot position shows
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`relatively how much of each marker is expressed. Id. Here, Cell #1 exhibits
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`relatively high expression of Surface Molecules #1 and #2, whereas Cell #2
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`expresses those molecules at a low level:
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`10
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`

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`
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`Id., ¶¶37-38.
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`The following plot shows a population in which most cells express both
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`Surface Molecules #1 and #2 at a high level, or express only Surface Molecule #1:
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`Id., ¶¶39-40.
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`Flow cytometers enable a user to draw a boundary around a subpopulation:
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`11
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`
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`Id., ¶41.
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`The user can instruct software to isolate cells within the boundary for further
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`analysis (a process called “gating”), including additional analysis of other molecules,
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`as depicted below:
`
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`Id., ¶42. In the example above, most cells expressing high levels of Surface
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`Molecules #1 and #2 are selected, as shown by the box on the left-hand plot. Id.,
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`¶43. The right-hand plot shows that, of these selected cells, most also express a high
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`12
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`
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`level of Surface Molecule #3, but a low level of Surface Molecule #4. Id. The arrow
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`from left to right indicates that the right-hand plot is a further analysis of the selected
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`(boxed) cells. Id., ¶¶42-43.
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`A flow cytometer thus allows researchers to measure expression of multiple
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`surface molecules-of-interest in a cell population, and sort cells into subpopulations.
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`Id., ¶¶44,104; Ex.1001, Figs.1,3,6-7,8A-8B.
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`E. Adoptive Immunotherapy
`By the 2000s, researchers were developing therapeutic compositions of
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`T cells genetically modified to express receptors targeting an antigen associated with
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`a disorder, such as cancer. Bramson, ¶45. Manufacturing these compositions
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`involved collecting a subject’s T cells, modifying them to target a specific
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`antigen-of-interest, and propagating, i.e., growing, those cells to therapeutically
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`acceptable numbers. These compositions are administered to the subject, a technique
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`known as adoptive immunotherapy. Id.
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`By at least March 23, 2011, researchers understood that T cells with certain
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`immunophenotypes, and in certain combinations, performed better than others in
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`adoptive immunotherapy compositions. Id., ¶46. For example, “[c]entral memory
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`T cells (TCM) have a unique ability to self-renew, proliferate, and differentiate into
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`effector TCM, which suggests that [TCM] will be most effective and persistent upon
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`adoptive transfer.” Ex.1017, 926; Bramson, ¶¶46-47.
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`13
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`
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`F. Chimeric Antigen Receptors
`Naturally occurring transmembrane receptors on a T cell comprise an
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`extracellular ligand-binding domain, a transmembrane domain, and at least one
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`intracellular signaling domain. Bramson, ¶¶48,137. In the 2000s, scientists
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`developed CARs. Id., ¶¶49-50. A CAR is a genetically modified receptor that
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`includes ligand-binding (e.g., antigen-binding), transmembrane, and signaling
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`domains from two or more proteins. Ex.1010, 645; Bramson, ¶¶48,137-38. In the
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`below example, the ligand-binding domain is a single-chain variable-fragment of an
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`antibody (“scFv”) and the signaling domains are from CD3-ζ and CD28:
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`Bramson, ¶49.
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`14
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`
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`Scientists have developed CAR-T-cell
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`therapies
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`targeting
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`infections
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`(e.g., HIV) and cancers (e.g., B-cell malignancies). Id., ¶51. B-cell malignancies
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`include leukemias, which affect bone marrow and blood, and lymphomas, which
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`affect the lymphatic system. Id., ¶¶51-52.
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`VII. PERSON OF ORDINARY SKILL IN THE ART
`A person of ordinary skill in the art (“POSA”) is skilled in developing
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`genetically engineered T-cell therapies. The person would possess a relatively high
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`level of skill and have at least a Ph.D., together with several years of experience in
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`researching and publishing academic articles concerning T-cell therapies. A POSA
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`would be knowledgeable about laboratory techniques related to engineering and
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`testing the function of genetically modified T cells. Id., ¶53.
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`VIII. THE ’308 PATENT
`The ’308 patent claims an adoptive cellular immunotherapy composition
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`containing CAR-modified, CD4+ and CD8+, T lymphocytes, where a percentage of
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`the T lymphocytes are surface-positive for specific phenotypic markers. Id., ¶54-55.
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`The dependent claims specify, inter alia, well-known antigens to which the CAR
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`binds, diseases associated with those antigens, commonly used CAR components,
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`and percentages of surface positivity for phenotypic markers. Id., ¶56.
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`The specification repeatedly calls out one particular T-cell composition: CD4+
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`TN cells combined with CD8+ TCM cells. Ex.1001, 17:37-39 (“[T]he CD8+ cytotoxic
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`
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`15
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`

`
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`T lymphocyte cell is a central memory T cell and the CD4+ helper T lymphocyte cell
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`is a naïve CD4+ T cell.”); Bramson, ¶¶57-59. This is consistent with the
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`specification’s examples, which state “maximum proliferation of the CD8+ CAR
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`CTL [cytotoxic-T lymphocytes] in response to stimulation…was observed after
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`co-culture of CD4+ N [naïve] CAR T cells with CD8+ CM [central-memory] CAR
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`CTL.” Id., 27:21-25; 27:29-31 (“sort purified N, rather than CM, EM or bulk CD4+
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`T cells may be best suited to augment the effector function of CD8+ CTL”).
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`Bramson, ¶¶60-61.
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`The claims, however, cover more than just a combination of CD8+ TCM cells
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`and CD4+ TN cells. Id., ¶62. Claim 1 recites:
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`immunotherapy composition
`An adoptive cellular
`containing chimeric antigen receptor-modified CD4+ T
`lymphocytes and chimeric antigen receptor-modified
`CD8+ T lymphocytes, wherein:
`(a) the chimeric antigen receptor-modified CD4+ T
`lymphocytes contain a chimeric antigen receptor that
`specifically binds to an antigen and at least 50% of the
`chimeric antigen receptor-modified CD4+ helper T
`lymphocytes in the composition are surface positive for
`CD62L and/or CD45RA, and
`(b) the chimeric antigen receptor-modified CD8+ T
`lymphocytes contain a chimeric antigen receptor that
`specifically binds to the antigen and at least 50% of CD8+
`cytotoxic T lymphocytes in the composition are surface
`positive for CD62L and/or CD45RO.2
`
`
`2 A Challenged Claims list is provid