IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Biocon Pharma Limited
`Petitioner,
`
`v .
`
`Novartis Pharmaceuticals Corporation
`Patent Owner.
`
`U.S. Patent No. 8,101,659 to Ksander et al.
`Issue Date: January 24, 2012
`Title: Methods of Treatment and Pharmaceutical Composition
`
`Inter Partes Review No.: IPR2020-01263
`
`Declaration #*% !-++’$-(-) "’,#& of Y. W. Francis Lam, Pharm.D., FCCP
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 001
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`

`

`Declaration of Prof. Y. W. Francis Lam
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Table of Contents
`INTRODUCTION .......................................................................................... 1
`
`MY EXPERIENCE AND QUALIFICATIONS ............................................ 2
`
`LIST OF MATERIALS CONSIDERED ....................................................... 9
`
`LEGAL STANDARD ..................................................................................12
`
`A. Obviousness .................................................................................................12
`
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”) .....................16
`
`BACKGROUND OF RELEVANT TECHNICAL CONCEPTS ................18
`
`A. Angiotensin II and NEP Inhibition ..............................................................18
`
`THE ’659 PATENT .....................................................................................28
`
`CLAIM CONSTRUCTION .........................................................................32
`
`OBVIOUSNESS ..........................................................................................32
`
`A. Claims 1-4 Would Have Been Obvious .......................................................33
`
`1. The Scope and Content of the Prior Art ...................................................33
`
`a) EP’072 ...................................................................................................33
`
`b) Trippodo ................................................................................................37
`
`c) Shetty .....................................................................................................40
`
`d) Gomez-Monterrey .................................................................................44
`
`e) Ksander .................................................................................................47
`
`f) The ’996 Patent .....................................................................................53
`
`g) PDR .......................................................................................................56
`
`2. Ground 1: Claims 1-4 Would Have Been Obvious over EP’072, Shetty,
`
`Gomez-Monterrey, and Ksander ......................................................................57
`
`i
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 002
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`

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`Declaration of Prof. Y. W. Francis Lam
`
`a) Claim 1 ..................................................................................................57
`
`b) Dependent Claims 2-4 ...........................................................................79
`
`3. Ground 2: Claims 1-4 Would Have Been Obvious over the PDR In View
`
`of the ’996 Patent, Gomez-Monterrey, and EP’072 ........................................86
`
`c) Claim 1 ..................................................................................................86
`
`d) Dependent Claims 2-4 ...........................................................................97
`
`4. No Secondary Considerations of Nonobviousness ................................101
`
`a) No Unexpected Results .......................................................................101
`
`ii
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 003
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`

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`I, Y. W. Francis Lam, Pharm.D., FCCP, do hereby declare and state as follows:
`
`1.
`
`I have been asked to provide testimony as to what one of ordinary skill
`
`in the art would have understood with respect to the patent at issue and various prior
`
`art discussed herein. I provide this testimony below:
`
`1.
`
`INTRODUCTION
`
`2.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`3.
`
`I have been retained as an expert witness on behalf of Petitioner Biocon
`
`Pharma Limited for the above-captioned inter partes review (“IPR”). I am being
`
`compensated for my time in connection with this IPR at my standard consulting rate,
`
`which is $500 per hour. My compensation is in no way dependent on the outcome
`
`of this IPR.
`
`4.
`
`I understand
`
`that
`
`the petition for IPR
`
`involves U.S. Patent
`
`No. 8,101,659 (“the ’659 patent”) (EX1001).
`
`5.
`
`The ’659 patent names Gary M. Ksander and Randy L. Webb as the
`
`purported inventors.
`
`1
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 004
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`Declaration of Prof. Y. W. Francis Lam
`
`6.
`
`For the purposes of this declaration, I have been told to assume the
`
`relevant priority date of the ’659 patent is January 17, 20021—the filing date of U.S.
`
`Provisional Application No. 60/349,660. I further understand that the ’659 patent is
`
`assigned to Novartis Pharmaceuticals Corporation (“Novartis,” “Patentee,” or
`
`“Patent Owner”).
`
`7.
`
`As explained below, it is my opinion that Claims 1-4 of the ’659 patent
`
`would have been obvious to the skilled artisan as of the time of the priority date of
`
`the ’659 patent. Therefore, these claims are invalid.
`
`2. MY EXPERIENCE AND QUALIFICATIONS
`
`8.
`
`I am an expert in the field of pharmacology, pharmaceutical sciences
`
`and pharmacokinetics.
`
` Specifically,
`
`I
`
`specialize
`
`in pharmacology,
`
`pharmacokinetics, drug metabolism, and clinical pharmacology, particularly the
`
`medical aspects of drugs acting on biological systems, such as the renin-angiotensin-
`
`aldosterone system (RAAS), and I have been an expert in this field since prior to
`
`2002. I have relied upon my training, knowledge, and experience in the relevant art
`
`to form my opinions.
`
`1 I have not been asked to analyze whether this is indeed the correct priority date but
`
`rather assume that it is for the purposes of my declaration. However, should this
`
`become an issue during the proceeding, I may be called upon to offer my opinion.
`
`2
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 005
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`Declaration of Prof. Y. W. Francis Lam
`
`9.
`
`In 1981, I graduated with honors from the School of Pharmacy at the
`
`University of Bradford, West Yorkshire, UK and received a Bachelor of Pharmacy
`
`degree. In 1984, I received a Pharm.D. from the College of Pharmacy at the
`
`University of Minnesota. From July 1984 to June 1985, I was in the postdoctoral
`
`residency program in cardiology and pharmacokinetics at the College of Pharmacy
`
`at the University of Minnesota. From July 1985 to June 1987, I was a postdoctoral
`
`fellow in clinical pharmacokinetics and pharmacodynamics at the School of
`
`Pharmacy and Drug Studies Unit at the University of California, San Francisco.
`
`During my graduate studies at the University of Minnesota and postdoctoral work at
`
`the University of California, San Francisco, I took courses in advanced and clinical
`
`pharmacokinetics, as well as bioanalytical theory and techniques.
`
`10.
`
`I am currently a tenured Professor in the Department of Pharmacology
`
`at the University of Texas Health Science Center San Antonio (UTHSCSA). I am
`
`also jointly appointed as an Associate Professor in the Department of Medicine at
`
`UTHSCSA, and as a Clinical Associate Professor and James O. Burke Endowed
`
`Centennial Fellow in Pharmacy at the College of Pharmacy at the University of
`
`Texas at Austin. I have taught and carried out research in clinical pharmacology at
`
`UTHSCSA since 1987. While at UTHSCSA, I have served as the Scientific Review
`
`Officer, Office of Vice President for Research (September 2016 to Present);
`
`Co-Leader of the Voelcker Biomedical Research Academy (August 2016 to
`
`3
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 006
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`Declaration of Prof. Y. W. Francis Lam
`
`Present); Co-Leader of the Human Health and Disease Track, Dental School
`
`(January 2016 to Present); Chair of the Committee on Graduate Studies for
`
`Pharmacology, Integrated Multidisciplinary Graduate Program, Graduate School of
`
`Biomedical Science (July 2016 to June 2019); Co-Leader of the Pharmacology
`
`Track, Integrated Multidisciplinary Graduate Program, Graduate School of
`
`Biomedical Science (July 2016 to June 2019); and Deputy Director of the
`
`Physiology and Pharmacology Discipline, Interdisciplinary Biomedical Sciences,
`
`Graduate School of Biomedical Science (September 2016 to March 2018).
`
`11. As a tenured Professor of Pharmacology at UTHSCSA, I have over
`
`33 years of experience in teaching all aspect of pharmacology related to drug
`
`development, including pharmacokinetics and pharmacodynamics, to both graduate
`
`and undergraduate students. In theory and laboratory courses that I have taught and
`
`continue to teach, I extensively cover pharmacokinetics, pharmacodynamics, and
`
`pharmacotherapeutics (treatment of diseases using various pharmaceuticals). I have
`
`also advised numerous doctoral students, master’s students, visiting scientists, and
`
`research fellows.
`
`12. My research interests include, among other things: (1) correlation of
`
`pharmacokinetics and pharmacodynamics in clinical pharmacology; (2) mechanisms
`
`and clinical implications of drug-drug interactions; (3) effects and mechanisms of
`
`environmental and host factors on drug disposition and integration of these
`
`4
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 007
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`Declaration of Prof. Y. W. Francis Lam
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`disciplines to studies of toxicology and drug response; (4) practical applications of
`
`population data analysis; and (5) in vitro models for drug metabolism and toxicity
`
`investigations.
`
`13. Over the course of my career I have published extensively. I have
`
`coauthored over 30 book chapters and more than 70 peer reviewed scientific articles.
`
`I have performed over 85 invited presentations and scientific symposium activities.
`
`The topics of these materials include, among other topics, pharmacokinetics, drug
`
`metabolism, and pharmacodynamics. I have been involved in and consulted on
`
`multiple projects over the years both in industry and academia about the
`
`aforementioned topics.
`
`14.
`
`I have served as a grant reviewer for numerous funding agencies,
`
`including the National Institutes of Health, the Qatar Foundation, the American
`
`College of Clinical Pharmacy, and UTHSCSA. I am a member of several
`
`professional and industrial societies, including the American College of Clinical
`
`Pharmacy, the American Society for Clinical Pharmacology and Therapeutics, and
`
`the Pacific Rim Association for Clinical Pharmacogenetics, and have participated as
`
`a reviewer for more than 30 scientific journals. I have also received a number of
`
`professional awards and honors, including the Minnie Stevens Piper Professor in
`
`2018; the University of Texas System Regents’ Outstanding Teaching Award in
`
`2015; the Advisory Committee Service Award, Food and Drug Administration in
`
`5
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 008
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`2004; and the Oncology Research Award, American College of Clinical Pharmacy
`
`Declaration of Prof. Y. W. Francis Lam
`
`in 1994.
`
`15. Over the course of my career, I have been involved in researching the
`
`pharmacodynamics and pharmacokinetics of various biologically active agents in
`
`the treatment of several diseases and disorders including cardiology-related
`
`disorders. Additionally, my research also focuses on efficacy and toxicity of
`
`medications and how ethnicity and genetic differences affect disposition and
`
`response to drugs.
`
`16.
`
`Throughout my career, I have been involved with the study, design and
`
`development of drugs involved in the treatment of cardiac diseases. For example,
`
`from July 1984 to June 1985, I did a postdoctoral residency in cardiology and
`
`pharmacokinetics at the College of Pharmacy, University of Minnesota.2 While
`
`there, I researched pharmacological management of hypertension and published in
`
`2 Around about this time at the University of Minnesota, I was a clinical instructor
`
`in pharmacokinetics, cardiology, and internal medicine, Doctor of Pharmacy
`
`Program, College of Pharmacy (July 1984 to June 1985) and I was an instructor at
`
`the Training Institute for
`
`the Clinical Application of Pharmacokinetics,
`
`Cardiovascular Section, Section of Clinical Pharmacology, February 1985 to March
`
`1985 at St. Paul-Ramsey Medical Center in Minnesota.
`
`6
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 009
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`Declaration of Prof. Y. W. Francis Lam
`
`the area of anti-hypertensive agents. Meir MR, Josselson J, Giard MJ, Warren JB,
`
`Posner JN, Lam YWF, Zaske DE, Saunders E. “Sustained-release diltiazem
`
`compared with atenolol monotherapy for mild to moderate systemic hypertension,”
`
`Am. J. Cardiol. 1987;60:36I-41I; Lam YWF, Giard MJ, Warren JB. “Calcium
`
`channel blockers and treatment of hypertension,” Drug Intell ClinPharm
`
`1986;20:187-98; Johnson BA, Javors MA, Lam YWF, Wells LT, Tiouririne M,
`
`Roache JD, Ait-Daoud N, Lawson K. “Kinetic and cardiovascular comparison of
`
`sustained-release and immediate-release isradipine among healthy volunteers,”
`
`Prog. Neuropsychopharmacol. Biol. Psychiatry 2005;29:15-20; Lam YWF.
`
`“Calcium metabolism, calcium channel blockers, and hypertension management,”
`
`Drug Intell. Clin. Pharm. 1988;22:659-71; Lam YWF, Morton TA. “Theophylline
`
`clearance in the obese patient with congestive heart failure,” Program Abstract of
`
`25th Annual American Society of Hospital Pharmacists Midyear Clinical Meeting
`
`and Exhibit 1990;25:141.
`
`17.
`
`In addition, I have received various grants in the area of cardiology.
`
`E.g., “Indolidan: Oral Radiocarbon Pharmacokinetics in Heart Failure”. Eli Lilly &
`
`Co. December 1988 to November 1989 (CoI; PI: Michael H. Crawford, M.D.); “The
`
`Effects of TA 3090 Tablets on Systemic and Regional Hemodynamics in Patients
`
`with Mild to Moderate Essential Hypertension”. Marion Laboratories. December
`
`1988 to May 1990. (CoI; PI: Alexander M.M. Shepherd, M.D., Ph.D.); “A Novel
`
`7
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 010
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`Declaration of Prof. Y. W. Francis Lam
`
`Non-polymeric Metallic Nano-porous Surface for Stent Based Drug Delivery.”
`
`American Heart Association Texas Affiliate (CoI) (July 2005 to June 2007);
`
`“Utilization of Metal-Oxide Nanoporous Films for Stent Based Drug Delivery”. San
`
`Antonio Life Science Institute September 2004 to August 2005 (CoI). I have also
`
`given invited presentations in cardiology. E.g., “Esmolol: An Ultra-Short Acting
`
`Beta-Blocker”, Department of Pharmacy Practice, College of Pharmacy, Ohio State
`
`University, Columbus, Ohio. February 1984; “An Overview of OTC Drugs: History,
`
`Concerns, Expectations, and Promise”, Dr. Walter M. Booker, Sr. Memorial
`
`Symposium: New Concepts in Cardiovascular Care: Research, Translation and
`
`Innovation. Association of Black Cardiologists, Orlando, Florida. November 2015.
`
`18. While I teach in all areas of pharmacology, my training and interest
`
`pertain specifically to the area of cardiovascular pharmacology. E.g., Human Health
`
`and Disease: Cardiovascular and Pulmonary Systems (Course Director since January
`
`2017); Pharmacotherapeutics-Cardiovascular; Advanced Pharmacotherapeutics of
`
`Cardiovascular Diseases.
`
`19.
`
`I understand that this matter involves antihypertensive agents,
`
`angiotensin receptor antagonists and neutral endopeptidase inhibitors. Well before
`
`my involvement with this matter, I have had experience with the pharmacological
`
`and medical aspects of drugs acting on the RAAS such as angiotensin converting
`
`enzyme inhibitors and angiotensin receptor antagonists, as well as neutral
`
`8
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 011
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`Declaration of Prof. Y. W. Francis Lam
`
`endopeptidase inhibitors that impact the clearance of endogenous peptides such as
`
`atrial natriuretic factor. Further, I have experience in pharmacological aspects of
`
`two drug combinations, including fixed dose combinations (FDC), e.g., FDC of
`
`diuretics as antihypertensives, FDC of antibiotics for management of bacterial
`
`infection, and FDC of antiretroviral agents for management of HIV infection.
`
`20. Well before my involvement with this matter, I was familiar with
`
`valsartan, sacubitril and ENTRESTO® and had reviewed a significant amount of
`
`literature on both active agents, the drug classes these drugs belong to, and
`
`ENTRESTO®.
`
`21. A true and correct copy of my curriculum vitae, which includes a list of
`
`the published papers that I have written, professional honors and memberships, and
`
`presentations that I have given, is attached to this report as EX1018. The matters in
`
`which I have testified include: Boehringer Ingelheim vs. HEC Pharm and Teva
`
`Pharmaceuticals vs. Helsinn and Roche.
`
`3.
`
`LIST OF MATERIALS CONSIDERED
`
`22.
`
`I have reviewed the ’659 patent, the prosecution history, and each of
`
`the documents cited herein, in consideration of general knowledge in the art as of
`
`January 2002. In forming my opinions, I have relied upon my experience in the
`
`relevant art. I have also considered the viewpoint of a POSA, as defined below, as
`
`of January 2002. I have considered all documents cited in this Declaration and all
`
`9
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 012
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`

`

`Declaration of Prof. Y. W. Francis Lam
`
`documents cited in the Petition for Inter Partes Review of the ’659 patent, as well
`
`as the following documents:
`
`Exhibit #
`
`Description
`
`1001
`
`U.S. Patent No. 8,101,659 (“the ’659 patent”)
`
`1002
`
`EP Patent Application No. 0726072A2 (“EP’072”)
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`Trippodo et al., “REPRESSION OF ANGIOTENSIN II AND
`POTENTIATION OF BRADYKININ CONTRIBUTE TO THE
`SYNERGISTIC EFFECTS OF DUAL METALLOPROTEASE
`INHIBITION IN HEART FAILURE”, Journal of Pharmacology
`and Experimental Therapeutics, Vol. 272, No. 2, February 01,
`1995, 619-627 (“Trippodo”)
`
`Shetty et al., “DIFFERENTIAL INHIBITION OF THE
`PREJUNCTIONAL ACTIONS OF ANGIOTENSIN II IN RAT
`ATRIA BY VALSARTAN, IRBESARTAN, EPROSARTAN,
`AND LOSARTAN”, Journal of Pharmacology and Experimental
`Therapeutics, Vol. 294, No. 1, July 01, 2000, 179-186 (“Shetty”)
`
`Gomez-Monterrey et al., “NEW THIOL INHIBITORS OF
`NEUTRAL ENDOPEPTIDASE EC 3.4.24.11: SYNTHESIS AND
`ENZYME ACTIVE-SITE RECOGNITION”, Journal of Medicinal
`Chemistry, Vol. 37, Issue 12, June 01, 1994, 1865-1873 (“Gomez-
`Monterrey”)
`
`Ksander et al., “DICARBOXYLIC ACID DIPEPTIDE NEUTRAL
`ENDOPEPTIDASE INHIBITORS”, Journal of Medicinal
`Chemistry, Vol. 38, Issue 10, May 01, 1995, 1689-1700
`(“Ksander”)
`
`Reserved
`
`US Patent No. 5,399,578 (“the ’578 patent”)
`
`US Patent No. 5,217,996 (“the ’996 patent”)
`
`The prosecution history for U.S. Patent No. 8,101,659 (“the ’659
`prosecution history”)
`
`10
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 013
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`

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`Declaration of Prof. Y. W. Francis Lam
`
`Description
`
`Thürmann, “VALSARTAN: A NOVEL ANGIOTENSIN TYPE 1
`RECEPTOR ANTAGONIST,” Expert Opinion on
`Pharmacotherapy, Vol. 1, Issue 2, January 2000, 337-350
`(“Thürmann”)
`
`Physician’s Desk Reference (2000), DIOVAN® (“PDR”)
`
`Roques et al., “NEUTRAL ENDOPEPTIDASE 24.11:
`STRUCTURE, INHIBITION, AND EXPERIMENTAL AND
`CLINICAL PHARMACOLOGY,” Pharmacological Reviews, Vol.
`45, Issue 1, March 01, 1993, 87-146 (“Roques”)
`
`U.S. Patent No. 7,468,390 (“the ’390 patent”)
`
`The prosecution history for U.S. Patent No. 7,468,390 (“the ’390
`prosecution history”)
`
`Ferrario, et al., “COUNTERREGULATORY ACTIONS OF
`ANGIOTENSIN,” Hypertension, Vol. 30, Issue 3, September
`1997, 535-541 (“Ferrario”)
`
`Orange Book Entry for ENTRESTO® (“Orange Book listing for
`ENTRESTO®”)
`
`Curriculum Vitae of Prof. Y.W. Francis Lam
`
`Physician’s Desk Reference (2000), NORVASC® (“PDR-
`Norvasc”)
`
`Physician’s Desk Reference (2000), TENORMIN® (“PDR-
`TENORMIN”)
`
`Physician’s Desk Reference (2000), TAGAMET® (“PDR-
`TAGAMET”)
`
`Physician’s Desk Reference (2000), LANOXIN® (“PDR-
`LANOXIN”)
`
`Physician’s Desk Reference (2000), Furosemide (“PDR-
`Furosemide”)
`
`Physician’s Desk Reference (2000), MICRONASE® (“PDR-
`MICRONASE”)
`
`Exhibit #
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`11
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 014
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`Declaration of Prof. Y. W. Francis Lam
`
`Exhibit #
`
`Description
`
`1025
`
`1026
`
`Physician’s Desk Reference (2000), HydroDIURIL® (“PDR-
`HydroDIURIL”)
`Physician’s Desk Reference (2000), INDOCIN® (“PDR-
`INDOCIN”)
`
`4.
`
`LEGAL STANDARD
`
`23. Although I am not a lawyer, I have been informed by counsel and
`
`provide my general understanding of the law of obviousness. I used these principles
`
`in conducting my analysis and drawing any conclusions.
`
`24.
`
`I understand that the first step in determining whether a patent claim
`
`would have been obvious is to construe the claims to determine claim scope and
`
`meaning. I understand that in IPR proceedings, the claims must generally be given
`
`“the meaning that the term would have to a person of ordinary skill in the art in
`
`question at the time of the invention.”
`
`A.
`
`Obviousness
`
`25.
`
`I understand that a patent claim is invalid if the differences between the
`
`claimed invention and prior art are such that the subject matter as a whole would
`
`have been obvious at the time the invention was made to a POSA.
`
`26.
`
`I have been told the following factors (sometimes referred to as the
`
`Graham factors) are used in making an obviousness determination: a) the scope and
`
`content of the prior art; b) the differences between the prior art and the claimed
`
`12
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 015
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`Declaration of Prof. Y. W. Francis Lam
`
`invention; c) the level of ordinary skill in the pertinent art; and d) any secondary
`
`considerations evidencing nonobviousness. The obviousness analysis looks to the
`
`state of the art that existed at the time the invention was made.
`
`27. Moreover, obviousness does not require absolute predictability of
`
`success; all that is required is a reasonable expectation of success. I have been
`
`informed that the person of ordinary skill need only have a reasonable expectation
`
`of success of developing the claimed invention. Another helpful formulation of this
`
`concept is to ask whether or not a skilled artisan would have perceived a reasonable
`
`expectation of success in making the invention in light of the prior art.
`
`28.
`
`Finally, obviousness cannot be avoided simply by a showing of some
`
`degree of unpredictability in the art so long as there was a reasonable probability of
`
`success.
`
`29.
`
`I also understand that obviousness can be established by combining or
`
`modifying the teachings of the prior art. A claimed invention can be obvious when,
`
`for example, there is some teaching, suggestion, or motivation in the prior art that
`
`would have led a POSA to modify the prior art reference or to combine prior art
`
`reference teachings to arrive at the claimed invention.3
`
`3 As a general matter, in my view, in science and technology, a POSA would not
`
`view any single disclosure as complete, and thus, look no further. Were that the case,
`
`13
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1018, p. 016
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`Declaration of Prof. Y. W. Francis Lam
`
`30.
`
`I also understand that the prior art references themselves do not have to
`
`provide an explicit teaching, suggestion, or motivation to combine prior art
`
`teachings; rather, the analysis may rely on interrelated teachings, market demands,
`
`the background knowledge possessed by a POSA, and/or common sense. A POSA
`
`can also take account of the inferences and creative steps that he or she would
`
`employ including fitting various pieces of prior art together like a jigsaw puzzle. Put
`
`another way, the motivation to combine or modify prior art references can come
`
`from any reason to do so and is not limited to the reasons that may have motivated
`
`the patentee.
`
`31.
`
`I also understand that a combination of familiar elements according to
`
`known methods is likely to be obvious when it does no more than yield predictable
`
`results. As such, when a POSA would have reached the claimed invention through
`
`routine experimentation, the invention may be deemed obvious.
`
`32.
`
`I understand that various rationales are utilized to determine whether a
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`claim
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`is obvious,
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`including, among others:
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`(i) simple substitution or
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`interchangeability of one known element for another to obtain predictable results;
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`(ii) use of known techniques to improve similar methods or products in the same
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`society would have halted progress long ago. Instead, ordinary artisans always seek
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`improvement in their respective fields.
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`14
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`Declaration of Prof. Y. W. Francis Lam
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`way; (iii) applying a known technique to a known method or product ready for
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`improvement to yield predictable results; (iv) “obvious to try”—choosing from a
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`finite number of identified, predictable solutions, with a reasonable expectation of
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`success; and (v) known work in one field of endeavor prompting variations of it for
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`use in either the same field or a different one based on design incentives or other
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`market forces if the variations would have been predictable to one of ordinary skill
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`in the art.
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`33. As stated above, I understand that secondary considerations of
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`nonobviousness are part of the obviousness inquiry. I understand that these
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`secondary considerations may include failure of others, copying, unexpectedly
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`superior results, perception in the industry, commercial success, and long-felt but
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`unmet need. I also understand that for secondary considerations of nonobviousness
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`to be applicable, they must have a nexus to the claimed subject matter. I understand
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`that this nexus (i.e., link) includes a connection between the subject matter of the
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`claims and the alleged secondary considerations.
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`34.
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`I understand that I cannot use hindsight in any obviousness analysis. In
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`connection with my opinions, I did not use hindsight, nor did I use the claims and/or
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`the disclosure of the ’659 patent as a blueprint for piecing together the prior art to
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`arrive at the claimed invention. As part of the obviousness analysis, and to avoid
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`hindsight, I thought back to the time of invention (i.e., the relevant priority date
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`Declaration of Prof. Y. W. Francis Lam
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`(discussed further below)) and considered the thinking of a POSA, guided only by
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`the prior art references and the then-accepted wisdom in the field.
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`5.
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`PERSON OF ORDINARY SKILL IN THE ART (“POSA”)
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`35.
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`In arriving at my opinions, I have relied on my experience in the
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`relevant art and have considered the point of view of a POSA as of the relevant
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`priority date. It is my understanding that a POSA is a hypothetical person who is
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`presumed to be aware of all pertinent art, thinks along conventional wisdom in the
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`art, and is a person of ordinary creativity.
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`36. As of the relevant priority date, a POSA would have had experience in
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`the fields of cardiology and pharmacology, including an understanding of drug-drug
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`interactions, rationales for drug combinations, and development and availability of
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`drugs for treatment of cardiovascular disorders. A POSA would have had: (i) a
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`doctoral degree in pharmacology, pharmacy, medicine, chemistry, biochemistry,
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`medical chemistry or in a related field, and with two years of the above-described
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`experience; (ii) a master’s degree in the same fields, and with seven years of the
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`above-described experience; or (iii) a bachelor’s degree in the same fields and with
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`ten years of the above-described experience. Furthermore, a POSA may consult
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`with individuals having specialized expertise, for example, a clinician or practitioner
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`with experience in the administration, dosing, and efficacy of drugs, and/or a
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`regulatory affairs specialist.
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`Declaration of Prof. Y. W. Francis Lam
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`37. A POSA would also have knowledge of the scientific literature
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`concerning the same as of the priority date. A POSA may also work as part of a
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`multidisciplinary team and draw upon not only his or her own skills, but also take
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`advantage of certain specialized skills of others in the team to solve a given problem.
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`38.
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`In determining the qualifications of a POSA, I considered, among other
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`factors, the field of the claimed invention and use thereof described in the ’659 patent
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`and my experience with the educational level of practitioners in related fields. In
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`addition, my opinion is based upon my background, education, and personal
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`experience.4
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`39. Based on my experience, I had the understanding and capabilities of a
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`POSA as defined above prior to, and on, the relevant priority date (January 17,
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`2002), and all testimony and opinions provided herein is from that perspective,
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`including the relevant time frame.
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`4 For example, Dr. Randy Lee Webb, the declarant of Patent Owner’s alleged
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`unexpected results and a named inventor of the ’659 patent has a Ph.D. in
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`Pharmacology. I have a Doctor of Pharmacy, have been a faculty member in the
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`Department of Pharmacology for 33 years, and currently I am a full professor.
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`Declaration of Prof. Y. W. Francis Lam
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`6.
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`BACKGROUND OF RELEVANT TECHNICAL CONCEPTS5
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`A.
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`Angiotensin II and NEP Inhibition
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`40.
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`I have been involved with the therapeutic use of pharmaceuticals in the
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`treatment of disease throughout my career. More specifically, I have experience in
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`field of antihypertensive agents and the renin-angiotensin system. Below, I provide
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`a discussion of these concepts.
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`41.
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`Treatment of high blood pressure is a major medical need as high blood
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`pressure can lead to heart disease, stroke, end stage renal failure and retinopathy.
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`EX1011, 337. “Depending on additional risk factors, e.g., diabetes, dyslipidemia,
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`smoking, older age and gender, and pre-existing target organ disease (e.g., left
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`ventricular hypertrophy, coronary heart disease, nephropathy, congestive heart
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`failure) drug therapy - in addition to lifestyle modifications - should be initiated soon
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`after the diagnosis of essential hypertension has been confirmed.” Id., 337-338.
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`While drug therapies such as angiotensin converting enzyme (ACE) inhibitors were
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`often used, a more selective approach is the direct blockade of the angiotensin
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`receptor, i.e., use of an angiotensin receptor antagonist (AT 1-antagonist). Id., 338.
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`5 Although I provide a discussion of some relevant concepts here, I discuss additional
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`concepts throughout this declaration.
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`Declaration of Prof. Y. W. Francis Lam
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`42. Drugs that interfere with the renin-angiotensin system were known to
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`be useful for the treatment of hypertension. EX1011, 339; EX1001, 1:55-57. One
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`such drug is valsartan, which is a highly selective, orally available antagonist of the
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`angiotensin Type 1 (AT1) receptor. EX1011, 338.
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`Valsartan is a highly selective, orally available antagonist of the
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`angiotensin Type 1 (AT1) receptor. It is indicated for treatment of mild
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`to moderate essential hypertension. Experimental studies have
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`confirmed the abolition or attenuation of angiotensin II (AII)-related
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`effects, such as vasoconstriction, cell growth promotion and
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`aldosterone release. In humans, valsartan is rapidly absorbed with
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`maximal plasma concentrations occurring 1 - 2 h after oral
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`administration. The elimination half-life comes to about 7 - 8 h,
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`valsartan is metabolised to a negligible extent and most of the drug is
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`excreted via the faeces.
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`Id., 337.
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`43. Valsartan “is a nonpeptide, orally active, and specific angiotensin II
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`antagonist acting on the AT1 receptor subtype. Valsartan is chemically described as
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`N-(1-oxopentyl)-N-[[2’-(1H-tetrazol-5-y1)(1,1’-biphenyl]-4-yl]methyl)-L-valine.
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`Its empirical formula is C24H29N5O2, its molecular weight is 435.5, and its structural
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`formula is:”
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`Declaration of Prof. Y. W. Francis Lam
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`EX1012, “Description”.
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`44. Valsartan was approved by the FDA in 1996 for the treatment of
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`hype