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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`BIOCON PHARMA LIMITED,
`Petitioner,
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`v.
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`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owner.
`
`
`Case IPR2020-01263
`Patent 8,101,659
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`
`
`EXPERT DECLARATION OF DR. REZA TABRIZCHI
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`NOVARTIS EXHIBIT 2004
`Biocon v. Novartis, IPR2020-01263
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`I, Reza Tabrizchi, declare as follows:
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`1.
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`I have been asked by counsel for Novartis Pharmaceuticals
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`Corporation to provide my opinion with respect to the state of the NEP inhibitor art
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`as of January 17, 2002 on three issues: (1) the number and types of NEP inhibitors
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`that were individually known, (2) whether Gomez-Monterrey (Ex. 1005) taught or
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`suggested replacing a thiol NEP inhibitor with a carboxylate NEP inhibitor for
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`optimal recognition of the zinc ligand of NEP, and (3) whether Gomez-Monterrey
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`taught or suggested the NEP inhibitors SQ 28603 or sacubitril. I have considered
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`these issues from the perspective of a person of ordinary skill in the art (“POSA”).
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`For the purpose of this declaration, I have been asked to assume that the POSA is
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`someone with experience in the fields of cardiology and pharmacology, including
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`an understanding of drug-drug interactions, rationales for drug combinations, and
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`development and availability of drugs for treatment of cardiovascular disorders. I
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`have been asked to assume that a POSA would have had: (i) a doctoral degree in
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`pharmacology, pharmacy, medicine, chemistry, biochemistry, medical chemistry
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`or in a related field, with two years of the above described experience; (ii) a
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`master’s degree in the same fields, with seven years of the above described
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`experience; or (iii) a bachelor’s degree in the same fields, with ten years of the
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`above described experience. I have also been asked to assume that the POSA may
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`consult with individuals having specialized expertise, for example, a clinician or
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`2
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`practitioner with experience in the administration, dosing, and efficacy of drugs
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`and/or a regulatory affairs specialist. I have been asked to assume that a POSA
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`would have knowledge of the scientific literature concerning the same as of the
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`priority date. I have been asked to assume 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
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`problem.
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`2. My opinions are based on the materials cited in this declaration and
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`my education, knowledge, and experience as a pharmacologist, including in the
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`field of cardiology, as of January 2002 to the present day.
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`I.
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`QUALIFICATIONS
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`3.
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`I am a Professor in the Division of BioMedical Sciences and
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`Associate Dean of Research and Graduate Studies in the Faculty of Medicine at
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`Memorial University of Newfoundland in Canada. I have been a tenured Professor
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`of Pharmacology (Cardiovascular) there since September 1998. My research
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`focuses on the influence of drugs that affect the function of the cardiovascular
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`system. I have been in the fields of cardiology and pharmacology for more than 30
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`years.
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`4.
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`I received my Bachelor of Science in Pharmacology with Honors from
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`the University of Sunderland in the United Kingdom in 1983. I obtained a Master
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`of Science and Doctor of Philosophy in Pharmacology and Therapeutics in 1986
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`and 1988, respectively, from the University of British Columbia. Thereafter, I
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`completed two post-doctoral fellowships and a research fellowship at Memorial
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`University, the University of Calgary, and the University of British Columbia
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`between 1988 and 1992. From 1992 to 1998, I was an Assistant Professor at the
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`University of British Columbia and then Memorial University. I received tenure in
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`1998 at Memorial University, becoming an Associate Professor there, and have
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`been a Professor at Memorial University since 2004.
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`5.
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`I am a member of the American Society for Pharmacology and
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`Experimental Therapeutics, the British Pharmacological Society, and the Canadian
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`Hypertension Society.
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`6.
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`I serve on the editorial boards of the Journal of Pharmacological &
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`Toxicological Methods, Vascular Health and Risk Management, and the Journal of
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`Cardiovascular Pharmacology. I have previously served on the boards of Expert
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`Review of Cardiovascular Therapy and BioMed Central – Pharmacology and
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`Toxicology.
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`7.
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`I am also a peer reviewer for many prominent cardiology and
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`pharmacology journals including the British Journal of Pharmacology, the
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`Canadian Journal of Physiology and Pharmacology, Cardiovascular Research,
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`Drug Development Research, the European Journal of Pharmacology, the Journal
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`4
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`of Cardiovascular Pharmacology, the Journal of Pharmacological & Toxicological
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`Methods, the Journal of Pharmacy and Pharmacology, Pharmacological Research,
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`Pharmacology & Therapeutics, The American Journal of Medicine, and The
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`Canadian Journal of Cardiology.
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`8.
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`I have received several fellowships for my work, including the
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`Canadian Heart Foundation Fellowship, the Medical Research Council Fellowship,
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`and the Heart and Stroke Foundation of Canada Scholarship. I have also received
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`research funding as the principal investigator for over two decades from charitable
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`organizations and national grant agencies in Canada.
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`9.
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`I have been involved in teaching in the discipline of pharmacology,
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`including at the undergraduate and graduate levels, since 1988. I have taught
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`subjects including drug absorption, distribution, excretion, and metabolism,
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`quantitative aspects of pharmacokinetics, drug interactions, antihypertensive drugs,
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`and drugs for the treatment of heart failure.
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`10.
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`I have been responsible for training and mentoring many graduate
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`students, medical residents, undergraduate students and research assistants. I have
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`also served on the academic supervisory committees of numerous graduate
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`students.
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`11.
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`I have served on many committees during my tenure, including the
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`Pharmacological Society of Canada Nominating Committee, the Heart and Stroke
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`Foundation of Canada Grant Review Committee, the Canadian Journal of
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`Physiology and Pharmacology Awards Committee, and Academic Council,
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`Promotion and Tenure Committee, and Faculty Search Committee for the School
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`of Pharmacy at Memorial University.
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`12.
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`I have co-authored more than 70 peer-reviewed publications, more
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`than 30 book chapters, editorials, opinions, and review articles, and more than 50
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`abstracts in the fields of cardiology and pharmacology.
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`13.
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`In sum, I have substantial experience in the fields of cardiology and
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`pharmacology, including in drug-drug interactions, rationales for drug
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`combinations, and development and availability of drugs for treatment of
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`cardiovascular disorders, as of January 2002 to the present day.
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`14. My curriculum vitae is attached to this declaration as Exhibit 2005.
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`II.
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`DISCUSSION
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` Many NEP Inhibitors Were Known As Of January 2002
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`15. Neutral endopeptidase (“NEP”) is a zinc-containing “metallopeptidase
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`involved in the metabolism of a variety of physiologically important peptides.” Ex.
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`1005, Gomez-Monterrey at 1865; Ex. 1013, Roques at 88.
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`16. NEP inhibitors were often classified by the chemical group that
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`chelated (i.e., bonded) the zinc ion in the NEP active site.1 Ex. 1013, Roques at 93.
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`As of January 2002, several zinc-chelating groups were reported, including thiol,
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`carboxylate (also called carboxyl), hydroxamate (also called bidentate), and
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`phosphorus-based, including phosphorylated compounds and phosphonamidates.
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`Ex. 1013, Roques at 93-96; Ex. 1005, Gomez-Monterrey at 1869.
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`17. Roques summarized the development of various series of NEP
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`inhibitors and reported the following “representative” compounds: thiol: (S)-
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`thiorphan, (R)-thiorphan, (S)-retrothiorphan, (R)-retrothiorphan, and prodrugs and
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`derivatives thereof, SQ 29 072, IGM 22, and RU 4404; carboxylate: SCH 39 370,
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`SCH 32 615, and UK 69 578; hydroxamate: HACBO-Gly, retro-HACBO-Gly,
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`JFH19, and RB 104; and phosphorus-based: phosphoramidon and “phosphorylated
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`[NEP] inhibitors.” Ex. 1013, Roques at 93-96. Based on my experience, including
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`with NEP inhibitors, I am aware of over a hundred NEP inhibitors that were
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`individually identified in the prior art. A literature search undoubtedly would
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`reveal many more NEP inhibitors known by 2002.
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`1 The active site of an enzyme is the portion of the enzyme that binds target
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`compounds. The active site may be divided into one or more “subsites.”
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` Gomez-Monterrey (Ex. 1005) Did Not Teach Or
`Suggest Replacing A Thiol Inhibitor With A Carboxylate
`Inhibitor For Optimal Recognition Of The NEP Active Site
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`18. Gomez-Monterrey et al. studied the active site of NEP. Ex. 1005,
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`Gomez-Monterrey at 1865. While “[NEP’s] three-dimensional structure
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`remain[ed] unknown,” NEP’s active site was hypothesized to include three subsites
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`(S1, S′1, and S′2), a zinc ion (Zn2+), and various amino acid residues. Ex. 1005,
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`Gomez-Monterrey at 1865, 1868; Ex. 1013, Roques at 93-94. NEP’s “putative” S1
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`subsite was the subject of Gomez-Monterrey. Ex. 1005, Gomez-Monterrey at Title,
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`Abstract, 1865-68.
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`19. As background, in research published before Gomez-Monterrey (Ex.
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`1005) was published, the same authors investigated compounds containing a thiol
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`group as the zinc-chelating ligand to elucidate the structure of NEP’s putative S1
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`subsite. Ex. 1005, Gomez-Monterrey at 1866. Although some of these compounds
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`were “very efficient” at binding NEP, the investigators were not able to elucidate
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`the features of the S1 subsite. Ex. 1005, Gomez-Monterrey at 1866. Gomez-
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`Monterrey described three hypotheses for why these compounds were unable to
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`characterize the S1 subsite, and focused on the hypothesis that “steric reasons”2
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`prevented the NEP inhibitor from interacting with the S1 subsite. Ex. 1005,
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`Gomez-Monterrey at 1866.
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`20. To test this hypothesis, Gomez-Monterrey introduced a methylene
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`spacer (-CH2-) into a known series of thiol (HS-) NEP inhibitors to reduce steric
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`hindrance (i.e., to increase the compounds’ ability to enter the S1 subsite),
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`synthesizing compounds of the general formula HS-CH(R1)-CH2-CH(R2)-CONH-
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`CH(R3)-COOH. Ex. 1005, Gomez-Monterrey at 1866. These compounds are
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`referred to in this Declaration and Gomez-Monterrey as the new series of thiol
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`inhibitors.
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`21. However, Gomez-Monterrey concluded that its new series of thiol
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`inhibitors did not elucidate the nature of the S1 subsite:
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`In conclusion, the new series of thiol inhibitors described in this
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`paper was not able to clarify the nature of the S1 subsite of NEP.
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`. . . Consequently, it seems more easy to explore the S1 subsite of
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`NEP with inhibitors which do not contain a thiol group as a zinc
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`2 The term “steric” refers to the arrangement of atoms in a molecule. The atoms
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`within a molecule occupy space, and may influence or limit the conformation (i.e.,
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`the shape) of the molecule.
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`ligand. Carboxylates have been intensively used, but hydroxamates
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`or phosphoryl groups may also be useful.
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`Ex. 1005, Gomez-Monterrey at 1869 (emphasis added).
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`22. Gomez-Monterrey hypothesized that “the hydrophobic character of
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`the S′1 subsite and the high tendency of the thiol group to optimize the
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`complexation of the Zn2+ ion” positioned the compound outside of the S1 subsite
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`and away from other stabilizing interactions, as shown in the hypothetical model
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`below (Ex. 1005, Gomez-Monterrey at 1868 (Chart 1C), 1869, color added). Said
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`another way, because the inhibitor’s thiol group interacted so strongly with the zinc
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`ion, and the R1 group interacted with S′1, the inhibitors oriented themselves away
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`from the S1 pocket of the enzyme, preventing clarification of the nature of S1.
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`23. To further study the S1 subsite, Gomez-Monterrey suggested using a
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`different zinc-coordinating group that did not coordinate zinc so strongly, and thus
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`may have more freedom within the NEP active site, such as hydroxamates,
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`phosphoryl groups, or carboxylates. Ex. 1005, Gomez-Monterrey at 1869 (a
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`carboxylate group has an “enhanced degree of freedom” in the NEP active site);
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`Ex. 1013, Roques at 88, 95 (“[A]ffinities of [certain carboxylate] compounds for
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`NEP were not modulated by the relative positions of the carboxyl group. . . .”).
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`24.
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`In sum, Gomez-Monterrey taught that the thiol group had a “high
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`tendency . . . to optimize the complexation of the Zn2+ ion.” Ex. 1005, Gomez-
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`Monterrey at 1869. Gomez-Monterrey suggested replacing a thiol NEP inhibitor
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`with a carboxylate NEP inhibitor for “more freedom” (i.e., less optimal
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`recognition) in the NEP active site, in order to explore the S1 subsite. Ex. 1005,
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`Gomez-Monterrey at 1869. Therefore, Gomez-Monterrey did not teach or suggest
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`replacing a thiol NEP inhibitor with a carboxylate NEP inhibitor to optimize
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`recognition of the NEP active site; Gomez-Monterrey taught the opposite by
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`suggesting the use of carboxylate, hydroxamate or phosphoryl groups, because
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`those groups would be expected to bind less optimally.
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`25. Moreover, as discussed below, others in the art reported that certain
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`thiol inhibitors had superior binding affinity for NEP compared to certain
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`carboxylate inhibitors, indicating that replacing a thiol inhibitor with a carboxylate
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`inhibitor would not necessarily increase recognition of the NEP active site.
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`26. Roques et al. compared the inhibitory constant “Ki” (a measure of the
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`binding affinity of a compound for an enzyme) of several NEP inhibitors.3 Ex.
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`1013, Roques at 94, Table 2. Roques reported several “potent” thiol inhibitors with
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`superior binding affinity for NEP (i.e., smaller Ki values) compared to certain
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`carboxylate inhibitors. Ex. 1013, Roques at 93-95.
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`27. Specifically, Roques et al. reported seven thiol NEP inhibitors having
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`Ki values between 2.3 nM and 200 nM, including four thiol NEP inhibitors, (S)-
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`thiorphan, (R)-thiorphan, (R)-retrothiorphan, and IGM 22, having Ki values
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`between 2.3 nM and 4 nM (Ex. 1013, Roques at 94, Table 2):
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`3 A smaller Ki means relatively higher binding affinity for the enzyme in vitro.
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`28. By comparison, Roques et al. reported two carboxylate NEP
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`inhibitors, SCH 39 370 and UK 69578, having Ki values of 11 nM and 28 nM,
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`respectively (Ex. 1013, Roques at 94, Table 2) (which are higher than the Ki values
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`of 2.3 to 4 nM for four of the thiol inhibitors discussed in the prior paragraph):
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`29. Similarly, Gomez-Monterrey reported that the inhibitory constants of
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`(S)-thiorphan (thiol) and SCH 39370 (carboxylate) were 1.9 nM and 11 nM for
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`NEP, respectively, indicating that the thiol inhibitor (S)-thiorphan had a stronger
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`binding affinity than the carboxylate inhibitor SCH 39370. Ex. 1005, Gomez-
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`Monterrey at 1865.
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` Gomez-Monterrey Did Not Teach
`Or Suggest SQ 28603 Or Sacubitril
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`30. The compounds tested in Gomez-Monterrey were structurally distinct
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`from SQ 28603 and sacubitril.
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`31. To study the S1 subsite, Gomez-Monterrey developed a series of new
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`thiol inhibitors having the general formula shown below (Ex. 1005, Gomez-
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`Monterrey at 1866):
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`32. Gomez-Monterrey evaluated two additional compounds, compound A
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`(a thiol) and compound B (a carboxylate), shown below (Ex. 1005, Gomez-
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`Monterrey at 1867):
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`compound A
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`compound B
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`33. The Gomez-Monterrey compounds were distinct from SQ 28603 and
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`sacubitrilat,4 shown below (Ex. 1002, EP ’072 at p. 2, ll. 26-31 (SQ 28603); Ex.
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`1009, ’996 Patent at col. 21, ll. 16-18 (sacubitrilat)):
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`SQ 28603
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`sacubitrilat
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`34. Gomez-Monterrey did not disclose SQ 28603 or sacubitril (or its
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`active metabolite, sacubitrilat).
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`4 Sacubitrilat is the active metabolite of the prodrug sacubitril, which is esterified.
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`Ex. 1009, ’996 Patent at col. 19, ll. 19-22 (sacubitril).
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`I hereby declare that all statements made herein of my own knowledge are
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`true and that all statements made on information and belief are believed to be true,
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`and further that these statements were made with the knowledge that willful false
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`statements and the like so made are punishable by fine or imprisonment, or both,
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`under Section 1001 of Title 18 of the United States Code and that such willful false
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`statements may jeopardize the validity of the application or any patent issued
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`thereon.
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`it:
`Dated: &0V. 1‘2. 35,20
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`
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`Reza "l“abrizchi, Ph.D.
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