Trials@uspto.gov
`571-272-7822
`
`Paper 10
`Date: September 25, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MILTENYI BIOMEDICINE GMBHand MILTENYI BIOTECINC.,
`Petitioner,
`
`Vv.
`FRED HUTCHINSON CANCER CENTER,
`Patent Owner.
`
`IPR2023-00760
`Patent 9,987,308 B2
`
`Before ULRIKE W. JENKS, ZHENYU YANG, and DAVID COTTA,
`Administrative Patent Judges.
`
`YANG,Administrative Patent Judge.
`
`DECISION
`Denying Institution of /nter Partes Review
`3S US.C. § 314
`
`
`571-272-7822
`
`Paper 10
`Date: September 25, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MILTENYI BIOMEDICINE GMBHand MILTENYI BIOTECINC.,
`Petitioner,
`
`Vv.
`FRED HUTCHINSON CANCER CENTER,
`Patent Owner.
`
`IPR2023-00760
`Patent 9,987,308 B2
`
`Before ULRIKE W. JENKS, ZHENYU YANG, and DAVID COTTA,
`Administrative Patent Judges.
`
`YANG,Administrative Patent Judge.
`
`DECISION
`Denying Institution of /nter Partes Review
`3S US.C. § 314
`
`
`
`IPR2023-00760
`Patent 9,987,308 B2
`
`I.
`
`INTRODUCTION
`
`Miltenyi Biomedicine GmbH and Miltenyi Biotec Inc. (collectively,
`
`Petitioner”) filed a Petition (Paper 1, “Pet.”), seeking an inter partes review
`
`of claims 1-16 and 18-31 of U.S. Patent No. 9,987,308 B2 (Ex. 1001,
`
`“the °308 patent’). Fred Hutchinson Cancer Center (“Patent Owner’’) filed a
`
`Patent Owner Preliminary Response. Paper 7 (Prelim. Resp.”). With our
`
`authorization, Petitioner filed a Reply (Paper 8) and Patent Ownerfiled a
`
`Sur-reply (Paper 9).
`
`We haveauthority under 35 U.S.C. § 314, which provides that an
`
`inter partes review maynotbeinstituted “unless .
`
`.
`
`. there is a reasonable
`
`likelihoodthat the petitioner would prevail with respect to at least 1 of the
`
`claims challenged in the petition.” 35 U.S.C. § 314(a).
`
`For the reasons provided below, we determine Petitioner has not
`
`demonstrated a reasonable likelihood that it would prevail with respectto at
`
`least one claim challenged in the Petition. Accordingly, we denyinstitution
`
`of an inter partes review.
`
`A.
`
`Related Matters
`
`According to the parties, there are no matters related to this
`
`proceeding. Pet. 4; Paper 5, 1.
`
`B.
`
`The ’308 Patent and Related Technology
`
`Before reviewing the purported invention of the °308 patent, wefirst
`
`explain the background of the technology. T cells are a type of lymphocyte.
`
`T cells include helper T cells, which express the CD4 membrane
`
`glycoprotein, and cytotoxic T cells (CTL), also knownaskiller T cells,
`
`which express the CD8 membraneglycoprotein. Ex. 1001, 7:7—9; Pet. 7
`
`(citing Ex. 1002 § 20); Prelim. Resp. 7.
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`Patent 9,987,308 B2
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`T cells can be categorized into several subpopulations. A naive T cell
`
`(Tn) is “anon antigen experienced T lymphocyte that expresses CD62L and
`
`CD45RA,and doesnot express or has decreased expression of CD45RO- as
`
`comparedto central memory cells.” /d. at 7:30—33. A central memory cell
`
`(Tcm) is a subset of the antigen experienced memory T cells (Ty). /d.
`
`at 1:51-52. A Tew is an antigen experienced CTL that expresses CD62L and
`
`CD45RO, and doesnot express or has decreased expression of CD45RA as
`
`comparedto Ty cells. /d. at 7:14-17. Another subset of Ty is effector
`
`memory cells (Tem). /d. at 1:51-53. A Tem 1s an antigen experienced CTL
`
`that does not express or has decreased expression of CD62L on the surface
`
`thereof as compared to Ty cells, and does not express or has decreased
`
`expression of CD45RA as compared to Ty cells. /d. at 7:21—26. In response
`
`to antigen stimulation, CD8* Tcy and Ty both differentiate into short-lived
`
`cytolytic effector T cells (Tg). /d. at 1:59-62. A Tris an antigen experienced
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`CTL that does do not express or have decreased expression of CD62L,
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`CCR7, CD28, andare positive for granzyme B and perforin as compared to
`
`Tom. /d. at 7:38-42.
`
`The ’308 patent relates to adoptive cellular immunotherapy. /d.
`
`at 2:3-4:3. “Adoptive cellular immunotherapy uses genetically modified
`
`cells originally isolated from a patient or a donorto treat disease.” Prelim.
`
`Resp. 8; see also Pet. 13 (similar explanation). CAR-T therapyis a type of
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`adoptive cellular immunotherapy whereby T cells are genetically modified
`
`to express a chimeric antigen receptor (CAR). Prelim. Resp. 8. A CAR
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`comprises “an extracellular variable domain of an antibody specific for an
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`antigen associated with the disease or disorder and an intracellular signaling
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`IPR2023-00760
`Patent 9,987,308 B2
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`domain of a T cell or other receptors, such as a costimulatory domain.”
`
`Ex. 1001, 7:56—60; Pet. 14; Prelim. Resp. 8 n.4.
`
`The °308 patent explains that for clinical applications of the adoptive
`
`immunotherapy,“it is necessary to isolate T cells of a desired antigen
`
`specificity or to engineer T cells to express receptorsthat target infected or
`
`transformed cells, and then expand these cells in culture.” /d. at 1:34—38.
`
`These cells, which can target pathogens or malignantcells, are then
`
`transferred to recipients to treat cancer and infections. /d. at 1:31—34; 38-45.
`
`Accordingto the ’308 patent, “it 1s apparent from clinical studies that
`
`the efficacy of cultured T cells, particularly cloned CD8" T cells,is
`
`frequently limited by their failure to persist after adoptive transfer.” 1:45—48.
`
`Thus, the °308 patentstates “[t]here is a need to identify cell populations and
`
`methods that provide enhanced survival of adoptively transferred T cells in
`
`vivo.” Id. at 1:65—67.
`
`The purported invention of the *308 patent relates to methods and
`
`compositions to “confer and/or augment immune responses mediated by
`
`cellular immunotherapy, such as by adoptively transferring tumor-specific,
`
`subset specific genetically modified CD4+T cells, wherein the CD4+T cells
`
`
`
`confer and/or augmentthe ability of CD8+ T cells to sustain anti-tumor
`
`reactivity and increase and/or maximize tumor-specific proliferation.” /d.
`
`at 2:3-10.
`
`C.
`
`Illustrative Claim
`
`Amongthe challenged claims, claim 1 is independent. Claim 1 is
`
`illustrative of the claimed subject matter and is reproduced below.
`
`1. An adoptive cellular immunotherapy composition containing
`chimeric antigen receptor-modified CD4* T lymphocytes and
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`
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`Patent 9,987,308 B2
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`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 andat least 50% of the chimeric
`antigen receptor-modified CD4+ helper T lymphocytesin 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.
`
`Ex. 1001, 31:45-59.
`
`D.—Asserted Challenges to Patentability
`
`Petitioner asserts the following challenges to patentability:
`
`
`
`
`
`
`
`1-7, 14, 16, 21, 26-28
`1-7, 14, 16, 21, 26-28
`
`Singh-1, Jensen?
`
`
`
`' The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29,
`125 Stat. 284, 287-88 (2011), amended 35 U.S.C. §§ 102, 103, effective
`March 16, 2013. The earliest priority date on the face of the ’308 patentis
`March 23, 2011. Ex. 1001, code 60. Because Petitioner has not challenged
`this priority claim (see Pet. 6), for this Decision, we apply the pre-AIA
`version of §§ 102, 103.
`? Singhet al., Redirecting specificity of T-Cell populationsfor CD19 using
`the sleeping beauty system, 68(8) CANCER RES. 2961-71 (2008) (Ex. 1003,
`“Singh-1”),
`3 Jensen et al., US Patent Publication No. 2004/0126363 A1, published
`July 1, 2004 (Ex. 1018, “Jensen”’).
`
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`Patent 9,987,308 B2
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`
`
`
`
`
`
` ingh-1,
`Jensen,
`Mitsuyasu,
`
`
`Cooper®, Hudecek I,’ Hudecek
`1,8 Abken,? Reckamp,!°
`Carpenito,!! Moeller,!? Wang,"
`YangI,'* YangII,’° Sallusto,'®
`
`
`
`* Petitionerlists the obviousness challenge of claims 1-16 and 18-31 asa
`single ground. See Pet. 6. However, Petitioner also indicatesthat “not all
`references are necessary for each claim” and breaks this groundinto four
`sub-parts: (1) claims 3 and 18—25 as being obvious over Singh, HudecekI,
`Abken, Hudecek II, Reckamp, or Carpenito; (2) claims 6 and 9-13 as being
`obvious over Singh, Wang, and/or Mitsuyasu; (3) claims 14 and 15 as being
`obvious over Singh, Moeller, and/or Mitsuyasu; and (4) claims 8 and 29-31
`as being obvious over Singh, Wang, Hudecek I, Yang I, YangII, Sallusto,
`and/or Sun. /d. 50-52.
`
`> Mitsuyasuet al., Prolonged survival andtissue traffickingfollowing
`adoptive transfer of CD4¢ gene-modified autologous CD4" and CD8* T
`cells in human immunodeficiency virus-infected subjects, 96(3) BLOOD 785—
`93 (2000) (Ex. 1004, “Mitsuyasu’”).
`© | ENCYCLOPEDIA OF CANCER Chimeric Antigen Receptor on T Cells (2009)
`(Ex. 1010, “Cooper’”).
`’ Hudeceket al., Adoptive T-cell therapyfor B-cell malignancies, 2(5)
`EXPERT REV. HEMATOL. 517-32 (2009) (Ex. 1011, “Hudecek I’).
`® Hudeceket al., CD8" T cells engineered to express a ROR1-specific
`chimeric antigen receptor specifically recognize ROR positive B cell
`tumors, 114(22) BLOOD 383 (2009) (Ex. 1012, “Hudecek IT’).
`” | ENCYCLOPEDIA OF CANCERChimeric T Cell Receptors (2009) (Ex. 1013,
`“Abken’’).
`© Reckampet al., CE7 epitope ofLICAM is a potential targetfor tumor
`specific T cell therapy in lung cancer, 49 PRoc. AACR ANNUAL MEETING
`1099 (2008) (Ex. 1014, “Reckamp”).
`
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`Petitioner relies on the declaration of Dr. Jonathan Bramsonas
`
`support for its Petition. Ex. 1002.
`
`II.
`
`ANALYSIS
`
`A.
`
`Level ofOrdinary Skill
`
`In determining the level of ordinary skill in the art, various factors
`
`may be considered, including the “type of problems encounteredin theart;
`
`prior art solutions to those problems; rapidity with which innovations are
`
`made; sophistication of the technology; and educational level of active
`
`workersin the field.” /n re GPAC, Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995).
`
`'! Carpenito et al., Control oflarge, established tumor xenografts with
`genetically retargeted human T cells containing CD28 and CD137 domains,
`106(9) PNAS 3360-65 (2009) (Ex. 1015, “Carpenito”).
`” Moelleret al., Adoptive transfer ofgene-engineered CD4* helperT cells
`induces potent primary and secondary tumorrejection, 106(9) BLOOD 2995—
`3003 (2005) (Ex. 1016, “Moeller’).
`'S Wanget al., The CD19 chimeric antigen receptor re-directs CMVspecific
`T cells derivedfrom central memory T cells (bi-specific T cells) against
`human acute lymphoid leukemia (ALL), 31(9) J. IMMUNOTHER. 926-27
`(2008) (Ex. 1017, “Wang”).
`4 Yanget al., In vitro generated anti-tumor T lymphocytes exhibit distinct
`subsets mimicking in vivo antigen-experienced cells, 60 CANCER IMMUNOL.
`IMMUNOTHER. 739-49 (2011) (Ex. 1027, “Yang I’).
`'S Yanget al., TCR engineered andin vitro expanded T lymphocytes
`recapitulate the properties of central memory T cells, 18 MOLECULAR
`THERAPY S184 (2010) (Ex. 1028, “Yang IT’).
`'6 Sallusto et al., 7wo subsets ofmemory T lymphocytes with distinct homing
`potentials and effectorfunctions, 401 NATURE 708-12 (1999) (Ex. 1029,
`“Sallusto”).
`'7 Sun et al., Dysfunction ofsimian immunodeficiency virus/simian human
`immunodeficiency virus-induced IL-2 expression by central memory CD4* T
`lymphocytes, 174(8) J. IMMUNOL. 4753-60 (2005) (Ex. 1032, “Sun”’).
`
`7
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`Furthermore, the prior art itself can reflect the appropriate level of ordinary
`
`skill in the art. Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001).
`
`Petitioner argues that an ordinarily skilled artisan “is skilled in
`
`developing genetically engineered T-cell therapies” and “would possessa
`
`relatively high level of skill and haveat least a Ph.D., together with several
`
`years of experience in researching and publishing academicarticles
`
`concerning T-cell therapies.” Pet. 15. Petitioner also contends that a person
`
`of ordinary skill in the art “would be knowledgeable about laboratory
`
`techniquesrelated to engineering and testing the function of genetically
`
`modified T cells.” /d. (citing Ex. 1002 4 53).
`
`Patent Ownerdisagrees with Petitioner’s proposed skill level. Prelim.
`
`Resp. 12-16. First, Patent Ownerargues that by excluding artisans with
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`M.D., but not Ph.D., degrees, Petitioner’s definition excludes “[a] number of
`
`authors or listed inventors from Petitioner’s exhibits” as well as the
`
`inventors of the ’308 patent, “which is strongly disfavored.” /d. at 13
`
`(citing Exs. 2004—2009). Second, Patent Ownerchallenges Petitioner’s
`
`definition of skill level for requiring experience “publishing academic
`
`articles,” because it “would exclude otherwise skilled artisans merely
`
`because their work is not yet published, cannot be published for business or
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`other reasons, or is purely clinical.” /d. at 14. Third, Patent Ownerpoints out
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`“Petitioner’s proposed POSAdefinition is inconsistent with the POSA it
`
`proposed in other IPR Petitions involving CAR-modified T cells.” /d.
`
`(footnote omitted).
`
`Patent Ownerarguesthat an ordinarily skilled artisan has:
`
`[a]n M.D. and/or Ph.D. degreein a field related to adoptive
`immunotherapy (for example, immunology, molecular biology,
`cell/cellular biology, genetics, biochemistry, biology,
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`biomedical sciences, or a related field), or an equivalent degree,
`and 2-4 years of work or research experience involving the
`manufacture of adoptively transferred T cells, as well as the
`assessment of the functions of adoptively transferred T cells in
`vivo.
`
`Id. at 16. Alternatively, Patent Owner proposesthat “a POSA could have a
`
`B.S. or a MLS. degree in a field related to adoptive immunotherapy, or an
`
`equivalent degree, and 4-6 years of the experience described above.”/d.
`
`Weagree with Patent Ownerthat an ordinarily skilled artisan should
`
`encompass the inventor. See Daiichi Sankyo Co., Ltd. v. Apotex, Inc., 501
`
`F.3d 1254, 1256-57 (Fed. Cir. 2007). On this record, we also decline to
`
`include publication of academicarticles as a requirement.
`
`After reviewing the record, for purposes of this Decision, we adopt
`
`Patent Owner’s definition as it is consistent with the prior art’s
`
`demonstration of the skill level at the time of the invention.
`
`B.
`
`Claim Construction
`
`In an inter partes review, we construe a claim term “using the same
`
`claim construction standard that would be used to construe the claim in a
`
`civil action under 35 U.S.C. [§] 282(b).” 37 C.F.R. § 42.100(b) (2020).
`
`Underthat standard, the words of a claim “are generally given their ordinary
`
`and customary meaning,” whichis “the meaning that the term would have to
`
`a person of ordinary skill in the art in question at the time of the invention,
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`1.e., as of the effective filing date of the patent application.” Phillips v. AWH
`
`Corp., 415 F.3d 1303, 1312-13 (Fed. Cir. 2005) (en banc).
`
`Petitioner discusses the preamble “adoptive cellular immunotherapy
`
`composition” and proposes the construction for “and/or.” We address these
`
`issues in turn.
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`1.
`
`“adoptive cellular immunotherapy composition”
`
`Petitioner argues that the preamble “adoptive cellular immunotherapy
`
`composition”is not limiting because it is merely a statement of intended use.
`
`Pet. 17-19. According to Petitioner, the ’308 patent’s “specification
`
`indicates that the preamble is an intended use”becauseits title 1s “Method
`
`and Compositions For Cellular Immunotherapy” and the “Field of the
`
`Invention” explains that “embodiments of the invention relate to methods
`
`and compositions for carrying out cellular immunotherapy.” /d. at 17-18
`
`(citing Ex. 1001, 1:1—2, 1:25-27, 16:26—46, 18:19-23; Ex. 1002 4 75)
`
`(emphasis added byPetitioner).
`
`In addition, Petitioner contends that the body of claim | recites a
`
`structurally complete invention, and the preamble “does not provide
`
`antecedent basis for any other claim element, does notrecite essential
`
`structure or steps, and is not necessary to give life, meaning, andvitality to
`
`any Challenged Claim.” /d. at 18 (quotation marks and brackets omitted).
`
`Further, Petitioner points out Patent Owner neverrelied on the preamble to
`
`traverse rejections during prosecution. /d. at 19.
`
`Petitioner arguesthat if the Board finds the preamble limiting,
`
`“adoptive cellular immunotherapy composition” should mean a
`
`“composition for adoptive cellular immunotherapy formulated to be suitable
`
`for administration to a mammal.” /d. (citing Ex. 1002 § 81).
`
`Patent Owner contendsthat the preamble is limiting because cellular
`
`immunotherapy “is not merely a potential intended use of a separate
`
`invention. Rather, it is the invention.” Prelim. Resp. 19. Patent Owner argues
`
`“Ta] POSA would understand from the specification of the ’308 patent that
`
`inventive compositions are inventive precisely because they afford clinically
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`10
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`relevant immunotherapeutic effect.” /d. at 20. Pointing to Figures 12
`
`and 13B of the °308 patent, Patent Ownerasserts “the specification
`
`emphasizes the dramatic therapeutic effect seen following in vivo testing
`
`with the claimed compositions.” /d. at 20-21. Thus, Patent Owner continues,
`
`the ’308 patent is directed to compositionsthat “actually provide clinically
`
`beneficial treatment, rather than mere cells per se that may or may not have
`
`effect.” /d. at 21-22. Patent Ownerfurther argues that the preambleis
`
`limiting becauseit serves as antecedentbasis for the term “composition”
`
`recited in the body of claim 1. /d. at 22—23 (citing Ex. 1001, 31:49-59).
`
`Asto how the preamble should be construed if given limiting effect,
`
`Patent Ownerdisagrees with Petitioner’s proposed construction. Instead,
`
`Patent Owner contends the preamble “adoptive cellular immunotherapy
`
`composition” should be given its plain and ordinary meaning, whichis “a
`
`composition comprising adoptively transferred cells that has therapeutic
`
`effect in vivo by causing or mediating an immuneresponse.” /d. at 24—25.
`
`Westart our analysis by first acknowledging that determining whether
`
`a preamble is limiting, despite (or perhaps because of) the numerouslegal
`
`canonson the topic, is not an easy task. “No litmus test defines when a
`
`preamble limits claim scope.” Catalina Mktg. Int’l, Inc. v. Coolsavings.com,
`
`Inc., 289 F.3d 801, 808 (Fed. Cir. 2002). Instead, “[w]hetherto treat a
`
`preambleasa limitation is determined on the facts of each casein light of
`
`the overall form of the claim, and the invention as described in the
`
`specification and illuminated in the prosecution history.” Deere & Co.v.
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`Bush Hog, LLC, 703 F.3d 1349, 1357 (Fed. Cir. 2012) (quotation marks
`
`omitted).
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`11
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`In general, “a preamble is not limiting where a patentee defines a
`
`structurally complete invention in the claim body and uses the preamble only
`
`to state a purpose or intendeduse for the invention.” Catalina, 289 F.3d
`
`at 808 (quotation marks omitted). But even then, “[w]hether a preamble
`
`stating the purpose and context of the invention constitutes a limitation of
`
`the claimed process is determined on the facts of each case in light of the
`
`overall form of the claim, and the invention as described in the specification
`
`and illuminated in the prosecution history.” Applied Materials, Inc. v.
`
`Advanced Semiconductor Materials Am., Inc., 98 F.3d 1563, 1572-73 (Fed.
`
`Cir. 1996).
`
`Wedeterminethat, read in view of the Specification, the preamble,
`
`even thoughit states an intended purpose,is limiting, because “‘itis
`
`necessary to give life, meaning, and vitality to the claim.” See Catalina,
`
`289 F.3d at 808 (quotation marks omitted). The ’308 patent discloses
`
`“an adoptive cellular immunotherapy composition comprising a genetically
`
`modified helper T lymphocyte cell [i.e., CD4* T cell] preparation that
`
`augments the genetically modified cytotoxic T lymphocytecell [i.e., CD8*
`
`T cell] preparation|’]s ability to mediate a cellular immuneresponse.”
`
`Ex. 1001, 9:4—8, see also id. at 9:36—42 (disclosing that in some
`
`embodiments, an adoptive cellular immunotherapy composition “comprises
`
`an antigen-reactive chimeric antigen receptor modified naive CD4+ T helper
`
`cell that augments the CD8+ immuneresponse.”’), 9:48—51 (the same).
`
`The ’308 patent also discloses that in some embodiments, an adoptive
`
`cellular immunotherapy composition further “comprises a chimeric antigen
`
`receptor modified tumor-specific CD8+ cytotoxic T lymphocyte cell
`
`preparation that elicits a cellular immune response.” /d. at 9:14—17, 23-26.
`
`12
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`Thus, the °308 patent describes the component CAR-modified CD8" T cells
`
`in an “adoptive immunotherapy composition”as eliciting a cellular immune
`
`response, and the component CAR-modified CD4‘ T cells as augmenting the
`
`CD8"* immuneresponse.
`
`The °308 patent discloses that, in an in vitro co-culture assay, “the
`
`addition of CAR-transduced, but not untransduced CD4"T cells to CD8*
`
`CAR CTLsignificantly increased specific proliferation of the CD8* subset
`
`compared to CD8* CAR CTL alone.” /d. at 24:57—-61, Fig. 7.
`
`The °308 patent also providesin vitro data, showing that naive CD4* T Cells
`
`are better helpers than memory CD4" T cells. Specifically, the data
`
`demonstrated that
`
`co-culture of CD8* N and CM CAR CTL with CD4* N CAR T
`cells resulted in significantly higher tumor-specific proliferation
`of the CD8* subset compared to co-culture with CD4* CM or
`EM CARTcells, or the CD8* CAR CTL alone (FIG.9). Out of
`all combinations, maximum proliferation of the CD8* CAR
`CTL in response to stimulation with ROR1-positive tumorcells
`was observedafter co-culture of CD4* N CART cells with
`CD8* CM CAR CTL(FIG. 9).
`
`Id. at 27:17-25, see also id. at 29:2—7 (“FIG. 10 showsthe superior ability of
`
`CD4+ CAR T-cell lines derived from the naive subset to augment
`
`tumor-specific proliferation of central memory-derived CD8+ CAR CTL in
`
`co-culture experiments with CD8+ CD19-CAR CTLs and CD4+
`
`CD19-CART-cell lines, stimulated with the CD19+ mantle cell lymphoma
`
`tumorline Jeko-1.”).
`
`In addition to the in vitro data showing CAR-modified CD4" T cells
`
`enhancethe proliferation of CAR-modified CD8" T cells, the ?308 patent
`
`also provides two examples using mouse models to show the adoptive
`
`transfer of RORI-CAR (Example 5) or CD19-CAR modified (Example 6)
`
`13
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`CD4* and CD8"*T cells confers “potent anti-tumor responses in an in vivo
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`model of aggressive systemic lymphomaand provide evidence for a
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`beneficial and synergistic effect of CD4* CARTcells on the anti-tumor
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`efficacy of CD8* CAR CTL.”/d. at 28:21—26, 29:50-56, see also id.
`
`at 28:15—19 (“Importantly, the reduction in tumor burdenafter
`
`administration of the CD8'/CD4* CARTcell combination was greater than
`
`that of the CD8* CAR CTL and CD4* CARTcell groups combined
`
`suggesting that CD4* CART cells and CD8* CAR CTL were working
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`synergistically.”), 29:18—26 (“FIG. 12 shows the augmentation and
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`synergistic effect CD4+ RORI-CAR modified T cells on the anti-tumor
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`efficacy of CD8+ ROR1-CAR CTLs in a mouse tumor model of systemic
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`mantle cell lymphoma (NSG/Jeko-1-ffLuc).”), 29:27-48 (“FIG. 13 shows
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`synergy of CD8+ and CD4+ CD19-CARTcells in a mouse modelof
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`systemic lymphoma (NSG/Raji).”).
`
`Thus, the ’308 patent’s Specification not only describes in detail that
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`CAR-modified CD4" T cells in an “adoptive immunotherapy composition”
`
`augment the CD8* immuneresponse,it provides both in vitro and in vivo
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`data to demonstrate the enhanced efficacy. These disclosures support Patent
`
`Owner’s argumentthat “the essence of the invention is that clinically
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`relevant therapeutic effect is achieved by virtue of the inventive T cell
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`compositions.” See Prelim. Resp. 19.
`
`We,of course, recognize that “there 1s sometimesa fine line between
`
`reading a claim in light of the specification, and reading a limitation into the
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`claim from the specification.” Phillips v. AWH Corp., 415 F.3d 1303, 1323
`
`(Fed. Cir. 2005). In this case, we find further support to our conclusion in
`
`the Summary of the Invention section of the Specification.
`
`14
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`IPR2023-00760
`Patent 9,987,308 B2
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`“Although a statement’s location is not “determinative,” the location
`
`can signal the likelihood that the statement will support a limiting definition
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`of a claim term.” C.R. Bard, Inc. v. U.S. Surgical Corp., 388 F.3d 858, 864
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`(Fed. Cir. 2004). Statements in the “Summary of the Invention” portion of
`
`the specification are not limited to describing preferred embodiments, but
`
`more broadly describe the overall invention, and therefore, are more likely to
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`support a limiting definition of a claim term. /d.
`
`In the “Summaryof the Invention,” the ’308 patent discloses thatits
`
`invention
`
`relates to methods and compositions to confer and/or augment
`immune responses mediated by cellular immunotherapy, such
`as by adoptively transferring tumor-specific, subset specific
`genetically modified CD4+ T cells, wherein the CD4+ T cells
`confer and/or augmentthe ability of CD8+ T cells to sustain
`anti-tumor reactivity and increase and/or maximize
`tumor-specific proliferation.
`
`Ex. 1001, 2:3-10.
`
`It states that “an adoptive cellular immunotherapy composition”
`
`includes (1) a genetically modified CD8* T cell preparation that “elicits a
`
`cellular immune response;” and (2) a genetically modified CD4" T cell
`
`preparation “exhibits a predominant Th! phenotype as well as produce other
`
`cytokines,elicits direct tumor recognition and augmentsthe ability of
`
`genetically modified cytotoxic T lymphocytecell [i.e., CD8* T cell]
`
`preparations|’] ability to mediate a cellular immuneresponse.”/d. at 2:43—
`
`44, 50-55, 64-65, see also id. at 2:11—26 (disclosing a method of
`
`performing cellular immunotherapy by administering the twocell
`
`preparations above), 3:7—14 (disclosing “‘an adoptive cellular
`
`immunotherapy composition having an antigen specific CD8+ cytotoxic
`
`T lymphocyte cell preparation that elicits a cellular immune response” and
`
`15
`
`
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`IPR2023-00760
`Patent 9,987,308 B2
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`“an antigen-reactive chimeric antigen receptor modified CD4+ T helpercell
`
`that elicits a Thl cytokine response and augments the CD8+ immune
`
`response to pathogens”), 3:20—24 (disclosing “an adoptive cellular
`
`immunotherapy composition with an antigen-reactive chimeric antigen
`
`receptor modified CD4+ T helpercell that elicits direct tumor recognition
`
`and augments the CD8+ immune response to pathogens”), 3:30—41
`
`(disclosing “a method of manufacturing an adoptive immunotherapy
`
`composition by obtaining a chimeric antigen receptor modified tumor-
`
`specific CD8+ cytotoxic T lymphocyte cell preparation that elicits a cellular
`
`immuneresponse .
`
`.
`
`. and obtaining a modified naive CD4+ T helper cell
`
`that elicits a Th] cytokine response”), 3:47—61 (the same).
`
`In sum, the Summary of the Invention, in describing the invention as a
`
`whole, confirms our determination that the *308 patent is directed to
`
`“therapeutically effective, clinically relevant compositions that provide
`
`‘adoptive cellular immunotherapy.’” See Prelim. Resp. 21. Thus, on this
`
`record, and in view of the Specification’s repeated disclosures of the
`
`clinically relevant therapeutic effects of the “adoptive cellular
`
`immunotherapy composition,” we agree with Patent Ownerthat the
`
`preambleis limiting, and requires relevant therapeuticeffect in vivo.'®
`
`Consequently, we also agree with Patent Ownerthat “Petitioner’s proposed
`
`construction would expand the claimed compositions to any composition
`
`'8 The parties dispute whether “adoptive cellular immunotherapy
`composition” serves as antecedent basis for the term “composition”recited
`in the body of claim 1, and thus, is limiting. See Prelim. Resp. 23;
`Reply 6—7. We do not needto resolve this issue because Patent Owner has
`shownsufficiently that, in view of the Specification, the preambleis
`limiting.
`
`16
`
`
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`IPR2023-00760
`Patent 9,987,308 B2
`
`that could be delivered to a mammal, irrespective of whether they have any
`
`clinically relevant therapeutic effect in vivo.” Prelim. Resp. 24.
`
`Patent Ownerargues that the plain and ordinary meaningof “adoptive
`
`cellular immunotherapy composition” should be “a composition comprising
`
`adoptively transferred cells that has therapeutic effect in vivo by causing or
`
`mediating an immuneresponse.” Prelim. Resp. 25. We agree. Indeed,
`
`the 308 patent requires its composition “to confer and/or augment immune
`
`responses mediated by cellular immunotherapy.” See, e.g., Ex. 1001,
`
`Abstract, 2:3-10. Thus, on this record, and for purposesof this Decision, we
`
`adopt Patent Owner’s proposed construction of the preamble “adoptive
`
`cellular immunotherapy composition.”
`
`2.
`
`“and/or”
`
`Claim | recites that at least 50% of the CAR-modified CD4"* T cells in
`
`the claimed composition are surface positive for “CD62L and/or CD45RA,”
`
`and the CAR-modified CD8* T cells are surface positive for “CD62L and/or
`
`CD45RO.”Petitioner proposesthat the term “and/or” includes
`
`“embodiments having the element preceding ‘and/or,’ the element following
`
`‘and/or,’ or both the element preceding ‘and/or’ and the element following
`
`‘and/or’.” Pet. 20 (citing Ex. 1002 { 86).
`
`Underthis construction, Petitioner argues, the CD4" T cells recited in
`
`claim | can be surface positive for CD62L, for CD45RA,or both. /d. (citing
`
`Ex. 1002 § 87). And because CD62L*can beeither Ty or Tew cells,
`
`Petitioner contends “claim 1’s CAR-modified CD4" T cells can be either
`
`majority Tew or Ty.”/d. at 17 (citing Ex. 1002 §] 62-66). For similar
`
`reasons, Petitioner argues that “claim 1’s CD8" T cells can be majority Ty,
`
`17
`
`
`
`IPR2023-00760
`Patent 9,987,308 B2
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`Tc, Tem, or Tr.” /d. (citing Ex. 1002 §§] 67—70); Jd. at 20 (citing Ex. 1002
`
`4] 87-88).
`
`Atthis stage, Patent Owner doesnot dispute Petitioner’s proposed
`
`construction or provide its own construction of “and/or.” Based on the
`
`current record, we agree with Petitioner’s proposed construction becauseitis
`
`supported by the claim languageandthe Specification of the °308 patent.
`
`Claim terms need only be construed to the extent necessary to resolve
`
`the controversy. Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361
`
`(Fed. Cir. 2011). On this record and for purposes of this Decision, we see no
`
`need to expressly address any other claim term.
`
`C.
`
`Alleged Anticipation by Singh-1
`
`Petitioner asserts that Singh-1 anticipates claims 1—7, 14, 16, 21, and
`
`26-28 of the ’308 patent. Pet. 31-48. Patent Ownerdisputes Petitioner’s
`
`challenge. Prelim. Resp. 17—32. Based on this record, and for at least the
`
`following reasons, we determine Petitioner has not established a reasonable
`
`likelihood that it would prevail in this assertion.
`
`1.
`
`Singh-1
`
`Singh-1 reports a new approach that employsthe Sleeping Beauty
`
`(“SB”) transposon/transposase system “to efficiently generat[e] T cells with
`
`redirected specificity.” Ex.1003, Abstract. According to Singh-1, “[w]hen
`
`coupled with numerical expansion on CD19"artificial antigen-presenting
`
`cells, this gene transfer method results in rapid outgrowth of CD4* and CD8*
`
`T cells expressing CARto redirect specificity for CD19* tumorcells.” /d.
`
`The CAR in Singh-1, designated CD19RCD28, includes an anti-CD19
`
`binding site, a CD28 costimulatory domain, and a CD3 intracellular
`
`signaling domain. /d. at 2961. Singh-1 used electroporation to introduce the
`
`18
`
`
`
`IPR2023-00760
`Patent 9,987,308 B2
`
`DNAexpression plasmids. /d. at 2963. Singh-1 “observed that peripheral
`
`blood- and umbilical cord blood-derived electroporated CD4* and CD8*
`
`T cells readily expressed the CAR transposon.”/d. at 2965 (stating “after 28
`
`to 35 days, the efficiency of two DNA plasmid SB-mediated genetransfer
`
`improved CAR expression by ~49 to 60-fold, compared with a single
`
`plasmid transposon control (Table 1)”). Singh-1 reports “a 20-fold growth of
`
`genetically modified T cells at the end of 4 weeks with continued and
`
`accelerated expansion thereafter (Fig. 44).” /d. at 2967. According to
`
`Singh-1, its approach “results in efficient and stable CAR genetransfer,
`
`which can be numerically expandedto clinically meaningful numbers within
`
`4 weeks... . and with the outgrowth of CD8* and CD4* CM andeffector
`
`CAR’T-cell subpopulations.” /d. at 2962.
`
`Singh-1 touts that its approach “provides for robust antigen-driven
`
`expansion of CD4* and CD8* CAR‘T cells to clinically meaningful
`
`numbers.” /d. at 2964, see also id. at 2961 (suggesting its approach
`
`“shortens the culture time to generate T cells with durably expressed
`
`transgene and maintains a desired T-cell immunophenotype”), id. at 2962
`
`(“This is predicted to greatly facilitate trial design infusing CD4* and CD8*
`
`CAR‘T cells that have desired immunophenotype, including Tcy.”).
`
`Singh-1 states that it has “incorporated ex vivo CAR-dependentproliferation
`
`to derive genetically modified T cells and will evaluate the CD19-specific
`
`T cells, using SB transposition and aAPC,in a next-generation clinical trial.”
`
`Id. at 2970-71.
`
`2.
`
`Analysis
`
`For purposesof this Decision, we focus our analysis on the preamble
`
`of claim 1. Petitioner argues that Singh-1 discloses the preamble; Patent
`
`19
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`
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`IPR2023-00760
`Patent 9,987,308 B2
`
`Ownerasserts that it does not. See Pet. 32—34; Prelim. Resp. 26—33. Forat
`
`least the reasons below, we agree with Paten
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