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`FIG.1
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`CONTROL GROUP
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`-66%
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`EPA GROUP
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`Hazard ratio : 0.45 (0.26-0.77)
`P=0.004 (adjusted)
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`1
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`2
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`3
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`4
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`5
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`FOLLOW-UP PERIOD (YEAR)
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`FIG.2
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`CONTROL GROUP
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`-53%
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`EPA GROUP
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`Hazard ratio : 0.47 (0.23-0.98)
`P=0.043 (adjusted)
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`1
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`2
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`3
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`4
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`5
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`FOLLOW-UP PERIOD (YEAR)
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`5.0
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`4.0
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`3.0
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`2.0
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`1.0
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`0
`0
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`5.0
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`4.0
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`3.0
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`2.0
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`1.0
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`0
`0
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`INCIDENCE (%) OF CORONARY EVENTS
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`INCIDENCE (%) OF CORONARY EVENTS
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`EP62825KG900aha
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`28.11.08
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`PCT/JP2007/061099
`Mochida Pharmaceutical Co., Ltd.
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`Translation of International Application
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`DESCRIPTION
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`Composition for Preventing the Occurrence of Cardiovascular
`
`Events in Multiple Risk Patients
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`TECHNICAL FIELD
`
`[0001)
`
`This invention is a composition for preventing the
`
`occurrence of cardiovascular events (primary prevention) in
`
`multiple risk patients, the composition containing at least
`
`ethyl icosapentate (hereinafter abbreviated as EPA-E).
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`BACKGROUND
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`[0002)
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`The Westernization of diets has resulted in an increase
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`in patients suffering from lifestyle-related diseases such as
`
`diabetes, hyperlipidemia, and hypertension. Some of these
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`diseases ultimately lead to arteriosclerotic diseases such as
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`myocardial infarction, angina pectoris, and cerebral
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`infarction. Treatment of lifestyle-related diseases is based
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`on lifestyle improvement and, more specifically, on alimentary
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`therapy and kinesitherapy. However, such improvements in
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`dietary lifestyles or a lack of exercise are often difficult
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`for patients suffering from "lifestyle-related diseases," and
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`ICOSAPENT DFNDTS00007061
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`they usually transition to pharmacotherapy to prevent poor
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`prognosis, for example, the onset of myocardial infarction or
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`cerebral infarction.
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`An exemplary compound having the action of improving
`
`such lifestyle-related diseases is polyunsaturated fatty
`
`acid. Polyunsaturated fatty acid is defined as a fatty
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`acid including two or more carbon-carbon double bonds in
`
`one molecule, and polyunsaturated fatty acids are
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`categorized by the position of the double bond into ω−3
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`fatty acid, ω−6 fatty acid, and the like. ω−3
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`polyunsaturated fatty acids include linolenic acid,
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`Eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).
`
`ω−6 polyunsaturated fatty acids include linoleic acid, y-
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`linolenic acid, and arachidonic acid. Polyunsaturated fatty
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`acids are derived from natural products, and exhibit various
`
`actions including antiarteriosclerotic action, platelet
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`aggregation inhibitory action, hypolipidemic action, anti-
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`inflammatory action, antitumor action, and central action, and
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`due to the high safety, polyunsaturated fatty acids are
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`incorporated in various kinds of food, or sold as a health food
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`or drug.
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`[0003]
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`A decrease in the death rate in patients who have a
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`history of suffering from myocardial infarction has been
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`reported for the administration of a mixture of ethyl ester of
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`an ω−3 polyunsaturated fatty acid EPA (EPA-El and ethyl ester
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`of an ω−3 polyunsaturated fatty acid DHA (DHA-E) for 3.5 years
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`(see Patent Document 1). However, the results disclosed in
`
`Patent Document 1 relate to secondary prevention, that is,
`
`prevention of recurrence, and drugs effective in secondary
`
`prevention are not always effective in primary prevention.
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`Based on the results of animal experiments and small-scale
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`clinical observations, many large-scale clinical trials have
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`been recently planned and conducted for the purpose of
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`confirming whether various drugs that are effective in
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`improving lifestyle-related diseases can also prevent
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`arteriosclerotic diseases in human. The results, however, have
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`not necessarily been as intended, and the situation remains
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`severe in the prevention of the occurrence of cardiovascular
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`events in the case of patients suf1ering from a plurality of
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`risk factors.
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`[0004]
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`
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`High purity EPA-E is commercially available under the
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`brand names Epadel™ and Epadel s™ (manufactured by
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`Machida Pharmaceutical Co., Ltd.) as therapeutic drugs for
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`hyperlipidemia. It has been reported that, when such
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`high purity EPA-E is orally administered at a 600 mg dose,
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`three times a day, immediately after meal (when TG is
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`abnormal, the dose is increased to 900 mg per dose, three
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`times a day), serum T-Cho concentration can be reduced by 3
`
`to 6%, and serum TG can be reduced by 14 to 20% (see Non-
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`Patent Document 1). It has also been reported in The Heart
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`Failure Society of America 2005 Annual Meeting that, based
`
`on such action, such high purity EPA-E was expected to have
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`the effect of improving cardiovascular events in
`
`hyperlipidemia patients, and combined use with HMG-CoA RI
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`was effective in inhibiting cardiac events in a large-scale
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`clinical trial. In this large-scale clinical trial (JELIS,
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`Japan EPA Lipid Intervention Study), statistically
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`significant suppression of the cardiac events by EPA-E was
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`confirmed for the total of the primary prevention patients
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`and secondary prevention patients, and for the secondary
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`prevention patients. On the other hand, in the analysis
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`limited to the primary prevention patients, the incidence of
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`the events was lower in the EPA-E group (the group
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`administered with EPA-E in combination with HMG-CoA RI)
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`compared to the control group (the group administered solely
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`with HMG-CoA RI), while this difference was not
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`statistically significant. This trial also revealed that,
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`five years from the start of the trial, the LDL-cholesterol
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`value was reduced by 26% in both the EPA-E group and control
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`group, that no significant difference was found between
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`these groups, and that the change in the HDL-cholesterol
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`value was slight in both groups (see Non-Patent Document 2).
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`This trial also revealed that the total cholesterol and LDL-
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`cholesterol decreased by 19% and 25%, respectively, in both
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`the EPA-E group and the control group, and that triglyceride
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`decreased by 9% (significant) and 4% in the EPA-E group and
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`the control group, respectively, with little change in HDL-C
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`in both the EPA-E group and the control group (see Non-
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`Patent Document 3). Thus far, no reports have analyzed
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`prevention of the occurrence of cardiovascular events in
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`cases involving patients with two or more risk factors.
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`[0005]
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`Patent Document 1: WO 00/48592 (JP 2002-537252 A)
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`Non-Patent Document 1: Drug Interview Form "EPA
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`preparation, Epadel capsule 300", revised July 2002 and
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`February 2004, version 21 issued in December 2004; pp. 21–
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`22.
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`Non-Patent Document 2: Medical Tribune, November 17, 2005
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`issue, Feature article 3, pp. 75-76.
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`Non-Patent Document 3 : Lancet, vol. 369, pp. 1090–
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`1098 (2007).
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`INVENTION DISCLOSURE
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`PROBLEMS TO BE SOLVED BY THE INVENTION
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`[0006]
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`In light of the serious issue that death from
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`cardiovascular disease remains a major cause of death, and
`
`many cases of cardiovascular events are still impossible to
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`prevent with HMG-CoA RI therapy, the present invention is
`
`intended to provide a composition for preventing t h e onset
`
`of cardiovascular events.
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`
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`MEANS TO SOLVE THE PROBLEM
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`[0007]
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`
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`o solve the problems described above, the inventors of
`
`the present invention conducted an extensive study
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`on a therapy for hypercholesterolemia patients and found
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`that EPA-E has is effective in preventing t h e occurrence of
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`cardiovascular events in patients suffering from multiple
`
`risk factors and, in particular, is effective in preventing
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`the occurrence of cardiovascular events in male patients
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`suffering from multiple risk factors. The present
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`invention has been completed on the bases of such findings.
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`Accordingly, the present invention is directed to the
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`following:
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`IPR2022-00215
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`(1) A composition for preventing t h e occurrence of a
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`cardiovascular event (primary prevention) in a
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`hypercholesterolemia patient, the composition containing at
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`least EPA-E as its effective component wherein the patient
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`also suffers from at least one risk factor selected from
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`the group consisting of
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`(1) obesity,
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`(2) hypertension or prehypertension,
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`(3) diabetes, prediabetes, or abnormal glucose
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`tolerance, and
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`(4) hypertriglyceridemia and/or low HDL
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`cholesterolemia.
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`(2) A composition for preventing t h e occurrence of a
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`cardiovascular event in a hypercholesterolemia patient, the
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`composition containing at least EPA-E as its effective
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`component, wherein the hypercholesterolemia patient is a
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`patient also suffering from two or more of the risk
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`factors.
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`(3) A composition for preventing the occurrence of a
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`cardiovascular event in a hypercholesterolemia patient, the
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`composition containing at least EPA-E as its effective
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`component, wherein the patient also suffers from at least
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`one of the risk factors as defined by a body mass index
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`(BMI) of at least 25 for obesity; by a systolic blood
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`pressure (SBP) of at least 140 mmHg or a diastolic blood
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`pressure (DBP) of at least 90 mmHg for hypertension or
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`prehypertension; by a fasting blood glucose (FBS) of at
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`least 126 mg/dL or a hemoglobin Ale (HbAlc) of at least
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`6.5% for diabetes, prediabetes, or abnormal glucose
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`tolerance; and by triglyceride (TG) of at least 150 mg/dL
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`and/or a HDL-C of less than 40 mg/dL for
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`hypertriglyceridemia and/or low HqL cholesterolemia.
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`(4) The composition according to any one of (1) to (3)
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`above, wherein the content of the EPA-E is at least 96.5%
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`by weight in relation to the total content of fatty acid and
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`derivatives thereof.
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`(5) The composition according to any one of (1) to (4).
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`above, wherein the EPA-E is orally administered at a dose
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`of 1.8 g/day to 2.7 g/day.
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`(6) The composition according to any one of (1) to (5)
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`above, wherein the composition is used in combination with
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`HMG-CoA RI.
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`(7) The composition according to any one of (1) to (6)
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`above, wherein the hypercholesterolemia patient is a male
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`patient.
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`(8) The composition according to any one of (1) to (7)
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`above, wherein the hypercholesterolemia patient is a patient
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`also suffering from hypertriglyceridemia and low HDL
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`cholesterolemia.
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`(9) A method for preventing the occurrence of a
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`cardiovascular event in a hypercholesterolemia patient by
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`administering the patient with the composition according to
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`any one of
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`(1) to (8) above.
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`(10) Use of the composition according to any one of (1) to
`
`(8) above for the manufacture of an agent for preventing the
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`occurrence of a cardiovascular event in a
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`hypercholesterolemia patient.
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`MERITS OF THE INVENTION
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`[0008]
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`The above-mentioned composition of the present
`
`invention containing at least EPA-E as its effective
`
`component is effective in preventing the occurrence of
`
`cardiovascular events in hypercholesterolemia patients, and
`
`in particular, in preventing the occurrence of cardiovascular
`
`events in hypercholesterolemia patients who have been
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`treated with HMG-CoA RI but still suffer from the risk of
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`cardiovascular events, or more particularly, in preventing
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`the occurrence of cardiovascular events in hypercholesterolemia
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`patients also suffering from at least one risk factor selected
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`from the group consisting of
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`(1) obesity,
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`(2) hypertension or prehypertension,
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`(3) diabetes, prediabetes, or abnormal glucose
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`tolerance, and
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`(4) hypertr1glyceridemia and/or low HDL
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`cholesterolemia.
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`The effect of the composition of the present invention
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`will be synergistically improved by combined use with HMG-CoA
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`RI, and such use of the composition of the present invention
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`with HMG-CoA RI has clinical utility since the effect of
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`preventing cardiovascular event occurrence is expected to be
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`improved.
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`BRIEF DESCRIPTION OF THE DRAWINGS
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`(0009)
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` [FIG. 1] FIG. 1 is a graph prepared by plotting the
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`incidence of the cardiovascular events on the Y-axis and the
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`time after the start of the trial on the X-axis for male
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`patients having at least two risk factors.
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`[FIG. 2] FIG. 2 is a graph prepared by plotting the
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`incidence of the cardiovascular event on the Y-axis and the
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`time after the start of the trial on the X-axis for patients
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`having the risk factors of a triglyceride (TG) of at least
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`150 mg/dL and a HDL-C of less than 40 mg/dL.
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`BEST MODE FOR CARRYING OUT THE INVENTION
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`[0010]
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`
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`Next, the present invention is described in detail.
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`The first aspect of the present invention provides a
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`composition for preventing the occurrence of a cardiovascular
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`event (primary prevention) in a hypercholesterolemia
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`patient, the composition containing at least EPA-E as its
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`effective component, wherein the patient also suffers from
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`at least one risk factor selected from the group consisting
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`of
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`(1) obesity,
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`(2) hypertension or prehypertension,
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`(3) diabetes, prediabetes, or abnormal glucose
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`tolerance, and
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`(4) hypertriglyceridemia and/or low HDL
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`cholesterolemia. Alternatively, the first aspect of the
`
`present invention provides a composition for preventing the
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`occurrence of a cardiovascular event (primary prevention)
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`in a hypercholesterolemia patient, the composition
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`containing at least EPA-E and/or DHA E as its effective
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`component, wherein the patient also suffers from at least
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`one risk factor selected from the group consisting of
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`(1) obesity,
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`(2) hypertension or prehypertension,
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`(3) diabetes, prediabetes, or abnormal glucose
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`tolerance, and
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`(4) hypertriglyceridemia and/or low HDL
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`cholesterolemia.
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`The prevention of the occurrence of cardiovascular events
`
`includes all cases of primary prevention, and exemplary cases
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`include prevention of cardiovascular death, fatal myocardial
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`infarction, sudden cardiac death, nonfatal myocardial
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`infarction, cardiovascular angioplasty, new occurrence of rest
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`angina and exercise-induced angina; and destabilization of the
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`angina. The composition of the present invention may be
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`administered to any person who needs prevention of the
`
`occurrence of cardiovascular events, and it is typical that
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`such patients are hypercholesterolemia patients.
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`[0011]
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`
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`A second aspect of the present invention provides a
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`composition for preventing t h e occurrence of a cardiovascular
`
`event in a hypercholesterolemia patient undergoing HMG(cid:173) CoA RI
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`therapy, the composition containing at least EPA-E, wherein the
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`patient also suffers from at least one risk factor selected
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`from the group consisting of
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`(1) obesity,
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`(2) hypertension or prehypertension,
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`(3) diabetes, prediabetes, or abnormal glucose
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`tolerance, and
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`(4) hypertriglyceridemia and/or low HDL
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`cholesterolemia. Alternatively, the second aspect of the
`
`present invention provides a composition for preventing the
`
`occurrence of a cardiovascular event in a
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`hypercholesterolemia patient undergoing HMG-CoA RI
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`therapy, the composition containing at least EPA-E and/or
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`DHA-E, wherein the patient also suffers from at least one
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`risk factor selected from the group consisting of
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`(1) obesity,
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`(2) hypertension or prehypertension,
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`(3) diabetes, prediabetes, or abnormal glucose
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`tolerance, and·
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`(4) hypertriglyceridemia and/or low HDL
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`cholesterolemia.
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`[0012]
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`
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`While HMG-CoA RI includes all those having inhibitory
`
`action for 3-hydroxy-3-methylglutaryl coenzyme A reductase,
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`the one used in the present invention is preferably a
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`pharmaceutically administrable inhibitor which is
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`preferably at least one member selected from the group
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`consisting of pravastatin, simvastatin, lovastatin,
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`fluvastatin, cerivastatin, atorvastatin, pitavastatin,
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`rosuvastatin, and salts and derivatives thereof, and more
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`preferably, pravastatin, l o v a s t a t i n , simvastatin,
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`fluvastatin, atorvastatin, pitavastatin, or rosuvastatin,
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`and most preferably, pravastatin or simvastatin. All salts
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`are included as long as they are pharmaceutically
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`administrable, with sodium and calcium salts such as
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`pravastatin sodium, fluvastatin sodium, cerivastatin
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`sodium, atorvastatin calcium, pitavastatin calcium, and
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`rosuvastatin calcium being preferred. In the present
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`invention, "pravastatin," for example, also includes
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`pravastatin in the form of a salt unless otherwise noted.
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`[0013]
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`A third aspect of the present invention provides a
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`composition for preventing t h e occurrence of a
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`cardiovascular event in a hypercholesterolemia patient, the
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`composition containing at least EPA-E as its effective
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`component, wherein the patient also suffers from at least two
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`risk factors selected from the group consisting of
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`(1) obesity,
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`(2) hypertension or prehypertension,
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`(3) diabetes, prediabetes, or abnormal glucose
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`tolerance, and
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`(4) hypertriglyceridemia and/or low HDL
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`cholesterolemia; namely, obesity, and hypertension or
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`prehypertension; obesity, and diabetes, prediabetes, or
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`abnormal glucose tolerance; obesity, and
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`hypertriglyceridemia and/or low HDL cholesterolemia;
`
`hypertension or prehypertension, and diabetes, prediabetes
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`or abnormal glucose tolerance; hypertension or
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`prehypertension, and hypertriglyceridemia and/or low HDL
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`cholesterolemia; diabetes, prediabetes, or abnormal glucose
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`tolerance, and hypertriglyceridemia and/or low HDL
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`cholesterolemia; obesity, and hypertension or
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`prehypertension, and diabetes, prediabetes, or abnormal
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`glucose tolerance; obesity, and hypertension or
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`prehypertension, and hypertriglyceridemia and/or low HOL
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`cholesterolemia; obesity, and diabetes, prediabetes, or
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`abnormal glucose tolerance, and hypertriglyceridemia and/or
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`low HDL cholesterolemia; hypertension or prehypertension,
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`and diabetes, prediabetes, or abnormal glucose tolerance,
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`and hypertriglyceridemia and/or low HDL cholesterolemia;
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`obesity, and hypertension or prehypertension, and diabetes,
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`prediabetes, or abnormal glucose tolerance, and
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`hypertriglyceridermia and/or low HDL cholesterolemia.
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`Alternatively, the third aspect of the present invention
`
`provides a composition for preventing t h e occurrence of a
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`cardiovascular event in a hypercholesterolemia patient, the
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`composition containing at least EPA-E and/or DHA-E as its
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`effective component, wherein the patient also suffers from
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`at least two risk factors selected from the group
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`consisting of
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`(1) obesity,
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`
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`(2) hypertension or prehypertension,
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`(3) diabetes, prediabetes, or abnormal glucose
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`tolerance, and·
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`(4) hypertriglyceridemia and/or low HDL
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`cholesterolemia.
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`[0014]
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`
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`A fourth aspect of the present invention provides a
`
`composition for preventing the occurrence of a
`
`cardiovascular event in a hypercholesterolemia patient, the
`
`composition containing at least EPA-E as its effective
`
`component, wherein the patient also suffers from at least
`
`one, and more preferably, at least two risk factors
`
`selected from the group consisting of
`
`(1) obesity,
`
`
`
`
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`(2) hypertension or prehypertension,
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`(3) diabetes, prediabetes, or abnormal glucose
`
`tolerance, and
`
`(4) hypertriglyceridemia and/or low HDL
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`cholesterolemia. In this case, the hypercholesterolemia
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`patient is preferably a male patient. Alternatively, the
`
`fourth aspect of the present invention provides a
`
`composition for preventing the occurrence of a
`
`cardiovascular event in a hypercholesterolemia patient, the
`
`composition containing at least EPA-E and/or DHA-E as its
`
`effective component, wherein the patient also suffers from
`
`at least one, and more preferably, at least two risk
`
`factors selected from the group consisting of
`
`(1) obesity,
`
`
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`
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`(2) hypertension or prehypertension,
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`(3) diabetes, prediabetes, or abnormal
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`glucose tolerance, and
`
`(4) hypertriglyceridemia and/or low HDL
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`cholesterolemia. In this case, the hypercholesterolemia
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`patient is preferably a mal patient.
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`[0015]
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`
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`A fifth aspect of the present invention provides a
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`composition for preventing the occurrence of a
`
`cardiovascular event in a hypercholesterolemia patient, the
`
`composition containing at least EPA-E as its effective
`
`component, wherein the patient also suffers from risk
`
`factors of hypertriglyceridemia and low HDL cholesterolemia,
`
`and more specifically, hypertriglyceridemia and low HDL
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1003, p. 20 of 50
`
`
`
`cholesterolemia with a serum triglyceride (TG)
`
`concentration of at least 150 rng/dl and a serum HDL-C
`
`concentration of less than 40 mg/dl, or serum TG/HDL-C
`
`ratio of at least 3.75. In this case, the
`
`hypercholesterolemia patient is preferably a male patient.
`
`Alternatively, the fifth aspect of the present invention
`
`provides a composition for preventing the occurrence of a
`
`cardiovascular event in a hypercholesterolemia patient, the
`
`composition containing at least EPA-E and/or DHA-E as its
`
`effective component, wherein the patient also suffers from
`
`risk factors of hypertriglyceridemia and low HDL
`
`cholesterolemia and, more specifically,
`
`hypertriglyceridemia and low HDL cholesterolemia with a
`
`serum triglyceride (TG) concentration of at least 150 mg/dl
`
`and a serum HDL-C concentration of less than 40 mg/dl, or a
`
`serum TG/HDL-C ratio of at least 3.75. In this case, the
`
`hypercholesterolemia patient is preferably a male patient.
`
`[0016]
`
`
`
`A sixth aspect of the present invention provides a
`
`composition containing at least EPA-E as its effective
`
`component, the composition exhibiting an excellent effect
`
`of preventing t h e occurrence of a cardiovascular event in
`
`a patient suffering from multiple risk factors who has been
`
`administered this composition for at least two years since
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1003, p. 21 of 50
`
`
`
`the start of administration. Alternatively, the sixth
`
`aspect of the present invention provides a composition
`
`containing at least E.PA-E and/or DHA-E as its effective
`
`component, the composition exhibiting an excellent effect
`
`of preventing t h e recurrence of a cardiovascular event in
`
`a patient-suffering from multiple risk factors who has been
`
`administered t his composition for at least two years since
`
`the start of administration. The hypercholesterolemia
`
`patient is preferably a male patient.
`
`[0017]
`
`
`
`A seventh aspect of the present invention provides a
`
`method for preventing the occurrence of a cardiovascular
`
`event in a patient suffering from multiple risk factors by
`
`continuously administering the patient a composition
`
`containing at least EPA-E as its effective component for at
`
`least two years. Alternatively, the seventh aspect of the
`
`present invention provides a method for preventing the
`
`occurrence of a cardiovascular event in a patient suffering
`
`from multiple risk factors by continuously administering the
`
`patient a composition containing at least EPA-E and/or DHA-E
`
`as its effective component for at least two years. The
`
`hypercholesterolemia patient is preferably a male patient.
`
`[0018]
`
`
`
`An eighth aspect of the present invention provides a
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1003, p. 22 of 50
`
`
`
`composition for preventing th e occurrence of a cardiovascular
`
`event (primary prevention) in a dyslipidemia patient, the
`
`composition containing at least EPA-E as its effective
`
`component, wherein the patient also suffers from at least
`
`one risk factor selected from the group consisting of
`
`(1) obesity,
`
`(2) hypertension or prehypertension,
`
`
`
`
`
`(3) diabetes, prediabetes, or abnormal glucose
`
`tolerance, and
`
`(4) hypertriglyceridemia and/or low HDL
`
`cholesterolemia. Alternatively, the eighth aspect of the
`
`present invention provides a composition for preventing the
`
`occurrence of a cardiovascular event (primary prevention)
`
`in a dyslipidemia patient, the composition containing at
`
`least EPA-E and/or DHA-E as its effective component,
`
`wherein the patient also suffers from at least one risk
`
`factor selected from the group consisting of
`
`(1) obesity,
`
`
`
`(2) hypertension or prehypertension,
`(3) diabetes, prediabetes, or abnormal glucose
`
`tolerance, and
`
`(4) hypertriglyceridemia and/or low HDL
`
`cholesterolemia.
`
`[0019]
`
`
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1003, p. 23 of 50
`
`
`
`A ninth aspect of the present invention provides a
`
`composition for preventing the occurrence of a
`
`cardiovascular event (primary prevention) in a
`
`hypercholesterolemia patient to be administered HMG-CoA RI,
`
`the composition containing at least EPA-E as its effective
`
`component, wherein the patient also suffers from at least
`
`one risk factor selected from the group consisting of
`
`(1) obesity,
`
`(2) hypertension or prehypertension,
`
`(3) diabetes, prediabetes, or abnormal glucose
`
`tolerance, and
`
`(4) hypertriglyceridemia and/or low HDL
`
`cholesterolemia. Alternatively, the ninth aspect of the
`
`present invention provides a composition for preventing the
`
`occurrence of a cardiovascular event (primary prevention)
`
`in a hypercholesterolemia patient to be administered HMG
`
`CoA RI, the composition containing at least EPA-E and/or
`
`DHA-E as its effective component, wherein the patient also
`
`suffers from at least one risk factor selected from the
`
`group consisting of
`
`(1) obesity,
`
`(2) hypertension or prehypertension,
`
`(3) diabetes, prediabetes, or abnormal glucose
`
`
`
`
`
`
`
`
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1003, p. 24 of 50
`
`
`
`tolerance, and
`
`(4) (4) hypertriglyceridemia and/or low HDL
`
`cholesterolemia.
`
`[0020]
`
`
`
`While the EPA-E content in the total fatty acid and
`
`dosage are not particularly limited as long as the intended
`
`effects of the present invention are attained, the EPA-E
`
`used is preferably one having a high purity, for example,
`
`one having a proportion of the EPA-E in the total fatty acid
`
`and derivatives thereof of preferably 40% by weight or
`
`higher, more preferably 90% by weight or higher, and still
`
`more preferably 96.5% by weight or higher. The daily dose in
`
`terms of EPA-E is typically 0.3 to 6 g/day, preferably 0.9
`
`to 3.6 g/day, and still more preferably 1.8 to 2.7 g/day.
`
`Another preferable daily dose is 0.3 to 2.7 g/day, and 0.3
`
`to 1.8 g/day. Another preferable fatty acid included is DHA-
`
`E. While the compositional ratio of EPA-E/DHA-E, content of
`
`EPA-E and DHA-E (hereinafter referred to as (EPA-E + DHA-E))
`
`in the total fatty acid, and dosage of (EPA-E + DHA-E) are
`
`not particularly limited as long as the intended effects of
`
`the present invention are attained, the composition is
`
`preferably one having a high purity of EPA-E and DHA-E, for
`
`example, one having a proportion of a (EPA-E + DHA-E) in
`
`the total fatty acid and derivatives thereof of preferably
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1003, p. 25 of 50
`
`
`
`40% by weight or higher, more preferably 80% by weight or
`
`higher, and still more preferably 90% by weight or higher.
`
`The daily dose in terms of EPA-E + DHA-E is typically 0.3
`
`to 10 g/day, preferably 0.5 to 6 g/day, and still more
`
`preferably 1 to 4 g/day. Another preferable daily dose is
`
`0.3 to 6 g/day, 0.3 to 4 g/day, and 0.3 to 1 g/day. The
`
`content of other long chain saturated fatty acids is
`
`preferably low, and among the long chain unsaturated fatty
`
`acids, the content of ω−6 fatty acids, and in particular, the
`
`content of arachidonic acid is preferably as low as less
`
`than 2% by weight, and more preferably less than 1% by
`
`weight.
`
`[0021]
`
`
`
`The composition of the present invention contains
`
`EPA(cid:173)E and/or DHA-E, and has the effect of preventing thw
`
`occurrence of cardiovascular events in healthy people or
`
`those suffering from the risk factors of hyperlipidemia,
`
`diabetes, and hypertension when the composition is orally
`
`administered, and in particular, of preventing the
`
`occurrence of cardiovascular events in hypercholesterolemia
`
`patients who have been treated with HMG-CoA RI but are still
`
`suffering from the risk of cardiovascular events. The
`
`composition of the present invention may also be used in
`
`combination with HMG-CoA RI, and such combination may
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1003, p. 26 of 50
`
`
`
`further prevent the occurrence of cardiovascular events.
`
`[0022]
`
`
`
`The composition of the present invention may be used
`
`with other drugs, for example, antiplatelet drugs such as
`
`aspirin, ticlopidine, clopidogrel, prasugrel, and
`
`cilostazol; anticoagulants such as warfarin, heparin, and
`
`ximelagatran; antihypertensive drugs such as angiotensin II
`
`receptor antagonists (candesartan, losartan, valsartan,
`
`etc.), angiotensin converting enzyme inhibitors, calcium
`
`channel antagonists (amlodipine, cilnidipine, etc.), and
`
`l blockers; diabetes drugs or abnormal glucose tolerance
`
`stimulants such as a-glucosidase inhibitors (voglibose,
`
`acarbose, etc.), biguanide drugs, thiazolidinedione drugs
`
`(pioglitazone, rosiglitazone, rivoglitazone, etc.), and
`
`prompt insulin release promoters (mitiglinide, nateglinide,
`
`etc.); antilipotropic drugs and antiarteriosclerotic drugs
`
`such as HMG-CoA RI as described above, fibrate drugs,
`
`squalene synthetase inhibitors (TAK-475, etc.), and
`
`cholesterol absorption inhibitors (ezetirnibe, etc.),
`
`probucol, anion exchange resin, nicotinic acid drugs,
`
`phytosterol, elastase, dextran sulfate sodium sulfur,
`
`pantothenic acid, and polyenephosphatidylcholine.
`
`[0023]
`
`
`
`he composition of the present invention contains
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1003, p. 27 of 50
`
`
`
`smaller amounts of impurities such as saturated fatty acids
`
`and arachidonic acid which are unfavorable for
`
`cardiovascular events compared to fish oil or fish oil
`
`concentrate and, accordingly, the intended effects can be
`
`attained without causing problems like overnutrition or
`
`excessive intake of vitamin A. In addition, since the
`
`effective component of the present composition is in the
`
`form of an ester, the effective component is more stable to
`
`oxidation compared to the case of fish oil, in which the
`
`effective component is in the form of a triglyceride, and a
`
`sufficiently stable composition can be produced by adding a
`
`conventional antioxidant. In other words, it is the use of
`
`the EPA-E that has, for the first time, enabled production
`
`of a composition for preventing the onset of cardiovascular
`
`events that can be used in clinical practice.
`
`[0024]
`
`
`
`In the present invention, the term "icosapentaenoic
`
`acid" designates all-cis-5,8,11,14,17-icosapentaenoic acid.
`
`
`
`In the present invention, the term
`
`"hypercholesterolemia patient" refers to patients with
`
`increased serum T Cho concentration or serum LDL-Cho
`
`concentration. In a narrower sense, this term means that
`
`patients suffering from hypercholesterolemia (serum T-Cho
`
`concentration of at least about 220 mg/dl, and in more
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1003, p. 28 of 50
`
`
`
`strict sense, at least 250 mg/dl) or high LDL
`
`cholesterolemia (serum LDL-Cho concentration of at least
`
`140 mg/dL).
`
`
`
`In the present invention, the term "dyslipidemia" is
`
`the condition that satisfies at least one of high LDL
`
`cholesterolemia (i.e., fasting serum LDL cholesterol value
`
`of at least 140 mg/dL), low HDL cholesterolemia (i.e.,
`
`fasting serum HDL cholesterol value of less than 40 mg/dL),
`
`and hypertriglyceridemia (i.e., fasting serum triglyceride
`
`value of at lea
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