UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`
`MILTENYI BIOMEDICINE GmbH and MILTENYI BIOTEC INC.
`Petitioners,
`
`v.
`
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`Patent Owner.
`
`
`____________________
`
`
`IPR 2022-00855
`Patent 9,540,445
`
`____________________
`
`
`PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`
`

`

`Case IPR2022-00855
`Patent 9,540,445
`
`
`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1 
`I. 
`The ’455 Patent ................................................................................................ 4 
`II. 
`III.  Technical Background ..................................................................................... 6 
`A. 
`T Cells and the Immune System. .......................................................... 6 
`B.  Graft-versus-Host Disease and NK Cells. ............................................. 7 
`Cancer Patient T Cells Are Different from Healthy Donor T
`C. 
`Cells. ...................................................................................................... 7 
`IV.  The Art Reflected Decades of Failure of a Wide Variety of CAR-T
`Therapies. ......................................................................................................... 8 
`V.  Miltenyi Mischaracterizes or Omits Portions of Its Key References. ........... 10 
`A. 
`Campana .............................................................................................. 10 
`B. 
`Jensen .................................................................................................. 13 
`C. 
`ClinicalTrials.gov ................................................................................ 14 
`D.  Milone.................................................................................................. 16 
`VI.  The Phrase “Anti-Tumor Effective Amount” Requires a Therapeutic
`Benefit. ........................................................................................................... 17 
`VII.  Grounds 1-3: None of the Challenged Claims Would Have Been
`Obvious. ......................................................................................................... 22 
`The POSA Would Not Have Had a Reason to Make the
`A. 
`Claimed Inventions. ............................................................................ 23 
`The POSA Would Not Have Started with Campana
`1. 
`Except Through Hindsight. ....................................................... 24 
`Beginning with Campana, the POSA Would Not Have
`Made a CAR with the Claimed VL-VH Orientation. ................. 27 
`a. 
`Ground 1: Campana and Nicholson .............................. 27 
`
`2. 
`
`i
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`

`3. 
`
`4. 
`
`Case IPR2022-00855
`Patent 9,540,445
`
`Ground 2: Campana and Jensen .................................... 34 
`b. 
`Ground 3: Campana and “Sequence Art” ...................... 35 
`c. 
`Campana Would Not Have Motivated the POSA To
`Make the Claimed Composition and In Fact Teaches
`Away from Autologous T Cells. ............................................... 35 
`The POSA Would Not Have Known How to Arrive at an
`Anti-Tumor Effective Amount of Cells. ................................... 39 
`The POSA Would Not Have Had A Reasonable Expectation of
`Success. ............................................................................................... 41 
`The Law Requires Miltenyi To Show That The POSA
`1. 
`Would Have Had a Reasonable Expectation of Success in
`Arriving at an “Anti-Tumor Effective Amount.” ..................... 42 
`2.  Miltenyi Cannot Demonstrate that the POSA Would
`Have Had a Reasonable Expectation of Success of
`Achieving An “Anti-Tumor Effective Amount.” ..................... 45 
`3.  Miltenyi’s References Fail to Demonstrate a Reasonable
`Expectation of Success Despite All the Prior Failures. ............ 48 
`VIII.  Grounds 2-3: Claim 3 Would Not Have Been Obvious. ............................... 55 
`The POSA Would Not Have Arrived at the Dose of Claim 3
`A. 
`from Jensen or Reasonably Expected It To Be Successful. ................ 55 
`The POSA Would Not Have Arrived At the Claimed Dose from
`ClinicalTrials.gov ................................................................................ 58 
`Identifying Claims 3’s Dose Would Not Be “Routine
`Optimization.” ..................................................................................... 60 
`IX.  The Objective Indicia of Non-Obviousness Here are Overwhelming. ......... 60 
`X.  Ground 4: Porter is Not Prior Art and Does Not Demonstrate
`Obviousness. .................................................................................................. 64 
`
`B. 
`
`B. 
`
`C. 
`
`
`
`ii
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`

`TABLE OF AUTHORITIES
`
`Case IPR2022-00855
`Patent 9,540,445
`
`
`Alcon Res., Ltd. v. Apotex, Inc.,
`687 F.3d 1362, 1367-68 (Fed. Cir. 2012) ........................................................... 21
`Allergan v. Sandoz,
`796 F.3d 1293 (Fed. Cir. 2015) .......................................................................... 57
`Apple v. Voip-Pal.com,
`976 F.3d 1316 (Fed. Cir. 2020) .............................................................. 23, 24, 26
`Ariosa Diagnostics v. Verinata Health, Inc.,
`805 F.3d 1359 (Fed. Cir. 2015) .......................................................................... 47
`Boehringer Ingelheim Vetmedica v. Schering Plough,
`320 F.3d 1339 (Fed. Cir. 2003)
` ....................................................................................................................... 44, 47
`Catalina Mkt’g v. CoolSavings.com,
`289 F.3d 801 (Fed. Cir. 2002) ............................................................................ 45
`Cumberland Pharms. v. Mylan Institutional,
`846 F.3d 1213 (Fed. Cir. 2017) .......................................................................... 43
`Genzyme Therapeutic Prods. v. Biomarin Pharm.,
`825 F.3d 1360 (Fed. Cir. 2016) .......................................................................... 47
`HZNP Medicines v. Actavis Labs.,
`940 F.3d 680 (Fed. Cir. 2019) ............................................................................ 57
`In re Katz,
`687 F.2d 450 (C.C.P.A. 1982) ............................................................................ 65
`Intelligent Bio-Sys. v. Illumina Cambridge,
`821 F.3d 1359 (Fed. Cir. 2016) .......................................................................... 42
`L’Oréal USA v. Olaplex,
`844 F. App’x 308 (Fed. Cir. 2021) ..................................................................... 21
`Leo Pharm. Prod. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .................................................................... 60, 63
`
`iii
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`

`Case IPR2022-00855
`Patent 9,540,445
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`
`MasterMine Software v. Microsoft Corp.,
`874 F.3d 1307 (Fed. Cir. 2017) .......................................................................... 20
`Novartis v. West-Ward,
`923 F.3d 1051 (Fed. Cir. 2019) .......................................................................... 49
`Ortho-McNeil Pharm. v. Mylan Labs.,
`520 F.3d 1358 (Fed. Cir. 2008) .............................................................. 21, 23, 26
`OSI v. Apotex,
`939 F.3d 1375 (Fed. Cir. 2019) .................................................................... 48, 49
`Polaris Indus. v. Arctic Cat,
`882 F.3d 1056 (Fed. Cir. 2018) .......................................................................... 36
`Riverwood Int’l v. R.A. Jones,
`324 F.3d 1346 (Fed. Cir. 2003) .................................................................... 64, 65
`Teva Pharm. USA v. Corcept Therapeutics,
`18 F.4th 1377 (Fed. Cir. 2021) ........................................................................... 42
`Univ. of Strathclyde v. Clear-Vu Lighting,
`17 F.4th 155 (Fed. Cir. 2021) ............................................................................. 48
`Valeant Pharms. v. Mylan Pharms.,
`955 F.3d 25 (Fed. Cir. 2020) .................................................................. 56, 57, 58
`WBIP v. Kohler,
`829 F.3d 1317 (Fed. Cir. 2016) .......................................................................... 60
`
`
`
`
`iv
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`

`Case IPR2022-00855
`Patent 9,540,445
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`PATENT OWNER’S EXHIBIT LIST
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`

`Introduction
`The ’455 patent claims a composition of particular CAR-T cells for human
`
`Case IPR2022-00855
`Patent 9,540,445
`
`
`I.
`
`therapeutic use. By the December 2011 priority date, the idea of chimeric antigen
`
`receptor (CAR) modified T-cells was more than two decades old, but despite
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`extensive experimentation, no one had made them into a working therapy.
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`Scientists’ choices were numerous, but their expectations were low. There were
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`many alternative CAR targets, myriad potential antibodies to use for each, different
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`ways of making CAR-T cells, and at least three different generations of CARs,
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`with various “co-stimulatory” domains and without. From this menu of options,
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`researchers had tried approach after approach. But successful clinical experiments
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`were rare, fleeting, and punctuated by unforeseen deaths. Many scientists had
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`given up hope that CAR-T cells would ever be successfully marshalled to treat
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`people.
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`Dr. Carl June and his co-inventors at the University of Pennsylvania had a
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`unique focus among these choices. They performed the first clinical trial on any
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`anti-CD19 CAR with a 4-1BB costimulatory domain, using a concentration of cells
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`far below what Miltenyi’s cited art recommended. It was anything but obvious
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`that this would work at all, let alone yield such astonishing results or become the
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`first FDA-approved CAR-T therapy.
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`1
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`Miltenyi’s Petition leaps directly to anti-CD19 4-1BB CAR-T cells. Only
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`Ground 4 cites clinical results involving such cells, but the Porter reference is the
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`inventors’ own work and therefore not prior art. Ground 1-3, of necessity, rely on
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`pre-clinical studies: in vitro data from Campana and mouse data from Milone. But
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`neither in vitro nor mouse models can come close to predicting anti-tumor efficacy,
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`as the history shows and science explains. The many failed clinical trials had all
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`been preceded by pre-clinical data viewed as promising. Ex.2071 ¶70.
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`Miltenyi’s obviousness arguments therefore fail. At the outset, none of
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`Miltenyi’s references even disclose the claimed CAR. Miltenyi looks to Nicholson
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`for the sequence used by Campana, but Nicholson discloses a sequence with the
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`heavy and light variable chains reversed (a point Miltenyi and its expert bury in the
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`hopes no one will notice).
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`Even if the Board overlooks this sleight of hand, Miltenyi cannot
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`demonstrate why the POSA would have arrived at the claimed composition, using
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`the claimed anti-CD19 4-1BB CAR, to transduce T cells from a cancer patient.
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`The POSA would not have been motivated to develop a new CAR that had never
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`been tested clinically with a co-stimulatory domain that had also barely been
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`tested. And none of Miltenyi’s references recommend making the claimed CAR
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`using a cancer patient’s T cells, as the claims require. Miltenyi relies on Campana
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`for this critical claim element, but it states expressly that this is only something that
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`2
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`“could” be considered for patients whose T cells had been “collected during
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`clinical remission” and who had “persistent minimal residual disease,” Ex.1003
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`¶0118, i.e., patients whose cancer is virtually undetectable. No one was
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`contemplating giving such dangerous, experimental therapies to those patients in
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`2011. Ex.2070 at 229:3-14. No one even gives CAR-T therapy to such patients
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`today. Ex.2071 ¶62. Campana instead focused on trying to create CARs using the
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`healthy cells of donors.
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`Miltenyi also cannot meet its burden of proof regarding reasonable
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`expectation of success. The facts on this legally required element of an
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`obviousness analysis overwhelmingly tilt towards Patent Owner. So does the law.
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`Miltenyi must, as a matter of law, show that the POSA would have expected to
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`achieve an “anti-tumor effective amount,” i.e., an amount that corresponds to a
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`therapeutic benefit, not just the ability to transduce a particular number of cells.
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`This is a direct consequence of the claim language, the specification, and the
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`opinions of Miltenyi’s own expert—who admits that the “anti-tumor effective
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`amount” is a substantive claim limitation, not merely an expression of a goal.
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`Miltenyi admits as much in its Petition when it tries to prove it. Miltenyi’s
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`preclinical data cannot come close to establishing that this was expected to be the
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`one time that CAR-T therapy would succeed in treating cancer.
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`3
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`Finally, Miltenyi cannot establish that the specific claimed concentration of
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`cells of Claim 3 would have been obvious. The relationship between concentration
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`and efficacy was, concededly, not understood. Miltenyi’s principal reference for
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`concentration, Jensen, addressed a different CAR, lacking a co-stimulatory
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`domain; envisioned using healthy human donor cells; reported only in vitro data;
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`and recommended higher concentrations. Miltenyi’s “ClinicalTrials.gov”
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`reference describes a potential pilot study not designed to demonstrate efficacy,
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`having no data, and that does not disclose the claimed range.
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`The patentability of the challenged claims should be confirmed.
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`II. The ’455 Patent
`The ’445 patent relates to novel pharmaceutical compositions of a particular
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`type of CAR-T cells made by transducing the cells of a human cancer patient.
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`Claims 1-3 recite:
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`1. A pharmaceutical composition comprising an anti-tumor effective
`amount of a population of human T cells wherein the T cells
`comprise a nucleic acid sequence encoding a chimeric antigen
`receptor (CAR), wherein the CAR comprises a CD19 antigen
`binding domain comprising, from the amino to the carboxy
`terminus, a light chain variable region and a heavy chain variable
`region of SEQ ID NO:20, wherein the CAR further comprises a
`transmembrane domain, a 4-1 BB co stimulatory signaling region,
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`4
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`and a CD3 zeta signaling domain, wherein the T cells are from a
`human having cancer.
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`2. The composition of claim 1, wherein the anti-tumor effective
`amount of T cells is 104 to 109 cells per kg body weight of a human
`in need of such cells.
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`3. The composition of claim 1, wherein the anti-tumor effective
`amount of T cells is 105 to 106 cells per kg body weight of a human
`in need of such cells.
`Ex.1001, 91:10-25.
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`Both parties agree that these claims are directed to compositions for use in
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`treating patients. Ex.2070 at 67:1-17; Paper 1 (“Pet.”) 20-21. Notably, the claims
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`require that the cells be “from a human having cancer”—not from healthy human
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`donors. The POSA would have understood, as Miltenyi’s expert, Dr. Junghans
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`explained, that no one would give one cancer patient cells from a different cancer
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`patient for fear of giving them a new form of cancer. Ex.2070 at 181:6-14. Thus,
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`as a practical matter, the claims are directed to a composition made from a cancer
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`patient’s own cells, i.e., “autologous” cells. Ex.2070 at 179:14-19.
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`For purposes of this Response, Patent Owner does not dispute the
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`application of a December 9, 2011 priority date or Miltenyi’s proposed POSA
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`definition. See Ex.1002 ¶48.
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`5
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`III. Technical Background
`The Petition provides an overview of this field that is, in places, incomplete.
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`The following additional aspects of technical background are critical to assessing
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`the issues properly. They are explained in greater detail in Exhibit 2071, a
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`declaration by Dr. Robert Negrin, a Professor of Medicine at Stanford University
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`with decades of experience in immunology and the treatment of blood cancers.
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`Ex.2071 ¶¶5-19.
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`A. T Cells and the Immune System.
`“T cells” are not all the same. Ex.2071 ¶¶39-49. One significant distinction
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`among types of T cells is based on the extent to which they express CD4 or CD8,
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`two cell surface receptors. “CD8+” T cells are “cytotoxic” T cells capable of
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`killing other cells like cancer cells. “CD4+” T cells can have several phenotypes.
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`Ex.1029 at 350. Not all of them help “activate cytotoxic T cells to kill other cells,”
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`as Dr. Junghans suggests. Ex.1002 ¶25. Some, particularly the Treg phenotype,
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`“suppress T-cell responses rather than activate them.” Ex.1029 at 351.
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`The human body is constantly balancing the activation and suppression of
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`the immune system. Ex.2071 ¶41. More cytotoxic T cells circulating in the body
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`is not necessarily a good thing, as overstimulation of the immune system can result
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`in auto-immunity. Id.
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`6
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`B. Graft-versus-Host Disease and NK Cells.
`T-cell transplantation creates a serious risk of Graft-versus-Host Disease
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`(“GvHD”), an extremely dangerous complication in which foreign T cells attack
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`the organs of the patient (i.e., host). Ex.2071 ¶¶50-51. This risk of GvHD is why
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`bone-marrow transplant patients must be “matched” with their donor.
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`By 2011, however, it was understood that transplanting donor Natural Killer
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`(“NK”) cells did not risk causing GvHD. NK cells are another type of white blood
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`cell with a potent ability to kill other cells. Ex.2071 §§V.A.2, V.B. The ability to
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`source NK cells from healthy donors, combined with their existing cytotoxic
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`capabilities, made them a significant focus of research related to CAR therapy.
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`Ex.2071 §§V.B, V.C.2.
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`C. Cancer Patient T Cells Are Different from Healthy Donor T
`Cells.
`Immunologists have long recognized that T cells sometimes fail to work as
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`they should, for example when they are “exhausted.” Ex.2071 §V.A.1; Ex.2053;
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`Ex.2054 at 223. T-cell dysfunction can result from e