`
`
`
`Docket Number|32219-US-DIV
`
`
`
`Date of Deposit
`
`FILING BY “EXPRESS MAIL” UNDER 37 CFR 1.10
`
`Express Mail Label Number
`
`Commissionerfor Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`UTILITY PATENT APPLICATION TRANSMITTAL AND FEE SHEET
`Transmitted herewith forfiling under 37 CFR §1.53(b)(1) is a divisional of prior
`Application No. 10/341,868, filed January 14, 2003.
`—
`
`Applicant (or identifier):. KSANDER ET AL.
`
`Title:
`
`Enclosed are:
`
`METHODS OF TREATMENT AND PHARMACEUTICAL
`‘COMPOSITION
`
`i.
`
`4.
`
`|X]
`
`LX Specification (Including Claims and Abstract) - 26 pages
`1.
`2. LJ Drawings -
`sheets
`3.
`Declaration and Powerof Attorney
`a.
`[] Newly executed (original or copy)
`b.
`[X] Copyfroma prior application (signed or with indication that original was
`signed)
`[J] Deletion of Inventors
`Signed statement attached deleting inventor(s) named in the prior
`application
`Incorporation By Reference
`The entire disclosure of the prior application, from which a copy of the Declaration
`and Powerof Attorney is supplied under Box 3b, is considered as being part of the
`disclosure of the accompanying application and is hereby incorporated by
`reference therein.
`Microfiche Computer Program (appendix)
`Nucleotide and/or Amino Acid Sequence Submission
`[_] Computer Readable Copy
`[] Paper Copy
`[] StatementVerifying Identity of Above Copies
`EX] Preliminary Amendment
`[] Assignment Papers (Cover Sheet & Document(s))
`(] English Translation of
`[X]
`Information Disclosure Statement
`(] Certified Copy of Priority Document(s)
`[_] Return Receipt Postcard
`[kK] Application Data Sheet
`[[] Other:
`
`O
`
`.
`6.
`
`7.
`8.
`9.
`10.
`11.
`12.
`13.
`14.
`
`{]
`
`Theright to elect an invention or species that is different from that elected in parent
`Application No. 10/341,868 in the eventof a restriction or election of species
`requirement that is identical or substantially similar to that made in said parent
`application is hereby reserved.
`.
`;
`
`Filing fee calculation:
`
`] Before calculating the filing fee, please enter the enclosed Preliminary Amendment.
`
`BIOCON PHARMALTD (IPR2020-01263) Ex. 1010, p. 001
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 001
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`whichis currently:
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`Pleasedirect all telephone calls to the undersigned at the number given below andall
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`Respectfully submitted,
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`BIOCON PHARMALTD(IPR2020-01263) Ex. 1010, p. 002
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 002
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`

`

`
`
`
`
`Docket Number|32219-US-DIV
`
`
`
`Date of Deposit
`
`FILING BY “EXPRESS MAIL” UNDER 37 CFR 1.10
`
`Express Mail Label Number
`
`Commissionerfor Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`UTILITY PATENT APPLICATION TRANSMITTAL AND FEE SHEET
`Transmitted herewith forfiling under 37 CFR §1.53(b)(1) is a divisional of prior
`Application No. 10/341,868, filed January 14, 2003.
`—
`
`Applicant (or identifier):. KSANDER ET AL.
`
`Title:
`
`Enclosed are:
`
`METHODS OF TREATMENT AND PHARMACEUTICAL
`‘COMPOSITION
`
`i.
`
`4.
`
`|X]
`
`LX Specification (Including Claims and Abstract) - 26 pages
`1.
`2. LJ Drawings -
`sheets
`3.
`Declaration and Powerof Attorney
`a.
`[] Newly executed (original or copy)
`b.
`[X] Copyfroma prior application (signed or with indication that original was
`signed)
`[J] Deletion of Inventors
`Signed statement attached deleting inventor(s) named in the prior
`application
`Incorporation By Reference
`The entire disclosure of the prior application, from which a copy of the Declaration
`and Powerof Attorney is supplied under Box 3b, is considered as being part of the
`disclosure of the accompanying application and is hereby incorporated by
`reference therein.
`Microfiche Computer Program (appendix)
`Nucleotide and/or Amino Acid Sequence Submission
`[_] Computer Readable Copy
`[] Paper Copy
`[] StatementVerifying Identity of Above Copies
`EX] Preliminary Amendment
`[] Assignment Papers (Cover Sheet & Document(s))
`(] English Translation of
`[X]
`Information Disclosure Statement
`(] Certified Copy of Priority Document(s)
`[_] Return Receipt Postcard
`[kK] Application Data Sheet
`[[] Other:
`
`O
`
`.
`6.
`
`7.
`8.
`9.
`10.
`11.
`12.
`13.
`14.
`
`{]
`
`Theright to elect an invention or species that is different from that elected in parent
`Application No. 10/341,868 in the eventof a restriction or election of species
`requirement that is identical or substantially similar to that made in said parent
`application is hereby reserved.
`.
`;
`
`Filing fee calculation:
`
`] Before calculating the filing fee, please enter the enclosed Preliminary Amendment.
`
`BIOCON PHARMALTD (IPR2020-01263) Ex. 1010, p. 003
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 003
`
`

`

` Basic Filing Fee
`
`
`
`Search Fee
`$
`510
`
`Examination Fee
`$
`210
`
`
` Multiple Dependent Claim Fee ($ 370
`
`Foreign Language Surcharge ($ 130
`Number
`For
`Number
`E
`Filed
`
`
`
`Claims
`
`
`Si, [wwcmne|[oloffs a=
`gen [eleGl
`eee
`
`
`Claims
`
`Application Size Fee
`
`
`Total
`Extra
`Number of each additional
`
`Sheets
`Sheets
`50 or fraction thereof .
`rounded up to a whole number
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`2 |-to0| |eol0£|x [s 2zo=|$|
`
`
`
`
`[]|Before calculating thefiling fee, please cancel claims
`
`
`
`.
`
`TOTAL FILING FEE |$
`
`
`
`1,450
`
`Please charge Deposit Account No. 19-0134 in the name of Novartis in the amountof
`$1,450. An additional copyof this paper is enclosed. The Commissioneris 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.
`
`Please addressall correspondenceto the address associated with Customer No. 001095,
`whichis currently:
`
`Novartis Pharmaceuticals Corp.
`Patents Pharma
`One Health Plaza, Building 104
`East Hanover, NJ 07936-1080
`
`Pleasedirect all telephone calls to the undersigned at the number given below andall
`telefaxes to (973) 781-8064.
`
`Respectfully submitted,
`
` Date: h/23/p x
`
`Attorney fof Applicants
`
`Reg. No. 36,134
`Tel. No. (862) 778-7831
`
`2
`
`BIOCON PHARMALTD (IPR2020-01263) Ex. 1010, p. 004
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 004
`
`

`

`INVENTOR INFORMATION
`
`Inventor One Given Name:: Gary M
`Family Name:: Ksander
`Postal Address Line One:: 37 The Flume
`City:: Amherst
`State or Province:: New Hampshire
`Country:: United States of America
`Postal or Zip Code:: 03031
`City of Residence:: Amherst
`State or Province of Residence:: New Hampshire
`Country of Residence:: United States of America
`Citizenship Country:: United States of America
`Inventor Two Given Name:: Randy L
`Family Name:: Webb
`Postal Address Line One:: 17 Honeyman Drive
`City:: Flemington
`State or Province:: New Jersey
`Country:: United States of America
`Postal or Zip Code:: 08822
`City of Residence:: Flemington
`State or Province of Residence:: New Jersey
`Country of Residence:: United States of America
`Citizenship Country:: United States of America
`
`CORRESPONDENCE INFORMATION
`
`Correspondence Customer Number:: 001095
`Fax One:: 973-781-8064
`
`APPLICATION INFORMATION
`
`Title Line One:: METHODS OF TREATMENT AND PHARMACEUTICAL
`Title Line Two::
`COMPOSITION
`Formal Drawings?:: No
`Application Type:: Utility
`Docket Number:: 32219-US-DIV
`Secrecy Order in Parent Appl.?:: No
`
`CONTINUITY INFORMATION
`
`This application is a:: DIVISION OF
`>Application One:: 10/341, 868
`Filing Date::01-14-2003
`
`Which is a:: NON PROV. OF PROVISIONAL
`>> Application Two:: 60/386,792
`Filing Date::06-07-2002
`
`BIOCON PHARMALTD (IPR2020-01263) Ex. 1010, p. 005
`
`
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 005
`
`

`

`And which is a:: NON PROV. OF PROVISIONAL
`>> Application Three:: 60/349, 660
`Filing Date::01-17-2002
`
`Source::
`
`PrintEFS Version 2.0
`
`
`
`BIOCON PHARMALTD (IPR2020-01263) Ex. 1010, p. 006
`
`
`
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 006
`
`

`

`IN THE UNITED STATES PATENT AND TRADEMARKOFFICE
`
`CASE 32219-US-DIV
`
`IN RE APPLICATION OF
`
`KSANDER ETAL.
`
`APPLICATION NO:
`
`Not yet Known
`
`FILED:
`
`Herewith
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`FOR: METHODS OF TREATMENT AND PHARMACEUTICAL
`COMPOSITION
`
`BIOCON PHARMALTD(IPR2020-01263) Ex. 1010, p. 007
`
`PRELIMINARY AMENDMENT
`
`Sir:
`
`Prior to the examination of the above-referenced patent application, please enter the
`
`following preliminary amendment.
`
`Amendmentto the Specification begin on page 2 of this paper.
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 007
`
`

`

`Amendmentto the Specification:
`
`Please insert the following as the first paragraph beneath thetitle on page 1:
`
`--This application is a Divisional of Application No. 10/341,868 filed on January 14,
`2003 and claims benefit of of U.S. Provisional Application No. 60/386,792, filed June 7, 2002
`and U.S. Provisional Application No. 60/349,660, filed January 17, 2002, the entire
`disclosures of which are hereby incorporated by reference.--
`
`-2-
`
`BIOCONPHARMALTD(IPR2020-01263) Ex. 1010, p. 008
`
`
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 008
`
`

`

`REMARKS/ARGUMENTS
`
`Respectfully submitted,
`
`
`.
`ttorney for Applicants
`Reg. No. 36,134
`
`The foregoing amendmentto the specification is to insert continutity information.
`No new matter has been added. Should the Examiner have any questions, please contact
`
`
`
`the undersigned attorney.
`
`Novartis Pharmaceuticals Corp.
`Patents Pharma
`One Health Plaza, Building 104
`East Hanover, NJ 07936-1080
`(862) 778-7831
`
`Date: b/e3/o8
`
`BIOCON PHARMALTD (IPR2020-01263) Ex. 1010, p. 009
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 009
`
`

`

`METHODS OF TREATMENT AND PHARMACEUTICAL COMPOSITION
`
`Backgroundof the Invention
`
`Case 4-32219A
`
`The renin angiotensin system is a complex hormonal system comprised of a large
`molecular weight precursor, angiotensinogen, two processing enzymes, renin and
`angiotensin converting enzyme (ACE), and the vasoactive mediator angiotensin Il (Ang II).
`SeeJ. Cardiovasc. Pharmacol., Vol. 15, Suppl. B, pp. $1-S5 (1990). The enzyme renin
`catalyzes the cleavage of angiotensinogen into the decapeptide angiotensin I, which has
`minimal biologicalactivity on its own andis convertedinto the active octapeptide AngII by
`ACE. Ang II 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 hormone andis involvedthe pathophysiology of
`several forms of hypertension.
`
`
`
`The vasoconstrictive effects of angiotensin II are produced byits action on the non-
`striated smooth musclecells, the stimulation of the formation of the adrenergenic hormones
`epinephrine and norepinephrine, as well as the increase of the activity of the sympathetic
`nervous system asa result of the formation of norepinephrine. AngI! also has an influence
`on electrolyte balance, produces,e.g., anti-natriuretic and anti-diuretic effects in the kidney
`and thereby promotes the release of, on the one hand, the vasopressin peptide from the
`pituitary gland and, on the other hand,of aldosterone from the adrenal glomerulosa. All
`these influences play an important part in the regulation of blood pressure, in increasing
`both circulating volume and peripheral resistance. AngII is also involvedin cell growth and
`migration and in extracellular matrix formation.
`
`It has been
`Ang Il 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 made to identify substances that bind to the AT 1-
`| receptor. Such active ingredients are often termed Ang I antagonists. Because of the
`inhibition of the AT 1-receptor such antagonists can be used,e.g., as anti-hypertensives or
`for the treatment of congestive heart failure, among otherindications. AngII antagonists
`are thereforeunderstood to be those active ingredients which bind to the AT 1-receptor
`subtype.
`
`BIOCON PHARMALTD (IPR2020-01263) Ex. 1010, p. 010
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 010
`
`

`

`Inhibitors of the renin angiotensin system are well-known drugs that lower blood |
`pressure and exert beneficial actionsin 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
`numberof 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 vasoconsirictor 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 ACEinhibitors has been demonstrated, and the activity of the
`ACEinhibitors in some conditions has been reportedin Circ. Res., Vol. 66, No. 1, pp. 242-
`248 (1990), to be mediated by elevation of bradykinin levels rather than inhibition of AngIl
`formation. Consequently, it cannot be presumedthat 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 enzymeinclude, but are not limited to,atrial natriuretic factors (ANFs),
`also known as AMPs, brain natriuretic peptide (BNP), met and leu enkephalin, bradykinin,
`
`neurokinin A and substance P.
`
`ANPsare a family of vasodilator, diuretic and anti-hypertensive peptides which have
`been the subject of many recent reports in theliterature. 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
`ANFis 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 responses to pharmacological injection 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.
`
`-2-
`
`-BIOCON PHARMALTD (IPR2020-01263) Ex. 1010, p. 011
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 011
`
`

`

`15, No. 2, pp. 152-161 (1990), while the potentiation of ANF by NEP in general was |
`disclosed in U.S. Patent No. 4,749,688.
`In U.S. Patent No. 4,740, 499, Olins disclosed the
`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'-monophosphate (cGMP) excretion in some forms of experimental
`hypertension. The anti-hypertensive action of NEP inhibitors is mediated through ANF
`because antibodies to AiNF wili neutraiize the reduction in blood pressure.
`
`Darrowetal. in European Patent Application No. 498361 disclose treating
`hypertension or congestive heart failure with a combination of certain Ang !I antagonists or
`certain renin inhibitors with certain NEPinhibitors.
`
`
`
`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'-(7H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-
`diazaspiro[4.4]nonan-4-one with a NEPinhibitor or a dual acting vasopeptidase inhibitor
`- (single molecular entity with both ACE and NEPinhibitory activities). Prolonged and
`uncontrolled hypertensive vascular disease ultimately leads to a variety of pathological
`changesin target organs, such asthe 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, beyondthoseof blood pressure lowering, to get further insightinto the benefits of
`combined treatment.
`
`The nature of hypertensive vascular diseasesis multifactorial. Undercertain
`circumstances, drugs with different mechanismsof action have been combined. However,
`just considering any combination of drugs having different mode of action does not
`necessarily lead to combinations with advantageouseffects. Accordingly, there is a need
`for more efficacious combination therapy which has less deleterious side effects.
`
`Otherobjects, features, advantages and aspects of the presentinvention will become
`apparentto thoseof skill 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
`
`-
`
`BIOCON PHARMALTD(IPR2020-01263) Ex. 1010, p. 012
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 012
`
`

`

`apparentto thoseskilled in the art from reading the following description and from reading the
`other parts of the present disclosure.
`
`Detailed Description of the Preferred Embodiments
`
`In another embodiment, the present invention relates to methodsof treating cardiac
`and renal related conditions by administration of the pharmaceutical composition comprising
`valsartan plus a NEPinhibitor.
`
`Valsartan is the AT 1-receptor antagonist (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-
`pentanoyl-N-[2;(7H-tetrazol-5-yl)biphenyl-4-yl-methyljamine of formula (1)
`CH, CH,
`Hc
`
`|
`
`CH,
`
`9
`
`_-C
`
`CH
`
`C
`
`O
`
`In one aspect, the present invention relates to pharmaceutical combinations
`comprising valsartan or pharmaceutically acceptable salts thereof and a NEP inhibitoror 2
`pharmaceutically effective salts thereof, optionally in the presence of a pharmaceutically
`acceptablecarrier and pharmaceutical compositions comprising them.
`
`
`
`
`
`.
`
`(I)
`
`OH
`
`\N
`HN~
`/
`\
`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 compoundof the formula (Il)
`Ry
`Oo
`R,
`:
`
`Hs—cH-CH—L—nn—bH—(CH,)-C—R,
`and pharmaceutically acceptable salts thereof,
`
`(It)
`
`wherein
`
`R; is alkyl of 1 to 7 carbons, trifluoromethyl, phenyl, substituted phenyl, -(CHa)+ to 4-
`phenyl, or -(CH2); to 4-substituted phenyl;
`
`-4-
`
`“BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 013
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 013
`
`

`

`R; is hydrogen, alkyl of 1 to 7 carbons, phenyl, substituted phenyl, -(CH2); to a-phenyl, or
`-(CH2), io«-Substituted phenyl;
`
`R, is hydroxy, alkoxy of 1 to 7 carbons, or NH;
`
`nis an integer from 1 to 15; and
`
`the term substituted phenyl refers to a substituent selected from lower alkyl of 1 to 4
`carbons, lower alkoxy of 1 to 4 carbons, loweralkylthio of 1 to 4 carbons, hydroxy, C!, Br or
`
`F.
`
`Preferred selective NEP inhibitors of formula(Il) include compounds,
`wherein
`|
`|
`
`Rz is benzyl;
`
`R; is hydrogen;
`
`nis an integerfrom 1 to 9; and
`
`R, is hydroxy.
`
`Even more preferred selective NEPinhibitors of formula (Il) are reported in the
`literature as SQ 28,603 whichis the compoundof formula(II),
`
`
`
`NEPinhibitors within the scope of the present invention include compounds .
`disclosed in U.S. Patent No. 4,610,816, herein incorporated by reference, including in
`particular N-[N-[1(S)-carboxyl-3-phenylproplyl]-(S)-phenylalanyl]-(S)-isoserine and N-[N-
`[((1S)-carboxy-2-phenyl)ethyl]-(S)-phenylalany!]-B-alanine; compoundsdisclosedin U.S.
`Patent No. 4,929,641, in particular, N-[2(S)-mercaptomethyl-3-(2-methylphenyl)-
`
`
`
`wherein
`
`Rz is benzyl;
`
`.
`
`Rg is hydrogen;
`
`nis one; and
`
`R, is hydroxy.
`
`The preparation of the selective NEPinhibitors of formula (Il), wherein Rz is other
`thantrifluoromethyl are disclosed by Delaneyet al. in U.S. Patent No. 4,722,810. The
`preparation of the selective NEPinhibitors of formula(Il), wherein R;is trifluoromethyl are
`disclosed by Delaneyetal. in U.S. Patent No. 5,223,516.
`
`-5-
`
`BIOCON PHARMALTD (IPR2020-01263) Ex. 1010, p. 014
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`propionyl]Jmethionine; SQ 28603 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-B-alanine),
`disclosed in South African Patent Application No. 84/0670; UK 69578 (cis-4-[[[1-[2-carboxy-
`3-(2-methoxyethoxy)propyl]-cyclopentyl]carbonyl]amino}-cyclohexanecarboxylic acid) andits
`active enantiomer(s); thiorphan and its enantiomers, retro-thiorphan; phosphoramidon; and
`SQ 29072 (7-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]-heptanoic acid). Also
`suitable for use are any pro-drug formsof the above-listed NEPinhibitors, e.g., compounds
`in which one or more carboxylic acid groups are esterified.
`NEPinhibitors 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-oxopropyl)-(4S)-p-
`phenylphenylmethyl)-4-amino-2R-methyibutanoic acid ethyl ester; the compoundsdisclosed
`in EP 00342850; particularly, (S)-cis-4-[1 -[2-(5-indanyloxycarbonyl)-3-(2-
`methoxyethoxy)propyl]-1 -cyclopentanecarboxamido]-1 -cyclohexanecarboxylic acid; the
`‘compounds disclosed in GB 02218983,particularly, 3-(1-[6-endo-
`|
`.
`hydroxymethylbicyclo[2,2,1 ]heptane-2-exo-carbamoyl]}cyclopentyl)-2-(2-
`methoxyethyl)propanoic acid; the compounds disclosed in WO 92/14706, particularly,
`N-(1 -(3-(N-t-butoxycarbony!-(S)-prolylamino)-2(S)-t-butoxy-
`carbonylpropyl)cyclopentanecarbonyl)-O-benzyl-(S)-serine methyl ester; the compounds
`disclosed in EP 00343911; the compoundsdisclosed in JP 06234754; the compounds
`disclosed in EP 00361365,particularly, 4-[[2-(mercaptomethyl)-1 ~Ox0-3-
`phenylpropyl]amino]benzoic acid; the compoundsdisclosed in WO 90/09374, particularly,
`3-[1 -(cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-r-1 -carboamoyl)cyclopentyl]-2S-(2-
`methoxyethoxymethyl)propanoic acid; the compoundsdisclosedin JP 07157459,
`particularly, N-((2S)-2-(4-biphenylmethyl)-4-carboxy-5-phenoxyvaleryl)glycine; the
`compounds disclosed in WO 94/15908, particularly, N-(1-(N-hydroxycarbamoylmethy))-1-
`cyclopentanecarbonyl)-L-phenylalanine; the compoundsdisclosed in U.S. Patent No.
`5,273,990, particularly, (S)-(2-biphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethylamino)
`methylphosphonic acid; the compounds disclosed in U.S. Patent No. 5,294,632, particularly,
`(S)-5-(N-(2-(phosphonomethylamino)-3-(4-biphenyl)propionyl)-2-aminoethy|)tetrazole; the
`compounds disclosed in U.S. Patent No. 5,250,522, particularly, B-Alanine, 3-[1,1'-biphenyl]-
`4-yl-N-[diphenoxyphosphiny!)methyl]-L-alanyl; the compoundsdisclosed in EP 00636621,
`particularly, N-(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)-(1-((2,2-
`dimethyl-1 3-dioxolan-4-yl)-methoxy)carbonyl)-2-phenylethyl)-L-phenylalanyl)-B-alanine, N-
`
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`[N-[(L)-[1-[(2,2-dimethyl-1 |3-dioxolan-4-yl)-methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-
`(R)-alanine, N-[N-[(L)-1-carboxy-2-phenylethy!]-L-phenylalanyl]-(R)-alanine, N-[2-
`acetylthiomethyl-3-(2-methyl-phenyl)propionyl]-methionine ethyl ester, N-[2-mercaptomethyl-
`3-(2-methylphenyl)propioyl]-methionine, N-[2(S)-mercaptomethyl-3-(2-
`_methylphenyl)propanoyl]-(S)-isoserine, N-(S)-[3-mercapto-2-(2-methylphenyl) propionyl]-(S)-
`2-methoxy-(R)-alanine, N-[1-[[1(S)-benzyloxycarbonyl-3-
`|
`phenylpropyijamincjcyciopentyicarbonylj-(S)-isoserine, N-[1-[[1(S)-carbonyl-3-
`phenylpropy]amino]-cyclopentylcarbonyl]-(S)-isoserine, 4 1'-[dithiobis-[2(S)-(2-
`methylbenzyl)-1 -Ox0-3, 1-propanediyl]]-bis-(S)-isoserine, 1,1 '_[dithiobis-[2(S)-(2-
`methylbenzyl)-1-0xo-3,1 -propanediy/]]-bis-(S)-methionine, N-(3-phenyl-2-(mercaptomethyl)-
`propionyl)-(S)-4-(methylmercapto)methionine, N-[2-acetylthiomethyl-3-phenyl-propionyl]-3-
`aminobenzoic acid, N-[2-mercaptomethyl-3-phenyl-propionyl]-3-aminobenzoic acid,
`N-[1-(2-carboxy-4-phenylbutyl)-cyclopentanecarbonyl]-(S)-isoserine,
`.
`—
`N-[1-(acetylthiomethyl)cyclopentane-carbonyl]-(S)-methionine ethyl ester,
`3(S)-[2-(acetylthiomethyl)-3-phenyl-propionyl]Jamimo-e-caprolactam; and the compounds
`disclosed in WO 93/10773, particularly, N-(2-acetylthiomethyl-3-(2-methylphenyl)propionyl)-
`methionine ethyl ester.
`
`
`
`.
`
`The compoundsto 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 compoundshaving at least one acid group, for
`example, COOH, canalso form salts with bases. Corresponding internal salts may
`furthermore be formed, if a compound comprises, e.g., both a carboxy and an amino group. |
`
`With respect to N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-
`methylbutanoic acid ethyl ester, preferred salts include the sodium salt disclosed in U.S.
`Patent No. 5,217,996,the triethanolamine salt and the tris(hydroxymethyl)aminomethane
`salt. Preparation of the triethanolamine salt and the tris(hydroxymethyl)aminomethanesalt
`may be carried out as follows:
`
`Triethanolamine
`
`To N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid.
`ethyl ester (349 mg, 0.848 mmol) is added 5 mLof ethyl ether and 0.113 mL (0.848 mmol)
`of triethanolamine in 1 mL of ethyl acetate. The solid was collected and dried melting at
`69-71°C.
`
`-7-
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`Ithas surprisingly been found that, a combination of valsartan and a NEPinhibitor
`achieves greater therapeutic effect than the administration of valsartan, ACE inhibitors or
`NEPinhibitors alone and promotes less angioedemathanis 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 aseither 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 changein blood pressurein millimeters of mercury (change in mmHg)
`and the duration of the effect (minutes, hours or days).
`
`
`
` O
`
`z
`, aj
`0
`worAy
`HN
`poHO
`
`HO
`
`|
`
`HO
`
`NH,
`
`O
`
`Tris(hydroxymethyl) 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(hydroxymethyl)aminomethane. The suspension is diluted with 45 mL of ethyl acetate
`and refluxed overnight (~20 hours). The reaction is cooled to 0°C,filtered, solid washed
`with ethyl acetate and dried melting at 114-115°C.
`
`Further benefits are that lower dosesof the individual drugs to be combined
`according to the present invention can be used to reduce the dosage,for example, that the
`dosages neednotonly often be smaller but are also applied less frequently, or can be used
`to diminish the incidence of side effects. The combined administration of valsartan or a
`pharmaceutically acceptable salt thereof and a NEPinhibitor 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
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`condition. This is in accordance with the desires and requirements of the patients to be
`
`treated.
`
`w
`
`It can be shownthat combination therapy with valsartan and a NEP inhibitor results
`_in amore effective anti-hypertensive therapy (whether for malignant, essential, reno-
`vascular, diabetic, isolated systolic or other secondary type of hypertension) through
`improved efficacy, as well as a greater responder rate. The compination is also useful in th
`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 arrhythmias, atrialfibrillation, atrial flutter or detrimental
`vascular remodeling.
`It can further be shown that a valsartan and NEPinhibitor therapy
`proves to be beneficial in the treatment and prevention of myocardialinfarction andits
`sequelae. A valsartan plus NEPinhibitor combination is also usefulin treating
`atherosclerosis, angina (whether stable or unstable), and renal insufficiency (diabetic and
`non-diabetic). Furthermore, combination therapy using valsartan and a NEPinhibitor can
`improve endothelial dysfunction, thereby providing benefit in diseases in which normal
`endothelial function is disrupted, such as heart failure, angina pectoris and diabetes.
`Furthermore, the combination of the present invention may be used for the treatment or
`prevention of secondary aldosteronism, primary and secondary pulmonary hypertension,
`renalfailure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma,
`glomerularsclerosis, proteinuria of primary renal disease and also renal vascular
`hypertension, diabetic retinopathy, the managementof other vascular disorders, such as
`migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive
`dysfunction, such as Alzheimer's; glaucoma andstroke.
`
`
`
`The personskilled in the pertinent art is fully enabled to select a relevant test model
`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-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid
`ethyl ester, e.g., applying the following methodology:
`
`Drug efficacy is assessed in various animal models including the
`deoxycorticosterone acetate-salt (DOCA-salt) rat and the spontaneously hypertensive rat
`
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`(SHR), either maintained on a normal!salt diet or with salt loading (4-8% salt in rat chow or
`1% NaCl as drinking water).
`The DOCA-salt test modelutilizes either an acute or chronic study protocol. An |
`acute study procedure involves assessmentofthe 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 substancesfor 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 preventor delaythe rise
`in blood pressure during the development phase of DOCA-salt hypertension. Therefore,
`blood pressure will be monitoredin the chronic study procedure by meansof a-
`radiotransmitter. The radiotransmitteris surgically implanted into the abdominal