Trials@uspto.gov
`571-272-7822
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`
`
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`Paper 10
`Entered: October 11, 2022
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MILTENYI BIOMEDICINE GmbH and MILTENYI BIOTEC INC.,
`Petitioner
`v.
`
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA,
`Patent Owner
`
`____________
`
`IPR2022-00855
`Patent 9,540,445 B2
`____________
`
`Before ULRIKE W. JENKS, SUSAN L. C. MITCHELL, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`JENKS, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`

`

`IPR2022-00855
`Patent 9,540,445 B2
`
`
`I.
`
`INTRODUCTION
`
`A. Background
`Miltenyi Biomedicine GmbH and Miltenyi Biotec Inc. (collectively,
`“Petitioner”) filed a Petition for an inter partes review of claims 1–19 and
`21–30 of U.S. Patent No. 9,540,445 B2 (“the ’445 Patent,” Ex. 1001).
`Paper 1 (“Pet.”). Trustees of the University of Pennsylvania (“Patent
`Owner”) timely filed a Preliminary Response. Paper 7. (“Prelim. Resp.”).
`Petitioner further filed an authorized Reply to the Preliminary Response
`(Paper 8, “Reply”); Patent Owner filed a responsive Sur-Reply (Paper 9,
`“Sur-Reply”).
`We have authority, acting on the designation of the Director, to
`determine whether to institute an inter partes review under 35 U.S.C. § 314
`and 37 C.F.R. § 42.4(a)(2020). Inter partes review may not be instituted
`unless “the information presented in the petition filed under section 311 and
`any response filed under section 313 shows that there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a). The Supreme Court
`held that a decision to institute under 35 U.S.C. § 314 may not institute on
`fewer than all claims challenged in the petition. SAS Inst., Inc. v. Iancu, 138
`S. Ct. 1348, 1359–60 (2018).
`For the reasons set forth below, upon considering the Petition,
`Preliminary Response, and supporting evidence of record, we determine that
`Petitioner has sufficiently shown for the purpose of institution that the
`information presented in the Petition establishes a reasonable likelihood that
`Petitioner will prevail with respect to at least one of the challenged claims.
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`Patent 9,540,445 B2
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`Accordingly, we institute inter partes review on all of the challenged claims
`based on all of the grounds identified in the Petition.
`Our findings of fact, conclusions of law, and reasoning discussed
`below are based on the evidentiary record developed thus far, and made for
`the sole purpose of determining whether the Petition meets the threshold for
`initiating review. This decision to institute trial is not a final decision as to
`the patentability of any challenged claim or the construction of any claim
`limitation. Any final decision will be based on the full record developed
`during trial.
`
`B. Real Parties-in-Interest
`Petitioner identifies itself, Miltenyi Biomedicine GmbH and Miltenyi
`Biotec Inc. as the real parties-in-interest. Pet. 11. Patent Owner, identifies
`itself, The Trustees of the University of Pennsylvania and its licensee,
`Novartis Pharma AG, as real parties-in-interest. Paper 5, 2.
`
`C. Related Matters and Chain of Priority
`The ’445 patent issued from application No. 14/997,136 (“the ’136
`application”) which is a continuation of application No. 13/992,622 (“the
`’622 application”), filed as application No. PCT/US2011/064191 (“the PCT
`application”) on December 9, 2011. The ’445 patent further claims benefit of
`priority to provisional application No. 61/421,470. filed on December 9,
`2010, and provisional application No. 61/502,649. filed on June 29, 2011.
`Petitioner reasonably contends that the challenged claims of the ’445
`patent are not entitled to benefit of the provisional applications. Pet. 13, 71
`(citing, e.g., Ex. 1021, 402). Patent Owner does not presently contest this
`assertion. See Prelim. Resp. 41. On the present record, we consider
`
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`IPR2022-00855
`Patent 9,540,445 B2
`
`December 9, 2011, filing date of the PCT application, to be the earliest
`possible priority date for the challenged claims.
`Petitioner concurrently challenges claims of related U.S. Patent Nos.
`9,518,123 B2 (“the ’123 patent) and 9,464,140 B2 (“the ’140 patent”) in
`IPR2022-00852 and IPR2022-00853, respectively. The ’123 and ’140
`patents similarly issued from continuation applications of the ’622 parent
`application and, thus, share the substantially the same specification. The
`’622 parent application issued as U.S. Patent No. 9,499,629 B2 (“the ’629
`patent.). The ’123, ’140, ’445, and ’629 patents were Examined by the same
`Examiner.
`
`4
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`

`

`Ground
`
`35 U.S.C §1
`
`1
`
`2
`
`§ 103
`
`§ 103
`
`Reference(s)/Basis
`Campana,2 Nicholson,3
`Honsik,4
`CART-19 ClinicalTrials.gov5
`Campana, Jensen,6 Honsik,
`CART-19 ClinicalTrials.gov
`Campana, Milone,7
`CART-19 ClinicalTrials.gov,
`Nicholson, Jensen,
`Littman,8 Sadelain,9 Honsik,
`Riddell10
`Campana, Porter,11 Nicholson,
`Jensen, Littman, Sadelain,
`Honsik, Riddell
`
`IPR2022-00855
`Patent 9,540,445 B2
`
`D. Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 5):
`Claims
`Challenged
`1–4, 6, 8, 9, 11,
`16, 21, 22, 27–
`30
`1–6, 8, 9, 11, 13,
`16, 21, 22, 27–
`30
`
`3
`
`4
`
`1–30
`
`§ 103
`
`1–30
`
`§ 103
`
`
`1 The Leahy-Smith America Invents Act (“AIA”) included revisions to
`35 U.S.C. § 103 that became effective on March 16, 2013. Because the ’140
`patent issued from an application that is a continuation of an application
`filed before March 16, 2013, we apply the pre-AIA version of the statutory
`basis for unpatentability.
`2 US 2005/0113564, publ. May 26, 2005. Ex. 1003 (“Campana”).
`3 Nicholson et al., “Construction and Characterisation of a Functional
`CD19 Specific Single Chain Fv Fragment for Immunotherapy of B Lineage
`Leukaemia and Lymphoma,” 34 MOL. IMMUNOL. 1157 (1997). Ex. 1004
`(“Nicholson”).
`4 US 4,844,893, issued July 4, 1989. Ex. 1005 (“Honisk”).
`5 “Pilot Study for Patients with Chemotherapy Resistant or Refractory CD19
`Leukemia and Lymphoma (CART-19),” https:/clinicaltrials.gov/ct2/show/
`NCT00891215. Ex. 1006 (includes Declaration of Duncan Hall).
`6 US 2004/0126363, published July 1, 2004. Ex. 1007 (“Jensen”) .
`7 Milone et al., “Chimeric Receptor Containing CD137 Signal Transduction
`Domains Mediate Enhanced Survival of T Cells and Increased Antileukemic
`Efficacy In Vivo,” 17 MOL. THERAPY 1453 (2009). Ex. 1008 (“Milone”).
`
`5
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`IPR2022-00855
`Patent 9,540,445 B2
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`
`Petitioner further relies on, inter alia, the Declaration of Richard P.
`Junghans, M.D., Ph.D. Ex. 1002. Patent Owner did not choose to submit
`testimony of a technical expert at this stage of the proceeding.
`
`E. The ’445 Patent
`1) Background and Specification
`The ’445 patent, titled “Compositions and Methods for Treatment of
`Cancer,” issued on January 10, 2017, naming Carl H. June, Bruce L. Levine,
`David L. Porter, Michael D. Kalos, and Michael C. Milone as inventors.
`Ex. 1001, code (45), (72). The ’445 patent discloses administering immune
`cells—including T cells—modified to express a chimeric antigen receptor or
`CAR construct. See generally, id. at code (57), 1:29–42, 2:40–43.12 The
`disclosed CARs generally
`comprise an extracellular domain having an antigen binding
`domain fused to an intracellular signaling domain of the T cell
`antigen receptor complex zeta chain (e.g., CD3 zeta). The CAR
`of the invention when expressed in a T cell is able to redirect
`antigen recognition based on the antigen binding specificity.
`
`Id. at 19:6–12.
`
`
`8 Littman et al., “The Isolation and Sequence of the Gene Encoding T8: A
`Molecule Defining Functional Classes of T Lymphocytes,” 40 CELL 237
`(1985). Ex. 1009 (“Litmann”).
`9 US 2004/0043401, published March 4, 2004. Ex. 1010 (“Sadelain”).
`10 US 2008/0131415 A1, published June 5, 2008. Ex. 1011 (“Ridell”).
`11 Porter et al., “Chimeric Antigen Receptor–Modified T Cells in Chronic
`Lymphoid Leukemia,” 365 N. ENGL J. MED. 725 (2011), Ex. 1012
`(“Porter”).
`12 The ’445 patent variously refers to T cells transduced with CAR
`constructs as CAR modified T cells, CART, CAR T, or CAR-T cells. Id. at
`3:59–62, 5:23–30, 52:46–48.
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`Patent 9,540,445 B2
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`
`The ’445 patent variously refers to T cells transduced with CAR
`constructs as CAR modified T cells, CART, CAR T, or CAR-T cells. Id. at
`3:59–62, 5:23–30, 52:46–48. The CAR modified cells may be autologous T
`cells from a patient in need of treatment. See e.g., id. at 3:5–15, 9:49–58.
`Dr. Junghans explains: “When a patient’s own T cells are transduced and
`infused into the same patient, the T cells are identified as ‘autologous.’ This
`is in contrast to a cancer patient receiving transduced T cells from a healthy
`donor, wherein the T cells would be considered ‘allogeneic.’” Ex. 1002 ¶ 42.
`The ’445 patent discloses that in some embodiments the treatment is directed
`against a B-cell malignancy, such as Chronic Lymphocytic Leukemia
`(CLL). Ex. 1001, 18:29–31. 65–67.
`According to the ’445 patent, “[a]ttempts in using genetically
`modified cells expressing CARs to treat [patients having B-cell
`malignancies] have met with very limited success.” Id. at 1:29–42 (citations
`omitted). “[A] major impediment to the clinical application of this
`technology to date has been limited in vivo expansion of CAR+ T cells,
`rapid disappearance of the cells after infusion, and disappointing clinical
`activity.” Id. at 1:48–54. (citations omitted).
`The ’445 patent discloses T cells modified to express a “CAR
`compris[ing] an antigen binding domain, a transmembrane domain, a
`costimulatory signaling region, and a CD3 zeta signaling domain.” Ex. 1001,
`code (57). In a preferred embodiment the CAR comprises an “anti-CD19
`scFv13 derived from FMC63 murine monoclonal antibody, human CD8α
`
`
`13A “scFV” or “single chain variable fragment” is a recombinant antibody
`fragment in which Vl and Vh antigen recognition elements are fused with a
`short peptide linker to form a single polypeptide chain having an antigen
`recognition moiety derived from the parent antibody. See Ex. 1002 ¶ 33.
`
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`hinge and transmembrane domain, and human 4-1BB and CD3zeta signaling
`domains.” Id. at 4:37–40 (referencing Figs. 1A–1C). “The CD 19-BB-z
`transgene (GeMCRIS 0607-793) was designed and constructed as described
`(Milone et al., 2009, Mol Ther. 17:1453-1464) [Ex. 1008].” Id. at 41:5–7.
`In the figure below, Dr. Junghans provides “A schematic of the major
`functional elements of a preferred embodiment of the CAR and an
`illustration how the CAR could appear when inserted into the T cell
`surface.” Ex. 1002 ¶ 51.
`
`The above figure illustrates a CAR protein anchored in the T cell
`membrane via a CD8α hinge and transmembrane domain with 4-1BB co-
`stimulatory and CD3ζ signaling domains in the interior of the T cell, and
`extracellular VL and VH ScFv domains interacting with CD19 antigen on
`the surface of a tumor cell. See id.
`
`8
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`

`IPR2022-00855
`Patent 9,540,445 B2
`
`
`2) Challenged Claims
`Petitioner challenges claims 1–30 of the ’445 patent, of which only
`claim 1 is independent. Claim 1 recites:
`([a]) A pharmaceutical composition comprising
`([b]) an anti-tumor effective amount of a population of human T
`cells,
`([c]) wherein the T cells comprise a nucleic acid sequence
`encoding a chimeric antigen receptor (CAR),
`([d]) wherein the CAR comprises a CD19 antigen binding
`domain comprising, from the ammo to the carboxy
`terminus, a light chain variable region and a heavy chain
`variable region of SEQ ID NO:20,
`([e]) wherein the CAR further comprises a transmembrane
`domain, a 4-1BB co stimulatory signaling region, and a
`CD3 zeta signaling domain,
`([f]) wherein the T cells are from a human having cancer.
`Ex. 1001, claim 1 (paragraphing and reference letters [a]–[f] as added by
`Petitioner (see Pet. 28–29)).
`The challenged dependent claims recite limitations directed to the
`amount or structure of the T cells (claims 2–4); the identity or nucleic acid
`sequence of the CAR or its components (claims 6, 8, 9, 11, 16); the source of
`the T cells (claims 21, 22); and components of a pharmaceutical composition
`comprising the CAR construct (claims 27–30).
`
`II. ANALYSIS
`
`A. Legal Standards
`“In an IPR, the petitioner has the burden from the onset to show with
`particularity why the patent it challenges is unpatentable.” Harmonic Inc. v.
`Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed. Cir. 2016) (citing 35 U.S.C.
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`§ 312(a)(3) (requiring inter partes review petitions to identify “with
`particularity . . . the evidence that supports the grounds for the challenge to
`each claim”)). This burden of persuasion never shifts to Patent Owner. See
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375, 1378
`(Fed. Cir. 2015) (discussing the burden of proof in inter partes review).
`Petitioner challenges claims 1–30 as obvious under 35 U.S.C. § 103.
`The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398
`(2007), reaffirmed the framework for determining obviousness set forth in
`Graham v. John Deere Co., 383 U.S. 1 (1966). The KSR Court summarized
`the four factual inquiries set forth in Graham (383 U.S. at 17–18) that are
`applied in determining whether a claim is unpatentable as obvious under 35
`U.S.C. § 103 as follows: (1) determining the scope and content of the prior
`art; (2) ascertaining the differences between the prior art and the claims at
`issue; (3) resolving the level of ordinary skill in the art; and (4) considering
`objective evidence indicating obviousness or non-obviousness, if present.
`KSR, 550 U.S. at 406.
`“[W]hen a patent ‘simply arranges old elements with each performing
`the same function it had been known to perform’ and yields no more than
`one would expect from such an arrangement, the combination is obvious.”
`Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273, 282 (1976)). But
`in analyzing the obviousness of a combination of prior art elements, it can
`also be important to identify a reason that would have prompted one of skill
`in the art “to combine . . . known elements in the fashion claimed by the
`patent at issue.” Id. at 418. A precise teaching directed to the specific subject
`matter of a challenged claim is not necessary to establish obviousness. Id.
`Rather, “any need or problem known in the field of endeavor at the time of
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`
`invention and addressed by the patent can provide a reason for combining
`the elements in the manner claimed.” Id. at 420. Accordingly, a party that
`petitions the Board for a determination of unpatentability based on
`obviousness must show that a skilled artisan would have been motivated to
`combine the teachings of the prior art references to achieve the claimed
`invention, and that the skilled artisan would have had a reasonable
`expectation of success in doing so. In re Magnum Oil Tools International,
`Ltd., 829 F.3d 1364, 1381 (Fed. Cir. 2016) (quotations and citations
`omitted). Under the proper inquiry, “obviousness cannot be avoided simply
`by a showing of some degree of unpredictability in the art so long as there
`was a reasonable probability of success.” Pfizer, Inc. v. Apotex, Inc., 480
`F.3d 1348, 1364 (Fed. Cir. 2007).
`
`B. Level of Ordinary Skill in the Art
`In determining the level of skill in the art, we consider the type of
`problems encountered in the art, the prior art solutions to those problems, the
`rapidity with which innovations are made, the sophistication of the
`technology, and the educational level of active workers in the field. See
`Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 955, 962
`(Fed. Cir. 1986); see also Orthopedic Equip. Co. v. United States, 702 F.2d
`1005, 1011 (Fed. Cir. 1983).
`In addressing the level of ordinary skill in the art, Petitioner contents
`
`that:
`
`A POSA is a person skilled in the art of administering CAR
`T-cell therapies. The person would possess a relatively high
`level of skill and have at least an MD, together with several
`years of experience in administering CAR T-cell therapies. The
`person would also have experience designing CARs. The POSA
`would have knowledge of the scientific literature pertaining to
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`Patent 9,540,445 B2
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`
`immunology, including CARs and methods for utilizing CARs
`before the priority date. A POSA would also be knowledgeable
`about laboratory techniques related to engineering and testing
`the function of CAR T cells. A POSA would also be
`knowledgeable about designing clinical trials, including
`selecting dose ranges, that evaluate CAR T-cell therapies.
`Pet. 18. Patent Owner does not presently contest this definition.
`Although Petitioner’s definition generally comports with our
`understanding of the high level of skill in the art, we are not persuaded all of
`the asserted qualifications must be embodied in a single person. For
`example, it seems unduly limiting to require that the person of ordinary skill
`in the art have “at least an MD” degree, and “be knowledgeable about
`laboratory techniques related to engineering and testing the function of CAR
`T cells,” as Petitioner suggests. Accordingly, we provisionally adopt
`Petitioner’s definition with the caveat that the asserted qualifications may be
`shared among multiple individuals working as part of a multidisciplinary
`team.
`
`C. Claim Construction
`We interpret a claim “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). Under this standard, we construe the
`claim “in accordance with the ordinary and customary meaning of such
`claim as understood by one of ordinary skill in the art and the prosecution
`history pertaining to the patent.” Id. Moreover, “the specification ‘is always
`highly relevant to the claim construction analysis. Usually it is dispositive; it
`is the single best guide to the meaning of a disputed term.’” In re Abbott
`Diabetes Care Inc., 696 F.3d 1142, 1149 (Fed. Cir. 2012) (quoting Phillips
`v. AWH Corp., 415 F.3d 1303, 1315 (Fed. Cir. 2005) (en banc)).
`
`12
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`Patent 9,540,445 B2
`
`
`1) “anti-tumor effective amount”
`Claim 1 recites “an anti-tumor effective amount of a population of
`human T cells.” Claim 2 limits the anti-tumor effective amount of T cells
`recited in claim 1 to “104 to 109 cells per kg body weight of a human in need
`of such cells.”14 Relying on the testimony of Dr. Junghans, Petitioner
`proposes that the term “anti-tumor effective amount” should be understood
`to encompass at least “104 to 109 cells/kg body weight,” and any other
`amount of CAR T cells that would have at least one of the biological effect
`specifically described in the specification, including “a decrease in the
`number of tumor cells.” Pet. 19–21 (citing Ex. 1001, 37:60–64, 12:28–37;
`Ex. 1002 ¶¶ 56–61); Reply 3–5.
`In support of this position, Petitioner argues that “[w]hile claim 1 does
`not expressly state a numerical range for an “anti-tumor effective amount,”
`claim 1 necessarily encompasses at least the numerical range stated in
`dependent claim 2.” Pet. 19–20. Petitioner further argues that one of
`ordinary skill in the art would understand that a dose outside the range of 104
`to 109 cells per kg can also satisfy the claim limitation of “anti-tumor
`effective amount” if it provides at least one “anti-tumor effect” as defined in
`the Specification. Id. at 20. In this respect, Petitioner points to the ’445
`patent’s express definition of “anti-tumor effect” as
`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
`
`
`14 Claim 3 further limits this range to “105 to 106 cells per kg.”
`
`13
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`Patent 9,540,445 B2
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`
`antibodies of the invention in prevention of the occurrence of
`tumor in the first place.
`Id. (quoting Ex. 1001, 12:28–37 (emphasis by Petitioner)).
`As we understand it, Patent Owner’s response does not appear to
`contest that “anti-tumor effect” can comprise a decrease in the number of
`tumor cells, but argues that the claim term requires “a palpable therapeutic
`effect,” which is more than “just the death of a single cancer cell or handful
`of cells.” Prelim. Resp. 17–21; Sur-reply 3–5. In support, Patent Owner
`points to the ’445 patent’s express definition of “[a]n ‘effective amount’” as
`meaning “an amount which provides a therapeutic or prophylactic benefit.”
`Prelim. Resp. 18 (citing Ex. 1001, 13:53–54). Relatedly, we note that the
`Specification also teaches that a “‘therapeutically effective amount’ includes
`that amount of a compound that, when administered, is sufficient to prevent
`development of, or alleviate to some extent, one or more of the signs or
`symptoms of the disorder or disease being treated.” Ex. 1001, 18:12–15.
`Patent Owner further contends that
`[t]he specification teaches that “an antitumor effective amount”
`is an amount to be administered that is “determined by a
`physician” as part of determining “[t]he optimal dosage and
`treatment regime for a particular patient . . . by monitoring the
`patient for signs of disease and adjusting the treatment
`accordingly.”
`Prelim. Resp. 20 (citing Ex. 1001, 37:53–38:5).
`Considering the argument and evidence of record at this stage of the
`proceeding, we agree with Patent Owner that one of ordinary skill in the art
`would understand an “anti-tumor effective amount” to require more than the
`killing of a single tumor cell. Accordingly, and consistent with our
`determination in IPR2022-00853, we provisionally construe “anti-tumor
`effective amount” as meaning any amount of CAR T cells when
`
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`administered to a patient in need of cancer treatment that reduces the
`frequency or severity of at least one clinically relevant sign or symptom of
`the disease.
`We note that the “anti-tumor effective amount” as recited in the
`independent claim could reasonably be construed as a functional
`limitation.15 The patentability of a composition claim, however, “depends on
`the claimed structure, not on the use or purpose of that structure.” Catalina
`Mktg. Int’l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 809 (Fed. Cir.
`2002). Although statements of intended use often appear in the preamble, a
`statement of intended use or purpose can appear elsewhere in a claim. In re
`Stencel, 828 F.2d 751, 754 (Fed. Cir. 1987). Here, the pharmaceutical
`composition of claim 1 is defined by elements (c)–(f) which describes the
`structure of the CAR T cells, while the “anti-tumor effective amount”
`limitation (element (b)) represents an intended use that is embedded in a
`composition claim. “An intended use or purpose usually will not limit the
`scope of the claim because such statements usually do no more than define a
`context in which the invention operates.” See Boehringer Ingelheim
`Vetmedica, Inc. v. Schering-Plough Corp., 320 F.3d 1339, 1345 (Fed. Cir.
`2003). As discussed above, we have provisionally construed the “anti-tumor
`effective amount” limitation as meaning the administration of an amount16
`
`15 As discussed in the preceding paragraph, we interpret the “anti-tumor
`effective amount” as requiring an embedded method step that requires
`administering CAR T cells to a subject so one can then select only those
`compositions that show relief “of at least one clinically relevant sign or
`symptom of the disease.” See MasterMine Software, Inc. v. Microsoft Corp.,
`874 F.3d 1307, 1312–16 (Fed. Cir. 2017) (explaining impermissibility of
`mixing products with processes in claims); see also MPEP 2173.05(p).
`16 The recitation of 104 to 109 CAR T cells/kg body weight as set forth in
`claim 2 could be construed as a structural limitation as urged by Petitioner.
`
`15
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`of CAR T cells to a patient in order to reduce the frequency or severity of at
`least one clinically relevant sign or symptom of the disease. As such, this
`limitation merely describes the context in which the CAR T cells operate –
`in a cancer patient – but does not further define the structure of the
`composition.
`The parties are invited to brief this issue further at trial, if deemed
`necessary.
`
`2) Remaining Claim Terms
`At this stage of the proceeding, no other term requires construction.
`See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. Ltd. v. Matal,
`868 F.3d 1013, 1017 (Fed. Cir. 2017) (“[W]e need only construe terms ‘that
`are in controversy, and only to the extent necessary to resolve the
`controversy.’” (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200
`F.3d 795, 803 (Fed. Cir. 1999))).
`
`D. Over view of Asserted References
`1) Campana (Exhibit 1003)
`Campana is a US Patent Application Publication, published May 26,
`2005, and listing Dario Campana and Chilhaya Imai as inventors. Ex. 1003,
`codes (43), (75). Campana discloses the results of in vitro studies using an
`anti-CD19 CAR having the same overall structure as the CAR described in
`claim 1 of the ’445 patent.
`
`
`See Pet. 38–39. As such, a product with the recited structure in the recited
`amount would reasonably meet the functional limitation of being “anti-
`tumor effective” because it is an inherent characteristic of the product.
`Pet. 41 (“a POSA would have been motivated to use the CART-19
`ClinicalTrials.gov dose (which necessarily satisfies the limitation of ‘anti-
`tumor effective amount’)”); see MPEP 2114.
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`Campana discloses the use of CARs containing a co-stimulatory 4-
`1BB signaling domain in T cells and natural killer (NK) cells. Id. at, code
`(57). With respect to T cells, Campana states:
`We constructed a chimeric T-cell receptor specific for CD19
`that contains a 4-1BB signaling domain. We determined
`whether T cells transduced with these receptors could
`effectively destroy B-lineage ALL cell lines and primary
`leukemic cells under culture conditions that approximate the in
`vivo microenvironment where leukemic cells grow. We
`compared the properties of T-cells expressing the 4-1BB-
`containing receptor to those of T-cells expressing an equivalent
`receptor lacking 4-1BB or containing CD28 instead.
`Id. ¶ 69. Figure 1 of Campana, reproduced below, is a schematic
`representation of constructs used in this work.
`
`Id. at Fig. 1, ¶ 20.
`Figure 1 discloses representative CAR CD19-BB-ζ comprising a
`CD8α signal peptide, an anti-CD19 scFv binding region, a CD8α hinge and
`transmembrane domain, a 4-1BB costimulatory domain, and a CD3-ζ
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`signaling domain. Id. at Fig. 1, ¶ 13; Ex. 1002, ¶ 63. Reflecting its antigen
`specificity, Campana elsewhere refers to this same construct as “anti-CD19-
`BB-ζ.” See, e.g., id. ¶¶ 21, 38, 53.
`Campana discloses that primary T-cells were transduced with anti-
`CD19-BB-ζ, expanded in culture, and tested for activity in vitro. Id. ¶¶ 50–
`51. According to Campana, “[t]hese results show that 4-1BB co-stimulation
`confers a survival advantage on lymphocytes, which overcomes a major
`obstacle with current chimeric receptors used in immunotherapy.” Id. ¶ 51.
`Subsequent experiments showed that “T-cells expressing the anti-CD19 BB-
`ζ receptor exhibited cytotoxic activity at the 1:1 and 0.1:1 ratios against all
`CD19+ cell lines tested.” Id. ¶ 52. Campana reports that other experiments
`“show[] that T-cells transduced with the anti-CD19-BB-ζ receptor exhibit
`cytotoxic activity in an environment critical for B-lineage leukemic cell
`growth,” and that anti-CD19-BB-ζ expression “caused higher levels of
`TRAIL stimulation” and increased IL-2-mediated T-cell expansion. Id.
`¶¶ 53, 115, 116 (noting that T cells require TRAIL for optimal graft-versus-
`tumor activity).
`
`According to Campana, “[r]esults of this study indicate that anti-
`CD19-BB-ζ receptors could help achieve effective T-cell immunotherapy of
`B-lineage ALL.” Id. ¶ 113; see also id. ¶ 54 (“These results further support
`the use of anti-CD19-BB-ζ receptor for immunotherapy.”). Campana
`concludes that, “[i]n view of the limited effectiveness and the high risk of
`the currently available treatment options for chemo therapy-refractory B-
`lineage ALL and other B cell malignancies, the results of our study provide
`compelling justification for clinical trials using T cells expressing anti
`CD19-BB- ζ receptors.” Id. ¶ 118. For example, “[d]onor-derived T cells
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`endowed with chimeric receptors could replace infusion of non-specific
`lymphocytes post-transplant.” Id. In addition, “[t]he reinfusion of autologous
`T cells collected during clinical remission could also be considered in
`patients with persistent minimal residual disease.” Id. Consistent with these
`assertions, Campana claims
`17. A method for treating an individual suffering from cancer
`by introducing into said individual a T lymphocyte or natural
`killer cell comprising a chimeric receptor wherein said chimeric
`receptor comprises an extracellular ligand binding domain, a
`transmembrane domain, and a cytoplasmic domain, wherein
`said cytoplasmic domain comprises the Signaling domain of 4-
`1BB.
`Id. at claim 17.
`2) CART-19 ClinicalTrials.gov (Exhibit 1006)
`CART-19 ClinicalTrials.gov is a printout of a government website
`disclosing “Pilot Study for Patients with Chemotherapy Resistant or
`Refractory CD19 Leukemia and Lymphoma (CART-19).” Ex. 1006, 5; see
`also id. at 1–2 (Declaration of Duncan Hall).
`In setting forth the purpose of the study, CART-19 ClinicalTrials.gov
`explains that “[t]he subject’s T cells will be modified in one or two different
`ways that will allow the cells to identify and kill the tumor cells (B cells).”
`Id. at 5. In particular,
`The two types of CART-19 T cells will be given back to
`subject's through an infusion. In addition to determining the
`safety of this approach, the purpose of the study is to determine
`which way of modifying the T cells works better in turning
`them “on” to fight cancer. This is done by monitoring levels of
`both types of modified cells in the subject's blood stream, and if
`possible, in the bone marrow and tumor tissue for four weeks
`after the infusion.
`
`Id.
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`The reference further discloses that the study, designated
`NCT00891215, would be conducted at the University of Pennsylvania,
`Philadelphia, and identifies Dr. Carl H. June and David Porter, MD, as the
`“Responsible Party” and “Principle Investigator,” respectively. Ex. 1006, 6.
`The reference describes the NCT00891215 as “an open label, single center,
`pilot study to evaluate the safety and tolerability, and differential persistence
`and engraftment of autologous T cells engineered to express a chimeric
`antigen receptor targeting CD19 which is linked either to the CD3 or CD3:4-
`1 BB signaling chains in a competitive repopulation setting.” Id. at 5.
`NCT00891215 was expected to enroll 10 patients, each of which
`would receive three infusions of CART-19 cells for a total dose of ~2xE9 -
`5xE10 cells. The reference also discloses an evaluation and monitoring
`schedule and notes that “[a]nnual follow-up for lentiviral vector safety will
`be carried out for 15 years in accordance with FDA guidelines for retroviral
`vectors.” Id.
`3) Nicholson (Exhibit 1004)
`Nicholson discloses “a single chain Fv (scFv) fragment from the
`mouse hybridoma cell line FMC63 which produces monoclonal antibody
`specific for CD19.” Ex. 1004, 1157, 1160 (DNA and amino acid sequence
`information).
`4) Honsik (Exhibit 1005)
`Honsik is a United States Patent issued July 4, 1989. Ex. 1005,
`code (45). Honsik discloses pharmaceuticals compositions for infusing
`activated leukocyte