UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`SANDOZ INC.,
`Petitioner,
`
`v.
`
`ACERTA PHARMA B.V.,
`Patent Owner.
`_____________________
`
`Case IPR2023-00478
`Patent 10,272,083 B2
`_____________________
`
`DECLARATION OF JOHN P. FRUEHAUF, M.D., Ph.D.
`
`SANDOZ INC.
`
`IPR2023-00478
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`Ex. 1002, p. 1 of 134
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`

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`TABLE OF CONTENTS
`
`
`
`Page
`
`V.
`
`
`LIST OF CITED EXHIBITS ................................................................................... iv
`I.
`INTRODUCTION ........................................................................................... 7
`II.
`BACKGROUND AND QUALIFICATIONS.................................................. 8
`III.
`SUMMARY OF OPINIONS ......................................................................... 10
`IV. LEGAL STANDARDS USED IN MY ANALYSIS ..................................... 13
`A.
`Effective filing date ............................................................................. 13
`B.
`Person of ordinary skill in the art ........................................................ 14
`C.
`Obviousness ......................................................................................... 14
`THE ʼ083 PATENT ........................................................................................ 18
`A.
`Specification ........................................................................................ 18
`B.
`Claims .................................................................................................. 20
`C.
`Prosecution history .............................................................................. 22
`VI. EFFECTIVE FILING DATE ......................................................................... 27
`VII. LEVEL OF ORDINARY SKILL .................................................................. 30
`VIII. CLAIM CONSTRUCTION .......................................................................... 30
`A.
`“A method of treating a mantle cell lymphoma (MCL) in a
`human subject suffering therefrom comprising the step of orally
`administering, to the human subject” (claim 8) .................................. 30
`“a compound of Formula (II):…” (claims 8-9) ................................... 31
`“wherein the Mantle Cell Lymphoma (MCL) increases
`monocytes and NK cells in peripheral blood after treatment with
`Formula (II) for a period selected from the group consisting of
`about 14 days, about 28 days, and about 56 days” (claim 10) ............ 32
`IX. TECHNICAL BACKGROUND ................................................................... 33
`X. GROUNDS REFERENCES .......................................................................... 36
`A.
`Barf (EX1005) ..................................................................................... 36
`B.
`Barf-PCT (EX1006) ............................................................................ 39
`C.
`Cheson (EX1008) ................................................................................ 40
`XI. OPINIONS REGARDING OBVIOUSNESS ............................................... 41
`
`B.
`C.
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`b.
`
`c.
`
`A. Ground 1: Claims 8-12 and 19-20 would have been obvious over
`Barf and Cheson. ................................................................................. 41
`1.
`Claim 8 ...................................................................................... 41
`a.
`“A method of treating a mantle cell lymphoma
`(MCL) in a human subject suffering therefrom
`comprising the step of” ................................................... 43
`“orally administering, to the human subject, … a
`BTK inhibitor, wherein the BTK inhibitor is a
`compound of Formula (II) … or a pharmaceutically-
`acceptable salt, hydrate, or solvate thereof.” .................. 43
`“a dose of 100 mg twice daily” ...................................... 46
`i.
`A 100 mg dose would have been obvious. ........... 46
`(1) Barf discloses and claims a range that
`encompasses the claimed dose. .................. 46
`(2) A POSA practicing Barf would have
`arrived at a 100 mg dose by conducting
`a routine dose-finding study. ..................... 53
`Twice-daily dosing would have been obvious. .... 61
`ii.
`Claim 9 ...................................................................................... 67
`2.
`Claim 10 .................................................................................... 69
`3.
`Claim 11 .................................................................................... 72
`4.
`Claim 12 .................................................................................... 74
`5.
`Claim 19 .................................................................................... 75
`6.
`Claim 20 .................................................................................... 76
`7.
`Ground 2: Claims 8-12 and 19-20 would have been obvious over
`Barf-PCT and Cheson. ........................................................................ 77
`1.
`Claim 8 ...................................................................................... 77
`a.
`“A method of treating a mantle cell lymphoma
`(MCL) in a human subject suffering therefrom
`comprising the step of” ................................................... 78
`“orally administering, to the human subject, … a
`BTK inhibitor, wherein the BTK inhibitor is a
`compound of Formula (II) … or a pharmaceutically-
`acceptable salt, hydrate, or solvate thereof.” .................. 79
`
`B.
`
`b.
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`C.
`
`c.
`“a dose of 100 mg twice daily” ...................................... 80
`Claim 9 ...................................................................................... 83
`2.
`Claim 10 .................................................................................... 84
`3.
`Claim 11 .................................................................................... 87
`4.
`Claim 12 .................................................................................... 88
`5.
`Claim 19 .................................................................................... 89
`6.
`Claim 20 .................................................................................... 89
`7.
`There are no probative secondary considerations. .............................. 90
`1.
`The results submitted during prosecution fail to
`demonstrate probative unexpected results. ............................... 90
`a.
`A daily dose of 200 mg acalabrutinib (100 mg BID)
`does not produce probative unexpected results. ............. 91
`Acalabrutinib’s twice-daily dosing does not produce
`probative unexpected results. ......................................... 95
`The results in the specification fail to demonstrate
`probative unexpected results. ..................................................100
`XII. CONCLUSION ............................................................................................103
`
`
`
`
`
`
`b.
`
`2.
`
`
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`LIST OF CITED EXHIBITS
`
`
`
`1008
`
`1009
`
`No. Description
`1001 U.S. Patent No. 10,272,083 to Hamdy et al. (the “ʼ083 patent”)
`1004
`Prosecution History of U.S. Patent No. 10,272,083
`(Application No. 15/112,968)
`1005 U.S. Patent No. 9,758,524 to Barf, et al. (“Barf”)
`1006
`PCT International Publication No. WO2013/010868 to Barf, et al.
`(“Barf-PCT”)
`1007 U.S. Provisional Application No. 61/509,397 to Barf, et al.
`(“Barf Provisional”)
`Bruce D. Cheson, et al., Advancements in the Treatment of B-Cell
`Malignancies (International Conference on Malignant Lymphoma),
`CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY, Vol. 11, Issue 9,
`Supplement 12 (Sept. 2013) (“Cheson”)
`Ranjana H. Advani, et al., Bruton Tyrosine Kinase Inhibitor Ibrutinib
`(PCI-32765) Has Significant Activity in Patients With
`Relapsed/Refractory B-Cell Malignancies, J. CLINICAL ONCOLOGY,
`31(1):88-94 (Jan. 2013) (“Advani”)
`John C. Byrd, et al., Acalabrutinib (ACP-196) in Relapsed Chronic
`Lymphomatic Leukemia, N. ENGL. J. MED. 374(4):323-32 (Jan. 2016)
`(“Byrd”)
`1011 U.S. Provisional Application No. 61/929,742
`1012 U.S. Provisional Application No. 61/974,665
`1013 U.S. Provisional Application No. 62/035,777
`1014
`Stefano A. Pileri, et al., Mantle cell lymphoma, HAEMATOLOLGICA
`94(11):1488-92 (2009) (“Pileri”)
`1015 M. Dreyling, et al., How to manage mantle cell lymphoma, LEUKEMIA
`28:2117-31 (2014) (“Dreyling”)
`1016
`IMBRUVICA™ (ibrutinib) Prescribing Information (2014)
`1017 U.S. Food and Drug Administration Office of Clinical Pharmacology
`Review of IMBRUVICA™ (ibrutinib), Application No. NDA 205552
`(Jan. 2014)
`1018 Akintunde Akinleye, et al., Ibrutinib and novel BTK inhibitors in
`clinical development, J. OF HEMATOLOGY & ONCOLOGY 6:59 (2013)
`(“Akinleye”)
`
`1010
`
`
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`1020
`
`1022
`
`No. Description
`1019
`Claire V. Hutchinson, et al., Breaking good: the inexorable rise of
`BTK inhibitors in the treatment of chronic lymphocytic leukaemia,
`BRITISH J. OF HAEMATOLOGY 166:12-22 (2014) (“Hutchinson”)
`Jennifer R. Brown, et al., Phase 1 Study Of Single Agent CC-292, a
`Highly Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, In
`Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL), BLOOD
`122(21):1630 (2013) (“Brown”)
`1021 Daniel W. Pierce, et al., Target Engagement, Pathway Inhibition, and
`Efficacy Of The Bruton’s Tyrosine Kinase (Btk) Inhibitor CC-292,
`BLOOD 122(21):4169 (2013) (“Pierce”)
`Simon Rule, et al., A Phase I Study Of The Oral Btk Inhibitor ONO-
`4059 In Patients With Relapsed/Refractory B-Cell Lymphoma, BLOOD
`122(21):4397 (2013) (“Rule”)
`1023
`Prosecution History of U.S. Patent No. 9,758,524
`1024 U.S. Food and Drug Administration, Good Review Practice: Clinical
`Review of Investigational New Drug Applications (Dec. 2013) (“FDA
`2013 Good Review Practice”)
`1025 U.S. Patent No. 7,732,454 (“Verner”)
`1026
`International Conference on Harmonisation; Dose-Response
`Information to Support Drug Registration; Guideline; Availability, 59
`Fed. Reg. 55,972 (Nov. 9, 1994)
`1027 U.S. Food and Drug Administration, Guidance for Industry - S9
`Nonclinical Evaluation for Anticancer Pharmaceuticals (March 2010)
`(“S9 Guidance”)
`1028 U.S. Food and Drug Administration, Guidance for Industry -
`Estimating the Maximum Safe Starting Dose in Initial Clinical Trials
`for Therapeutics in Adult Healthy Volunteers (July 2005) (“MSSD
`Guidance”)
`Erica K. Evans, et al., Inhibition of Btk with CC-292 Provides Early
`Pharmacodynamic Assessment of Activity in Mice and Humans, J.
`PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 346:219-228
`(Aug. 2013) (“Evans”)
`Tjeerd Barf, et al., Irreversible Protein Kinase Inhibitors: Balancing
`the Benefits and Risks, J. MED. CHEM. 55:6243-62 (2012) (“Barf
`2012”)
`
`1029
`
`1030
`
`
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`1032
`
`1033
`
`1034
`
`1035
`1036
`
`No. Description
`1031 Amit Mahipal, et al., Risks and Benefits of Phase 1 Clinical Trial
`Participation, CANCER CONTROL 21:193-99 (July 2014) (“Mahipal”)
`Sarah Brumskill, et al., Conference Scene: Recent developments in the
`understanding and treatment of hematological malignancies, INT’L J.
`HEMATOLOGIC ONCOLOGY, Vol. 2, No. 5, published online at
`https://doi.org/10.2217/ijh.13.52 (Oct. 8, 2013) (“Brumskill”)
`Toshio Yoshizawa, et al., ONO-4059—a Potent and Selective
`Reversible Bruton’s Tyrosine Kinase (Btk) Inhibitor: Single Agent,
`Twice Daily (BD) Dosing and Dosing with Food Results in Sustained,
`High Trough Levels of ONO-4059, Translating into 100% Tumour
`Remission in a TMD-8 Xenograft Model, BLOOD, 124(21):4502 (2014)
`(“Yoshizawa”)
`Plaintiffs’ Initial Infringement Contentions to Defendant Sandoz Inc.,
`C.A. No. 22-154-GBW-SRF (Consolidated) (D. Del. Sept. 26, 2022)
`CALQUENCE® (acalabrutinib) Prescribing Information (2017)
`Jan de Jong, et al., Effect of CYP3A perpetrators on ibrutinib exposure
`in healthy participants, PHARMACOLOGY RESEARCH & PERSPECTIVES,
`Vol. 3, Issue 4 (2015) (“de Jong”)
`1037 Dominique Levêque, Evaluation of Fixed Dosing of New Anticancer
`Agents in Phase I Studies, ANTICANCER RESEARCH 28:3075-78 (2008)
`(“Levêque”)
`ZYDELIG® (idelalisib) Prescribing Information (2014)
`TASIGNA® (nilotinib) Prescribing Information (2007)
`JAKAFI™ (ruxolitinib) Prescribing Information (2011)
`LYNPARZA™ (olaparib) Prescribing Information (2014)
`Betty Y. Chang, et al., Egress of CD191CD51 cells into peripheral
`blood following treatment with the Bruton tyrosine kinase inhibitor
`ibrutinib in mantle cell lymphoma patients, BLOOD 122(14):2142
`(2013) (“Chang”)
`1043 Yan Bao, et al., Tyrosine Kinase Btk Is Required for NK Cell
`Activation, J. Biological Chemistry 287(28):23769 (2012)
`
`
`1038
`1039
`1040
`1041
`1042
`
`
`
`
`
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`
`
`I, John P. Fruehauf, M.D., Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION
`1.
`I have been retained by Sandoz Inc. (“Petitioner”) in connection with
`
`its request for inter partes review of U.S. Patent No. 10,272,083 (“the ’083
`
`patent”). I understand that a copy of the ’083 patent has been marked EX1001. I
`
`have been asked to provide my expert opinions regarding the patentability of
`
`claims 8-12 and 9-20 of the ’083 patent (the “challenged claims”). I have personal
`
`knowledge of the facts stated in this declaration and, if called upon to testify in
`
`person, could and would competently testify thereto.
`
`2.
`
`This declaration discusses my background and qualifications, the legal
`
`standards that I applied in my expert analysis, an overview of the ʼ083 patent from
`
`the perspective of a person of ordinary skill in the art as of the patent’s effective
`
`filing date (a “POSA”) of January 21, 2015, and my opinions regarding the
`
`patentability of the challenged claims as of that date.
`
`3. My work in this proceeding is being charged to Petitioner at a
`
`standard rate of $750 per hour. My compensation is in no way contingent on the
`
`substance of my opinions or the outcome of this proceeding.
`
`4.
`
`I reserve the right to supplement or amend this declaration based on
`
`any new information that is relevant to my opinions.
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`5.
`
`In addition to my experience, education, and training, I have reviewed
`
`the materials listed in the List of Cited Exhibits above in connection with forming
`
`the opinions set forth in this declaration.
`
`II. BACKGROUND AND QUALIFICATIONS
`6.
`I am currently Professor of Clinical Medicine at the University of
`
`California, Irvine and Director of Clinical Pharmacology and Developmental
`
`Therapeutics at the University of California at Irvine’s (“UC Irvine”) Chao Family
`
`Comprehensive Cancer Center (“CFCCC”).
`
`7.
`
`I am involved in the direct oversight of multiple clinical trials at the
`
`CFCCC in the role of principal investigator. Several of the trials I have brought
`
`into our Cancer Center were phase I first-in-man studies, which means they were
`
`the first clinical study conducted in humans for a drug. Among other
`
`responsibilities, I work on the development and execution of clinical trials that
`
`incorporate translational endpoints, including phase I, II and III clinical trials. I
`
`also teach undergraduate students, graduate students, medical students, residents,
`
`and medical oncology fellows the principles of clinical trials in various courses.
`
`8.
`
`Since starting to work as a medical oncologist faculty member in the
`
`Division of Hematology/Oncology, Department of Internal Medicine in 1993, I
`
`have participated in weekly UC Irvine cancer clinics in the outpatient setting as a
`
`clinician and instructor for medical oncology fellows. I have also rotated on an
`
`
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`annual basis as the in-patient Attending Physician overseeing the cancer patient
`
`service at the UC Irvine University Hospital. I have experience treating patients
`
`with mantle-cell lymphoma (“MCL”), among other types of cancers (including
`
`lymphomas and leukemias). I also have clinical experience using the Bruton’s
`
`Tyrosine Kinase (“BTK”) inhibitor ibrutinib (brand name: Imbruvica).
`
`9.
`
`I obtained an M.D. from Rush University in 1985 and a Ph.D. in
`
`Pharmacology from Rush University. I received my undergraduate degree in
`
`Cellular and Organismal Biology, with a minor in Chemistry, from the University
`
`of California, Santa Barbara, in 1977.
`
`10.
`
`I completed my Internal Medicine Residency at UC Irvine in 1987. I
`
`completed my Medical Oncology Fellowship in 1990 at the National Cancer
`
`Institute in Bethesda, Maryland, which was followed by a biotechnology
`
`fellowship at the same institution, which was completed in 1992.
`
`11.
`
`I am a member of the American Association for Cancer Research, the
`
`American Society of Clinical Oncology, the Breast and Melanoma Committees of
`
`SWOG (a National Cancer Institute supported organization that conducts clinical
`
`trials in adult cancers), and the Medical Oncology Association of Southern
`
`California (“MOASC”).
`
`12.
`
`I have published more than 91 peer reviewed articles, book chapters,
`
`and reviews in the field of oncology. I am an inventor on eight U.S. patents. I am
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`also a peer reviewer for the following journal publications: Gynecologic Oncology,
`
`Breast Cancer Research and Treatment, Clinical Cancer Research, Anti-Cancer
`
`Drugs. The Cancer Journal, European Journal of Cancer, Pharmacological
`
`Research, and Cancer.
`
`13. A current copy of my curriculum vitae is attached as an Appendix to
`
`this declaration.
`
`III. SUMMARY OF OPINIONS
`14. The challenged claims of the ’083 patent are generally directed to
`
`treating MCL by orally administering 100 mg twice daily of acalabrutinib, which is
`
`a previously known inhibitor of BTK. E.g., EX1001, claim 8. As set forth more
`
`fully below, it is my opinion that the challenged claims are unpatentable under the
`
`following two grounds, which set forth the combinations of prior art references that
`
`would have rendered these claims obvious to a POSA. The full citations for these
`
`and other references cited in this Declaration are provided in the List of Cited
`
`Exhibits above. A POSA would have read the references listed below with the
`
`context provided by other background references discussed in this Declaration.
`
`Ground
`
`Claims
`
`References
`
`1
`
`2
`
`8-12, 19-20 Barf (EX1005), Cheson (EX1008)
`
`8-12, 19-20 Barf-PCT (EX1006), Cheson (EX1008)
`
`
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`15. Under Ground 1, it is my opinion that all challenged claims would
`
`have been obvious to a POSA in view of teachings in Barf (EX1005) and Cheson
`
`(EX1008). Infra §XI.A. Barf is an issued patent with an effective filing date in
`
`2011, whose sole independent claim recites a method of treating MCL by
`
`administering acalabrutinib. EX1005, 150:2-32. Barf’s claim 12 narrows this
`
`method by reciting a dosing range for acalabrutinib that overlaps with the 100 mg
`
`dose claimed in the ’083 patent. Id., 151:14-16. As I explain in more detail below,
`
`I understand that this overlap triggers a presumption of obviousness. Moreover,
`
`other information that would have been available to a POSA in the prior art would
`
`have further guided a POSA toward the claimed 100 mg dose, which a POSA
`
`would have arrived at through routine experimentation by conducting a dose-
`
`finding study focused on maximizing BTK occupancy, which was successfully
`
`done for other BTK inhibitors in the prior art.
`
`16. Administering the claimed dose twice daily would have been obvious
`
`over Cheson’s teachings and a POSA’s understanding based on other references in
`
`the prior art. For example, Cheson discloses the theory that “BTK inhibitors are
`
`being evaluated in a twice-daily schedule in an attempt to overcome the synthesis
`
`of new BTK molecules,” and further discloses that twice-daily dosing “appeared to
`
`be more effective” than once-daily dosing in clinical trials. EX1008, 4, 10. As I
`
`explain in more detail below, Cheson’s disclosures and the reported results of
`
`
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`studies on other BTK inhibitors would have made it obvious to attempt twice-daily
`
`dosing with a new BTK inhibitor like acalabrutinib. At a minimum, twice-daily
`
`dosing would have been obvious to try as one of two options that were used in the
`
`prior art for BTK inhibitors (once-daily dosing and twice-daily dosing).
`
`17. Under Ground 2, I have been asked to assume in the alternative that
`
`Barf is not prior art. In that case, it remains my opinion that all challenged claims
`
`would have been obvious over Barf-PCT (EX1006) and Cheson. Infra §XI.B. I
`
`understand that Barf-PCT is the international application counterpart to Barf,
`
`which was published in 2013. EX1006, 1. Thus, Barf-PCT provides the same
`
`disclosures as Barf, including the structure of acalabrutinib, its use to treat MCL,
`
`and the overlapping dosing range. See id., 35:16-36:2, 22:15-16, 20:24-25.
`
`Accordingly, even if Barf is ultimately found not be prior art, the challenged
`
`claims would still have been obvious over the disclosures of Barf-PCT in
`
`combination with Cheson and the knowledge and skill of a POSA.
`
`18.
`
`I understand that during the prosecution of the ’083 patent, the
`
`Examiner at the Patent Office reviewing the patent application repeatedly found
`
`the proposed claims obvious, allowing them only after the applicants alleged
`
`unexpected results. Infra §V.C. As I explain below, however, the results that the
`
`applicants alleged were neither probative nor unexpected. Infra §XI.C.1. Thus, in
`
`my opinion, the basis for allowing the claims of the ’083 patent was incorrect.
`
`
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`IV. LEGAL STANDARDS USED IN MY ANALYSIS
`19.
`I am not a patent attorney, nor have I independently researched patent
`
`law. Counsel for Petitioner have explained certain legal standards to me that I
`
`have relied upon in forming my opinions set forth in this Declaration. I set forth
`
`some of these legal standards below and set forth additional legal standards in my
`
`analysis in later sections of this Declaration where appropriate.
`
`A. Effective filing date
`20.
`I understand that an assessment of patentability must be undertaken
`
`from the perspective of a POSA as of the effective filing date of the challenged
`
`claims. I further understand that a POSA is presumed to have had access to all
`
`information relevant to the challenged claims that was publicly available as of the
`
`effective filing date. Such information is known as “prior art.”
`
`21.
`
`I understand that the effective filing date of a patent claim is the
`
`earliest of (i) the actual filing date of the patent or the application for the patent
`
`containing the claimed invention; or (ii) the filing date of the earliest application
`
`for which the patent or application is entitled to claim priority. I understand that in
`
`order to claim priority to an earlier-filed patent application, that application must
`
`provide written-description support for the claimed invention.
`
`22.
`
`I understand that a patent application provides sufficient written-
`
`description support for a claimed invention if the disclosure of the application
`
`
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`reasonably conveys to a POSA that the named inventors had possession of the
`
`claimed subject matter as of the application’s filing date.
`
`23.
`
`I provide my opinions regarding the ’083 patent’s effective filing date
`
`using these legal standards below in §VI.
`
`B.
`24.
`
`Person of ordinary skill in the art
`I understand that a POSA is a hypothetical person who is presumed to
`
`have known all the relevant prior art as of the effective filing date.
`
`25.
`
`I understand that the factors that may be considered in determining the
`
`level of ordinary skill of a POSA include (i) the types of problems encountered in
`
`the art, (ii) prior art solutions to those problems, (iii) rapidity with which
`
`innovations are made, (iv) sophistication of the technology, and (v) educational
`
`level of active workers in the field. I understand that in a given case, every factor
`
`may not be present, and one or more factors may predominate.
`
`26.
`
`I understand that a POSA is considered to be a person of ordinary
`
`creativity, not an automaton.
`
`27.
`
`I provide my opinions regarding the level of ordinary skill for a POSA
`
`using these legal standards below in §VII.
`
`C. Obviousness
`28.
`I have been informed that a claim is unpatentable if the differences
`
`between the claimed invention and the prior art are such that the claimed invention
`
`
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`as a whole would have been obvious before the effective filing date of the claimed
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`invention to a person having ordinary skill in the art to which the claimed
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`invention pertains. For purposes of obviousness, I understand that a POSA may
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`rely on multiple prior art references in combination.
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`29.
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`I have been informed that the following four factors are considered
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`when determining whether a patent claim would have been obvious to a POSA: (a)
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`the level of ordinary skill in the art; (b) the scope and content of the prior art; (c)
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`the differences between the prior art and the claim; and (d) any “secondary
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`considerations” tending to prove nonobviousness. These secondary considerations,
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`which are also called “objective indicia” or “objective evidence,” may include
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`factors such as: (i) the invention’s satisfaction of a long-felt unmet need in the art;
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`(ii) unexpected results of the invention; (iii) skepticism of the invention by experts;
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`(iv) commercial success of an embodiment of the invention; and (vii) praise by
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`others for the invention. I understand that there must be an adequate nexus or
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`connection between the evidence that is the basis for an asserted secondary
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`consideration and the scope of the invention claimed in the patent.
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`30.
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`I understand that when every limitation of a claim is disclosed in the
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`cited prior art references, the question of obviousness turns on whether a POSA
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`would have been motivated to combine those teachings to derive the claimed
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`subject matter with a reasonable expectation of success.
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1002, p. 16 of 134
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`31. With respect to the reasonable expectation of success, I understand
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`that obviousness does not require absolute predictability; only a reasonable
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`expectation of success of achieving the claimed invention is necessary.
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`32.
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`I have been informed that a claimed invention can be rendered
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`obvious by combinations of teachings in the prior art even if there is no explicit
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`teaching to combine them. Instead, any problem known in the field at the time of
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`the alleged invention can provide a sufficient rationale to combine the elements of
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`the prior art in the manner claimed in the patent.
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`33.
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`In addition to the references that are cited in an asserted obviousness
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`combination, I understand that background prior art references can legitimately
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`serve to document the knowledge that a POSA would bring to bear in reading the
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`prior art identified as producing obviousness.
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`34.
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`I have been informed that examples of sufficient rationales for
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`establishing obviousness include the following:
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`• combining prior art elements according to known methods to yield
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`predictable results;
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`• substituting known elements for other known elements to obtain
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`predictable results;
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`• using a known technique to improve similar devices, methods, or
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`products in the same way;
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`IPR2023-00478
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`Ex. 1002, p. 17 of 134
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`• choosing from a finite number of identified, predictable solutions that
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`would be obvious to try; and
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`• providing some teaching, suggestion, or motivation to modify the
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`prior art reference or to combine teachings in prior art references to
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`arrive at the claimed invention.
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`35.
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`I understand that where there is a range disclosed in the prior art, and
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`the claimed invention falls within that range, the burden of production falls upon
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`the patentee to come forward with evidence that (1) the prior art taught away from
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`the claimed invention; (2) there were new and unexpected results relative to the
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`prior art; or (3) there are other pertinent secondary considerations.
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`36. For purposes of this analysis, I understand that a prior art reference
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`“teaches away” from a claimed invention if it criticizes, discredits, or otherwise
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`discourages investigation into the invention claimed.
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`37.
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`I understand that where the general conditions of a claim are disclosed
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`in the prior art, it is not inventive to discover the optimum or workable ranges by
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`routine experimentation.
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`38.
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`I understand that an invention is obvious to try when there is a design
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`need or market pressure to solve a problem and there are a finite number of
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`identified, predictable solutions. I understand that in order for this analysis to
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`apply, the number of solutions must be small or easily traversed in the context of
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1002, p. 18 of 134
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`the relevant art. By contrast, I understand that an obvious-to-try analysis does not
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`apply where it would only have been obvious (a) to vary all parameters or try every
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`available option until one succeeds, where the prior art gave no indication of
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`critical parameters and no direction as to which of many possibilities is likely to be
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`successful; or (b) to explore a new technology or general approach in a seemingly
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`promising field of experimentation, where the prior art gave only general guidance
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`as to the particular form or method of achieving the claimed invention.
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`39.
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`I provide my opinions regarding the obviousness of the challenged
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`claims using these legal standards below in §XI. I also discuss additional legal
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`standards in this Declaration where they are pertinent to my analysis.
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`V. THE ʼ083 PATENT
`A.
`Specification
`40.
`I have reviewed and am familiar with the ’083 patent, which is titled
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`“Methods of treating chronic lymphocytic leukemia and small lymphocytic
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`leukemia using a BTK inhibitor.” EX1001.
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`41. The specification of the ’083 patent begins with a “Background of the
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`Invention” section, which purports to describe the state of the art at the time the
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`patent application was filed in January 2015. This section acknowledges that BTK
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`is a “protein kinase expressed in B cells” whose physiological function “is well
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`established” in the prior art. EX1001, 1:14-18. Citing the prior art, the
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`IPR2023-00478
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`Ex. 1002, p. 19 of 134
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`specification of the ’083 patent admits that “[t]he reported role for BTK in the
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`regulation of proliferation and apoptosis [i.e., death] of B cells indicates the
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`potential for BTK inhibitors in the treatment of B cell lymphomas,” and “BTK
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`inhibitors have thus been developed as potential therapies.” Id., 1:28-32.
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`42. Like the title of the ’083 patent, the specification largely focuses on
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`methods for treating “B cell chronic lymphocytic leukemia (CLL)” (id., 1:34) and
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`“[s]mall lymphocytic leukemia (SLL)” (id., 1:45). In particular, the specification
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`of the ’083 patent discloses treatments for these conditions by administering a
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`compound of “Formula (II),” which is the name that the ’083 patent uses for the
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`compound that is known today as acalabrutinib. E.g., id., 2:37-47.
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`43. The only recited clinical data in the ’083 patent is from a study on
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`patients with CLL. See id., 7:24-61, Figs. 2-8. Notably, the ’083 patent does not
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`contain any in vivo or clinical data on treating MCL.
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`44. The specification of the ’083 patent does not ascribe any particular
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`significance to the doses used for treatment with acalabrutinib. Rather, the
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`specification generally recognizes that “[t]he amounts of BTK inhibitors
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`administered” may vary in “the discretion of the prescribing physician.” EX1001,
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`42:29-33. The ’083 patent also states that “an effective dosage is in the range of
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`about 0.001 to about 100 mg per kg body weight per day,” with a number of
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`exemplary ranges listed that span anywhere from 1-500 mg. Id., 42:33-34, 43:12-
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1002, p. 20 of 134
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`38. As to