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`DOALL,TOWHOMTHESE: PRESENDS; SHAT, COME:
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`
`March 4), 2016
`
`THIS IS TO CERTIFY THAT ANNEXED HERETOIS A TRUE COPY FROM
`THE RECORDSOF THIS OFFICE OF:
`
`
`
`Certifying Officer
`
`By Authority of the
`att
`UnderSecretary of Commercefor Intellectual Property
`and Director of the United States Patent and Trademark Office |77)
`
`U.S. PATENT: 5,968,979 ©
`ISSUE DATE: October 19, 1999
`
`Cundrad Bunce
`
`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 of 6
`
`

`

`United States Patent
`Brusilow
`
`115
`
`[54] TRIGLYCERIDES AND ETHYL ESTERS OF
`PHENYLALKANOIC ACID AND
`PHENYLALKENOIC ACID USEFUL IN
`TREATMENT OF VARIOUS DISORDERS
`
`[75]
`
`Inventor: Saul W. Brusilow, Baltimore, Md.
`
`[73] Assignee: Brusilow Enterprises LLC, Baltimore,
`Md.
`
`[21] Appl. No.: 09/006,432
`[22]
`Filed:
`Jan. 13, 1998
`
`Related U.S. Application Data
`
`[63] Continuation of application No. 08/384,935, Feb. 7, 1995,
`abandoned.
`
`AOIN 37/10; A61K 31/235
`Int. CL...
`(51)
`(52) US. Ch cccsccssens SL4533; 514/532; 514/547;
`514/549; 514/552; 514/558; 514/814; 514/815;
`514/885; 554/227; 554/220; 554/218; 554/219;
`560/8; 560/76
`‘oration S422, 220,
`[58] Field of Search
`554/218, 219; 560/8, 76; 514/532, 547,
`549, 552, 558, 814, 815, 885
`
`[56]
`
`References Cited
`FOREIGN PATENT DOCUMENTS
`
`94-22494 10/1994 WIPO —...—21eecenenes AGIK 49/02
`OTHER PUBLICATIONS
`
`Georges Darzenset al.: “Préparation de quelques glycérides
`phénylaliphatiques et
`leur
`réduction en alcools .
`.
`.”,
`Comptes Rendus Hebdomadaires Des Seances De
`T’academie Des Sciences., vol. 205, Oct. 18, 1937, pp.
`682-684,
`Walshet al., Chemical Abstract vol. 112, No. 231744.
`Chemical Abstract, vol. 116, No. 46308, Seiki et al,
`“Homogenous Pharmaceutical Emulsions Containing Non-
`steriodal Analogesics and Inflammation Inhibitors”.
`
`US005968979A
`
`[11] Patent Number:
`
`[45] Date of Patent:
`
`5,968,979
`Oct. 19, 1999
`
`Walshet al., The Journal of Biological Chemistry, vol. 265,
`No.8, pp. 4374-4381 (1990), sn—1,2-Diacylgylcerol Kinase
`of Escherichia coli.
`
`Newmarket al., “Butyrate and Phenylacetate as Differenti-
`ating Agents: Practical Problems and Opportunities”, Jour.
`of Cell. Biochem., Supplement 22: 247-253(1995).
`Chen et al., “Tributyrin: A Prodrug of Butyric Acid for
`Potential Clinical Applicaita in Differentiation Therapy”,
`Cancer Res., 54:3494-3499(1994),
`Lea et al., “Butyramide and Monobutyrin: Growth Inhibi-
`tory and Differentiating Agents”, Anticancer Res., 13:
`145-150 (1993).
`Acdémie Des Sciences., Chimie Organique, “Préparation de
`quelques glycérides phénylaliphatiques et leur réduction en
`alcools ...”, pp. 682-684.
`j
`
`Brusilow et al., Metabolism, vol. 42, No. 10 Oct., 1993, pp.
`1336-1339, “Restoration of Nitrogen Homeostasis in a Man
`with Ornithine Transcarbamylase Deficiency”.
`
`Maestri et al., “Prospective treatment of urea cycle disor-
`ders”, pp. 923-928,
`
`Primary Examiner—Gary Geist
`Assistant Examiner—Deborah D Carr
`Attorney, Agent, or Firm—Nikaido Marmelstein Murray &
`Oram LLP
`
`[57]
`
`ABSTRACT
`
`Two new forms of prodrug for phenylacetate, of even
`congeners of phenylalkanoic acid and phenylalkenoic acids,
`which are the phenylalkanoic or phenylalkenoic esters of
`glycerol, or the ethyl esters of phenylalkanoic acid or
`phenylalkenoic acids. These forms of the drugs provide a
`convenient dosage form of the drugs. The prodrugs of the
`invention are useful to treat patients with diseases of nitro-
`gen
`accumulation, patients with certain
`f-hemoglobinopathies, anemia, and cancer.
`
`10 Claims, No Drawings
`
`
`
`Copy provided by USPTO from the PIRS Image Database on 03/21/2016
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 2 of 6
`
`

`

`5,968,979
`
`1
`TRIGLYCERIDESAND ETHYL ESTERS OF
`PHENYLALKANOIC ACID AND
`PHENYLALKENOIC ACID USEFUL IN
`TREATMENT OF VARIOUS DISORDERS
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`
`This application is a continuation of Ser. No. 08/384,935,
`filed Feb. 7, 1995, now abandoned.
`BACKGROUNDOF THE INVENTION
`
`10
`
`The presentinvention relates to compounds, pharmaceu-
`tical compositions, and methods for treating several condi-
`tions with prodrugs for phenylacetate as therapeutic agents.
`FIELD OF THE INVENTION
`
`Phenylalkanoic acids are known therapeutic agents for a
`variety of disorders. Phenylacetate is used for the treatment
`of nitrogen metabolism disorders, beta-hemoglobinopathies,
`anemia and cancer. Various phenylalkenoic acids can be
`used in the treatment of the same disorders. The prodrugs
`disclosed in the present invention are useful
`therapeutic
`agents for a number of disorders, and possess some advan-
`tages over the forms of the drugs administered in the prior
`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 suffer 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 mor-
`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, variousnitrog-
`enous metabolites accumulate in the body, the most toxic
`being ammonium, although other materials, such as
`glutamine and alanine also increase.
`Previous therapeutic approaches fortreating patients with
`urea cycle enzymopathies (as well as other nitrogen accu-
`mulation diseases cited earlier) have been designed to
`reduce the requirement for urea synthesis by quantitative
`and qualitative manipulation of dietary protein, amino acids
`and/or their nitrogen free analogues. Generally speaking,
`however, the mortality of inborn errors of the urea-cycle
`remained high and success was measured in terms of
`increased survival time. Thus, for example, even with the
`above-cited therapeutic approaches, children with the neo-
`natal form of these diseases rarely survive past one year of
`age (Maestri, et al., The Journal ofPediatrics, Vol. 119, No.
`6, 923-928 (1991)).
`DESCRIPTION OF RELATED ART
`
`Amore recent approach to remedy this pervasive problem
`is described in U.S, Pat. No. 4,284,647 to Saul W. Brusilow,
`wherein benzoic acid, phenylacetic 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-
`glutamine whichis subsequently excreted by the body. Since
`sucha reaction is in no way dependenton the urea synthesis
`or excretion,it is an effective treatment for those suffering
`from nitrogen accumulation diseases. See also “Treatment of
`Inborn Errors of Urea Synthesis,” New England Journal of
`Medicine, 306; 1387-1392 (1982).
`
`20
`
`25
`
`40
`
`55
`
`65
`
`2
`U.S, 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-
`Ikanoic acids, such as phenylbutyrate, can be broken down
`by betaoxidation, two carbon atoms at a time, to eventually
`yield phenylacetate which, as described above, has been
`found useful for removing waste nitrogen from the blood
`stream. The administration of even numbered phenylal-
`kanoic acids such as phenylbutyrate has the advantage that
`the higher molecular weight compounds do not have the
`offensive odor which phenylbutyrate has.
`The above treatments, although effective, have a substan-
`tial disadvantage. The dose of sodium phenylbutyrate for an
`adult with a urea cycle disorder is 20 grams/day. This
`requires that the patient take forty (40) tablets of 0.5 grams
`each, per day. Problems of patient compliance arise when
`such large daily doses are required. The administration of
`sodium phenylbutyrate has a second disadvantage to many
`patients—patients who should restrict their daily dose of
`sodium. The above daily dose of sodium phenylbutyrate
`provides 2.5 gm of sodium per day, every day (it is recom-
`mended that adults consume less than 2.4 grams/day total
`sodium).
`The substitution in therapy of phenylacetate or
`phenylbutyrate, 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
`compounds by beta-oxidation is a gradual process.
`In
`addition, the Na componentofthe priorart is replaced with
`glycerol, which is a normal product of metabolism.
`Cancer
`Phenylbutyrate and phenylacetate are being investigated
`as a treatment for various malignant diseases. The exact
`mechanism by whichthis therapy causes improvementin the
`patient is not entirely clear.
`It has been observed that primary central nervous system
`tumors are reminiscent of immature brain, and the immature
`brain is known to be more vulnerable to damage by pheny-
`lacetate than the mature brain (as is observed in
`phenylketonuria). Sodium phenylacetate appears to promote
`the differentiation of cultured humanglioblastoma cell lines
`with reduced expression of malignant phenotype.
`Systemic treatment of rats bearing intracranial gliomas
`with phenylacetate resulted in significant tumor suppression
`with no apparent toxicity to the host. Early clinical results
`suggest that phenylacetate may become an importanttool in
`the management of certain tumors in light of its demon-
`strated efficacy, and lack of toxicity (Samid et al., Cancer
`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 phenylacetate. The phenylacetate is thought to
`act as a differentiation inducer of leukemic and other less
`differentiated tumorcells, such as hormonerefractory pros-
`tate cancer.
`Cultured cells of androgen dependent prostate cell lines
`with sodium phenylacetate show inhibition ofcell prolifera-
`tion. In addition, such cells show reversion to non-malignant
`phenotype byin vivo andin vitro assessments (Samid etal.,
`The Journal of Clinical Investigation, Vol. 19, 2288-2295,
`1993).
`Phenylacetate may exert an anti-tumor affect by another
`mechanism. Glutamine is the major nitrogen source for
`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 USPTO from the PIRS Image Database on 03/21/2016
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 3 of 6
`
`

`

`3
`glutamine along with accelerated utilization and catabolism,
`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 phenylacetylglutamine. This
`pathway is the reason that phenylacetate administration is
`useful in the treatment of nitrogen accumulation diseases.
`Because phenylacetate removes glutamine, administration
`of phenylacetate may limit the growth rate of rapidly divid-
`ing cells such as tumor cells.
`By one or more of the above mechanisms, phenylacetate
`causes a decrease in tumor characteristics of a variety of
`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-hemoglobinopathies because the sodium phe-
`nylbutyrate induces the expression of fetal hemoglobin.
`‘Thus the absent or aberrant §-hemoglobinis substituted with
`fetal hemoglobin.
`Numerous agents which induce the expression of fetal
`hemoglobin have been used to treat sickle cell anemia and
`B-thalassemias. Some of the agents which increase the
`production of fetal hemoglobin however, have serious side
`effects that are not consistent with their use as long term
`and n is zero or an even number, m is an even number and
`therapeutic agents. However, sodium phenylacetate and
`at least one of R,, R,, and R, is not H.
`sodium phenylbutyrate have been previously used to treat
`The mostpreferred compounds are those wherein none of
`urea cycle disorders and are knownto be very well tolerated
`R,, R, andR,is H. The advantage over the prior art of
`decreased dosage is greater with such triglycerides.
`and free of adverse reactions in clinical use. Preliminary
`The present invention also utilizes ethyl esters of the
`clinical studies of patients with beta thalassemia indicate
`formula II
`that
`treatment with sodium phenylbutyrate results in a
`response in many patients. The response is particularly
`in patients with relatively high erythropoietin levels. Thus,
`combination therapy of the phenylbutyrate and erythropoi-
`etin may be effective. Hydroxyurea givenorally has also
`been shown to increase hemoglobin levels in some thalas-
`semia patients. Clinical studies of thalassemia patients
`treated with a combination of hydroxyurea and sodium
`phenylbutyrate has produced increased hemoglobin levels in
`some patients.
`SUMMARY OF THE INVENTION
`
`5,968,979
`
`4
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`The present invention utilizes compoundsof the formula:
`H
`peedGare
`H—C—o—R,
`
`H—C—0—R;
`H
`
`15
`
`wherein R,, R,, and R, are independently, H,
`Qo
`—
`
`Eee gS
`
`°o
`ll
`or ——C— CyHon.2— CH,
`
`'
`
`C,Hs—O—C—R,
`
`i
`
`ty
`
`wherein R, is
`
`eof) -
`—ons-ar()
`
`The compoundsof the present invention, triglycerides of
`phenylalkanoic acids or phenylalkenoic acids, and ethyl
`esters of phenylalkanoic acids or phenylalkenoic acids,
`provide a more convenient dosage form of drugs for treat-
`ment of nitrogen accumulation disorders, cancer, anemia
`and hemoglobinopathies. The compounds of the invention
`and n is zero or an even number, and m is an even number.
`are oils or soft fats. Where the prior art dose for an adult
`The compounds ofthe invention inchide compounds with
`would have been forty 0.5 g tables/day, the present invention
`substituents of even numbered congeners of phenylalkanoic
`provides the same amount of active compound in approxi-
`and
`phenylalkenoic acids. Preferably the substituents con-
`mately four (4) teaspoonfuls per day. The dosage form of the
`
`
`, 2,4or 6.
`present invention also decreases sodium intake in patients,
`which is advantageous in certain patients, and may also
`The compounds of the present invention can be used
`separately or in the form of mixtures. The amountof the
`provide the active component of the drug, the phenylal-
`compounds ofthe present invention which is administered to
`kanoic or phenylalkenoic acid, at a more constant level.
`patients for the
`present purposes can vary widely from case
`The compounds of the invention may be used for the
`to case. Normally, however, the daily dosage for the com-
`treatment of nitrogen accumulation disorders, portal sys-
`pounds should fall in the r:
`of 450 to
`mg/kg body
`temic encephalopathy, and diseases involving impaired
`weight for children, and from 9,9 to 13 grams for adults. The
`hepatic function. Additionally, the use of triglycerides and/or
`size and frequency ofthe dosages given at any time may be
`the esters of the present invention alone or in combination
`varied as described provided the indicated total daily does is
`with hydroxyurea and/or erythropoietin, may be used for the
`not significantly modified. Preferably the compounds ofthe
`invention are administered orally, although in some
`treatment of beta chain hemoglobinopathies. The com-
`circumstances, administration may be other routes such as
`pounds of the invention are suitable for the treatment for
`various leukemias and solid tumors.
`topically or parenterally.
`Metabolic Fates of the Compounds of the Invention
`Pancreatic lipase is able to hydrolyse the triglyceride
`compounds of the invention to produce glycerol and phe-
`
`ro4 or oecarbon atoms. Mostpreferably, n and m are
`
`60
`
`The compounds of the invention can be produced by
`standard esterification procedures. Additionally, many of the
`compounds of the invention are commercially available.
`
`Copy provided by USPTO from the PIRS Imaae Dalabase on 03/21/2016
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 4 of 6
`
`

`

`5
`nylalkanoic acids or phenylalkenoic acids. The glycerol is
`then metabolized in the usual manner.
`
`6
`2. Acompound of formula I
`
`5,968,979
`
`@
`
`H
`
`H—c—o—R,
`
`H—C—o—R,
`
`H—c—o—R,
`H
`
`wherein R,, R,, and R, are independently
`
`1
`—c— (cH), —cie—
`Pa srs
`i
`or ——C— C35.— CH2— CeHs,
`
`25
`
`30
`
`3. A pharmaceutical composition comprising (a) a com-
`pound of formula I
`
`0
`
`H—C—o—R,
`
`H—-C—O—R,
`
`H-—-c-—-0O-k,
`
`
`
`In their experiments with dogs, Raper and Wagner
`(Biochem Journal 22:188 (1928)) demonstrated that pheny-
`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
`of phenylacetate. Unlike dogs, man only produces an acety-
`lation product of glutamine from phenylacetate. Thus, when
`phenylbutyrate is administered to a human as either a fatty
`acid or a salt thereof, the phenylacetate formed as a result of
`beta oxidation will acetylate the glutamine thus causing the
`formation of phenylacetylglutamine which will be excreted
`by the kidney. The beta oxidation process is not limited to
`phenylbutyrate. In fact, any even numbered phenylalkanoate
`can be metabolized to phenylacetate. Thus phenylhexanoate,
`phenyloctanoate and phenyldecanoate are also effective to
`control waste nitrogen levels.
`Unsaturated fatty acids are oxidized by the same general
`pathway as saturated fatty acids. Two additional enzymes
`may be used, one which can reversibly shift the double bond
`and n and m are an even numberfrom2to 24.
`from cis to trans configurations, and one which hydrates the
`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-
`lized by spontaneous degradation in the intestine.
`It
`is anticipated that the toxicity of tri-glycerides of
`phenylbutyrate and other compounds of this invention to
`patients would be low when these compoundsare 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.
`For the ethyl esters, ethanol is produced, but in such small
`quantities as to be non-harmful. The phenylacetate meta-
`bolic product, on the other hand, has no known toxicity and
`is approved for investigational use in humans (IND #17123).
`We claim:
`1. Amethod oftreating a nitrogen metabolism disorder in
`a patient in need of such treatment, comprising administer-
`ing to said patient an effective amount of a compound of
`formula (I)
`
`wherein R,, R2, and R, are independently H,
`
`o I
`
`— C— (CHa), — CHa— Cells,
`Oo
`I
`or —~C— CyBon.3— CH) CoH,
`
`45
`
`@
`
`and n is zero or an even number from 2—24, m is an even
`number from 2~24, wherein at least one of R,, R,, and R,
`50 is not H, and (b) a component selected from the group
`consisting of hydroxyurea and erythropoietin.
`
`4. A pharmaceutical composition suitable for the treat-
`ment of nitrogen metabolism disorders,
`ss B-hemoglobinopathies, anemia or cancer comprising a com-
`poundof formula I
`
`a
`
`65
`
`©
`
`H
`|
`aTO—R,
`H—C—O—R,
`H—C—o—R,
`
`|
`H—C—o—R,
`| ro
`=a =
`H—C—O—R,
`
`|H
`
`wherein R,, R, and R, are independently H,
`
`—C— (CH),—CH—CHis,
`oO
`ll
`or ——C—CyHom.2—- CH2— CeHs,
`
`n is zero or an even number from 2-24 and m is an even
`number from 2-24, providedthat at least one of R,, R, and
`R, is other than H.
`
`|
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`niedbyUSPTOFSrage5of 6
`BE
`‘opy provided by USPTOfrom the PIRS Image Database on 03/21/2016
`
`

`

`7
`wherein R,, R;, and R, are independently
`
`8
`R, is a compound of the formula
`
`5,968,979
`
`5
`
`i
`—C— CaHin-2— CHa — Cells,
`
`and a pharmaceutically acceptable excipient.
`7. Acompound of the formula I
`
`—C— (CH), — CHa— Cols,
`
`° |
`
`of —~C— CyHom-2 — CHa Ces,
`
`n is zero or an even number from 2~24, and m is an even i
`number from 2-24 and a pharmaceutically acceptable
`excipient.
`3. A pharmaceutical composition suitable for the treat-
`ment
`of nitrogen metabolism disorders,
`§-hemoglobinopathies, anemia and cancer comprising ethyl
`esters of the formula II
`
`15
`
`©
`
`a
`H—C—o—R,
`
`H—C—o—R,
`
`H—C—o—R;
`
`oe
`
`ap
`
`i
`
`wherein R, is C,,H>,,2—CH,—C,H, and m is an even
`number from 2-24, together with at least one pharmaceuti-
`cally acceptable excipient.
`6. A pharmaceutical composition suitable for the treat-
`ment of nitrogen metabolism disorders,
`B-hemoglobinopathies, anemia or cancer comprising a com-
`pound of formula I
`
`20
`
`as
`
`wherein R,, R,, and R, are independently H,
`
`ll
`oO(Cia) = CHa=Cols,
`°
`I
`or = C= CaHam.2 —~ CHa CoH,
`
`H
`H—c—o—R,
`H—Cc—0—R,
`raiwee
`H
`
`©
`
`3g and nis zero or an even numberfrom 2-24, and mis aneven
`number from 2-24, with the provisosthatat least one of R,,
`R,, and R, is not H, and that when n is 0 or 2, then one of
`R,, R,, and R, is a compoundof the formula
`°
`— C—CaHoq-2—CHg—CoH,
`
`as
`
`8. The compound ofclaim 7, whereinnis 0, 2,4, or 6, and
`wherein R,, R,, and R, are independently H,
`40 m is 2, 4, or 6.
`9. A pharmaceutical composition suitable for the treat-
`ment of nitrogen metabolism disorders,
`B-hemoglobinopathies, anemia or cancer, comprising the
`compound of claim 7, and a pharmaceutically acceptable
`oO
`45 excipient.
`I
`2 = 2ee 10. The composition of claim 9, whereinnis 0, 2, 4, or 6,
`and m is 2,4, or 6,
`
`= a
`eS
`
`n is zero or an even number from 2-24, and m is an even
`number from 2-24,provided that at least one of R,, R, and
`
`*
`
`*¢
`
`#
`
`oe
`
`#
`
`Par Pharmaceutical, Inc. Ex. 1019
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
` ——e—ee—E——FRage6of 6
`|
`Copy provided by USPTOfrom the PIRS Image Database on 03/21/2016
`
`