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`March 3|), 20”:
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO {S A TRUE COPY FROM
`
`THE RECORDS OF THIS OFFICE OF:
`
`U.S. PATENT: 5,968,979 '
`
`ISSUE DATE: October 19, 1999
`
`COMMERCE
`UNITED STATES DEPARTMENT
`United States Patent and Trademark Oi‘fice
`
`Certifying Officer
`
`By Authority of the
`
`1
`Under Secretary of Commerce for Intellectual Property
`and Director of the United States Patent and Trademark Office :
`
`;
`_
`
`I
`
`WAMW
`ANDREA T BENNETT
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 1 of6
`
`

`

`i||||l|l|||i||||l|lll|lll|i||i|||l|||l|||||ll|||||l||ll
`U8005968979A
`
`1191
`United States Patent
`
`Brusiiow
`
`[11] Patent Number:
`
`5,968,979
`
`[45] Date of Patent:
`
`Oct. 19, 1999
`
`[54] TRIGLYCERIDES AND ETHYL ESTERS 0F
`PHENYLALKANOIC ACID AND
`PHENYLALKENOIC ACID USEFUL 1N
`TREATMENT OF VARIOUS DISORDERS
`
`[75]
`
`Inventor: Saul W. Brusllow, Baltimore, Md.
`
`[73] Assignee: Brusllow Enterprises LLC, Baltimore,
`Md.
`
`[21] App]. No.2 “[006332
`[22]
`Filed:
`Jan. 13, 1998
`
`Related U.S. Appllcation Data
`
`[63] Continuation of application No. 0&‘384,935, Feb. 7, 1995,
`abandoned.
`
`.
`
`r,
`
`AfllN 37110;.5511: 311235
`[111.1316 .
`[51]
`514533; 51415325141547;
`[52] us. c1.
`5141549; 5141552; 514555; 514(814; 5144815;
`5144335; 5541227; 5541220; 554r21s;554rz19;
`560/8; 5501715
`554227.220,
`1.
`[53] FienotSemh
`5541215, 219; 550/3, 76; 5141532, 547,
`549, 552, 553, 314, 315, 335
`
`[56]
`
`References Cited
`FOREIGN PATENT DOCUMENTS
`
`94142494 1mm WIPO -...._...._....__...-. MIK 49.02
`OTHER PUBIJCAIIONS
`
`Georges Demons et al.: “Preparation de quelques glycérides
`phénylaliphatiqucs ct
`Ieur
`réduciinn en almols .
`.
`.”,
`Comptes Rendtts Hebdomadaires Des Seances De
`I.’acadernie Des Sciences, vol. 205, Oct. 18, 1937, pp.
`682—684.
`Walsh et al.. Chemical Abstract vol. 112, No. 231744.
`Chemical Abstract, vol. 116, No. 46308, Seiki et a],
`“Homogenous Pharmaceutical Emulsions Containing Non-
`steriodal Analogesics and Inflammation Inhibitors”.
`
`
`
`Walsh ct IL. The Journal of Biological Chemistry, vol. 265,
`No. 8, pp. 4374—4381 (1990), sn71,2—Diacylgylcerol Kinnse
`of Escherichia coli.
`
`Newmark et al.. “Butyrate and Phenylacetate as Differenti-
`ating Agents: Practical Problems and Opportunities”, lows.
`of Cell. Biochem., Supplement 22: 247453-(1995).
`Chen el 31., “Tributyrin: A Prodrug of Butyric Acid for
`Potential Clinical Applicaitn in Differentiation 'lhcrapr’,
`Cancer Res, 54349444990994).
`Lea ct. al., “Bulyramide and Monobuiyrin: Growth Inhibi-
`tory and Difi'erentiating Agents", Anticancer Res, 13:
`1457150 (1993).
`
`Mdémie Des Sciences, Chimie Organique, “Preparation dc
`quelques glycérides phénylaliphatiques et leur reduction en
`alcools .
`.
`. ”, pp. fiSHSIL
`'
`
`Brnsilow et al., Metabolism, vol. 42, No. 10 Oct., 1993, pp.
`1336—1339, “Restoration of Nitrogen Homeostasis in a Man
`with Ornithine Transcarbamylasc Deficiency”.
`
`Maestri et al., “Prospective treatment of urea cycle disor-
`ders", pp. 923—928.
`
`Primary Examiner— Gary Geist
`Assistant Examiner-v—Deborah D Carr
`Attorney; Agent. or Firm- Nikaido Marmcletein Murray &
`Oran] LLP
`
`[57]
`
`ABSTRACT
`
`TWO new toms of pmdrug for phenylacetate, of even
`congeners of phenylalltanoic acid and phenylaikenoic acids,
`which are the phenylalkanoic or phenylalkenoic esters of
`glycerol, or the ethyl esters of phenylalkanoic acid or
`phenylalkcnoic acids. 111:5: forms of the drugs provide a
`convenient dosage form of the drugs. The prodng of the
`invention are useful to treat patients with diseases of nitro-
`gen
`accumulation, patients with certain
`B-hemoglobinopathies, anemia, and cancer.
`
`10 Claims, No Drawings
`
`Copy provided by USP'I'O from the PIES image Database on 031211201 6
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 2 of6
`
`

`

`5,968,979
`
`1
`TRIGLYCERIDES'AND METERS OF
`PHENYLAIKANOIC ACID AND
`PBENYLALKENDIC ACID USEFUL IN
`TREATMENT OF VARIOUS DISORDERS
`
`CROSS REFERENCE TO REIATED
`APPLICATION
`
`This application is a continuation of Ser. No. 081384.935,
`flied Feb. 7, 1995, now abandoned.
`BACKGROUND OF THE INVENTION
`
`The present invention relates to compounds, pharmaceu—
`tical compositions, and methods for heating several condi-
`tions with prodnlgs for phenylaoetate as therapeutic agents.
`FIELD OF THE INVENTION
`
`Phenylalltanoic acids are known therapeutic agents for a
`variety of disorders. Phenylacetate is used for the treatment
`of nitrogen metabolism disorders, ben-hemoglohinopathies,
`anemia and cancer. Various phenylallreuoie acids can be
`used in the treatment of the same disorders. The prodrugs
`disclosed in the present invention are useful therapeutic
`agents for a ntuuber of disorders, and poesess some advan-
`tagesover mefiormsol'thedrufiachninisteredinlhepricr
`art.
`Nitrogen Metabolism Disorders
`In a healthy person.
`the potentially toxic nitrogenous
`compounds which accumulate as the body degrades proteins
`are synthesized into urea which is rapidly excreted into the
`urine. However, for those who sufi‘er kidney failure, liver
`failure or inborn errors of urea synthesis, this pathway is
`defective. The accumulation of nitrogenous compounds
`resulting from such a blockage leads to considerable mon-
`bidity and mortality.
`In the case of an inborn error of urea synthesis, the major
`metabolic abnormality is the inability of the body to convert
`waste nitrogen into urea. As a consequence, various nitrog-
`enous metabolites accrmmlate in the body, the most toxic
`being ammonium, although other materials, such as
`glutamine and alanine also increase.
`Previous therapeutic approaches for treating patients with
`urea cycle enzymopathies (as well as other nitrogen acm-
`mulation dbeeses cited earlier) have been designed to
`reduce the requirement tier urea synthesis by quantitative
`and qualitative manipulation of dietary protein, amino acids
`andlor their nitrogen free analogues. Generally speaking,
`however, the mortality of inborn errors of the urea-cycle
`remainedhighandsnccesswasmeasuredintermsof
`increased survival time. Time, for example, even with the
`abovocited therapeutic approaches. children with the neo-
`natal form of these diseases rarely survive past one year of
`age (Maestri, et aL, Helena-mt ofPediarrics, Vol 119, No.
`6, 923—928 (1991)).
`DECRIPI'ION 0F RELATED ART
`
`Aurore recent approach to remedy th'n pervasive problem
`is described in 05. Pat. No. 4,284,647 to SaulW. Brusilow,
`wherein benmic aoid,pheny1aoetic acid, or the salts thereof,
`convert the waste nitrogen into amino acid acylation prod-
`ucts which the body can successfully excrete as urinary
`nitrogen. More specifically, the patent teaches that pheny-
`lacetate reacts with the nitrogen to form phenylacetyl-
`ghrtamine which is subsequently exde by the body. Since
`such a reaction is inno way dependent on the urea synthesis
`or excretion, it is an efieetive treatment for those sufliering
`from nitrogen accrmulation diseases. See also "Treatment of
`Inbnrn Errors of Urea Synthesis,” New England Jamaal of
`Medicine, 306; 1387—1392 (1982).
`
`10
`
`15
`
`35
`
`SI]
`
`55
`
`55
`
`2
`US. Pat. No. 4,457,942, also to Saul W. Brusilow, dis-
`closes that even-numbered phenylalkanoic acids can be
`advantageously used for the treatment of nitrogen accumu-
`lation diseases.
`When administered to humans, even numbered phenyla-
`llranoic acids, such as phenylbutyrate, can be broken down
`by betaoxidation, two carbon atoms at a time, to eventually
`yield phenylaoetate which, as described above, hm been
`ticund useful] for removing waste nitrogen born the blood
`stream. The administration of even numbered phenylal-
`kancic acids such as phenylbutyrate has the advantage that
`the higher molecular weight compounds do not have the
`offensive odor which phenylbutyrate has.
`"fine above treatments, although efective, have a substan-
`tial disadvantage. The dose of sodium phenylbutyrate for an
`adultwilhaureacycledisorderismgramslda.1'his
`requires that the patient take forty (40) tablets of 0. grams
`each, per day. Problem of patient compliance arise when
`such large daily doses are required. The administration of
`sodium phenylbutynte has a second disadvantage to many
`patients—patients who should restrict their daily dose of
`sadium. The above daily dose of sodium phenylbutyrale
`provides 2.5 gm of sodium per day, every day (it is recom-
`mended that adults consume less than 2.4 gramslday total
`sodium).
`The substitution in therapy of phenylacetate or
`phenylb‘utyrate, by the compounds of the present invention,
`provides the therapeutic compound in a more convenient
`dosage form. In addition, the compounds of the present
`invention may eliminate the peaks and valleys in drug levels
`since the breakdown of these higher molecular Weight
`on
`by beta-oxidation is a gradual process.
`In
`addition, the Na component of the prior art is replaced with
`gyeerol, which is a normal product of metabolinn.
`Phenylbutyrate and phenylacetate are being investigated
`as a treatment for various malignant diseases. The exact
`mechanism by which this therapy causes improvement in the
`patient is not entirely clear:
`It has been observed that primary central nervous system
`tumors ate reminiscent of immature brain, and the immature
`brain
`known to be more vulnerable to damage by pheny-
`lacetate than the mature brain (as is observed in
`phenylketonnria). Sodium phenylscetate appears to promote
`the difierentiation of cultured human glioblsstoma cell lines
`with reduced expression of malignant phenotype.
`Systemic treatment of rats bearing inuacranial gliomas
`with phenylacetate resulted in significant tumor suppression
`with no apparent toxicity to the host. Early clinical results
`suggest that phenylaoetate may become an important tool in
`the management of certain tumms in light of its demon-
`strated efficacy, and lack of toxicity (Samid et al., Comer
`Research, 54, 891—895, 1994, and Cinatl et al., Cancer
`Letters, 70, 15-24, 1993).
`A similar theory may be applied in treating prostate
`cancer with phenylaeetate. The phenylacetaje is thought to
`act as a difierentiation inducer of leukemic and other lees
`difierentiated mmor cells, such as hormone refractory pros-
`tate cancer.
`Cultured cells of androgen dependent prostate cell lines
`with sodium phenylacetste show inhibition of cell prolifera-
`tion. In addition, such cells show reversion to non-malignant
`phenotype by in vivo and in vitro assessments (Samid et al.,
`{3353mm of Clarion! Investigation, “31. 19, 2288—2295,
`Phenylacetate may exert an anti-tumor aflect by another
`mechanism. Glutamine is the major nitrogen source fior
`nucleic acid and protein synthesis, and substrate for energy
`in rapidly dividing normal and tumor cells. Compared to
`normal tissue, most tumors, due to decreased synthesis of
`
`
`
`Copy provided by USFTO from the Pitts Image Database on 03.91.2015
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 3 of6
`
`

`

`5,968,979
`
`4
`DESCRIPTION OF THE PREFERRED
`EMBODMEN'IS
`The present invention utilizes compounds of the formula:
`
`I
`H— (ii—o—nl
`H—f—O—Rg
`H—C—D—R;
`[:1
`
`wherein R1, Rg, and R3 are independently, H.
`
`0
`
`0 I
`
`I
`
`w —il=—C.Hm—cag—©I
`
`andnisnerooranevennumher,misanevennumberand
`at least one of Raul? and R3 is not H.
`T'hemost
`refe
`oompoundsarethosewhereinnone of
`R1, R3 and
`is H. The advantage over the prior art of
`decreased
`isgreaterwithsuch ' ycertdes.
`The present invention also utilims e
`l esters of the
`fiormula I]
`
`(11)
`
`Giro—L34
`
`wherein R, is
`
`or
`w
`
`and n is zero or an even number, and m is an even number.
`The compounch ofthe invention include compounds with
`substituents of even numbered
`coats of henylalltanoic
`and p4henylalkenoic acids. Prefer
`ly the
`con-
`,
`or
`.
`bairé 4 or ffiewer carbon atoms. Most preferably, 11 and to. are
`The compounds of the
`resent invention can be used
`separately or in the form 0 mixtures. The amount of the
`compounds ofthepresent invention which is administered to
`patients hat- the present purposes can vary widel
`from case
`to case. News 1! however, the
`e
`the com-
`ponndsshouldfaflinther
`o£4 Oto
`mfipbody
`children, afodmefrom .9 to is gramst’or
`ts. TE:
`sine
`frequency 0
`dosages
`ven at any time may
`variedasdescribedprovidedthe
`totaldail doesis
`not significantly modified. Preferably the compo
`of the
`invention are administered orally, although in some
`circumstances, administration may be other routes such as
`topically or parenterally.
`Metabolic Fates of the Compounds of the Invention
`Pancrech ‘ use is able to hydrolyse the triglyceride
`compounds cglpthe invention to produce glycerol and phe-
`
`3
`with accelerated utiliution and catsholism,
`glutamine
`operate at limiting levels of glutamine availability and
`consequently are sensitive to further glutamine depletion. In
`the body, phenylacetate conjugates with glutamine, With
`subsequent renal excretion of phenylaoerylglutamlne. This
`pathway is the reason that phenylacetate administration is
`useful in the treatment of nitrogen accumulation diseases.
`Because phenylaoetate removes glutamine, administration
`of phenylacetate may limit the growth rate of rapidly divid-
`ing cells such as tumor cells.
`nylacetate
`By one or more ofthe above mechanisms,
`a. variety of
`causes a decrease in humor characteristics
`tumor cells. Because of its known non-toxicity, phenylac-
`etate is a promising therapeutic agent, either alone or in
`combination with other anti-tumor agents.
`Hemoglobinopathies
`Sodium phenylbutyrate is thought to cause improvement
`in certain B-hemoglobinopatbies because the sodium phe-
`nylbutynte induces the expression of fetal hemoglobin.
`Thus the absent or aberrant [ta-hemoglobin is substituted with
`fetal hemoglobin.
`Numerous agents which induce the expression of fetal
`hemoglobin have been used to treat sickle cell anemia and
`fl-flralassemias Some of the agents which increase the
`production of fetal hemoglobin however, have serious side
`efiectsthatarenotconsistemwithtbeiruse aslongterm
`therapeutic agents. However, sodium phenylacetate and
`sodium phenylhutyrate have been previously used to treat
`nreaeycledisordersandareknowntobeverywelltolerated
`and free of adverse reactions in clinical use. Preliminary
`clinical studies of patients with beta. thalassemia indicate
`that
`treatment with sodium phenylburyrate results in a
`response inmany patients. The response isparticularly good
`in patients with relatively high erythropoletin levels. Thus,
`combimfion therapy of the phenylbutyrate and erythropoi-
`etin may be elfective. Hydroxymea given orally has also
`been shown to increase hemoglobin levels in some thalas-
`semia patients. Clinical studies of thalassemia patient
`treated with a combination of hydroxyurea and sodium
`phenylbutyrate has produced increased hemoglobin levels in
`some patients.
`SMARY OF THE INVENTION
`
`The compounds of the present invention, triglycerides of
`phenylalkanoic acids or phenylalkenoic acids, and ethyl
`esters of phenylalkanoic acids or phenylalloenoic acids,
`provide a more convenient dosam fiorm of drugs for treet-
`rnerrt of nitrogen acmrmulafion disorders, cancer, anemia
`and hemoglobinopathics. The compounds of the invention
`are oilsorsoflfats. Where thepriorartdoeefcranadult
`would have been forty 0.5 g tableyday, the present invention
`provides the same amount of active compound in approxi-
`mately tour (4) teaspoonfuls per day. The dosage form ofthe
`present invention also decreases sodium intake in patients,
`which is advantageous in certain patients, and may also
`provide the active component of the drug, the phenylal-
`kanoic or phenylallnenoic acid, at a more constant level.
`The compounds of the invention may be used for the
`treatment of nitrogen accumulation disorders, portal sys-
`temic encephalopathy. and diseases involving impaired
`hepatic functionAdditionally, the use of triglycerides audio:
`the esten; of the present invention alone or in combination
`with hydroxyucea andJor erythropoietin, may be used forthe
`treatment of beta chain hemoghhimpathiea. The com.
`pounds of the invention are suitable for the treatment for
`various leukemiss and solid tumors.
`
`The compounds of the invention can be produced by
`standard esterification procedures. Additionally, many of the
`compounds of the invention are commercially available.
`
`10
`
`15
`
`35
`
`SD
`
`55
`
`65
`
`ccpy provided by USPTD tram the PIRS lmstae Database on 03mm“
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 4 of6
`
`

`

`S
`nylalkanoic acids or phenylallnenoic acids. The glycerol is
`then metabolized in the usual manner.
`
`6
`2. Acompound of formula I
`
`5,968,979
`
`In their experiments with dogs, Raper and Wagner
`(Biochem Journal 22:188 (1923)) demonstrated that pheny- 5
`lalkanoic acids are oxidized at the beta carbon during
`metabolism to cause cleavage of two carbons at a time.
`Thus, they found that 80% of the phenylbutyrate adminis-
`tered to dogs appeared in the urine as the glycine conjugate
`ofphenylaeetate. Unlike do , man only produces an acety-
`lation product of ghttamine m phenylacetate. Thus, when 1”
`phenylbutyrate is administered to a human as either a fatty
`acid or a salt thereof, the phenylaeetate formed as a result of
`beta oxidation will aoetylate the glutamine thus causing the
`formation of phenylacetylglutamine which will be excreted
`by the kidney. The beta oxidation process ‘n not limited to 15
`phenylbutyrate. In fact, any even numbered phenylalkanoate
`can he metabolized to phenylacetate. Thus phenylhexanoate,
`phenyloctanoate and phenyldecanoate are also eflecflve to
`control waste nitrogen levels.
`Unsaturated fatty acids are oxidised by the same general 20
`pathway as saturated fatty acids. Tm additional enzymes
`may be used, one which can reversibly shift the double bond
`fiomcismmmmnfigmafiomandonewhichhydratesthe
`double bond to form hydroxy fatty acids. The compounds
`are then substrates for the beta oxidation enzymes.
`The ethyl esters of formula II are thought to be metabo-
`lined by spontaan degradation in the intestine.
`It
`is anticipated that the toxicity of triglycerides of
`phmylbutyrate and other compounrk of this invention to so
`patients would be low when these compounds are adminis-
`tered to patients because the fate of such compounds is
`phenylbutyrate which is beta oxidized to form phenylac~
`etate. Glycerol is also produced, but it is a normal body
`constituent which is either converted to glucose or oxidized. 35
`For the ethyl esters, ethanol is produced, but in such small
`quantities as to be non-harmful. The phenylacetate meta-
`boflcpmducuontheotherhand, hasnoltnowntoxicityand
`is approved for investigations] use in humans (IND #17123).
`We claim:
`1. Amethod of treating a nitrogen metabolism disorder in
`a patient in need of such treatment, comprising administer—
`ingtosaidpatientanelfectiveamountofacompoundof
`
`40
`
`25
`
`‘0
`
`H
`I
`u—cmo—g,
`
`H‘“°"‘°_R¢
`H_é_o_h
`I
`a
`
`wherein R1, R2, and R3 are independently
`
`E
`_c_(cm_cur. cam.
`0
`||
`“ —C-C"H""“_ai’—%
`
`andnandmareaneven numberfromZto24.
`I
`.
`,
`,
`_
`3- A 13133111130“qu Wm“ commas (a) a 9091'
`pound f formula I
`o
`
`(0
`
`H
`I
`H_‘f_°—R'
`H_C_O_Ra
`
`H—c—o—n,
`I
`H
`
`wherein R1, R2, and R3 are independently H,
`
`till
`_
`_
`_ _
`Comm” C“: an"
`
`Iii
`H—c—o—nr
`I
`[I—T—OHRQ
`H_.c._o_R3
`ill
`
`wherein R1, R2 and R3 are independently H,
`
`m 45
`
`or HC—Caflm—Gh—(‘efls
`
`and u is zero or an even number from 2—24, m is an even
`number from 2—24, wherein at least one of R1, R2, and R43
`50 is not H, and (b) a component selected from the group
`comisting of hydroxyurea and erythropoietin.
`4. A pharmaceutical composition suitable tor the treat-
`ment of nitrogen metabolism disorders,
`55 B—hemoglobinopathies, anemia or cancer comprising a com-
`pound of formula I
`
`o
`II
`_C‘—(CHa)a—CHB—CeHsr
`o
`II
`or —-c-—-C,.HM--C'E1-C5H§,
`
`w
`
`niszerocranevennumberhomZ-ztlandmisaneven as
`number from 2—24, pmlded' that at least one ole, R2 and
`R, is other than H.
`
`(D
`
`B
`l
`H—tfh-O—RJ
`n—tiz—o—n,
`H—C—o—'Rg
`1!:
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`i‘h—c———%_~___~——aagg of6
`opy provided by uspro tram the PIRS Image Database on oemtzme
`
`
`
`
`
`

`

`7
`wherein R1, R2, and R3 are independeolly
`
`8
`R3 is a compound of the formula
`
`5,968,979
`
`5
`
`i
`—C_CnHm—Gh—C6Hs
`
`and a pharmaceuticaily acceptable excipient.
`7. A compound of the formula I
`
`l’
`—C—(Cfiz)n_CHa"'CeHa.
`
`I
`or —C_C1aH2n-l— (112-th
`
`0 I
`
`niamerooranevennumbcrfromz—n,andm‘maneven 10
`number from 2—24 and a pharmaceutically acceptable
`excipient.
`5. A pharmaceutical compoaition suitable for the treat-
`311:3]: olff nitg'ogen
`nneatnajbcliam diaordelit-lsi
`-
`mopa 1:8, mm cancer compnsmg e y
`esterso the bmulall
`
`15
`
`gig—O—L
`
`(m
`
`‘1)
`
`III
`_ _ _
`H (I: o R’
`_ _ _.
`H (I:
`O
`Ra
`H—C—o—Rg
`
`H
`
`9” wherein R1, R7, and R, are independently 1-1,
`
`wherein R4 is Cflllfihz—CHg—CGH, and m is an even
`number from 2—24, together with at least one pharmaceuli-
`cally acceptable excipient.
`IS. A pharmaceutical composition suitable for the treat-
`ment of nitrogen metabolism disorders,
`fl-hemoghbinopelhies, anemia orcancer comprising a com-
`pound of fiormula I
`
`25
`
`0
`II
`_C—(CEPJI—cn3—Cfifib
`11'
`_ _
`_ _
`C W as m
`
`or
`
`H
`H—c|:-—-o—k
`I
`1
`E—(IJ—O—R,
`H—(IE—O—Rg
`H
`
`whueinR1,R2,andR,awindependenflyH,
`
`_ _ _
`(m can cal-13'
`
`0
`__!£_
`
`°'
`
`_
`__
`m“ “H3 m"
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`30 andniszeroor an evennumberfromZ—‘M, andmiaaneven
`mnnher from 2—24; with the provisos that at least one of R1,
`Ramdksianotl-Landtliatwhennis00r2,thenoneof
`R1. R2: and R5 is a compound of the fiomula
`
`35
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`—C—Cnfla..:—Gh—Cafls.
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`{LThe compoundofclaim 7,whereinniao,2,4,or6,and
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`H
`.
`9. A phat-mammal compoaanon autable for the treat-
`ment of nitrogen metabolism disorders,
`fl-hennglohinopathies, anemia or cancer, compr‘ning the
`compound of claim 7, and a pharmaceutiwa acceptable
`45 excipient.
`10.1hecompoeitionofc1aim9,whereinniao,2,4,or6,
`and m is 2, 4, or 6.
`
`nisurooranevennumberfromzrzti, andmisaneven
`numberfirom2—24,providedthatatleastoneofR1,R2,and
`
`t
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`t
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` 5
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`\—__._.——_————-+———————___—._._—__—__.—Bage_6 of 6
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