Doc u_er
`32219-US-DIV
`Date of Deposit
`
`FILING BY “EXPRESS MAIL” UNDER 37 CFR 1.10
`
`Express Mail Label Number
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`UTILITY PATENT APPLICATION TRANSMITTAL AND FEE SHEET
`
`Transmitted herewith for filing 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
`
`1.
`2.
`3.
`
`4.
`
`[Z Specification (Including Claims and Abstract) - 26 pages
`1:! Drawings -
`sheets
`Declaration and Power of Attorney
`a.
`[:| Newly executed (original or copy)
`b.
`IE Copy from a prior application (signed or with indication that original was
`signed)
`|:I Deletion of Inventors
`Signed statement attached deleting inventor(s) named in the prior
`application
`IX Incorporation By Reference
`The entire disclosure of the prior application, from which a copy of the Declaration
`and Power of 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.
`
`i.
`
`'
`
`5.
`6.
`
`El Microfiche Computer Program (appendix)
`Nucleotide and/or Amino Acid Sequence Submission
`1:] Computer Readable Copy
`El Paper Copy
`[I Statement Verifying Identity of Above Copies
`IX Preliminary Amendment
`7.
`[:l Assignment Papers (Cover Sheet & Document(s))
`8.
`El English Translation of
`9.
`[XI
`Information Disclosure Statement
`10.
`11. El Certified Copy of Priority Document(s)
`12. El Return Receipt Postcard
`13.
`[Z Application Data Sheet
`14.
`[Z] Other:
`
`[Z
`
`The right to elect an invention or species that is different from that elected in parent
`Application No. 10/341,868 in the event of 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:
`
`E Before calculating the filing fee, please enter the enclosed Preliminary Amendment.
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`BIOCON PHARMA LTD (IPR2020-01263) EX. 1010, p. 001
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`El
`
`Before calculating the filing fee, please cancel claims
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`Basic Filino Fee
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`Multi-le De-endent Claim Fee $ 370
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`Please charge Deposit Account No. 19—0134 in the name of Novartis in the amount of
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`required in connection with this application, or credit any overpayment, to Deposit
`Account No. 19—0134 in the name of Novartis.
`
`Please address all correspondence to the address associated with Customer No. 001095,
`which is currently:
`
`Novartis Pharmaceuticals Corp.
`Patents Pharma
`
`One Health Plaza, Building 104
`East Hanover, NJ 07936-1080
`
`Please direct all telephone calls to the undersigned at the number given below and all
`telefaxes-to (973) 781-8064.
`
`Respectfully submitted,
`
`Date:
`
`,
`
`,
`
`'
`
`é, /2,_3/’D y '
`
`Gr gory D.
`
`
`A torney fo Applicants
`
`
`Reg. NO. 36,134
`Tel. No. (862) 778-7831
`
`.
`
`2
`
`.
`
`
`
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1010, p. 002
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 002
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`

`

`Doc u_er
`32219-US-DIV
`Date of Deposit
`
`FILING BY “EXPRESS MAIL” UNDER 37 CFR 1.10
`
`Express Mail Label Number
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`UTILITY PATENT APPLICATION TRANSMITTAL AND FEE SHEET
`
`Transmitted herewith for filing 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
`
`1.
`2.
`3.
`
`4.
`
`[Z Specification (Including Claims and Abstract) - 26 pages
`1:! Drawings -
`sheets
`Declaration and Power of Attorney
`a.
`[:| Newly executed (original or copy)
`b.
`IE Copy from a prior application (signed or with indication that original was
`signed)
`|:I Deletion of Inventors
`Signed statement attached deleting inventor(s) named in the prior
`application
`IX Incorporation By Reference
`The entire disclosure of the prior application, from which a copy of the Declaration
`and Power of 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.
`
`i.
`
`'
`
`5.
`6.
`
`El Microfiche Computer Program (appendix)
`Nucleotide and/or Amino Acid Sequence Submission
`1:] Computer Readable Copy
`El Paper Copy
`[I Statement Verifying Identity of Above Copies
`IX Preliminary Amendment
`7.
`[:l Assignment Papers (Cover Sheet & Document(s))
`8.
`El English Translation of
`9.
`[XI
`Information Disclosure Statement
`10.
`11. El Certified Copy of Priority Document(s)
`12. El Return Receipt Postcard
`13.
`[Z Application Data Sheet
`14.
`[Z] Other:
`
`[Z
`
`The right to elect an invention or species that is different from that elected in parent
`Application No. 10/341,868 in the event of 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:
`
`E Before calculating the filing fee, please enter the enclosed Preliminary Amendment.
`
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1010, p. 003
`
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`
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 003
`
`

`

`El
`
`Before calculating the filing fee, please cancel claims
`
`Basic Filino Fee
`Search Fee
`Examination Fee
`
`Multi-le De-endent Claim Fee $ 370
`
`Foreio n Lano uaoe Surchar-e ($ 130
`For
`
`Extra
`Claims
`
`Total Claims
`
`Independent
`Claims
`A lication Size Fee
`Total
`Sheets
`
`Extra
`Sheets
`
`Number of each additional
`50 or fraction thereof ,
`rounded u to a whole number
`
`
`
`26
`
`.-100 - ,50
`
`me =_
`
`,
`
`TOTAL FILING FEE
`
`1,450
`
`Please charge Deposit Account No. 19—0134 in the name of Novartis in the amount of
`$1,450. 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.
`
`Please address all correspondence to the address associated with Customer No. 001095,
`which is currently:
`
`Novartis Pharmaceuticals Corp.
`Patents Pharma
`
`One Health Plaza, Building 104
`East Hanover, NJ 07936-1080
`
`Please direct all telephone calls to the undersigned at the number given below and all
`telefaxes-to (973) 781-8064.
`
`Respectfully submitted,
`
`Date:
`
`,
`
`,
`
`'
`
`é, /2,_3/’D y '
`
`Gr gory D.
`
`
`A torney fo Applicants
`
`
`Reg. NO. 36,134
`Tel. No. (862) 778-7831
`
`.
`
`2
`
`.
`
`
`
`BIOCON PHARMA LTD (IPR2020-01263) EX. 1010, p. 004
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1010, p. 004
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`

`

`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 azzNON PROV. OF PROVISIONAL
`
`>> Application Two:: 60/386,792
`Filing Date::O6—07—2002
`
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`

`And which is a:: NON PROV. OF PROVISIONAL
`
`>>_Application Three:: 60/349,660
`Filing Date::Ol—17—2002
`
`Sourcezz
`
`PrintEFS Version 2.0
`
`
`
`
`
`BIOCON PHARMA LTD (IPR2020—01263) EX. 1010, p. 006
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`

`

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

`

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

`

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

`

`METHODS OF TREATMENT AND PHARMACEUTICAL COMPOSITION
`
`Case 4-32219A
`
`Background of the Invention
`
`The renin angiotensin system isa 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 ll (Ang II).
`See J. Cardiovasc. Pharmacol., Vol. 15, Suppl. B, pp, 81-85 (1990). The enzyme renin
`
`catalyzes the cleavage of angiotensinogen into the decapeptide angiotensin I, which has
`
`minimal biological activity on its own and is converted into the active octapeptide Ang II 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 ofvascular growth and stimulation of cardiac
`
`growth. Ang II functions as a pressor hormone and is involved the pathophysiology of
`several forms of hypertension.
`
`The vasoconstrictive effects of angiotensin II 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 well as the increase of the activity of the sympathetic
`
`nervous system as a result of the formation of norepinephrine. Ang II 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, cf 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. Ang II is also involved in cell growth and
`
`migration and in extracellular matrix formation.
`
`It has been
`Ang'll 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-
`I receptor. Such active ingredients are often termed Ang II antagonists. Because of the
`inhibition of the AT 1—reCeptor such antagonists can be used, e.g., as anti-hypertensive's or
`for the treatment of congestive heart failure, among other indications. Ang ll antagonists
`
`are therefore‘understood to be those active ingredients which bind to the AT 1-receptor
`
`subtype.
`
`
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`Inhibitors of the renin angiotensin system are well-known drugs that lower blood I
`
`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, ben‘azepril and spirapril; Although a major mode of action of ACE inhibitors
`involves prevention of formation of the vasocohstrictor peptide Ang II, 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 substanceP. Prevention of the
`
`degradation of bradykinin by ACE inhibitors has been demonstrated, and theactivity 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 ll
`formation. Consequently, it cannot be presumed that the effect of an ACE inhibitor is due
`
`solely to prevention of angiotensin formation and subsequent inhibition 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 not limited to, atrial natriuretic factOrs (ANFs),
`
`also known as ANPs, brain natriuretic peptide (BNP), met and leu enkephalin, bradykinin,
`
`neurokinin A and substanceP.
`
`ANPs are a family of vasodilator, diuretic and anti-hypertensive peptides 'which have
`been the subject of many recent reports in the literature. see, 6.9., 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 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-
`
`
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`

`

`15, No. 2, pp. 152—161 (1990), while the potentiation of ANF by NEP in general was ‘
`
`In US Patent No. 4,740, 499, Olins disclosed the
`disclosed in US. 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'-monophosphate (cGMP) excretion in some. forms of experimental
`hypertension. The anti-hypertensive action of NEP inhibitors is mediated through ANF
`
`because antibodies to ANF wiii neutraiize 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.
`
`_
`
`I
`
`'
`
`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-b'utyl-
`6,7,8,9-tetrahydro—3—[[2'—(1H—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
`changes in 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, beyond 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 aneed
`for more efficacious combination therapy which has less deleterious side effects.
`
`Other objects, features, advantages and aspects of the present invention will become
`apparent to those of 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 way of illustration only. Various changes and.
`
`-
`
`modifications within the spirit and scope of the disclosed invention will become readily
`
`
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`BIOCON PHARMA LTD (IPR2020-01263) EX. 1010, p. 012
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`

`apparent to those skilled 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 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 of treating 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—methy|—prop—1—y|)—N—
`
`pentanoyl-N-[2;(1H-tetrazoI-54yi)biphenyl-4—yl—methyl1amine of formula (I)
`
`/CH3
`
`CH3\
`”‘1’
`ii
`c
`,c
`2\CH2 \N/HY
`
`o
`
`OH
`
`.
`
`(I)
`
`HN \N
`\
`/
`N=N
`
`CH
`
`-
`CH
`
`3\CH2,
`
`
`
`and is disclosed in EP 0443983 A and US. 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 formula (II)
`
`R2
`0
`R3
`. o
`Hs—CHz—cH—g—NH—cle—(CHZ),,—cl—R,
`
`(II)
`
`and pharmaceutically acceptable salts thereof,
`
`wherein
`
`R2 is alkyl of 1 to 7. carbons, trifluoromethyl, phenyl, substituted phenyl, -(CH2)1 to 4-
`
`phenyl, or -(CH2)1 to 4-substituted phenyl;
`
`- 4 -
`
`
`
`'BIOCON PHARMA LTD (IPR2020-01263) EX. 1010, p. 013
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`

`R3 is hydrogen, alkyl of 1 to 7 carbons, phenyl, substituted phenyl, —(CH2)1,°4-phenyl, or
`
`—(CH2)1 M-substituted phenyl;
`
`,
`
`R1 is hydroxy, alkoxy of 1 to 7 carbons, or NH2;
`
`n is an integer from 1 to 15; and
`
`the term substituted phenyl refers to a substituent selected from lower alkyl of 1 to 4
`
`Dr nr
`carbons, lower alkoxy of 1 to '4 carbons, lower‘alkylthio of 1 to 4 carbons, hydroxy, Cl, ... c.
`
`F.
`
`Preferred selective NEP inhibitors of formula (II) include compounds,
`wherein
`
`R2 is benzyl;
`
`R3 is hydrogen;
`
`n is an integer from 1 to 9; and
`
`R1 is hydroxy.
`
`Even more preferred selective NEP inhibitors of formula (II) are reported in the
`
`literature as SQ 28,603 which is the compound of formula (II),
`
`wherein
`
`R2 is benzyl;
`
`-
`
`R3 is hydrogen;
`
`n is one; and
`
`R1 is hydroxy.
`
`The preparation of the selective NEP inhibitors of formula (ll), wherein R2 is other
`
`than trifluoromethylare disclosed by Delaney et al. in US. Patent No. 4,722,810. The
`
`preparation of the selective NEP inhibitors of formula (II), wherein R2 is trifluoromethyl are
`
`disclosed by Delaney et al. in US. Patent No. 5,223,516.
`
`NEP inhibitors Within the scope of the present invention include compounds
`
`disclosed in US. 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— 7
`
`[((1S)-carboxy-Z-phenyl)ethyl]-(S)—phenylalanyl]-B-aIanine; compounds disclosed in US.
`
`Patent No. 4,929,641, in particular, N-[2(S)-mercaptomethyl-3—(2-methylphenyl)-
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`propionyl]methionine; SQ 28603 (N-[2-(mercaptomethyI)-1-oxo—3-phenylpropyl]-B—alanine),0
`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) and its
`active enantiomer(s); thiorphan and its enantiomers; retro-thiorphan; phosphoramidon; and
`SQ 29072I(7-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]-heptanoic 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—oxopropyl)-(4S)-p-
`phenylphenylmethyI)—4-amino-2R-methylbutanoic acid ethyl ester; the compounds disclosed
`in EP 00342850, particularly, (S)-cis-4-[1-[2-(5-indanyloxycarbonyI)-3—(2-
`methoxyethoxy)propyl]-1-cyc|opentanecarboxamido]-1-cyclohexanecarb0xylic acid; the
`compounds disclosed in GB 02218983, particularly, 3-(1-[6-endo— I
`'
`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—butoxycarbonyl-(S)-prolylamino)-2(S)-t—butoxy-
`carbonylpropyl)cyclopentanecarbonyI)-O-benzyl-(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-
`phenylpropyl]amino]benzoic acid; the compounds disclosed in WO 90/09374, particularly,
`3-[1-(cis-4-carboxycarbonyl-cis-3-butylcyclohexyI-r-1-carboamoyl)cyclopentyl]-28—(2-
`methoxyethoxymethyl)propanoic acid; the compounds disclosed in JP 07157459,
`particularly, N-((2S)-2-(4-biphenylmethyI)—4-carboxy-5-phenoxyvaleryl)glycine; the
`compounds disclosed in WO 94/15908, particularly, N-(1-(N-hydroxycarbamoylmethyl)-1-
`cyclopentanecarbonyl)-'L-phenylalanine; the compounds disclosed in U.S. Patent No.
`5,273,990, particularly, (S)-(2—biphenyl-4-yI)-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)propionyI)-2-aminoethyl)tetrazole; the
`compounds disclosed in U.S. Patent No. 5,250,522, particularly, B-Alanine, 3—[1,1'-biphenyl]-
`4-yl-N-[diphenoxyphosphinyl)methyll-L-alanyl; the compounds disclosed in EP 00636621,
`particularly, N-(2-carboxy-4-thienyl)-3-mercapto-2-benzylpropanamide; the compounds
`disclosed in WO 93/09101, particularly, 2-(2-mercaptomethyI-3—phenylpropionamido)thiazol—
`4—ylcarboxylic acid; the compounds disclosed in EP 00590442, particularly, ((L)-(1—((2,2—
`dimethyl-1 ,3-dioxolan-4-y|)-methoxy)carbonyl)-2-phenylethy|)-L—phenylaIanyl)-13-alanine, N-
`- 6 _
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`[N-[(L)-{1-[(2,2—dimethyl-1,3-dioxolan—4—yl)-methoxy]carbonyl]-2—phenylethyl]—L—phenylalanyl]-
`(R)-a|anine, N-[N-[(L)-1-carboxy-2—phenylethyI]-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)propionyI]—(S)-
`2-methoxy—(R)-alanine, N-[1-[[1(S)-benzyloxycarbonyl-3-
`i
`phenylpropyl]amincicyciopentylcarbonyl}-(S)-iSOSerine, N-[1 -[[1 (S)-carbonyl-3—
`phenylpropy]amino]-cyclopentylcarbonyl]-(S)~isoserine, >1,1'-[dithiobis-[2(S)-(2a
`methylbenzyl)—1-oxo-3,1-propanediyl]]-bis-(S)-isoserine, 1,1 '-[dithiobis-[2(S)-(2-
`methylbenzyl)-1-oxo-3,1-propanediyl]]-bis-(S)—methionine,iN-(3—phenyl-2-(mercaptomethyl)4 '
`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,
`I
`
`'
`N-[1-(acetylthiomethyl)cyclopentane—carbonyl]-(S)-methionine ethyl ester,
`3(S)-[2—(acetylthiomethyl)-3-phenyl-propionyl]amimo-a-caprolactam; and the compounds
`
`disclosed in WO 93/10773, particularly, N-(2-acetylthiomethyl-3-(2—methylphenyl)propionyl)-
`
`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 having at least one acid group,- for
`
`example, COOH, can also form salts with bases. Corresponding internal salts may
`furthermore be formed, if a compound comprises, e.g., both a carboxy and an amino group. V
`
`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 US.
`Patent No. 5,217,996, the triethanolamine salt and the tris(hydroxymethyl)aminomethane
`salt. Preparation of the triethanolamine salt and the tris(hydroxymethyl)aminomethane salt
`
`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 mL of 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.
`’
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`III”
`
`I 2
`
`0
`
`I
`
`I :IIII”
`
`HO
`
`.
`
`HO
`
`. NHZ
`
`HO
`
`Tris(hydroxymethyl) aminomethane
`
`To N—(3-carboxy-1—oxopropyl)‘—(4S)-p—phenylphenylmethyl)-4-amino-ZR-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.
`
`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 vasopeptidase inhibitor 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 doses of the individual drugs to be combined
`
`according to the present invention can be used to reduce the 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. The 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 responder rate 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.
`
`It can be shown that combination therapy with valsartan and a NEP inhibitor results
`
`_ in a more 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 combination is also useful is“ th
`
`(1i
`
`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, atrial fibrillation, atrial flutter or detrimental
`vascular remodeling.
`It can further be shown that 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 inhibitor 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,
`renal failure conditions, sUch as diabetic nephropathy, glomerulonephritis, scleroderma,
`
`glomerular sclerosis, proteinuria of primary renal disease and also renal vascular
`
`‘
`
`hypertensidn, 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 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-oxopropyI)-(4S)-p-phenylphenylmethyI)-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 model utilizes either an acute or chronic study protocol. An I
`acute study procedure involves assessment of 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 pr