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`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`
`
`MILTENYI BIOMEDICINE GmbH and MILTENYI BIOTEC INC.,
`Petitioners,
`
`v.
`
`TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA,
`Patent Owner.
`
`_________________________________________________
`
`
`Case IPR 2022-00853
`Patent 9,464,140
`
`__________________
`
`PRELIMINARY RESPONSE OF PATENT OWNER
`TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`AND REAL PARTY IN INTEREST NOVARTIS PHARMA AG
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`Case IPR2022-00853
`Patent 9,464,140
`
`TABLE OF CONTENTS
`TABLE OF AUTHORITIES .......................................................................................................... ii 
`EXHIBIT LIST .............................................................................................................................. iv 
`I. 
`INTRODUCTION ...............................................................................................................1 
`II. 
`BACKGROUND .................................................................................................................4 
`A. 
`The State of CAR-T Cell Therapy Before 2011 ......................................................4 
`B. 
`The “Lazarus Moment” — The Inventors’ Breakthrough .......................................7 
`C. 
`The ’140 Patent ......................................................................................................12 
`PETITIONERS FAIL TO SHOW A REASONABLE LIKELIHOOD OF
`DEMONSTRATING OBVIOUSNESS OF ANY CLAIM ...............................................14 
`Petitioners Misconstrue the Claims To Avoid the Treatment and
`A. 
`Effectiveness Limitations .......................................................................................16 
`1. 
`The Preamble Is Limiting ..........................................................................17 
`2. 
`“Antitumor Effective Amount” ..................................................................19 
`Petitioners Cannot Demonstrate a Reasonable Expectation of Success ................23 
`The Art Reflected Decades of Failures and Tremendous
`1. 
`Skepticism That Petitioners Ignore ............................................................23 
`Petitioners’ Cherry-Picked References Do Not Support Reasonable
`Expectation of Success ..............................................................................28 
`Porter Is Not Prior Art............................................................................................41 
`Objective, Contemporaneous Evidence Proves the Non-Obviousness of
`the Claimed Methods .............................................................................................42 
`THE BOARD SHOULD DENY INSTITUTION UNDER § 325(d) ................................44 
`The Same or Substantially the Same Art Previously Was Presented to the
`A. 
`Examiner ................................................................................................................46 
`Petitioners Have Not Demonstrated that the Office Erred in a Manner
`Material to the Patentability of Challenged Claims ...............................................51 
`The File History of U.S. Patent Application No. 15/353,899 Is Irrelevant ...........52 
`C. 
`CONCLUSION ..................................................................................................................54 
`
`III. 
`
`IV. 
`
`V. 
`
`
`2. 
`
`B. 
`
`C. 
`D. 
`
`B. 
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`Case IPR2022-00853
`Patent 9,464,140
`
`TABLE OF AUTHORITIES
`CASES
`Advanced Bionics, LLC v. Med-El Elektromedizinische Gerate GmbH,
`IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) .........................................passim
`Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034 (Fed. Cir. 2016) (en banc) ........ 43
`Ariosa Diagnostics v. Verinata Health, Inc., 805 F.3d 1359 (Fed. Cir. 2015) ........ 23
`Biocon Pharma Ltd. v. Novartis Pharmaceuticals Corp., IPR2020-01263,
`Paper 12 (PTAB Feb. 16, 2021) ................................................................... 50, 51
`Broad Institute v. Regents of the Univ. of California, Patent Interference No.
`106,048 (DK), 2017 WL 657415 (PTAB Feb. 15, 2017) ................................... 34
`Coalition For Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-01136,
`Paper 23 (PTAB Sept. 2, 2015 Denying Institution of Inter Partes
`Review) ............................................................................................................... 36
`Eli Lilly & Co. v. Teva Pharmaceuticals Int’l GmbH, 8 F.4th 1331 (Fed. Cir.
`2021) ................................................................................................. 15, 17, 18, 36
`Envtl. Designs v. Union Oil Co. of Cal., 713 F.2d 693 (Fed. Cir. 1983) ................ 40
`Genzyme Therapeutic Prods. Ltd. P’ship v. Biomarin Pharma. Inc., 825
`F.3d 1360 (Fed. Cir. 2016) ................................................................................. 23
`Graham v. John Deere Co. of Kansas City, 383 U.S. 1 (1966) ............................... 40
`Gustafson v. Alloyd Co., 513 U.S. 561 (1995)......................................................... 21
`In re Chu, 66 F.3d 292 (Fed. Cir. 1995) ............................................................ 24, 40
`In re Cyclobenzaprine HCl Extended-Release Capsule Pat. Litig., 676 F.3d
`1063 (Fed. Cir. 2012) .......................................................................................... 42
`In re Katz, 687 F.2d 450 (C.C.P.A. 1982) ..................................................... 3, 41, 42
`In re Wesslau, 353 F.2d 238 (C.C.P.A. 1965) ......................................................... 30
`Kayak Software Corp. v. IBM, CBM2016-00075, Paper 16 (PTAB Dec. 15,
`2016) ................................................................................................................... 49
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`Case IPR2022-00853
`Patent 9,464,140
`Leo Pharm. Products, Ltd. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013) ........................ 43
`Novartis Pharmaceuticals Corp. v. West-Ward Pharmaceuticals Int’l Ltd.,
`923 F.3d 1051 (Fed. Cir. 2019) .................................................................... 36, 37
`OSI Pharms., LLC v. Apotex Inc., 939 F.3d 1375 (Fed. Cir. 2019) ...... 24, 25, 32, 40
`Phillips Corp. v. AWH, 415 F.3d 1303 (Fed. Cir. 2005) (en banc) ......................... 22
`Univ. of Strathclyde v. Clear-Vu Lighting LLC, 17 F.4th 155 (Fed. Cir.
`2021) ................................................................................................. 24, 25, 27, 28
`OTHER AUTHORITIES
`35 U.S.C. § 102(a) ......................................................................................... 3, 41, 42
`35 U.S.C. § 102(b) ................................................................................................... 41
`35 U.S.C. § 314(a) ................................................................................................... 14
`35 U.S.C. § 325(d) ................................................................................... 3, 44, 49, 50
`
`
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`Case IPR2022-00853
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`
`EXHIBIT LIST
`
`Title
`Jason Fagone, Has Carl June Found a Key to Fighting Cancer?,
`PHILA. MAG. (Aug. 1, 2013).
`Denise Grady, An Immune System Trained to Kill Cancer, N.Y. TIMES
`(Sept. 12, 2011),
`https://www.nytimes.com/2011/09/13/health/13gene.html.
`Jasone Fagone, Walt Keller, Leukemia Survivor, Has Passed, PHILA.
`MAG. (Feb. 20, 2014),
`https://www.phillymag.com/news/2014/02/20/walt-keller-leukemia-
`survivor-obituary-1953-2014/.
`Gina Kolata, A Cancer Treatment Makes Leukemia Vanish, but Creates
`More Mysteries, N.Y. TIMES (Feb. 2, 2022),
`https://www.nytimes.com/2022/02/02/health/leukemia-car-t-
`immunotherapy.html.
`Denise Grady, In Girl’s Last Hope, Altered Immune Cells Beat
`Leukemia, N.Y. TIMES (Dec. 9, 2012),
`https://www.nytimes.com/2012/12/10/health/a-breakthrough-against-
`leukemia-using-altered-t-cells.html.
`Denise Grady, F.D.A. Approves First Gene-Altering Leukemia
`Treatment, Costing $475,000, N.Y. TIMES (Aug. 30, 2017),
`https://www.nytimes.com/2017/08/30/health/gene-therapy-cancer.html.
`FOOD AND DRUG ADMIN., FDA APPROVAL BRINGS FIRST GENE THERAPY
`TO THE UNITED STATES (Aug. 30, 2017), https://www.fda.gov/news-
`events/press-announcements/fda-approval-brings-first-gene-therapy-
`united-states.
`FOOD AND DRUG ADMIN., BREAKTHROUGH THERAPY (Jan. 4, 2018),
`https://www.fda.gov/patients/fast-track-breakthrough-therapy-
`accelerated-approval-priority-review/breakthrough-therapy.
`FOOD AND DRUG ADMIN., PRIORITY REVIEW (Jan. 4, 2018),
`https://www.fda.gov/patients/fast-track-breakthrough-therapy-
`accelerated-approval-priority-review/priority-review.
`Barbara Savoldo et al., CD28 costimulation improves expansion and
`persistence of chimeric antigen receptor-modified T cells in lymphoma
`patients, 121 J. CLINICAL INVESTIGATION 1822 (2011).
`Brian G. Till et al., Adoptive immunotherapy for indolent non-Hodgkin
`lymphoma and mantle cell lymphoma using genetically modified
`autologous CD20-specific T cells, 112 BLOOD 2261 (2008).
`iv
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`
`
`Ex.
`2001
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`2002
`
`2003
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`2004
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`2005
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`2006
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`2007
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`2008
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`2009
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`2010
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`2011
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`Renier J. Brentjens et al., Safety and persistence of adoptively
`transferred autologous CD19-targeted T cells in patients with relapsed
`or chemotherapy refractory B-cell leukemias, 118 BLOOD 4817 (2011).
`Renier Brentjens et al., Treatment of chronic lymphocytic leukemia
`with genetically targeted autologous T cells: case report of an
`unforeseen adverse event in a phase I clinical trial, 18 MOLECULAR
`THERAPY 666 (2010).
`Renier J. Brentjens et al., A Phase I Trial for the Treatment of Chemo
`refractory Chronic Lymphocytic Leukemia with CD19-Targeted
`Autologous T Cells, 16 MOLECULAR THERAPY S15 (2008).
`Jennifer Couzin-Frankel, The dizzying journey to a new cancer arsenal,
`340 SCI. 1514 (2013).
`Jennifer Couzin-Frankel, Breakthrough of the Year 2013: Cancer
`Immunotherapy, 342 SCI. 1432 (2013).
`David L. Porter et al., Chimeric Antigen Receptor Modified T Cells
`Directed Against CD 19 (CTL0l 9 cells) Have Long-Term Persistence
`And Induce Durable Responses In Relapsed, Refractory CLL, 122
`BLOOD 4162 (2013).
`David L. Porter et al., Randomized, Phase II Dose Optimization Study
`Of Chimeric Antigen Receptor Modified T Cells Directed Against CD
`19 (CTL019) In Patients With Relapsed Refractory CLL, 122 BLOOD
`873 (2013).
`Stephan A. Grupp et al., T Cells Engineered With A Chimeric Antigen
`Receptor (CAR) Targeting CD 19 (CTL0l 9) Produce Significant In
`Vivo Proliferation, Complete Responses And Long-Term Persistence
`Without GVHD In Children And Adults With Relapsed, Refractory
`ALL, 122 BLOOD 67 (2013).
`James N. Kochenderfer et al., B-cell depletion and remissions of
`malignancy along with cytokine-associated toxicity in a clinical trial of
`anti-CD 19 chimeric-antigen-receptor transduced T cells, 119 BLOOD
`2709 (2012).
`Carl June Named One of Time’s 100 Most Influential People in the
`World, PENN MEDICINE (Apr. 26, 2018),
`https://pathology.med.upenn.edu/news/carl-june-named-one-times-
`100-most-influential-people-world.
`Holly Auer, Penn Medicine Immunotherapy Pioneer Carl June, MD,
`Awarded 2015 Paul Ehrlich and Ludwig Darmstaedter Prize, PENN
`TODAY (Mar. 11, 2015), https://penntoday.upenn.edu/news/penn-
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
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`2022
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`40295342.2
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`

`

`2023
`
`2024
`
`2025
`
`2026
`
`Case IPR2022-00853
`Patent 9,464,140
`medicine-immunotherapy-pioneer-carl-june-md-awarded-2015-paul-
`ehrlich-and-ludwig-darmstaed.
`Andrew Pollock, Setting the Body’s ‘Serial Killers’ Loose on Cancer,
`N.Y. TIMES (Aug. 1, 2016),
`https://www.nytimes.com/2016/08/02/health/cancer-cell-therapy-
`immune-system.html.
`2015 Watanabe Award Winner Carl H. June, IND. CLINICAL AND
`TRANSLATIONAL SCIS. INST., https://indianactsi.org/awards/watanabe-
`award-winners/2015-watanabe-award-winner-carl-h-june/ (last visited
`July 12, 2022).
`Agilent Presents Thought Leader Award to Drs. Carl H. June and
`Michael Milone, AGILENT TECHS. INC. (Nov. 17, 2020),
`https://www.agilent.com/about/newsroom/presrel/2020/17nov-
`ca20030.html.
`Information Disclosure Statement Initialed by Examiner (Feb. 22,
`2016), U.S. Patent Application No. 14,996,953.
`Supplemental Information Disclosure Statement Initialed by Examiner
`2027
`(June 17, 2016), U.S. Patent Application No. 14,996,953.
`2028 World Intell. Prop. Org. Patent Application No. WO 02/077029 A2.
`Pilot Study for Patients with Chemotherapy Resistant or Refractory
`CD19 Leukemia and Lymphoma (CART-19), CLINICALTRIALS.GOV
`(April 29, 2009),
`[http://web.archive.org/web/20090903002304/http://clinicaltrials.gov/c
`t2/show/NCT00891215].
`2030 Amendments to the Claims (Nov. 13, 2018), U.S. Patent Application
`No. 15,353,899.
`Steven A. Rosenberg et al., Use of Tumor-Infiltrating Lymphocytes and
`Interleukin-2 in the Immunotherapy of Patients with Metastatic
`Melanoma, 319 NEW ENG. J. MED. 1676 (1988).
`Michael C. Jensen et al., Antitransgene Rejection Responses Contribute
`to Attenuated Persistence of Adoptively Transferred CD20/CD19-
`Specific Chimeric Antigen Receptor Redirected T Cells in Humans, 16
`BIOLOGY BLOOD AND MARROW TRANSPLANTATION 1245 (2010).
`Richard A. Morgan et al., Case Report of a Serious Adverse Event
`Following the Administration of T Cells Transduced With a Chimeric
`Antigen Receptor Recognizing ERBB2, 18 MOLECULAR THERAPY 843
`(2010).
`
`2029
`
`2031
`
`2032
`
`2033
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`2034
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`2035
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`2036
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`2038
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`2039
`
`2040
`
`2041
`
`Case IPR2022-00853
`Patent 9,464,140
`David L. Porter et al., A phase 1 trial of donor lymphocyte infusions
`expanded and activated ex vivo via CD3/CD28 costimulation, 107
`BLOOD 1325 (2006).
`Grazyna Lipowska-Bhalla, Targeted immunotherapy of cancer with
`CAR T cells: achievements and challenges, 61 CANCER IMMUNOLOGY,
`IMMUNOTHERAPY 953 (2012).
`Latest paper from the father of CAR-T: CAR-T really completely cured
`cancer, MEDICALTREND.ORG,
`https://medicaltrend.org/2022/02/03/latest-paper-from-the-father-of-
`car-t-car-t-really-completely-cured-cancer/ (last visited July 13, 2022).
`2037 Bipulendu Jena et al., Redirecting T-cell specificity by introducing a
`tumor-specific chimeric antigen receptor, 116 BLOOD 1035 (2010).
`Michael H. Kershaw et al., A Phase I Study on Adoptive
`Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer, 12
`CLINICAL CANCER RSCH. 6106 (2006).
`Cor H.J. Lamers et al., Treatment of Metastatic Renal Cell Carcinoma
`With Autologous T-Lymphocytes Genetically Retargeted Against
`Carbonic Anhydrase IX: First Clinical Experience, 24 J. CLINICAL
`ONCOLOGY e20 (2006).
`ASH honors Bruce R. Blazar, M.D., and Carl H. June, M.D., with 2012
`Ernest Beutler Lecture and Prize, SCIENCEX (Aug. 27, 2012),
`https://sciencex.com/wire-news/107531358/ash-honors-bruce-r-blazar-
`md-and-carl-h-june-md-with-2012-ernest.html.
`Renier J. Brentjens et al., Genetically Targeted T Cells Eradicate
`Systemic Acute Lymphoblastic Leukemia Xenografts, 13 CLINICAL
`CANCER RSCH. 5426 (2007).
`2042 U.S. Patent No. 7,402,431.
`Cancer treatment myths: Any truth to these common beliefs?, MAYO
`CLINIC (March 22, 2022), https://www.mayoclinic.org/diseases-
`conditions/cancer/in-depth/cancer/art-20046762.
`2044 Adam Bagg Aff., July 19, 2022.
`SITC Smalley Award 2013 Recipient, SOC’Y FOR IMMUNOTHERAPY OF
`CANCER, https://www.sitcancer.org/funding/named-funds-and-
`awards2/smalley/2013 (last visited July 19, 2022).
`AAI-Steinman Award for Human Immunology Research Past
`Recipients, AM. ASS’N OF IMMUNOLOGISTS,
`https://www.aai.org/Awards/Career-Awards/AAI-Steinman-Award-
`for-Human-Immunology-Research/Past-Recipients.aspx (last visited
`July 19, 2022).
`
`2043
`
`2045
`
`2046
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`
`
`I.
`
`INTRODUCTION
`Curing cancer has proven so elusive that it is synonymous in popular culture
`
`with a revolutionary scientific breakthrough. According to the Mayo Clinic,
`
`“[f]inding the cure for cancer is proving to be more complex than mastering the
`
`engineering and physics required for spaceflight.” Ex. 2043 at 1. Here, curing
`
`cancer is, quite literally, what the inventors did. The invention is one of the most
`
`important breakthroughs in the history of oncology: a method of cancer treatment
`
`using a cancer patient’s own T cells, genetically modified to express particular
`
`chimeric antigen receptors (“CARs”), to attack and kill cancer cells. Unlike previous
`
`efforts in the field, this invention was the first CAR-T cell therapy to effectively and
`
`reproducibly treat—and in many cases, to completely eradicate—cancer in patients.
`
`And it did so in hard cases: cancers that had stopped responding to conventional
`
`treatments such as chemotherapy, radiation, and stem cell transplantation.
`
`Upon the invention’s announcement, others in the field described it as “a
`
`major breakthrough,” “a major advance,” “a turning point,” a “Lazarus moment,”
`
`“unprecedented,” “remarkable, exciting, and significant,” and “very, very, big.”
`
`Exs. 2001 at 3, 13; 2002 at 1–2; 2005 at 1; 2015 at 1515, 1517. It was described as
`
`“a bold experiment” that “may change medicine forever.” Exs. 2001 at 21; 2002 at
`
`1. When approving Novartis’s Kymriah® product embodying the claimed
`
`technology in 2017, FDA took the unusual step of issuing its own press release.
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`FDA described its approval as “a historic action” that was “ushering in a new
`
`approach to the treatment of cancer.” Ex. 2007 at 1. The Commissioner described
`
`it as “entering a new frontier in medical innovation.” Id. at 1. And the director of
`
`the FDA’s Center for Biologics Evaluation and Research described it as “a first-of-
`
`its-kind treatment approach that fills an important unmet need for children and young
`
`adults with this serious disease.” Id. at 2.
`
`So how do Petitioners endeavor to argue that the claimed inventions would
`
`have been obvious? In Grounds 1–3, they cobble together an obviousness case that
`
`requires the POSA to combine not two or three but four separate references for claim
`
`1 alone. The Petition’s primary focus is to try to prove that the pieces of the CAR
`
`used in the claimed methods were known as of the priority date. But whether
`
`Petitioners are ultimately able to prove that disputed proposition is, respectfully,
`
`beside the point. The ’140 patent at issue in this Petition does not simply require
`
`that someone make the CAR that is described in the claims—it requires that they
`
`administer “an anti-tumor effective amount” of a population of cells expressing it
`
`for “treating cancer in a human.” In so doing, Petitioners and their expert ask this
`
`Board, in violation of clear precedent, to throw away common sense, plain meaning,
`
`and the text of the specification to conclude that “treating cancer in a human” means
`
`nothing more than killing a single cancer cell. And they must do this because their
`
`expert has not said—and cannot say—that the POSA would have had a reasonable
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`expectation of success of performing the claimed methods if construed to mean what
`
`they say. The literature was so riddled with failed CAR-T cell therapy experiments
`
`that “[i]nfluential scientists [at the National Institutes of Health] didn’t think
`
`engineered T cells could ever work.” Ex. 2001 at 9.
`
`With nothing to support a reasonable expectation of success argument,
`
`Petitioners resort in Ground 4 to relying on a publication of the inventors’ own work
`
`(Porter), in contravention of § 102(a).1 This reference is not prior art. In re Katz,
`
`687 F.2d 450, 454 (C.C.P.A. 1982).
`
`In sum, the USPTO did not err in issuing this patent. All of Petitioners’
`
`references that are prior art were considered by or cumulative to references
`
`considered by the Examiner. And it is hardly surprising that the USPTO did not
`
`address on the record Petitioners’ convoluted, and incomplete, obviousness theory.
`
`Thus, institution of this Petition should also be denied under § 325(d).
`
`Dr. Carl June is known as “the father of CAR-T.” Ex. 2036 at 1. After years
`
`of failures in the industry, he and his co-inventors discovered how to treat patients
`
`with CAR-T cell therapy successfully. Petitioners have not demonstrated a
`
`reasonable likelihood of proving that this breakthrough invention, as claimed here,
`
`would have been obvious.
`
`
`1 All statutory references are to the pre-AIA version.
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`II. BACKGROUND
`A. The State of CAR-T Cell Therapy Before 2011
`The field of CAR-T cell therapy was first conceived in the 1980s. Ex. 2002
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`Case IPR2022-00853
`Patent 9,464,140
`
`at 2. Scientists tried to develop CAR-T cell therapy for the next several decades,
`
`but no one achieved therapeutic success: the field was littered with failures.
`
`Although researchers had designed and published many different CAR sequences
`
`and made some strides in using CAR-T cells in vitro and in mice, “scientists can
`
`cure a lot of diseases in mice that they can’t cure in people.” Ex. 2001 at 9. When
`
`it came to human trials before 2011, CAR-T cells “had scarcely worked in cancer,
`
`anywhere in the world.” Ex. 2001 at 2–3. “Influential scientists [at the National
`
`Institutes of Health] didn’t think engineered T cells could ever work.” Ex. 2001 at
`
`9. Even leaders in the field acknowledged that in 2010 the therapy “was way out
`
`there.” Ex. 2004 at 1.
`
`To make matters worse, in some human trials, the results had been
`
`affirmatively harmful, with engineered T cells attacking healthy tissue and killing
`
`patients. Ex. 2002 at 4. For example, in a study at the National Cancer Institute, a
`
`patient with advanced colon cancer died from multiorgan failure shortly after
`
`infusion of engineered T cells. Exs. 2002 at 4; 2033 at 845. Researchers at Memorial
`
`Sloan Kettering also reported a death in a CAR-T cell trial for leukemia that targeted
`
`the same CD-19 antigen targeted by the claimed methods. Exs. 2002 at 4; 2035 at
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`958. And even where patients did not die, “[s]ignificant toxicities including
`
`hypotension, fevers, and renal insufficiency” had been reported. Ex. 2020 at 2709.
`
`Further, in trials where the engineered T cells did not kill the patients, the
`
`results were unencouraging. “A typical gene-therapy experiment in cancer was as
`
`exciting as a sip of warm tea. Nothing happened, good or bad.” Ex. 2001 at 2. As
`
`one article put it:
`
`To make T-cells search out and destroy cancer, researchers must equip
`them to do several tasks: recognize the cancer, attack it, multiply, and
`live on inside the patient. A number of research groups have been
`trying to do this, but the T-cells they engineered could not accomplish
`all the tasks. As a result, the cells’ ability to fight tumors has generally
`been temporary.
`
`Ex. 2002 at 2.
`
`By the time of the invention, studies had made scientists skeptical that they
`
`could ever design CAR-T cells that would expand and persist in the patient’s blood.
`
`A number of teams “had run their own trials of engineered T cells in cancer patients”
`
`and found that “the cells didn’t replicate well and simply died in the blood.” Ex.
`
`2001 at 8. “In one trial, they only lasted a day. The cells had no effect. They didn’t
`
`work. The whole idea was starting to seem like a bust.” Ex. 2001 at 8; see also Ex.
`
`2032 at 1250–51, 1255 (discussing a human trial in which only one of four patients
`
`even had “a detectable level of transferred T cells at 1 week after the first infusion,”
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`and acknowledging that “[p]oor in vivo persistence is the major problem in the
`
`cancer [adoptive therapy] field in general”); Ex. 2035 at 956 (“Unfortunately,
`
`despite promising preclinical results, the majority of these initial CAR T cell trials
`
`showed little evidence of anti-tumor activity with limited activation, persistence, and
`
`homing to tumor sites being the main barriers.”).
`
`Researchers attempted to overcome these obstacles by designing new CAR-T
`
`cells, in some cases by including a costimulatory domain such as CD28. But even
`
`those experiments showed little promise. Indeed, between 2008 and 2013, at least
`
`four different research groups published results testing CAR-T cells for leukemia
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`and lymphoma, none of which showed sustained engraftment and expression of
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`CAR-T cells. Exs. 2010 at 1824–25; 2011 at 2264; 2012 at 4817; 2020 at 2717–18.
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`In analyzing the results of one trial involving a CAR-T cell using a CD28
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`costimulatory domain, the researchers acknowledged that the cells “still may be too
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`short lived to produce meaningful clinical benefits” and no patients “showed
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`evidence of sustained tumor regression at the cell doses used.” Ex. 2010 at 1824–
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`25. One study described its “[o]bjective clinical responses” as “modest” and another
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`suggested that the therapy might be “more likely to show clinical benefit in the
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`setting of prior conditioning chemotherapy and low tumor burden or minimal
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`residual disease.” Exs. 2011 at 2269; 2012 at 4817. In other words, the results were
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`so lackluster that scientists should lower their hopes to, at best, treating mild cases.
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`The authors of Petitioners’ principal reference, Campana, shared that view,
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`suggesting that engineered autologous T cells might, at most, be considered for
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`patients “with persistent minimal residual disease,” and instead chose to focus on a
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`different type of immune cell, known as a “natural killer” or “NK” cell. Ex. 1003
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`[0118], [0119].
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`In short, the breakthrough described in the ’140 patent was as unexpected as
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`it was revolutionary; no one had expected it to exhibit meaningful clinical efficacy.
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`The inventors themselves thought that the CAR-T cells “would be gone in a month
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`or two.” Ex. 2004 at 1. Underscoring that skepticism, some people involved in the
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`initial clinical trial even suggested that one of the first patients should “sign a consent
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`that he knows this is futile.” Ex. 2001 at 11–12.
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`B.
`The “Lazarus Moment” — The Inventors’ Breakthrough
`“As it turned out, combatting cancer was in the details.” Ex. 2015 at 1517.
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`While other clinical research groups were focused on CARs with a CD28
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`costimulatory domain because of a growing consensus that these CARs “looked the
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`most promising,” Ex. 2015 at 1516, the inventors selected from the various potential
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`options a CAR with a different costimulatory domain—a 4-1BB costimulatory
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`domain that had been published more than five years earlier and then languished
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`without clinical attention, including from its own authors. See Exs. 1001 at 41:5–7;
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`1003. The inventors made their own modifications to that CAR and then, “[u]nlike
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`the other groups, . . . used a disabled HIV virus to genetically engineer the T cells
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`and a different recipe for growing them in the lab.” Ex. 2015 at 1517.
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`Surprisingly, when the inventors infused these CAR-T cells into patients, the
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`cells not only identified and killed huge volumes of cancer cells—in some cases,
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`pounds of them—but also achieved two never-before-seen milestones. The CAR-T
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`cells (1) multiplied a thousand-fold in patients’ bodies, and (2) persisted long after
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`infusion. Ex. 2001 at 12. The patient whose treatment was supposedly “futile” was
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`a particularly astonishing case: his T cells did not grow well in the lab and he
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`therefore received only “a mouse-sized dose,” yet the treatment still worked.
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`Ex. 2015 at 1514. His cancer disappeared completely, and he is still cancer free, ten
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`years later. Ex. 2004 at 1.
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`Ironically, Petitioners now attempt to use a 2011 article in the New England
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`Journal of Medicine (Porter, Exs. 1012; 1013) against the inventors as a basis to
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`invalidate their patent. But this Porter article is not prior art because it is the
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`inventors’ own work. See infra Section III.C.
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`Their invention has received worldwide acclaim and has led to numerous
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`awards and recognitions for the inventors. As the American Society of Hematology
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`put it, in awarding Carl June its 2012 Ernest Beutler Lecture and Prize, “[r]esults
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`from th[e] landmark study” reporting the inventors’ successful use of CAR-T cells
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`for treatment “are considered to be some of the greatest breakthroughs in leukemia
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`research in recent years.” Ex. 2040 at 3. Dr. June has also received many other
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`prestigious awards in the various fields to which the claimed invention relates,
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`including the Richard V. Smalley Award from the Society for Immunotherapy of
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`Cancer, the Ralph Steinman Award for Human Immunology Research from the
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`American Association of Immunologists, and the Ehrlich and Ludwig Darmstaedter
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`Prize for outstanding work in cancer immunotherapy. E.g., Exs. 2022 at 1; 2045 at
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`1; 2046 at 1; see also Ex. 2024 at 1 (Watanabe Award); Ex. 2025 at 1 (Agilent
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`Thought Leader Award). As described above, the invention also received enormous
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`praise from others working in the field, the FDA, and the popular press. Science
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`magazine listed “Cancer Immunotherapy” as its #1 breakthrough—in any science or
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`engineering field—in 2013, and the magazine reported the “eye-catching” result of
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`“patients with pounds of leukemia that melted away.” Ex. 2016 at 1433. Dr. June
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`was even named one of the 100 most influential people in the world by TIME
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`magazine in 2018. Ex. 2021 at 1. The success of the invention led to a significant
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`increase in investment and interest in CAR-T cell technology, including by
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`Petitioners. Indeed, today, thanks to the invention, Dr. June is now known as “the
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`father of CAR-T.” Ex. 2036 at 1.
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`More important than the awards and accolades, however, is the tremendous
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`impact the invention has had on the lives of patients and their families. Not only
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`does the invention prolong life; for many patients, it has dramatically improved the
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`quality of that life. While it does not work for everyone, for many patients
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`considered “hopeless cases” it has saved their lives and caused sustained remission
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`of cancer. Ex. 2005 at 1; see also Exs. 2002 at 1; 2017 at 1–2; 2018 at 1–2; 2019 at
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`1–3. Some patients are still cancer-free nearly a decade later. Ex. 2004 at 1. For
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`children with relapsed or refractory B-cell acute lymphoblastic leukemia, the results
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`have been especially extraordinary: a remission rate of 83% three months after
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`infusion, with many experiencing sustained remission lasting years (and still going).
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`Ex. 2006 at 1; see also Exs. 2005 at 2; 2007 at 2; 2019 at 1–2.
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`Bill Ludwig was “weak, suffered repeated bouts of pneumonia and was
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`wasting away” when he was treated with the invention; one year later, he was “full
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`of energy,” walking 18 holes on the golf course, had “gained 40 pounds,” and felt
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`“normal, like [he] did 10 years before [he] was diagnosed.” Ex. 2002 at 5. After
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`two rounds of chemotherapy, radiation, and stem cell transplants, Walter Keller’s
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`cancer returned for a third time, leaving his body “groan[ing] with tumors potentially
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`weighing as much as seven pounds.” Ex. 2001 at 2, 6. Following treatment with the
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`invention, “doctors couldn’t find any trace of the disease,” and Keller was back
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`coaching baseball, jogging around the field, and “thinking about expanding his
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`wood-finishing business.” Id. at 18, 20. And at six years old, Emma Whitehead
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`“was near death from leukemia,” having relapsed twice after chemotherapy and run
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`out of options. Ex. 2005 at 1. After being treated with the invention, she emerged
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`cancer-free and was able to return to school, where “her favorite subjects are lunch
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`and recess.” Id at 2. In the words of her father, “[i]t’s time for [Emma] to be a kid
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`again and get her childhood back.” Id.
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`These results stunned even the inventors—who, at the time, were already
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`longtime leaders in the field of CAR-T cell therapy. Exs. 2001 at 4; 2002 at 1. These
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`individuals—Drs. Carl June, Bruce Levine, David Porter, Michael Kalos, and
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`Michael Milone—had spent years working to push the field of CAR-T cell therapy
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`forward, as illustrated by the many re