UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`GENOME AND COMPANY,
`Petitioner,
`v.
`THE UNIVERSITY OF CHICAGO,
`Patent Owner.
`
`Case PGR2019-XX
`U.S. Patent No. 9,855,302 B2
`
`DECLARATION OF JONATHAN BRAUN, M.D., Ph.D., IN SUPPORT OF
`PETITION FOR POST GRANT REVIEW OF U.S. PATENT NO. 9,855,302
`
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`TABLE OF CONTENTS
`
`A.
`B.
`C.
`
`Page(s)
`INTRODUCTION ........................................................................................... 1
`I.
`BACKGROUND AND QUALIFICATIONS ................................................. 2
`II.
`III. APPLICABLE LEGAL PRINCIPLES ........................................................... 5
`A.
`Burden of Proof ........................................................................................... 5
`B.
`Prior Art ....................................................................................................... 5
`C.
`Obviousness ................................................................................................. 6
`D.
`Enablement Requirement .......................................................................... 10
`IV.
`PERSON OF ORDINARY SKILL IN THE ART ........................................ 12
`V.
`THE ‘302 PATENT ....................................................................................... 13
`Summary Of The ‘302 Patent .................................................................... 13
`The Only Data In The ‘302 Patent Is Mouse Data .................................... 25
`Prosecution Of The ‘302 Patent And A Continuing Application of the
`‘302 Patent ................................................................................................. 27
`1. Prosecution of US Patent Application 15/170,284 Which Issued As The
`‘302 Patent ............................................................................................. 27
`Prosecution of Child US Patent Application 15/718,735 .......................... 33
`Claim Construction for the Claims of the ‘302 Patent .............................. 38
`STATE OF THE ART AT THE TIME OF THE CLAIMED INVENTION 39
`It Was Known At The Tme Of The Invention That Cancer Is A Term
`Covering A Variety Of Specific Diseases With Disparate Etiologies,
`Outcomes, And Therapies And that Cancer Treatment Is Highly
`Unpredictable. ............................................................................................ 39
`It Was Known At The Time Of The Invention That Immune Checkpoint
`Inhibitors Work Only On A Subset Of Cancers And Are Highly
`Unpredictable ............................................................................................. 44
`It Was Known At The Time Of The Invention That Gut Microbiota
`Influence Health And The Immune System In Unpredictable Ways ........ 46
`It Was Known At The Time Of The Invention That Some Species and
`Strains of Bifidobacterium Had Anti-Tumor Activity. ............................. 49
`
`D.
`E.
`VI.
`A.
`
`B.
`
`C.
`
`D.
`
`i
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`VII. THE CLAIMS OF THE ‘302 PATENT ARE INVALID ............................. 52
`A. Claims 1-29 Are Invalid For Failing To Meet The Enablement Requirement
`Under §112(a) ................................................................................................ 52
`1. The Nature of the Invention – Treating Cancer In A Human Subject ...... 53
`2. The Level of Ordinary Skill in the Art Is High ......................................... 54
`3. The Claims Are Extremely Broad - Treating All Cancers With All
`Immune Checkpoint Inhibitors and All Species of Bifidobacterium .... 55
`4. The Working Examples Are Limited To a Few Mouse Experiments
`Involving Two Types of Cancer, A Single Immune Checkpoint
`Inhibitor, And A Few Species of Bifidobacterium ................................ 58
`5. The ‘302 Patent Provides Nearly No Guidance ........................................ 59
`6. Cancer Treatment Employing Immune Checkpoint Inhibitors and
`Bifidobacterium Is Highly Unpredictable ............................................. 60
`7. Extensive and Undue Experimentation Is Required To Practice The Full
`Scope of the Claimed Invention ............................................................ 62
`VIII. CLAIMS 1-29 OF THE ‘302 PATENT ARE OBVIOUS ............................ 66
`A.
`Korman ‘401 In View Of Singh And Dong Render Obvious Claims 1-9,
`12-17, and 19-25, and 27-28 ...................................................................... 66
`Korman ‘401 In View Of Singh And Dong And Further In View Of Van
`Der Waaij Renders Obvious Claims 10, 11 And 26.................................. 68
`Korman ‘401 In View Of Singh And Dong And Further In View Of
`Topalian Renders Obvious Claims 18 And 29 .......................................... 69
`Korman ‘401 In View Of Kohwi Render Obvious Claims 1-4, 7-9, 12-17,
`19-25, And 27-28 ....................................................................................... 80
`Korman ‘401 In View Of Kohwi And Further In View Of Singh Render
`Obvious Claims 5-6 And 23-24 ................................................................. 83
`Korman ‘401 In View Of Kohwi And Further In View Of Van Der Waaij
`Renders Obvious Claims 10, 11 And 26 ................................................... 83
`Korman ‘401 In View Of Kohwi And Further In View Of Topalian
`Render Obvious Claims 18 And 29 ........................................................... 84
`Korman ‘401 In View Of Mohania And Prakash ‘449 Render Obvious
`Claims 1-9, 12-17, And 19-25, And 27-28 ................................................ 95
`Korman ‘401 In View Of Mohania And Prakash ‘449 And Further In
`View Of Van Der Waiij Renders Obvious Claims 10, 11 And 26 ............ 98
`
`D.
`
`B.
`
`C.
`
`E.
`
`F.
`
`G.
`
`A.
`
`B.
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`C.
`
`Korman ‘401 In View Of Mohania And Prakash And Further In View Of
`Topalian Renders Obvious Claims 18 And 29 .......................................... 99
`IX. CONCLUSION ............................................................................................ 111
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`I, Jonathan Braun, M.D., Ph.D., being of legal age, hereby declare affirm, and
`
`state the following:
`
`I.
`
`INTRODUCTION
`1.
`I have been retained on behalf of Genome & Company/Petitioner, to
`
`serve as an independent expert and provide expert opinions regarding U.S. Patent
`
`No. 9,855,302 (“the ‘302 patent”) (Ex. 1001). I have personal knowledge of the
`
`facts and opinions set forth in this declaration, and, if called upon to do so, I would
`
`testify competently thereto. All of the opinions and conclusions found in this
`
`declaration are my own.
`
`2.
`
`I have been informed that Genome & Company is petitioning the
`
`Patent Trial and Appeal Board (“PTAB”) to institute a post-grant review of the
`
`‘302 patent and requests that the PTAB cancel all of the claims of the ‘302 patent
`
`on the basis that the claims are not enabled and the claims are obvious.
`
`3.
`
`I have been asked to consider and provide my opinions regarding the
`
`‘302 patent claims, including the technical subject matter of the ‘302 patent and the
`
`application of various references that are prior art to the ‘302 patent. In particular, I
`
`have been asked to consider what a person of ordinary skill in the art would have
`
`understood from the ‘302 patent, whether the specification teaches a person of
`
`ordinary skill in the art how to make and use the claimed invention without undue
`
`1
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`experimentation, and whether the prior art discussed herein rendered the claimed
`
`invention obvious to a person of ordinary skill in the art
`
`4.
`
`I have also relied on the knowledge and experience I acquired from
`
`more than 33 years of practicing, researching, and teaching oncology, pathology,
`
`microbiology and immunology.
`
`5.
`
`I am being compensated at a rate of $550.00 per hour for my services.
`
`This compensation is in no way based on the content of my opinions or the
`
`outcome of this matter.
`
`II.
`
`BACKGROUND AND QUALIFICATIONS
`6.
`My qualifications as an expert in this field are established by my
`
`curriculum vitae, which is attached as attached as Appendix A and the experience
`
`and publications cited there.
`
`7.
`
`I am Professor and Chair of Pathology and Laboratory Medicine at the
`
`UCLA David Geffen School of Medicine in Los Angeles, California. In addition, I
`
`have served from 1991 to 2018 as the co-Director and Director of the Tumor
`
`Immunology Program for the UCLA Jonsson Comprehensive Cancer Center.
`
`8.
`
`I received my undergraduate degree from Stanford University in 1975.
`
`I subsequently earned my Ph.D. (Immunology) and M.D. from Harvard University
`
`and Harvard Medical School in 1980 and 1981. I completed a pathology residency
`
`at Brigham and Women’s Hospital of Boston and Harvard Medical School
`
`2
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`between 1981 and 1985. Concurrently, I completed postdoctoral studies in
`
`molecular biology (with David Baltimore) at M.I.T. and the Whitehead Institute in
`
`1984 and 1985.
`
`9.
`
`I joined the faculty of the Department of Pathology and Laboratory
`
`Medicine at the UCLA School of Medicine in 1985, and was precociously
`
`appointed permanent Department Chair and full professor in 1995, positions I
`
`continue to the present (2018). During this period, I also served in a joint
`
`appointment with the UCLA Department of Molecular and Medical Pharmacology
`
`(2006-2015), and as the Co-Director to Director (Assistant Vice Chancellor) of the
`
`UCLA Clinical and Translational Sciences Institute.
`
`10.
`
`I have devoted my career to academic clinical practice and scientific
`
`research. My clinical practice includes my roles as clinical service chief, and
`
`executive leadership of Pathology and Clinical Laboratory services of the UCLA
`
`Health System. My research concerns the immunology and microbiome biology of
`
`chronic inflammatory disease and cancer. Overall, I have published 175 peer-
`
`reviewed scientific studies.
`
`11. One specific area of my research area is defining the function and
`
`disease roles of the human intestinal microbiome via human genetics and
`
`multi’omic analysis. Discoveries from this work included host genetic Crohn’s
`
`disease susceptibility traits that modify the intestinal microbiome. See Chang YL,
`
`3
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`et al. 2018 Mucosal Immunol (in press); Ni J, et al. Science Transl. Med. 2017
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`Nov 15; 9 (416), and Li D, et al. Gastroenterology 2016;151:724-32.
`
`12. A second area of my research has uncovered mechanisms linking the
`
`microbiome to inflammation and cancer associated with inflammation. This work
`
`uncovered the microbiome causes changes in CD4+ T cell effector and regulatory
`
`functions key to inflammatory mucosal disease and colonic epithelial cancer. It
`
`also uncovered members of the intestinal microbiome which cause systemic
`
`changes in the immune system that substantially alter penetrance of genetic cancer
`
`susceptibility traits for lymphoma and other cancer types. Liu L, et al. PLoS
`
`Pathog. 2013 Dec; 9(12); Bergstrom K, et al. Gastroenterology 2016;151:152-164;
`
`Yamamoto ML et al. Cancer Res. 2013 Jul 15;73(14):4222-4232.
`
`13.
`
`I have also earned numerous professional awards and honors in the
`
`fields of immunology and the microbiome.
`
`14.
`
`For instance, in 2001 I was appointed Fellow of the American
`
`Association for the Advancement of Sciences; in 2009, I served as President of the
`
`Federation of Clinical Immunology Societies; in 2008, I served as President of the
`
`Clinical Immunology Society; in 2011, I was appointed Fellow of the American
`
`Gastroenterological Society; in 2015, I received the Modell Award of the Crohn’s
`
`and Colitis Foundation of America; and in 2018, I was the Ramzi Cotran Lecture at
`
`4
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`the Brigham and Women’s Hospital, and the Charles M. Mansbach Lecture of the
`
`American Gastroenterological Association.
`
`III. APPLICABLE LEGAL PRINCIPLES
`15.
`In this section, I describe my understanding of certain legal standards.
`
`I have been informed of these legal standards by Petitioner’s attorneys. I am not an
`
`attorney, and I am relying only on instructions from Petitioner’s attorneys for these
`
`legal standards. I have applied these understandings in my analysis of the validity
`
`of the ‘302 patent as detailed below.
`
`A.
`16.
`
`Burden of Proof
`I have been informed that a post-grant review may be instituted if
`
`Petitioner shows it is more likely than not that at least one claim of the challenged
`
`patent is unpatentable. I have been informed that Petitioner bears the ultimate
`
`burden of proving the challenged claims are unpatentable by a preponderance of
`
`the evidence.
`
`17.
`
`I have been informed that “preponderance of evidence” is just enough
`
`evidence to make it more likely than not that the fact the party seeks to prove is
`
`true. My opinion that the claims of the ‘302 patent are invalid take the
`
`preponderance of evidence burden of proof into account.
`
`B.
`18.
`
`Prior Art
`I have been informed that the “effective filing date” of a patent claim
`
`is the actual filing date of the patent, unless the patent properly claims the benefit
`
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`of an earlier filing date from a parent application that discloses the claimed
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`invention in compliance with the written description and enablement requirements.
`
`19.
`
`I have been informed that patents, published patent applications, and
`
`other printed publications that were published before the effective filing date of a
`
`patent are prior art to a patent in a post-grant review proceeding.
`
`C.
`20.
`
`Obviousness
`I have been informed that an alleged invention is not patentable if it
`
`would have been obvious to a person of ordinary skill in the art at the time the
`
`invention was made. I have been informed that it is improper to conduct the
`
`obviousness analysis by working backwards from the claimed invention with the
`
`aid of hindsight.
`
`21.
`
`I have been informed that the standard regarding obviousness is set
`
`forth in 35 U.S.C. §103, which provides, in relevant part, as follows:
`
`A patent for a claimed invention may not be obtained…if the
`differences between the claimed invention and the prior art are such that
`the claimed invention as a whole would have been obvious before the
`effective filing date of the claimed invention to a person having
`ordinary skill in the art to which the claimed invention pertains.
`Patentability shall not be negated by the manner in which the invention
`was made.
`
`22.
`
`I have been informed that in the Supreme Court case of Graham v.
`
`John Deere Co., the Supreme Court instructed courts to address the question of
`
`obviousness against the “background” of three inquiries: 1) the scope and content
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`of the prior art; 2) differences between the prior art and the claims at issue; and 3)
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`the level of ordinary skill in the pertinent art. In addition, under Graham, courts
`
`are to consider “secondary considerations” that may be relevant to obviousness,
`
`such as “commercial success” and “long felt but unsolved needs.” In order to be
`
`relevant, there must be a nexus between these secondary considerations and the
`
`claimed invention.
`
`23.
`
`I have been informed that a “patent composed of several elements is
`
`not proved obvious merely by demonstrating that each of its elements was,
`
`independently, known in the prior art.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
`
`418 (2007). “The combination of familiar elements according to known methods
`
`is likely to be obvious when it does no more than yield predictable results.” Id. at
`
`416. “[A] court must ask whether the improvement is more than the predictable
`
`use of prior art elements according to their established functions.” Id. at 417.
`
`“[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. (quoting Sakraida v.
`
`Ag Pro, Inc., 425 U.S. 273, 282 (1976)). “It can be important to identify a reason
`
`that would have prompted a person of ordinary skill in the relevant field to
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`combine the elements in the way the claimed new invention does.” Id. at 418. It
`
`may also be “helpful” to ask whether there was a “teaching, suggestion, or
`
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`motivation to combine known elements” that would have rendered an invention
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`obvious (“the TSM test”). Id. “Common sense teaches . . . that familiar items may
`
`have obvious uses beyond their primary purposes, and in many cases a person of
`
`ordinary skill will be able to fit the teachings of multiple patents together like
`
`pieces of a puzzle.” Id. at 420.
`
`24.
`
`I have been informed that in KSR, the Supreme Court decided that the
`
`Federal Circuit had applied the TSM test too rigidly by holding that the patent
`
`examiner should look only to the question the patentee was trying to resolve in
`
`determining whether there was a motivation to combine elements found in prior
`
`art. Id. at 420. The Court explained, “[t]he question is not whether the combination
`
`was obvious to the patentee but whether the combination was obvious to a person
`
`with ordinary skill in the art.” Id. Therefore, “any need or problem known in the
`
`field of the endeavor at the time of the invention and addressed by the patent can
`
`provide a reason for combining the elements in the manner claimed.” Id.
`
`25.
`
`I have been informed that while the conclusion of obviousness is a
`
`legal question, it is based upon underlying facts. In re Icon Health and Fitness Inc.,
`
`496 F.3d 1374, 1378 (Fed. Cir. 2007).
`
`26.
`
`I have been informed the “[u]nderlying facts include the scope and
`
`content of the prior art, the level of ordinary skill in the art at the time of the
`
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`invention, objective evidence of non-obviousness, and differences between the
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`prior art and the claimed subject matter.” Id. (citing Graham, 383 U.S. at 17-18).
`
`27.
`
`I have been informed and understand that obviousness may be shown
`
`by demonstrating that it would have been obvious to modify what is taught in a
`
`single piece of prior art to arrive at the claimed invention or by showing that it
`
`would have been obvious to combine the teachings of more than one item of prior
`
`art. Further, there must be a motivation in the prior art for a person of skill in the
`
`art to combine the teachings.
`
`28.
`
`I have been informed that because of my opinion that the claims of the
`
`‘302 patent are not enabled, the effective filing date of the claims of the ‘302
`
`patent is June 1, 2016, the actual filing date of the ‘302 patent.
`
`29.
`
`The patents, patent applications, and publications I rely on to allege
`
`that the claims of the ‘302 patent were obvious to POSITA all predate June 1,
`
`2015, the day the first provisional application 62/169,112 was filed. My opinion
`
`that the claims of the ‘302 patent were obvious to a POSITA assumes that the
`
`effective filing date of the ‘302 patent is June 1, 2015. My opinion applies with
`
`equal force to an effective filing date of October 30, 2015 (the filing date of second
`
`provisional application 62/248,741) or June 1, 2016 (the filing date of the ‘302
`
`patent).
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`D.
`30.
`
`Enablement Requirement
`I have been informed that the statutory basis for the enablement
`
`requirement is found in 35 U.S.C. §112(a), which provides in relevant part:
`
`(a) IN GENERAL.—The specification shall contain a written
`description of the invention, and of the manner and process of making
`and using it, in such full, clear, concise, and exact terms as to enable
`any person skilled in the art to which it pertains, or with which it is most
`nearly connected, to make and use the same…
`31.
`I have been informed that a claimed invention is not enabled under 35
`
`U.S.C. §112(a) if the specification does not teach those of ordinary skill in the art
`
`how to make and use the invention as broadly as it is claimed, without undue
`
`experimentation.
`
`32.
`
`I have been informed that the full scope of the claimed invention must
`
`be enabled.
`
`33.
`
`I have been informed that the assessment of undue experimentation is
`
`based on the state of the art as of the earliest filing date of the applications on
`
`which the ‘302 Patent claims priority. In this case, I have been informed that date
`
`is June 1, 2015, the filing date of provisional application 62/169,112. My opinion
`
`expressed herein regarding enablement applies with equal force to a filing date of
`
`October 30, 2015 (the filing date of second provisional application 62/248,741) or
`
`June 1, 2016 (the filing date of the application that issued as the ‘302 patent).
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`34.
`
`I have been informed that a finding of undue experimentation must
`
`consider multiple factors to determine if there is sufficient evidence to support
`
`such a determination. I have been informed that these factors, which are referred to
`
`as Wands factors, include (1) the nature of the invention, (2) the relative skill of
`
`those in the art, (3) the breadth of the claims, (4) the presence or absence of
`
`working samples, (5) the amount of direction or guidance presented, (6), the state
`
`of the prior art, (7) the predictability or unpredictability of the art, and (8) the
`
`quantity of experimentation necessary.
`
`35.
`
`I have been informed that to determine whether there is a reasonable
`
`correlation between the scope of the claims and the scope of enablement, the
`
`degree of predictability of the relevant art need to be considered. I have been
`
`informed that chemical and physiological inventions, unlike mechanical and
`
`electrical inventions, are often considered “unpredictable” arts because a slight
`
`variation in method can yield an unpredictable result or may not function at all.
`
`(“[I]n cases involving chemicals and chemical compounds, which differ radically
`
`in their properties it must appear in an applicant’s specification . . . , that the
`
`chemicals or chemical combinations included in the claims are capable of
`
`accomplishing the desired result.”) Accordingly, “[t]ypically, patent applications
`
`claiming new [chemical] methods of treatment are supported by test results.” In re
`
`‘318 Patent Infringement Litig. 583 F.3d at 1324 (Fed.Cir. 2009). I have been
`
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`informed that in unpredictable arts, there must be some quantum of data or
`
`reasoning that supports the inventor’s contention that a therapy operates as
`
`claimed. See Id. at 1326. While every aspect of a generic claim certainly need not
`
`have been carried out by an inventor, or exemplified in the specification,
`
`reasonable detail must be provided in order to enable members of the public to
`
`understand and carry out the invention.” Genentech, 108 F.3d at 1366.
`
`36.
`
`I have been that the specification need not teach what is well known
`
`in the art. Hybritech v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384 (Fed.
`
`Cir. 1986).
`
`37.
`
`I have been informed that the determination of non-enablement must
`
`be based on the evidence as a whole.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`38. With respect to the level of ordinary skill in the art, I understand that
`
`factors such as the education level of those working in the field, the sophistication
`
`of the technology, the types of problems encountered in the art, the prior art
`
`solutions to those problems, and the speed at which innovations are made may help
`
`establish the level of skill in the art.
`
`39.
`
`I have been asked to consider the level of one of ordinary skill in the
`
`art as it relates to the ‘302 patent as of its earliest filing date, June 1, 2015. My
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`opinions do not change if the level of ordinary skill in that art was determined as of
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`October 30, 2015 or June 1, 2016.
`
`40. A POSITA would have an advanced degree or its substantial
`
`equivalent in the biological sciences, including specifically in the fields of
`
`immunology, microbiology and the microbiome, and oncology, coupled with
`
`research experience in those fields.
`
`V.
`
`THE ‘302 PATENT
`A.
`Summary Of The ‘302 Patent
`41.
`The ‘302 patent issued from U.S. application serial no. 15/170,284,
`
`filed June 1, 2016 and titled “Treatment of Cancer by Manipulation of Commensal
`
`Microflora.” The ‘302 patent claims priority to provisional application
`
`62/169,112, filed on June 1, 2015 (Ex. 1012) and provisional application
`
`62/248,741, filed on October 30, 2015 (Ex. 1013).
`
`42.
`
`The ‘302 patent purports to describe methods of treating or preventing
`
`cancer in humans by manipulating levels of commensal microbes found in the gut,
`
`including commensal bacteria, to facilitate co-treatment with a “immune
`
`checkpoint inhibitor” – a known therapeutic agent to treat cancer.
`
`43. While the ‘302 patent lists a broad range of bacteria spanning many
`
`different genera that may be used for the co-treatment:
`
`[T]he bacteria are selected from the genera Adlercreutzia, Oscillopira,
`Mollicutes, Butyrivibrio, Bacteroides, Clostridium, Fusobacterium,
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`Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus,
`Bifidobacterium, Rikenella, Alistipes, Marinilabilia, Anaerostipes,
`Escherichia, and/or Lactobacillus. [Ex. 1001 at 2:13-19]
`nearly all of the data reported in the ‘302 patent pertains to a single genus of
`
`bacteria, i.e, Bifidobacterium, and more specifically, to a few species of
`
`Bifidobacterium.
`
`44.
`
`The claims of the ‘302 patent claim a method of treating cancer in a
`
`human subject by co-administering to the subject an immune checkpoint inhibitor
`
`and a bacterial formulation comprising bacteria of the genus Bifidobacterium.
`
`Claim 1, the only independent claim of the ‘302 patent, recites:
`
`1. A method of treating cancer in a human subject comprising co-
`administering to the subject an immune checkpoint inhibitor and a
`bacterial formulation comprising bacteria of the genus Bifidobacterium.
`Ex. 1001 at 41:62-64. The issued claims of the ‘302 patent thus recite three
`
`essential elements.
`
`45.
`
`The first element of the claims is “treating cancer.” Cancer is a group
`
`of diseases involving abnormal cell growth with the potential to invade or spread to
`
`other parts of the body.
`
`46.
`
`The ‘302 patent lists 165 disorders and 22 broad categories of cancers
`
`and describes them as “[n]on-limiting examples of cancers that may be treated with
`
`the compositions and methods described herein.” Ex. 1001 at 28:54-55. The ‘302
`
`patent states:
`
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`Non-limiting examples of cancers that may be treated with the
`compositions and methods described herein include, but are not limited
`to: cancer cells from the bladder, blood, bone, bone marrow, brain,
`breast, colon, esophagus, gastrointestine, gum, head, kidney, liver,
`lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue,
`or uterus. In addition, the cancer may specifically be of the following
`histological type, though it is not limited to these: neoplasm, malignant;
`carcinoma; carcinoma, undifferentiated; giant and spindle cell
`carcinoma; small cell carcinoma; papillary carcinoma; squamous cell
`carcinoma;
`lymphoepithelial carcinoma; basal cell carcinoma;
`pilomatrix carcinoma; transitional cell carcinoma; papillary transitional
`cell
`carcinoma;
`adenocarcinoma;
`gastrinoma, malignant;
`cholangiocarcinoma;
`hepatocellular
`carcinoma;
`combined
`hepatocellular
`carcinoma
`and
`cholangiocarcinoma;
`trabecular
`adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma
`in
`adenomatous polyp; adenocarcinoma, familial polyposis coli; solid
`carcinoma;
`carcinoid
`tumor, malignant;
`branchiolo-alveolar
`adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma;
`acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma;
`clear cell adenocarcinoma; granular cell carcinoma; follicular
`adenocarcinoma;
`papillary
`and
`follicular
`adenocarcinoma;
`nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma;
`endometroid carcinoma; skin appendage carcinoma; apocrine
`adenocarcinoma;
`sebaceous
`adenocarcinoma;
`ceruminous
`adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma;
`papillary cystadenocarcinoma; papillary serous cystadenocarcinoma;
`mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring
`cell carcinoma; infiltrating duct carcinoma; medullary carcinoma;
`lobular carcinoma;
`inflammatory carcinoma; paget’s disease,
`mammary; acinar cell carcinoma; adenosquamous carcinoma;
`adenocarcinoma w/squamous metaplasia;
`thymoma, malignant;
`ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell
`tumor, malignant; and roblastoma, malignant; sertoli cell carcinoma;
`leydig cell
`tumor, malignant;
`lipid cell
`tumor, malignant;
`paraganglioma, malignant; extra-mammary paraganglioma, malignant;
`pheochromocytoma; glomangiosarcoma; malignant melanoma;
`amelanotic melanoma; superficial spreading melanoma; malig
`melanoma in giant pigmented nevus; epithelioid cell melanoma; blue
`nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma,
`malignant;
`myxosarcoma;
`liposarcoma;
`leiomyosarcoma;
`
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`alveolar
`rhabdomyosarcoma;
`embryonal
`rhabdomyosarcoma;
`rhabdomyosarcoma; stromal sarcoma; mixed
`tumor, malignant;
`mullerian mixed
`tumor;
`nephroblastoma;
`hepatoblastoma;
`carcinosarcoma; mesenchymoma, malignant; brenner
`tumor,
`malignant; phyllodes
`tumor, malignant;
`synovial
`sarcoma;
`mesothelioma, malignant; dysgerminoma; embryonal carcinoma;
`teratoma, malignant; struma ovarii, malignant; choriocarcinoma;
`mesonephroma,
`malignant;
`hemangiosarcoma;
`hemangioendothelioma,
`malignant;
`kaposi’s
`sarcoma;
`hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma;
`juxtacortical osteosarcoma;
`chondrosarcoma;
`chondroblastoma,
`malignant; mesenchymal chondrosarcoma; giant cell tumor of bone;
`ewing’s sarcoma; odontogenic
`tumor, malignant; ameloblastic
`odontosarcoma;
`ameloblastoma,
`malignant;
`ameloblastic
`fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant;
`ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary
`astrocytoma;
`astroblastoma;
`glioblastoma;
`oligodendroglioma;
`oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma;
`ganglioneuroblastoma; neuroblastoma;
`retinoblastoma; olfactory
`neurogenic
`tumor; meningioma, malignant; neurofibrosarcoma;
`neurilemmoma, malignant; granular cell tumor, malignant; malignant
`lymphoma; Hodgkin’s disease; Hodgkin’s lymphoma; paragranuloma;
`malignant lymphoma, small lymphocytic; malignant lymphoma, large
`cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other
`specified non-Hodgkin’s lymphomas; malignant histiocytosis; multiple
`myeloma; mast cell sarcoma; immunoproliferative small intestinal
`disease;
`leukemia;
`lymphoid
`leukemia; plasma cell
`leukemia;
`erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia;
`basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast
`cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy
`cell leukemia. In some embodiments, the cancer is a melanoma (e.g.,
`metastatic malignant melanoma), renal cancer (e.g. clear cell
`carcinoma), prostate cancer (e.g. hormone refractory prostate
`adenocarcinoma), pancreatic cancer (e.g., adenocarcinoma), breast
`cancer, colon cancer, gallbladder cancer, lung cancer (e.g. non-small
`cell lung cancer), esophageal cancer, squamous cell carcinoma of the
`head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid
`cancer, glioblastoma, glioma,
`leukemia,
`lymphoma, and other
`neoplastic malignancies. In some embodiments, the cancer is a solid
`tumor cancer.
`
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`In some embodiments, the methods provided herein relate to the
`treatment and/or prevention of a leukemia. The term “leukemia” is
`meant broadly progressive, malignant diseases of the hematopoietic
`organs/systems and
`is generally characterized by a distorted
`proliferation and development of leukocytes and their precursors in the
`blood and bone marrow. Non-limiting examples of leukemia diseases
`include, acute nonlymphocytic
`leukemia, chronic
`lymphocytic
`leukemia, acute granulocytic leukemia, chronic granulocytic leukemia,
`acute promyelocytic leukemia, adult T-cell leukemia, aleukemic
`leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell
`leukemia, bovi