`
`o\”
`
`.
`| Docket Number| 4-32219A
`
`pS.
`eo
`2 === 2
`FILING BY “EXPRESS MAIL” UNDER 37 CFR 1.10
`==
`at—— iv195228853_
`January 14, 2003
`i —_
`Express Mail Label Number
`Date of Deposit
`==
`=== 3 Address to Assistant Commissionerfor Patents
`SSO
`Box Patent Application
`Washington, DC 20231
`UTILITY PATENT APPLICATION TRANSMITTAL AND FEE SHEET
`
`
`
`Transmitted herewithforfiling under 37 CFR §1.53(b)is the utility patent application of
`
`Applicant (or identifier}: KSANDER ETAL.
`
`Title:
`
`Enclosed are:
`
`METHODS OF TREATMENT AND PHARMACEUTICAL
`COMPOSITION
`
`Specification (Including Claims and Abstract) - 26 pages
`Drawings -
`sheets
`Executed Declaration and Power of Attorney (original or copy)
`Microfiche Computer Program (appendix)
`Nucleotide and/or Amino Acid Sequence Submission
`[|] Computer Readable Copy
`[|] Paper Copy
`[] Statement Verifying Identity of Above Copies
`Preliminary Amendment
`Assignment Papers (Cover Sheet & Documeni(s))
`English Translation of
`Information Disclosure Statement
`Certified Copy of Priority Document(s)
`Return Receipt Postcard
`Other: unsigned Declaration and Application Data Sheet
`
`Fiting fee calculation:
`{]
`Before calculating the filing fee, please enter the enclosed Preliminary Amendment.
`(|
`Before calculating the filing fee, please cancel claims
` Basic Filing Fee
`740.
`$
`Multiple Dependent Claim Fee ($ 280)
`$
`
`| ForeignLanguage Surcharge ($ 900)
`$
`
`For
`Number
`Number
`
`Filed
`_
`Extra
`Rate
`.
`
`
`Extra|Total Claims 5 -20 0 x |$ isl =|
`
`
`
`
`
`
`
`
`
`Independent
`_
`_
`Claims
`8
`3
`°
`x1
`84
`
`Claims|| . }
`
`LOU
`KIBUOOCU
`
`
`$
`
`
`
`
`
`
`740
`$
`TOTAL FILING FEE |
`
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 001
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 001
`
`

`

`ond
`
`
`x] Please charge Deposit Account No. 19-0134 in the name of Novartis Corporation in the
`amount of $740. An additional copy of this paper is enclosed. The Commissioner is
`hereby authorized to charge any additional fees under 37 CFR §1.16 and §1.17 which may
`be required in connection with this application, or credit any overpayment, to Deposit
`Account No. 19-0134 in the name of Novartis Corporation.
`
`Please addressall correspondenceto the address associated with Customer No, 001095, which
`iS Currently:
`Thomas Hoxie
`Novartis Pharmaceuticals Corporation
`Patent and Trademark Dept.
`One Health Plaza
`East Hanover, NJ 07936-1080
`
`Pleasedirectall telephone calls to the undersigned at the number given below, and all telefaxes
`to (862) 778-8064.
`
`Respectfully submitted,
`
` Date: January 14, 2003
`
`Attorney for Xpplicants
`Reg. No. 36,134
`Tel. Ne. (862) 778-7831
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 002
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 002
`
`

`

`
`
`o\”
`
`.
`| Docket Number| 4-32219A
`
`pS.
`eo
`2 === 2
`FILING BY “EXPRESS MAIL” UNDER 37 CFR 1.10
`==
`at—— iv195228853_
`January 14, 2003
`i —_
`Express Mail Label Number
`Date of Deposit
`==
`=== 3 Address to Assistant Commissionerfor Patents
`SSO
`Box Patent Application
`Washington, DC 20231
`UTILITY PATENT APPLICATION TRANSMITTAL AND FEE SHEET
`
`
`
`Transmitted herewithforfiling under 37 CFR §1.53(b)is the utility patent application of
`
`Applicant (or identifier}: KSANDER ETAL.
`
`Title:
`
`Enclosed are:
`
`METHODS OF TREATMENT AND PHARMACEUTICAL
`COMPOSITION
`
`Specification (Including Claims and Abstract) - 26 pages
`Drawings -
`sheets
`Executed Declaration and Power of Attorney (original or copy)
`Microfiche Computer Program (appendix)
`Nucleotide and/or Amino Acid Sequence Submission
`[|] Computer Readable Copy
`[|] Paper Copy
`[] Statement Verifying Identity of Above Copies
`Preliminary Amendment
`Assignment Papers (Cover Sheet & Documeni(s))
`English Translation of
`Information Disclosure Statement
`Certified Copy of Priority Document(s)
`Return Receipt Postcard
`Other: unsigned Declaration and Application Data Sheet
`
`Fiting fee calculation:
`{]
`Before calculating the filing fee, please enter the enclosed Preliminary Amendment.
`(|
`Before calculating the filing fee, please cancel claims
` Basic Filing Fee
`740.
`$
`Multiple Dependent Claim Fee ($ 280)
`$
`
`| ForeignLanguage Surcharge ($ 900)
`$
`
`For
`Number
`Number
`
`Filed
`_
`Extra
`Rate
`.
`
`
`Extra|Total Claims 5 -20 0 x |$ isl =|
`
`
`
`
`
`
`
`
`
`Independent
`_
`_
`Claims
`8
`3
`°
`x1
`84
`
`Claims|| . }
`
`LOU
`KIBUOOCU
`
`
`$
`
`
`
`
`
`
`740
`$
`TOTAL FILING FEE |
`
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 003
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 003
`
`

`

`ond
`
`
`x] Please charge Deposit Account No. 19-0134 in the name of Novartis Corporation in the
`amount of $740. An additional copy of this paper is enclosed. The Commissioner is
`hereby authorized to charge any additional fees under 37 CFR §1.16 and §1.17 which may
`be required in connection with this application, or credit any overpayment, to Deposit
`Account No. 19-0134 in the name of Novartis Corporation.
`
`Please addressall correspondenceto the address associated with Customer No, 001095, which
`iS Currently:
`Thomas Hoxie
`Novartis Pharmaceuticals Corporation
`Patent and Trademark Dept.
`One Health Plaza
`East Hanover, NJ 07936-1080
`
`Pleasedirectall telephone calls to the undersigned at the number given below, and all telefaxes
`to (862) 778-8064.
`
`Respectfully submitted,
`
` Date: January 14, 2003
`
`Attorney for Xpplicants
`Reg. No. 36,134
`Tel. Ne. (862) 778-7831
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 004
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 004
`
`

`

`eaiall
`fii
`INVENTOR INFORMATION
`
`Inventor One Given Name:: Gary M
`Family Namet: Kaander
`Postal Address Line One:: 342 Woolf Road
`City:: Milford
`Stale or Provinee:: New Jersey
`Countey:: United States of America
`Postal or Zip Code:: D848
`City of Residence:: Milford
`State or Province of Residence:: New Jersey
`Country of Residence:: United States of America
`Citizenship Country:: United States of America
`Tnventor wo Given Name:: Randy 1.
`Family Name:: webb
`Postal Address Linc One::
`Cityi: Flemington
`State or Provinee:: New Jersey
`Country:: United States of America
`Postal or “Zip Code:: O8822
`.
`City of Residence:: Flemington
`State or Province of Reasidence:: New Jerscy
`Country of Residence:: United States of America
`Citizenship Country:: United States of America
`
`17 Honeyman Prive
`
`
`
`CORRESPONDENCE INFORMATION
`
`Correspondence Customer Number:: 001095
`
`APPLICATION INFORMATION
`
`
`
`
`Title Line One:: METHODS OF TREATMENT ANI PHARMACMUTICA
`Titie Line Twor:
`COMPOSIT LON
`Formal Drawings?:: No
`Application Type:: Utility
`Docket. Number:: 4-32219A
`Secrecy Order in Parant Appl.?:: No
`
`
`
`
`CONTINULTY INFORMATION
`
`NON PROV. OF PROVISTONAL
`This application is at:
`60/386, 792
`> Application One::
`
`Filing Date::
`06--07-27002?
`
`NON PROV. OF PROVISIONAL
`This application is ar:
`60/3493, 660
`> Application Two:r:
`Filing Date::
`O1-17-2002
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 005
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 005
`
`

`

`Souraci:
`
`Print&eFS Version 1.0.1
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 006
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 006
`
`

`

`
`
`Case 4-32219A
`
`METHODS OF TREATMENT AND PHARMACEUTICAL COMPOSITION
`
`Background of the Invention
`
`The renin angiotensin system is a complex hormonal system camprised of a large
`molecular weight precursor, angiotensinogen, two processing enzymes, renin and
`angiotensin converting enzyme (ACE}, and the vasoactive mediator angiotensin II {Ang II.
`See J. Cardiovasc. Pharmacol, Vol. 15, Suppl. B, pp. $1-S5 (1890). The enzyme renin
`catalyzes the cleavage of angiotensinogen into the decapeptide angiotensin |, which has
`minimalbiological activity on its own and is converted into the active octapeptide Ang Il by
`ACE. Ang || has multiple biological actions on the cardiovascular system, including
`vasoconstriction, activation of the sympathetic nervous system, stimulation of aldosterone
`production, anti-natriuresis, stimulation of vascular growth and stimulation of cardiac
`growth. Ang II functions as a pressor hormoneand is involved the pathophysiology of
`several farms of hypertension.
`
`The vasoconstrictive effects of angiotensin I! are produced by its action on the non-
`striated smooth muscle cells, the stimulation of the formation of the adrenergenic hormones
`epinephrine and norepinephrine, as weil as the increase of the activity of the sympathetic
`nervous system as a result of the formation of norepinephrine. Ang ll also has an influence
`on electrolyte balance, produces, e.g., anti-natriuretic and anti-ciuretic effects in the kidney
`and thereby promotesthe release of, an the one hand, the vasopressin peptide fram the
`pituitary gland and, on the other hand, of aldosterone from tne adrenal glomerulesa. Ali
`these influences play an important part in the regulation of blood pressure, in increasing
`both circulating volume and peripheral resistance. Ang II is also involved in cell growth and
`migration and in extracellular matrix formation.
`
`It has been
`Ang II interacts with specific receptors on the surface of the target cell.
`possible to identify receptor subtypes that are termed, e.g., AT 1- and AT 2-receptors.
`In
`recent times great efforts have been madeto identify substances that bind ta the AT 1-
`receptor. Such active ingredients are often termed Ang Il antagonists. Because of the
`inhibition of the AT 1-receptor such antagonists can be used, €.g., as anti-hypertensives or
`for the treatment of congestive heart failure, among other indications. Ang 1! antagonists
`are therefore understood to be those active ingredients which bind to the AT 1-receptor
`
`subtype.
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 007
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 007
`
`

`

`
`
`Inhibitors of the renin angiotensin system are well-known drugs that lower blood
`
`pressure and exert beneficial actions in hypertension and in congestive heart failure as
`
`described. See, e.g, N. Eng. J Med, Vol. 316, No. 23, pp. 1429-1435 (1987). A large
`
`number of peptide and non-peptide inhibitors of the renin angiotensin system are known, the
`
`most widely studied being the ACE inhibitors, which includes the drugs captopril, enalapril,
`lisinopril, benazepril and spirapril. Although a major mode of action of ACE inhibitors
`involves prevention of formation of the vasoconstrictor peptide Ang Il, it has been reported
`in Hypertension, Vol. 16, No. 4, pp. 363-370 (1990), that ACE cleaves a variety of peptide
`substrates, including the vasoactive peptides bradykinin and substance P. Prevention of the
`degradation of bradykinin by ACE inhibitars has been demonstrated, and the activity of the
`ACE inhibitors in some conditions has been reported in Circ. Res., Vol. 66, No. 1, pp. 242-
`248 (1990), to be mediated by elevation of bradykinin levels rather than inhibition of Ang Il
`formation. Consequently, it cannot be presumed that the effect of an ACE inhibitor is due
`solely to prevention of angiotensin formation and subsequentinhibition of the renin
`
`angiotensin system.
`
`Neutral endopeptidase (EC 3.4.24.11; enkephalinase; atriopeptidase; NEP) is a zinc-
`containing metalloprotease that cleaves a variety of peptide substrates on the amino
`terminal side of aromatic amino acids. See Biochem. J., Vol. 241, pp. 237-247 (1987).
`Substrates for this enzyme include, but are notlimited to, atrial natriuretic factors (ANFs)},
`also known as ANPs, brain natriuretic peptide (BNP), met and leu enkephalin, bradykinin,
`
`neurokinin A and substance P.
`
`ANPs are a family of vasodilator, diuretic and anti-hypertensive peptides which have
`been the subject of many recent reports in the literature. See, e.g., Annu. Rev. Pharm.
`Tox., Vol. 29, pp. 23-54 (1989). One form, ANF 99-126, is a circulating peptide hormone
`which is released from the heart during conditions of cardiac distension. The function of
`ANF is to maintain salt and water homeostasis, as well as to regulate blood pressure. ANF
`is rapidly inactivated in the circulation by at least two processes: a receptor-mediated
`clearance reported in Am. J. Physiol, Vol. 256, pp. R469-R475 (1989), and an enzymatic
`inactivation via NEP reported in Biochem. J., Vol. 243, pp. 183-187 (1987).
`It has been
`previously demonstrated that inhibitors of NEP potentiate the hypotensive, diuretic,
`natriuretic and plasma ANF responsesto pharmacologicalinjection of ANF in experimental
`animals. The potentiation of ANF by two specific NEP inhibitors is reported by Sybertz et
`al., J. Pharmacol, Exp. Ther., Vol. 250, No. 2, pp. 624-631 (1989), and in Hypertension, Vol.
`15, No. 2, pp. 152-161 (1990), while the potentiation of ANF by NEP in general was
`
`-2.-
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 008
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 008
`
`

`

`
`
`In U.S. Patent No. 4,740, 499, Olins disclosed the
`| disclosed in U.S. Patent No. 4,749,688.
`use of thiorphan and kelatorphan to potentiate atrial peptides. Moreover, NEP inhibitors
`
`lower blood pressure and exert ANF-like effects, such as diuresis and increased cyclic
`
`guanosine 3',5'-menaphosphate (cGMP) excretion in some forms of experimental
`hypertension. The anti-hypertensive action of NEP inhibitors is mediated through ANF
`
`because antibodies to ANF will neutralize the reduction in blood pressure.
`
`Darrow et al. in European Patent Application No. 498361 disclose treating
`
`hypertension or congestive heart failure with a combination of certain Ang II antagonists or
`
`certain renin inhibitors with certain NEP inhibitors.
`
`Powell et al. in European Patent Application No. 726072 disclose treating
`hypertension or congestive heart failure with a combination of the Ang II antagonist 2-butyl-
`6,7,8,9-tetrahydro-3-[[2'-(14-tetrazol-5-yl)[1 , 1'-biphenyl]-4-yl]methyl]-1 ,3-
`diazaspiro[4.4]nonan-4-one with a NEP inhibitor or a dual acting vasopeptidase inhibitor
`{single molecular entity with both ACE and NEP inhibitory activities). Prolonged and
`uncontrolled hypertensive vascular disease ultimately leads to a variety of pathological
`changesin target organs, such as the heart and kidney. Sustained hypertension can lead
`as well to an increased occurrence of stroke. Therefore, there is a strong need to evaluate
`the efficacy of anti-hypertensive therapy, an examination of additional cardiovascular |
`endpoints, beyand those of blood pressure lowering, to get further insight into the benefits of
`combined treatment.
`
`The nature of hypertensive vascular diseases is multifactorial. Under certain
`circumstances, drugs with different mechanisms of action have been combined. However,
`just considering any combination of drugs having different mode of action does not
`necessarily lead to combinations with advantageous effects. Accordingly, there is a need
`for more efficacious combination therapy which has less deleterious side effects.
`
`Other objects, features, advantages and aspects of the present invention will become
`apparentto thoseofskill from the following description.
`It should be understood, however,
`that the following description and the specific examples, while indicating preferred
`embodiments of the invention, are given by wayofillustration only. Various changes and
`modifications within the spirit and scope of the disclosed invention will become readily
`apparentto those skilled in the art from reading the following description and from reading the
`other parts of the present disclosure.
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 009
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 009
`
`

`

`Detailed Description of the Preferred Embodiments
`
`
`
`in one aspect, the present invention relates to pharmaceutical combinations
`comprising valsartan or pharmaceutically acceptable salts thereof and a NEP inhibitor or a
`pharmaceutically effective salts thereof, optionally in the presence of a pharmaceutically
`acceptable carrier and pharmaceutical compositions comprising them.
`
`In another embodiment, the present invention relates to methods oftreating cardiac
`and renal related conditions by administration of the pharmaceutical composition comprising
`
`valsartan plus a NEP inhibitor.
`
`Valsartan is the AT 1-receptor antagonist (S)-N-(1-carboxy-2-methyl-prop- 1-yl)-N-
`pentanoyl-AN_[2;(7H-tetrazol-5-yi)biphenyl-4-yl-methyl]amine of formula (1}
`
`aN OU
`
`3
`
`iY
`“
`Cc
`* cH, “NOH
`
`CH,
`CH
`3 CH;
`
`o
`
`OH
`
`(t)
`
`HN* ~N
`\
`/
`N=_N
`
`and is disclosed in EP 0443983 A and U.S. Patent No. 5,399,578, the disclosures of which
`
`are incorporated herein in their entirety as if set forth herein.
`
`A NEP inhibitor useful in said combination is a compound of the formuia (I)
`7 UP
`1
`HS—CH;-CH—C— NH—CH—(CH,)--C—R,
`
`(tl)
`
`and pharmaceutically acceptable salts thereof,
`
`wherein
`
`R: is alkyl of 1 to 7 carbons, trifluoromethyl, phenyl, substituted phenyl, -(CHy); ta 4-
`phenyl, or -(CH2), 1 4-substituted phenyl;
`
`R; is hydrogen, alkyl of 1 to 7 carbons, phenyl, substituted phenyl, -(CH2)1 to 4-phenyl, or
`
`-(CHz), tg -SUbstituted phenyl:
`
`R, is hydroxy, alkoxy of 1 ta 7 carbons, or NH2;
`
`-4-
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 010
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 010
`
`

`

`
`
`nis an integer from 1 to 15: and
`
`the term substituted pneny! refers to a substituent selected from lower alkyl of 1 to 4
`carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, hydroxy, Cl, Br or
`F.
`
`Preferred selective NEP inhibitors of formula (II) include compounds,
`wherein
`
`Ra is benzyt:
`
`Rg is hydrogen:
`
`nis an integer from 1 to &: and
`
`R, is nydroxy.
`
`Even more preferred selective NEP inhibitors of formula (Il) are reported in the
`literature as SQ 28,603 which is the compound of formula (II),
`wherein
`
`Re is benzyl:
`
`Ra is hydrogen:
`
`nis one; and
`
`R, is hydroxy.
`
`The preparation of the selective NEP inhibitors of formula (Il), wherein R3 is other
`
`than trifluoromethyl are disclosed by Delaney et al.
`
`in US. Patent No. 4,722,810. The
`
`preparation of the selective NEP inhibitors of formula (Il), wherein Rzis trifluoromethyl are
`
`disclosed by Delaney et al. in U.S. Patent No. 5,223,516.
`
`NEP inhibitors within the scope of the present invention include compounds
`
`disclosed in U.S. Patent No. 4,610,846, herein incorporated by reference, including in
`
`particular N-[A-[1(S}-carboxyl-3-phenylproplyl]-(S)-phenylalanyl]-(S}-isoserine and ALLA
`
`[((7S)-carboxy-2-phenyljethyl]-(S)-phenylalanyl]-B-alanine; compounds disclosed in U.S.
`
`Patent No. 4,929,641, in particular, N-[2(S)-mercaptomethy!-3-(2-methylphenyl)-
`
`propionyl]methionine; SQ 28603 (NV-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl)-[j-alanine),
`
`disclosed in South African Patent Application No. 84/0670; UK 69578 (c/s-4-[[[1-[2-carboxy-
`
`3-(2-methoxyethoxy)propyl]-cyclopentyl]carbonyijamine]-cyclohexanecarboxylic acid) and its
`
`active enantiomer(s); thiorphan and its enantiomers; retro-thiorphan; phosphoramidon; and
`
`-5-
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 011
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 011
`
`

`

`
`
`SQ 29072 (7-[[2-(mercaptomethyl)- 1-oxo-3-phenylpropyllamino]-heptancic acid). Also
`Suitable for use are any pro-drug forms of the above-listed NEP inhibitors, e.g., compounds
`in which one or more carboxylic acid groups are esterified.
`
`NEP inhibitors within the scope of the present invention also include the compounds
`disclosed in U.S. Patent No. 5,217,996, particularly, N-(3-carboxy-1-oxopropyi)-(4S8)-p-
`phenylphenylmethy!)-4-amino-2R-methylbutanoic acid ethyl ester; the compounds disclosed
`in EP 00342850, particularly, (S)-cis-4-[1-[2-(5-indanytoxycarbony!)-3-(2-
`methoxyethoxy) propy!]-1-cyclopentanecarboxamido]-1-cyclohexanecarboxylic acid: the
`compounds disclosed in GB 02218983, particularly, 3-(4-[6-endo-
`hydroxymethylbicyclo[2,2, 1 ]heptane-2-exo-carbamoyljcyclopentyl)-2-(2-
`methoxyethyl)propanoic acid; the compounds disclosed in WO 92/14706, particularly,
`A-(1-(3-(A-E butoxycarbonyl-(S)-prolylamino)-2(S)--butoxy--
`carbonylpropyljcyclopentanecarbonyl)-O-benzy!-{(S)-serine methyl ester; the compounds
`disclosed in EP 00343911; the compounds disclosed in JP 06234754; the compounds
`disclosed in EP 00361365, particularly, 4-[[2-(mercaptomethyl)-1-oxo-3-
`phenylpropyljaminojbenzoic acid; the compoundsdisclosed in WO 90/09374, particularly,
`3-[1-(cis-4-carboxycarbony|-cis-3-butyleyclohexyl--1 -carboamoyl)cyclopentyl]-2S-(2-
`methoxyethoxymethyl)prapancic acid; the compounds disclosed in JP 07157459,
`
`particularly, A-((2S)-2-(4-biphenylmethyl)-4-carboxy-5-phenoxyvaleryliglycine; the
`
`compounds disclosed in WO 94/15908, particularly, N-(1-(NV-hydroxycarbamaylmethyl)-1-
`
`cyclopentanecarbonyl--phenylalanine; the compounds disclosed in U.S. Patent No.
`
`5,273,990, particularly, (S)-(2-biphenyl-4-yl)-1-(1 H4-tetrazol-5-yhethylamino}
`
`methylphosphonic acid; the compounds disclosed in U.S. Patent No. 5,294 632, particularly,
`
`(S)-5-(A-(2-(phosphonomethylamino)-3-(4-biphenyl)propionyl)-2-aminoethyltetrazale, the
`
`compounds disclosed in U.S. Patent No. 5,250,522, particularly, B-Alanine, 3-[1, 1'-biphenylj-
`
`4-yl-A-[diphenoxyphosphinyl)methyll-i-alanyl; the compounds disclosed in EP 00636621,
`
`particularly, A-(2-carboxy-4-thienyl}-3-mercapto-2-benzylpropanamide; the compounds
`
`disclosed in WO 93/09101, particularly, 2-(2-mercaptomethyl-3-phenylpropionamido}thiazol-
`4-ylcarboxylic acid; the compounds disclosed in EP 00590442, particularly, ((L)--(2,2-
`dimethyH1 ,3-dioxolan-4-yl)-methoxy}carbony!)-2-phenylethyl)-L-phenylalany!}-B-alanine, W-
`
`[A-[(L}-[1-[(2,2-dimethyl-1,3-diaxolan-4-yl})-methoxy]carbonyl]-2-phenylethy!]-L-phenylalanyl]-
`
`(R)-alanine, A-EA-[(L}-1-carboxy-2-phenylethy!]-l-phenylalanyl)-(R)-alanine, Av-[2-
`
`acetylthiomethyl-3-(2-methyi-phenyl)propionyl]-methionine ethyl ester, A-[2-mercaptomethyl-
`
`3-(2-methylphenylpropioyl]-methionine, N-[2(S)-mercaptomethyl-3-(2-
`
`methylphenyl) propanoyl)-(S)-isoserine, A-(S)-[3-mercapto-2-(2-methylphenyl}propionyl)-(S)-
`
`-6-
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 012
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 012
`
`

`

`we i Ga eetit Mog yes fia Fh
`Aha Saat a SM HIAINE aLIPBare
`
`2-methoxy-(A)-alanine, N-[1-[[1(S)-benzyloxycarbonyt-3-
`
`phenylpropyjjaminojcyclopentylcarbonyl}-(S)-isoserine, A/-[1-[[4(S)-carbonyl-3-
`
`phenylpropyjamino)-cyclopentylcarbonyl]-(S)-isoserine, 1,1'-[dithiobis-[2(S)-(2-
`
`methyibenzyl-1-oxo-3, 1-propanediy|]]j-bis-(S)-isoserine, 1,1'-[dithicobis-[2(S)-(2-
`
`methylbenzyl)-1-oxo-3, 1-propanediyl]]-bis-(S)-methionine, N-(3-phenyl-2-(mercaptomethyl)-
`
`propionyl)-(S)-4-(methylmercaptojmethionine, N-[2-acetylthiomethyl-3-phenyl-propionyl]-3-
`
`aminobenzoic acid, N-[2-mercaptomethyl-3-phenyi-propionyi]-3-amincbenzoic acid,
`
`N-[1-(2-carboxy-4-phenylbuty!)-cyclopentanecarbonyl]-(S)-isoserine,
`
`A-[1-(acetylthiomethylhcyclopentane-carbonyl]-(S)-methionine ethyl ester,
`
`3(S)-[2-(acetylthiomethyl}-3-phenyl-propionyllamimo-c-caprolactam, and the compounds
`
`disclosed in WO 93/10773, particularly, N-(2-acetylthiamethyl-3-(2-methylpheny|)prepionyl)-
`
`methionine ethyl ester.
`
`The compounds to be combined can be present as pharmaceutically acceptable
`If these compounds have, for example, at least one basic center, they can form acid
`salts.
`addition salts. Corresponding acid addition salts can also be formed having, if desired, an
`additionally present basic center. The compounds havingat least one acid group, for
`example, COGH, can also form salts with bases. Corresponding internal saits may
`furthermore be formed, if a compound comprises, ¢.g., both a carboxy and an amino group.
`
`With respect to N-(3-carboxy-1-oxoprapyl)-(4S)-p-phenylpheny!lmethy!)-4-aming-2f-
`methylbutanoic acid ethyl ester, preferred salts include the sodium salt disclosed in LS.
`Patent No. 5,217,996, the triethanolamine salt and the tris(hydroxymethyl)aminomethane
`salt. Preparation of the triethanolaminesalt and the fris(hydroxymethyl)aminomethane salt
`
`may be carried out as follows:
`
`Triethanclamine
`
`To N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methyibutanaic acid
`ethyl ester (349 mg, 0.848 mmol) is added 5 mL of ethyl ether and 0.113 mL (0.848 mmol)
`of triethanclamine in 1 mL of ethyl acetate. The solid was callected and dried melting at
`
`69-71°C.
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 013
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 013
`
`

`

`\Ff
`
`\)
`
`
`
`HN ce
`
`o
`
` | UT,
`” s r
`
`HO
`
`—NH,
`
`HO
`
`“Ty
`
`oO
`
`HO
`
`Oo
`
`Tris(hydroxymethy|) aminomethane
`
`To N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid
`
`ethyl ester (3.2 g, 7.78 mmol) is added 32 mL of ethyl acetate and 940 mg (7.78 mmol}
`
`tris(hydroxymethyhaminomethane. The suspension is diluted with 45 mL of ethyl acetatc
`
`and refluxed overnight (~20 hours). The reaction is cooled ta 0°C, filtered, solid washed
`
`with ethyl acetate and dried melting at 114-115°C.
`
`It has surprisingly been found that, a combination of valsartan and a NEP inhibitor
`achieves greater therapeutic effect than the administration of valsartan, ACE inhibitors or
`NEP inhibitors alone and promotes less angioedema than is seen with the administration of
`a vasopeptidaseinhibitor alone. Greater efficacy can also be documented as a prolonged
`duration of action. The duration of action can be monitored as either the time to return to
`
`baseline prior to the next dose or as the area under the curve (AUC) and is expressed as
`the product of the change in blood pressure in millimeters of mercury (change in mmHg)
`
`and the duration of the effect (minutes, hours or days).
`
`Further benefits are that lower dases of the individual drugs to be combined
`
`according to the present invention can be used to reduce tne dosage, for example, that the
`dosages need not only often be smaller but are also applied less frequently, or can be used
`to diminish the incidence of side effects. Tne combined administration of valsartan or a
`
`pharmaceutically acceptable salt thereof and a NEP inhibitor or a pharmaceutically
`acceptable salt thereof results in a significant response in a greater percentage of treated
`patients, that is, a greater responderrate results, regardless of the underlying etiology of the
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 014
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 014
`
`

`

`
`
`
`
`condition. This is in accordance with the desires and requirements of the patients to be
`treated.
`
`It can be shown that combination therapy with valsartan and a NEP inhibiter results
`
`ina more effective anti-hypertensive therapy (whether for malignant, essential, reno-
`
`vascular, diabetic, isolated systolic or other secondary type of hypertension) through
`
`improved efficacy, as weil as a greater responder rate. The combination ts also useful in the
`
`treatment or prevention of heart failure, such as (acute and chronic) congestive heart failure,
`
`left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy,
`
`supraventricular and ventricular arrnythmias, atrial fibrillation, atrial flutter or detrimental
`
`vascular remodeling.
`
`It can further be shownthat a valsartan and NEP inhibitor therapy
`
`proves to be beneficial in the treatment and prevention of myocardial infarction and its
`sequelae. A valsartan plus NEP inhibitor combination is also useful in treating
`atherosclerosis, angina (whether stable or unstable), and renal insufficiency (diabetic and
`
`non-diabetic). Furthermore, combination therapy using valsartan and a NEP inhibiter can
`
`improve endcthelia! dysfunction, thereby. providing benefit in diseases in which normal
`
`endothelial function is disrupted, such as heart failure, angina pectoris and ciabetes.
`
`Furthermere, the combination of the present invention may be used for the treatment or
`
`prevention of secondary aldosteronism, primary and secondary pulmonary hypertension,
`
`renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma,
`
`glomerular sclerosis, proteinuria of primary renal disease and also renal vascular
`hypertension, diabetic retinopathy, the management of other vascular disorders, such as
`migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive
`
`dysfunction, such as Alzheimer's; glaucoma and stroke.
`
`The person skilled in the pertinent art is fully enabled to select a relevant test mode!
`to prove the efficacy of a combination of the present invention in the hereinbefore and
`hereinafter indicated therapeutic indications.
`
`Representative studies are carried out with a combination of valsartan and
`N-(3-carboxy- 1-oxopropyl)-(4S)-p-phenylpheny!methy|)-4-amino-2R-methylbutanoic acid
`ethyl ester, e.g., applying the follawing methodology:
`
`Drug efficacy is assessed in various animal models including the
`deoxycorticosterone acetate-salt (DOCA-salt) rat and the spontaneously hypertensive rat
`(SHR), either maintained on a normal salt diet or with salt loading (4-8% salt in rat chow or
`1% NaCl as drinking water).
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 015
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 015
`
`

`

`
`
`vei
`it
`ti
`molt ee
`
`The DOCA-salt test model utilizes either an acute or chronic study protocol. An
`
`acute study procedure involves assessmentof the effects of various test substances over a
`
`six-hour experimental period using rats with indwelling femoral arterial and venous
`
`catheters. The acute study procedure evaluates test substances for their ability to reduce
`
`blood pressure during the established phase of DOCA-salt hypertension.
`
`In contrast, the
`
`chronic study procedure assesses the ability of test substances to prevent or delay the rise
`
`in blood pressure during the development,phase of DOCA-salt hypertension. Therefore,
`
`blood pressure will be monitored in the chronic study procedure by means of a
`
`radiotransmitter. The radiotransmitter is surgically implanted into the abdominal aorta of
`
`rats, prior to the initiation of DOCA-salt treatment and thus, prior to the induction of
`
`hypertension. Blocd pressure !s chronically monitored for periods of up to six weeks
`
`{approximately one week prior to DOCA-salt administration and for five weeks thereafter).
`
`Rats are anesthetized with 2-3%isoflurane in oxygen inhalant followed by Amytal
`
`sodium (amobarbital) 100 mg/kg, i.p. The level of anesthesia is assessed by a steady
`
`rhythmic breathing pattern.
`
`Acute study procedure:
`
`Rats undergo a unilatera! nephrectomy at the time of DOCA implantation. Hair is clipped on
`the left flank and the back of the neck and scrubbed with sterile alcohol swabs and
`
`povidone/icdine. During surgery rats are placed on a heating pad to maintain body
`
`temperature at 37°C.
`
`A 20 mm incision is made through the skin and underlying muscle to expose the left kidney.
`The kidney is freed of surrounding tissue, exteriorized and two ligatures (3-0 silk) are tied
`securely around the renal artery and vein proximal to their juncture with the aorta. The renal
`artery and vein are then severed and the kidney removed. The muscle and skin wounds are
`closed with 4-0 silk suture and stainless steel wound clips, respectively. At the same time, a
`
`15 mm incision is made on the back of the neck and a three-week-release pellet (Innovative
`
`Research of America, Sarasota, FL) containing DOCA (100 mg/kg) is implanted
`subcutaneously (s.c.). The wound is then ciosed with stainless-steel clips and both wounds
`are treated with povidone/odine; the rats are given a post-surgical intramuscular (i.m.}
`injection of procaine penicillin G (100,000 U) and buprenorphine (0.05-0.1 mg/kg) s.c. The
`rats are immediately placed on 1% NaCl + 0.2% KCI drinking water; this treatment continues
`for at least 3 weeks at which time the animals have become hypertensive and available for
`
`experimentation.
`
`-10-
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 016
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1015, p. 016
`
`

`

`
`
`Forty-eight hours prior ta experimentation, animals are anesthetized with isoflurane and
`
`catheters are implanted in the femora! artery and vein for measuring arterial pressure,
`
`collection of blood and administration of test compounds. Rats are allowed to recover for
`
`48 hours while tethered in a Plexiglas home cage, which also serves as the experimental
`
`chamber.
`
`Chronic study procedure:
`
`This procedure is the same as above except that rats are implanted with a radictransmitter,
`
`7-10 days prior to the unilateral nephrectomy andinitiation of DOCA and salt.
`
`In addition,
`
`rats do not undergo surgery for placement of femoral arterial and venous catheters.
`
`Radiotransmitters are implanted as described in Bazil et al., ''Telemetric Monitoring of
`
`Cardiovascular Parameters in Conscious Spontaneously Hypertensive Rats", J. Cardiovasc.
`
`Pharmacoil., Vol. 22, pp. 897-905 (1993).
`
`Protocols are then set-up on the computer for measurement of blood pressure, heart
`
`rate, etc., at pre-determined time points. Baseline data is collected at various time points
`and over various time intervals. For example, baseline or pre-dase values usually consist of
`
`data collection and averaging over three consecutive, 24-hour time periods prior to drug
`
`admin