UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`UNITED STATES DEPARTMENT OF COMMERCE
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`
`APPLICATION
`NUMBER
`
`FILING or
`371(c) DATE
`
`GRP ART
`UNIT
`
`
`
`
`
`F
`
`60/983,446
`
`10/29/2007
`
`FEE REC'D
`
`210
`
`72960
`Casimir Jones, S.C.
`
`:tflfgigice Drive
`
`Madison, WI 53711
`
`ATTY.DOCKET.NO
`
`TOT CLAIIVIS IND CLAIMS
`
`NATNUT-30224/US/PRO
`CONFIRMATION NO. 5450
`
`FILING RECEIPT
`
`llllllllllllllllllllllIllmiwifllifllifllfllflllllfllflllIllllIlllllllllllllllll
`
`Date Mailed: 11/09/2007
`
`It will not be examined for patentability and will
`Receipt is acknowledged of this provisional patent application.
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
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`
`Applicant(s)
`
`Inge Bruheim, Volda, NORWAY;
`Mikko Griinari, Espoo, FINLAND;
`Jeffrey Cohn, Sydney, AUSTRALIA;
`Power of Attorney: The patent practitioners associated with Customer Number 72960
`
`If Required, Foreign Filing License Granted: 11/01/2007
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`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 60/983,446
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`Projected Publication Date: None, application is not eligible for pre-grant publication
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`Non-Publication Request: No
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`Early Publication Request: No
`Title
`
`Method Of Improving Adipose Tissue Functioning And Lipid Metabolism
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
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`Since the rights granted by a US. patent extend only throughout the territory of the United States and have no
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`Application Data Sheet 37 CFR 1.76
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`document may be printed and included in a paper filed application.
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`Title of Invention
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`Method of improving adipose tissue functioning and lipid metabolism
`
`The application data sheet is part of the provisional or nonprovisional application for which it is being submitted. The following form contains the
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`Inge
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`Bruheim
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`Volda
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`Volda
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`ESpOO
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`Citizenship under 37 CFR1.41(b)
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`Kultarinnantie 1 b
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`City
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`Espoo
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`A o licant 3
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`State/Province
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`FI
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`Applicant Authority @lnventor OLegal Representative under 35 U.S.C. 117
`Prefix Given Name
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`QParty of Interest under 35 U.S.C. 118
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`Jeffrey
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`PTO/SB/14 (06-07)
`Approved for use through 06/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
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`Application Data Sheet 37 CFR 1.76
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`Title of Invention
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`Method of improving adipose tissue functioning and lipid metabolism
`
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`72960
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`Email Address
`
`jmjones@casimirjones.com
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`Application Information:
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`Title of the Invention
`
`Method of improving adipose tissue functioning and lipid metabolism
`
`Provisional
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`Small Entity Status Claimed
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`eighteen months after filing.
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`PTO/SB/14 (06-07)
`Approved for use through 06/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
`
`Application Data Sheet 37 CFR 1.76
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`.
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`. Title of Invention
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`Method of improving adipose tissue functioning and lipid metabolism
`
`Customer Number
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`72960
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`Aker BioMarine ASA
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`Fjordalleen 16
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`Method of improving adipose tissue functioning and lipid metabolism
`
`Inventors: Inge Bruheim (Volda, Norway), Mikko Griinari (Espoo, Finland) and Jeffrey Cohn
`
`(Sydney, Australia)
`
`FIELD OF THE lN VEN TlON
`
`This invention relates to the specific uses of krill oil
`
`BACKGROUND OF THE INVENTION
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Krill oil has been disclosed targeting classical health problems such as cardiovascular risk
`
`factors, joint pain, cognitive problems,controlling diabetes and menstrual pain [1-5]. More
`
`specifically, krill oil compositions have been described as being effective for decreasing
`
`cholesterol,
`
`inhibiting platelet adhesion,
`
`inhibiting artery plaque formation, preventing
`
`hypertension, controlling athritis symptoms, preventing skin cancer, enhancing transdermal
`
`transport, reducing the symptoms of premenstrual symptoms or controlling blood glucose
`
`levels in a patient [l]. Krill oil has not been disclosed as being effective in treating one ofthe
`
`most important life style problem of modern societies i.e. excess weight gain and obesity.
`
`Excess adipose tissue mass
`
`(overweight and obesity)
`
`is associated with low grade
`
`inflammation in adipose tissue and in the whole body reflecting the inflammatory mediators
`
`“spilling over” from fat tissue [6]. Inflammation appears to be an important link between
`
`obesity and metabolic syndrome/type—II diabetes as well as cardiovascular disease [7]. Thus,
`
`excess adipose tissue is an unhealthy condition. Weight
`
`reduction will
`
`improve the
`
`inflammatory condition, but persistent weight reduction is difficult to achieve. Omega-3 fatty
`
`acid supplementation may alleviate the inflammatory condition in adipose tissue and thus
`
`ideally complement the principal strategies of weight reduction i.e.
`
`low calorie diet and
`
`exercise. There are Clinical studies in humans that demonstrate that omega-3 enhance the
`
`effect of very low calorie diet [8] and exercise [9] in reducing body fat mass. Although diet
`
`and exercise regime may fail to result in consistent decrease in weight in long term, the effect
`
`of omega—3 fatty acids alleviating the inflammatory condition in the adipose tissue may persist
`
`generating a condition that can be described as "healthy adipose tissue". Previously, it was
`
`shown [10] that dietary omega-3 fatty acids can be used to reduce inflammation in adipose
`
`tissue without influencing level of obesity. Reduction in adipose tissue inflammation was
`
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`demonstrated by an increase in circulating levels of adiponectin. Adiponectin is an adipose
`
`tissue derived anti—inflammatory hormone. Results on the treatment of obese people with
`
`omega-3 fatty acids to alleviate circulating levels of inflammatory markers are inconclusive
`
`[11]. However, duration of these studies may not have been sufficient given the slow turnover
`
`of adipose tissue in humans. Itoh et al. [12] found that 1.8 g/d of EPA increased adiponectin, a
`
`marker of adipose tissue derived inflammation,
`
`in a group of overweight subjects with
`
`metabolic syndrome.
`
`SUMMARY OF THE INVENTION
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`This invention relates to the specific uses of krill oil. In some embodiments, the
`
`present invention provides methods of reducing diet-induced hyperinsulinemia, insulin
`
`insensitivity, muscle mass hypertrophy, scrum adiponcctin reduction or hepatic stcatosis
`
`comprising in a subject exposed to a high fat diet: administering to said subject exposed to a
`
`high fat diet an effective amount of a krill oil composition under conditions such that a
`
`condition selected from the group consisting of diet-induced hyperinsulinemia, insulin
`
`insensitivity, muscle mass hypertrophy, serum adiponectin reduction and hepatic steatosis is
`
`reduced. The present invention is not limited to any particular krill oil composition. In some
`
`embodiments, the krill oil composition is a Euphausia superba krill oil composition. The
`
`present invention is not limited to any particular formulation of krill oil. In some
`
`embodiments, the krill oil composition is encapsulated. In some preferred embodiments, the
`
`effective amount of a krill oil composition is from 0.2 grams to 10 grams of said krill oil
`
`composition. In some embodiments, the krill oil composition comprises: from about 45% to
`
`55% w/w phospholipids; from about 35% to 45% w/w triglycerides; and from about 400 to
`
`about 1500 ppm astaxanthin. In some embodiments, the krill oil composition comprises a
`
`blend of lipid fractions obtained from Euphausia superba. In some embodiments, the krill oil
`
`composition comprises from about 25% to 30% omega-3 fatty acids as a percentage of total
`
`fatty acids and wherein from about 80% to 90% of said omega—3 fatty acids are attached to
`
`said phospholipids. In some embodiments, the krill oil composition comprises from about
`
`30% to 60% w/w phospholipids; from about 30% to 50% triglycerides; from about 400 to
`
`about 1500 ppm astaxanthin; and from about 20% to 35% omega-3 fatty acids as a percentage
`
`of total fatty acids in said composition, and wherein from about 70% to 95% of said omega-3
`
`fatty acids are attached to said phospholipids.
`
`In some embodiments, the present invention provides methods of reducing diet-
`
`induced hyperinsulinemia, insulin insensitivity, muscle mass hypertrophy, serum adiponectin
`
`2
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`reduction or hepatic steatosis comprising in a subject consuming a high fat diet or a normal fat
`
`diet: administering to said subject consuming a high fat diet or a normal fat diet an effective
`
`amount of a krill oil composition under conditions such that a condition selected from the
`
`group consisting of diet-induced hyperinsulinemia, insulin insensitivity, muscle mass
`
`hypertrophy, serum adiponectin reduction and hepatic steatosis is reduced. The present
`
`invention is not limited to any particular krill oil composition. In some embodiments, the krill
`
`oil composition is a Euphausia superba krill oil composition. The present invention is not
`
`limited to any particular formulation of krill oil. In some embodiments, the krill oil
`
`composition is encapsulated. In some preferred embodiments, the effective amount of a krill
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`oil composition is from 0.2 grams to 10 grams of said krill oil composition. In some
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`embodiments, the krill oil composition comprises: from about 45% to 55% w/w
`
`phospholipids; from about 35% to 45% w/w triglyccridcs; and from about 400 to about 1500
`
`ppm astaxanthin. In some embodiments, the krill oil composition comprises a blend of lipid
`
`fractions obtained from Euphausia superba. In some embodiments, the krill oil composition
`
`comprises from about 25% to 30% omega-3 fatty acids as a percentage of total fatty acids and
`
`wherein from about 80% to 90% of said omega-3 fatty acids are attached to said
`
`phospholipids. In some embodiments, the krill oil composition comprises from about 30% to
`
`60% w/w phospholipids; from about 30% to 50% triglycerides; from about 400 to about 1500
`
`ppm astaxanthin; and from about 20% to 35% omega—3 fatty acids as a percentage of total
`
`fatty acids in said composition, and wherein from about 70% to 95% of said omega-3 fatty
`
`acids are attached to said phospholipids.
`
`DEFINITIONS
`
`As used herein, "phospholipid" refers to an organic compound having the following general
`
`structure:
`
`1O
`
`15
`
`20
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`25
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`RIMFROST EXHIBIT 1003
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`RIMFROST EXHIBIT 1003 page 0011
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`page 0011
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`O
`
`o—c—R1
`
`o
`
`—o—c—R2
`
`o
`
`o—P—o—R3
`
`l-
`
`wherein R1 is a fatty acid residue, R2 is a fatty acid residue or 70H, and R3 is a 7H or
`
`nitrogen
`
`containing
`
`compound
`
`choline
`
`(HOCHZCH2N+(CH3)3OH'),
`
`ethanolamine
`
`(HOCHZCHZNHZ), inositol or serine. R1 and R2 cannot simultaneously be OH. When R3 is
`
`an —OH, the compound is a diacylglycerophosphate, while when R3 is a nitrogen-containing
`
`compound, the compound is a phosphatide such as lecithin, cephalin, phosphatidyl serine or
`
`plasmalo gen.
`
`As used herein, the term omega-3 fatty acid refers to polyunsaturated fatty acids that have the
`
`final double bond in the hydrocarbon chain between the third and fourth carbon atoms from
`
`the methyl end of the molecule. Non—limiting examples of omega—3 fatty acids include,
`
`5,8,1l,l4,l7-eicosapentaenoic acid (EPA), 4,7,10,l3,l6,l9-docosahexanoic acid (DHA) and
`
`7,10,13,16,19-docosapentanoic acid (DPA).
`
`10
`
`15
`
`As used herein, astaxanthin refers to the following chemical structure:
`
`
`
`As used herein, astaxanthin esters refer to the fatty acids esterified to OH group in the
`
`astaxanthin molecule.
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`RIMFROST EXHIBIT 1003
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`RIMFROST EXHIBIT 1003 page 0012
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`page 0012
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`DETAILED DESCRIPTION OF THE INVENTION
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`1O
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`15
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`20
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`25
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`30
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`An embodiment of the invetion is the use of krill oil to increase serum adiponectin levels.
`
`Adiponectin is a protein hormone that modulates a number of metabolic processes, including
`
`glucose regulation and fatty acid catabolism. Adiponectin is exclusively secreted from adipose
`
`tissue into the bloodstream and is very abundant in plasma relative to many hormones. Levels
`
`of the hormone are inversely correlated with body mass index (BMI). The hormone plays a
`
`role in alleviating the metabolic dysregulation that may result in type 2 diabetes, obesity,
`
`atherosclerosis and non—alcoholic fatty liver disease (NAFLD) [13—14].
`
`Another embodiment of the invention is to use krill oil in an overweight and obese subjects
`
`for alleviating diet induced adipose tissue dysfunction and diet induced changes in the lipid
`
`metabolism.
`
`This invention discloses that krill oil is effective in reducing risk factors of type 2 diabetes
`
`such as hyperinsulinemia and insulin resistance and cardiovascular disease risk factors in
`
`overweight subjetcs. In addition this invention discloses that krill oil is effective in preventing
`
`accumulation of fat in muscles and in the liver (liver steatosis).
`
`In some embodiments, the methods of the present invention utilize a krill oil composition,
`
`preferably a Euphausia superba krill oil composition, comprising from about 40% to about
`
`60% w/w phospholipids, preferably from about 45% to 55% w/w phospholipids and from
`
`about 300 ppm astaxanthin to about 2000 ppm astaxanthin, preferably from about 400 to
`
`about 1500 ppm astaxanthin.
`
`In filrther embodiments, the compositions comprise from about
`
`35% to 45% w/w triglycerides; and from about 400 to about 1500 ppm astaxanthin.
`
`In some
`
`embodiments, the compositions comprise from about 20% to 35%, preferably from about 25%
`
`to 35%, omega—3 fatty acids as a percentage of total fatty acids in the composition, wherein
`
`from about 70% to 95%, preferably from about 80% to 90% of the omega-3 fatty acids are
`
`attached to the phospholipids.
`
`In some embodiments,
`
`the compositions of this invention are contained in acceptable
`
`excipients and/or carriers for oral consumption. The actual form of the carrier, and thus, the
`
`composition itself, is not critical. The carrier may be a liquid, gel, gelcap, capsule, powder,
`
`5
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`RIMFROST EXHIBIT 1003
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`RIMFROST EXHIBIT 1003 page 0013
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`page 0013
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`solid tablet (coated or non—coated), or the like. The composition is preferably in the form of a
`
`tablet or capsule and most preferably in the form of a soft gel capsule. Suitable excipient
`
`and/or carriers include maltodextrin, calcium carbonate, dicalcium phosphate,
`
`tricalcium
`
`phosphate, microcrystalline cellulose, dextrose, rice flour, magnesium stearate, stearic acid,
`
`croscarmellose sodium, sodium starch glycolate, crospovidone, sucrose, vegetable gums,
`
`lactose, methylcellulose, povidone, carboxymethylcellulose,
`
`corn starch, and the like
`
`(including mixtures thereof). Preferred carriers include calcium carbonate, magnesium
`
`stearate, maltodextrin, and mixtures thereof The various ingredients and the excipient and/or
`
`carrier are mixed and formed into the desired form using conventional techniques. The tablet
`
`or capsule of the present invention may be coated with an enteric coating that dissolves at a
`
`pH of about 6.0 to 7.0. A suitable enteric coating that dissolves in the small intestine but not
`
`in the stomach is cellulose acetate phthalatc. Further details on techniques for formulation for
`
`and administration may be found in the latest edition of Remington's Pharmaceutical Sciences
`
`(Maack Publishing Co., Easton, PA).
`
`The dietary supplement may comprise one or more inert ingredients, especially if it is
`
`desirable to limit the number of calories added to the diet by the dietary supplement. For
`
`example,
`
`the dietary supplement of the present
`
`invention may also contain optional
`
`ingredients
`
`including,
`
`for example, herbs, vitamin