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`
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`SHEEIS
`TOTAL
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`FILED COUNTRY DRWGS.
`
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`'
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`
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`us. new: OF comm PA1'..&m-.-m.4asnl (name-94 '
`
`Form PTO-436A
`
`USPIabs EXHIBIT 1010
`
`USPlabs EXHIBIT 1010
`
`

`

`8/637665. PATENT APPLICATION SERIAL g!
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`FEE RECORD SHEET
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`PTO-1556
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`BAR CODE LABEL
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`I
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`U-S. PATENT APELICATION
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`SERIAL NUMBER
`
`08/637,666
`
`FILING DATE
`
`06/28/96
`
`GROUP ART UNIT
`
`1302
`
`THOMAS OLIN, TABY, SWEDEN.
`
`APPLICANT
`
`**CONTINUING Hyman-*1:********w*w*******
`
`‘VERIFIED
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`THIS APPLN IS A 371 OF
`
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`2500-007
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`‘ U.S. PATENT APPLICATION
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`1113
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`:94/07/95
`08/419,588
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`I:
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`GIJSBERTUS A. C. M. SPIERINGIES, EINDHOVEN, NETHERLANDS; WILLEH L. C.
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`COMMISSIONER OF PATENTS AND TRADEMARKS
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`METHOD OF PHOTOLITHOGRAPHICALLY METALLIZING AT LEAST THE INSIDE OF
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`US. DEPARTMENT OF COMMERCE PATENT AND TRADEMARK OFFICE
`‘
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`FORM PTO-1390 “\w 1'
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`TRANSMITl'AL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/EOIUS)
`CONCERNING A FILING UNDER 35 U.S.C. 371
`
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`m I'OFINEY'S oocxsr NUMBER
`2500-007
`
`
`
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`U.S. APP O. NO. (if known, see 37 CFR 1.
`
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`68/637663
`
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`PRIORITY DATE CLAIMED
`INTERNATIONAL APPLICATION NO.
`INTERNATIONAL FILING DATE
`
`
`
`
`
`PCT/SE94/01048
`
`November 3. 1994
`November 9. 1993
`TITLE OF INVENTION
`
`
`NEW BEVERAGE
`
`
`APPLICANT(S) FOFI DOIEO/US
`
`
`Thomas OLIN
`
` Applicant herewith submits to the United States Designated/Elected Office (DO/EOIUS) the following Items and other information:
`
`
`1.
`[X]
`This Is a FIRST submission of items concerning a tiling under 35 U.S.C. 371.
`
`
`
`This express request to begin national examination procedures (35 U.S.C. 371 (1)) at any time rather than delay examination
`until the expiration of the applicable time limit set in 35 U.S.C. 371 (b) and PCT Articles 22 and 39(1).
`
`
`date.
`A proper Demand for International Preliminary Examination was made by the 191h month from the earliest claimed priority
`
`A copy of the international Application as filed (35 U.S.C. 371(c)(2))
`a.
`[X]
`Is transmitted herewith (required only if not transmitted by the International Bureau).
`b.
`[X] has been transmitted by the international Bureau.
`
`
`c.
`[l
`is not required. as the application was filed in the United States Receiving Office (HO/US)
` 6.
`
` 7.
`
`
`
` A translation of the amendments to the claims under PCT Article 19 (35 U.S.C. 371(c)(3)).
` 10.
`
`
`
`
`
`
`
`2.
`
`3.
`
`4.
`
`9.
`
`[]
`
`[X]
`
`[]
`
`[]
`
`[]
`
`[]
`
`[]
`
`This is a SECOND or SUBSEOUENT submission of items concerning a filing under 35 U.S.C. 371.
`
`A translation of the International Application into English (35 U.S.C. 371(c)(2)).
`
`Amendments to the claims of the International Application under POT Article 19 (35 U.S.C. 371(c)(3))
`a.
`[] are transmitted herewith (required only if not transmitted by the International Bureau).
`b.
`[] have been transmitted by the-International Bureau.
`c.
`i] have not been made; however, the time limit for making such amendment has NOT expired.
`d.
`[] have not been made and will not be made.
`
`An oath or declaration of the inventor(s) (35 U.S.C. 371(c)(4)).
`
`A translation of the annexes to the International Preliminary Examination Report under PCT Article 36 (35 U.S.C. 371(c)(5)).
`
`
`
`
`
`
`
`items 11. to 18. below concern other documenfls) or infonnation included:
`
`
` 11. [] An information Disclosure Statement under 37 CFFI 1.97 and 1.98.
`
`
`
`
`
`12.
`[]
`An assignment document for recording. A separate cover sheet in compliance with 37 CFFI 3.28 and 3.31 is included.
`
`
`13.
`[X]
`A FIRST preliminary amendment.
`[]
`A SECOND or SUBSEQUENT preliminary amendment.
`
`
` 14.
`[]
`A substitute specification.
` 15.
`[]
`A change of power of attorney and/or address letter.
`16.
`Other items or information.
` [X]
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`
` -Veri1ied Small Entity Statement -— Small Business Concern
`Swedish International Search Report
`
`
`
`

`

`
` ‘ .
`
`
`
`
`
`U.S. APPLIC. NO. (in .
`.1. sue 37'CF'FI 1.50)
`
`2500-007
`
`
`
`_ cmuurrous
`17.
`[X] The following fees are submitted:
`
`
`
`Basie National Fee (37 CFR 1.492(a)(1)-(5)):
`
`Search Report has been prepared by the EPO or JPO
`$880.00
`
`
`
` international preliminary examination fee paid to USPTO (37 CFR 1.482) $680.00
`No international preliminary examination fee paid to USPTO (37 CFR 1.482)
`
`but international search fee paid to USPTO (37 CFR 1.445(a)(2))
`$750.00
`
`
`Neither international preliminary examination fee (37 CFR 1.482) nor
`
`
`$1010.00
`international search fee (37 CFR 1.445(a)(2)) paid to USPTO
`
`
`International preliminary examination fee paid to USPTO (37 CFR 1.482)
`$94.00
`and all claims satisfied provisions of PCT Article 33(2)-(4)
`
`
`
`
`INTERNATIONAL APPLICATION NO.
`
`ATTORNEY'S DOCKET NUMBER
`
`PCT/SE94/01048
`
`ENTER APPROPRIATE BASIC FEEAMOUNT =
`
`Surcharge of $130.00 for furnishing the oath or declaration later than [] 20
`months from the earliest claimed priority date (37 CFR 1.492(e)).
`
`[X] 30
`
`$ 1,010.00
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`$ 130.00
`
`Claims
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`Number Filed
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`Number Extra
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`Rate
`
`Total Claims
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`Independent Claims
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`Multiple dependent claim(s) (if applicable)
`
`x $22.00
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`at $78.00
`
`+ $250.00
`
`TOTAL OF ABOVE CALCULATIONS =
`
`$ 1,140.00
`
`
`
`
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`
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`Reduction by 1/2 for flllng by small entity, ll applicable. Verified Small Entity Statement must
`also be flied.
`(Note 37 CPR 1.9. 1.27. 1.28).
`SUBTOTAL =
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`Processing fee of $130.00 for furnishing the English translation later than the I] 20 [l 30
`
`months from the earliest claimed priority date (37 CFR 1.492(1)).
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`
`
`Fee for recording the enclosed assignment (37 CFR 1.21(h)). The assignment must be
`accompanied by an appropriate cover sheet (37 CFR 3.28. 3.31). $40.00 per property
`
`+
`
`TOTAL FEES ENCLOSED =
`
`+
`
`TOTAL NATIONAL FEE -
`
`$ (570.00)
`
`$ 570.00
`
`$ 570.00
`
`$ 570.00
`
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`- Amounttobe:
`
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`refunded
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`charged
`
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`[]
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`enclosed.
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`Account No. 12-2237. A duplicate copy oi this sheet ls enclosed.
`
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`NOTE: Where an appropriate time limit under 37 CFFl 1.494
`
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`filed and granted to restore the application to pending
`
`SEND ALL CORRESPONDENCE TO:
`
`
`SIGNATURE
`
`
`Christopher W. Brody
`
`
`Christa her W. Brod
`LOWE, PRICE, LEBLANC 8r BECKER
`99 Canal Center Plaza, Suite 300
`NAME
`Alexandria. VA 22314
`
`(703) 684-1111
`
`
`
`1.495 has not been met, a petition to revive (37 CFFl 1.137(a) or (5)) must be
`
`'33 613
`REGISTRATION NUMBER
`
`May 21 1996
`DATE
`
`‘
`
`

`

`WO 95112991
`
`88 flesh PGTIPTC ogmm 1995
`08/637566
`
`1
`
`PCT/51394101048
`
`New Beverag 9
`
`Technical field
`
`The present invention is related to an energy supply composi-
`
`tion particularly suitable for use before, during and after
`physical exertion.
`
`10
`
`15
`
`20
`
`25
`
`The object of the invention is to facilitate extended physi—
`cal exertion by providing energy that is efficiently utilized
`in mammals. A further object of the invention is to facili—
`
`tate the accretion of muscle tissue asra result of physical
`training by sustaining an adequate energy status and permit-
`ting rapid build—up of the body's stored energy levels upon
`rest. A further object is to reduce the loss of water from
`
`the body during physical exertion by retaining a high rate of
`
`water absorption in the gastrointestinal tract from an energy
`rich beverage.
`
`Background of the invention
`
`Individuals undergoing significant physical exertion, whether
`
`for athletic or other purposes increase their nutritional
`
`needs substantially in order to maintain the body's energy
`
`storage and to develop its muscular capacity. If physical
`
`training is not accompanied by a proportional increase in nu—
`
`tritional intake,
`
`the muscle glycogen depot is not replenished
`
`unless proteins, principally from muscle sources,
`
`is broken
`
`down into constituent amino acids, chiefly alanine and glut-
`
`amine,
`
`to be used as required energy or converted to glucose.
`
`30
`
`In the last decades, so called sports beverages have enjoyed
`an increased use by athletes and others doing exercise. Such
`
`beverages have largely been based on sugars, salt, minerals
`
`and proteins and fragments thereof. For example,
`
`in Dialog
`
`Abstract No 02331774 (World Food & Drink Report, October 19,
`
`35
`
`1989) a sports drink named GatorPro is described including
`water, glucose, soy protein isolate and soy oil. Various
`
`attempts have been made to provide a beverage, based on a
`
`sound scientific concept, for athletes and other healthy
`
`SUBSHTUTESHEET
`
`

`

`W0 95!12991
`
`PCT/SE94I01048
`
`2
`
`individuals with a high energy demand, e.g. certain convae
`lescents. However,
`the demand for improved beverages is still
`great. By a healthy individual in the context of this
`invention is intended a human and, as applicable, another
`
`5
`
`mammal individual who is not subject to neither in-patient
`
`nor out-patient care-for conditions relevant herein by a
`hospital or a medical or_veterinary practitioner. Thus the
`term excludes patients requiring parenteral, or equivalent
`
`enteral, supply of the entire or a very large proportion of
`the energy, electrolyte, fat or amino acid demand of such
`
`10
`
`the term includes those athletes
`patient. 0n the other hand,
`and convalescents just mentioned and other individuals.in a
`
`similar physical state, although they may have deficiencies
`
`or surplus in their body tissues and liquids as compared to
`
`15
`
`an avarage non-diseased and fit individual.
`
`Normally, physical exertion is accompanied by an increase in
`
`.food intake, and the energy requirements of the intestine,
`
`i.e. the small intestine, for digestion are thus also
`
`increased in order to provide active transport of substances
`
`into the blood stream and to sustain the turnover in
`
`epithelial cells that makes up the luminal lining of the
`
`intestine.
`
`In situations of substantially increased food
`
`intake,
`
`the intestinal abSorption efficiency (i.e.
`
`the supply
`
`of energy) may be decreased. Thus, an increased demand for
`
`energy must be accompanied by a proportionally even higher
`
`food intake to avoid metabolic imbalance.
`
`In contrast to seme other tissues,
`
`the small intestine's
`
`primary energy source is the amino acid glutamine. During a
`meal, glutamine is mainly obtained directly from the food.
`
`Between meals, however, glutamine is transported from the
`muscles, where it is derived from protein breakdown,
`to the
`intestine.
`
`In the healthy individual, glutamine is classified as a non—
`
`essential nutrient, that is,
`
`the body provides enough
`
`20
`
`25
`
`30
`
`35
`
`SUBSWTUTESHEET
`
`

`

`,WO 95112991
`
`‘
`
`_
`
`PCT/SE94/01048
`
`3
`
`glutamine to satisfy the metabolic demand for said amino
`acid. After physical trauma, whether accidental or inten—
`tional (e.g. surgery),
`some non-essential nutrients seem to
`become semi-essential in order to preserve physical functions
`such as nitrogen balance and immune function (Kirk S J and
`Barbul A,
`JPEN 14, 226-229, 1990; Ziegler TR et al Clin Nutr
`12(1), 82—90, 1993). A person in nitrogen balance ingests as
`much nitrogen (primarily in the form of protein) as is lost
`in feces, urine and by transpiration. A person in positive
`nitrogen balance ingests more nitrogen than is lost. External
`glutamine supply decreases the loss of muscle protein after
`physical trauma and supports the intestinal barrier against
`infections caused by microorganisms of the gastrointestinal
`tract. Due to the chemical instability of glutamine, which
`cyclesizes to a toxic compound during storage, only a few
`nutritional products are supplemented with this amino acid.
`
`The main energy depots of the body comprise large molecules
`synthesized from monomers of glucose, amino acids or fatty
`acids and glycerol. The formation of these large molecules
`makes it possible to store a large amount of energy without
`changing osmotic pressure beyond acceptable limits within the
`mammal or disturbing substrate and product based regulation
`of metabolism. On the other hand,
`the energy depots of the
`muscle admit a fairly slow inter organ transport of energy.
`See the Cori cycle, figure 1. The Cori cycle is a pathway
`.describing the exchange of fuel molecules and building blocks
`for biosynthesis, between muscle and liver. The evolution of
`.energy transport cycles and depots is well adjusted to a
`natural situation of intermittent nutrient intake.
`
`A drawback of the natural energy depot system is the rather
`inefficient replenishment of the rapid cellular energy
`sources such as ATP and creatine phosphate from glucose, and
`the accumulation of metabolic waste products, such as lactic
`acid. The accumulation of lactic acid, resulting in an obvi—
`ous oxygen debt,
`is a well known limiting factor for physical
`
`10
`
`15
`
`20'
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`25
`
`30
`
`35
`
`n
`
`a
`I
`e/1
`
`SUBSWTUTESHEET
`
`

`

`‘ W0 95/12991
`
`PCT/SE94/01048
`
`4
`
`In MEDLINE/93009547 (Clin Sci 1992
`performance.
`Sep;83(3):367-74) Harris et al show that creatine givan as a
`supplement to normal subjects resulted in an increase in the
`total.creatine content in muscle. However, a larger creatine
`Content does not directly increase the stored energy, but
`increases the ability to store energy.
`
`The citric acid cycle is the final common pathway for the
`oxidation of fuel molecules. It also serves as a source of
`building blocks for biosynthesis. See figure 2. Clinical
`settings on humans and animal studies have suggested that the
`keto acid a-ketoglutaric acid, a glutamine related metabolite
`of the citric acid cycle, has an impact similar to glutamine,
`on the muscle protein balance during stress and medical
`treatment (Patent SE 462 463, US 5.183.674; Wernerman J. et
`al, Lancet 335, 701-703, 1990). Intravenous administration of
`c-ketoglutaric acid, but not glutamine,
`improves the energy
`status of the muscle in critically ill patients (Gamrin L,
`ESPEN 1993, abstract 0 48),
`indicating a metabolic discrep-
`ancy between the two nutrients as regards impact on energy
`status.
`
`In the healthy individual, glucose and fatty acids are the
`predominant energy substrates for the muscle. During physical
`exertion glucose is the most rapidly mobilized energy source
`in skeletal muscle. However,
`the normal storage capacity of
`glucose is limited and, more importantly, the muscular work
`in so—called "fast and medium fast fibres" is not balanced by
`a corresponding increase in glucose uptake from the blood
`stream, and such loss of balance causes reduction in the
`glucose (glycogen) reserve. As the glycogen reserve is dimin—
`ished,
`there is an increased utilization of fatty acids in
`the muscle. The change from glycogen (glucose) to a fatty
`acid derived energy production is concomitant with a
`decreased muscular efficiency.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`SUBSTWUTESHEET
`
`

`

`. W0 95/ 12991
`
`‘
`
`PCT/SE94l01048
`
`5
`
`Although the muscle glycogen depot is the predominant carbo~
`
`there is some transport
`hydrate source in the working muscle,
`of blood glucose into the muscle. Closer to the.point of
`exhaustion, blood derived glucose becomes increasingly impor-
`tant to the muscle as a carbohydrate source. Nevertheless,
`the fall in plasma insulin during exercise counteracts the
`
`transport of glucose into.the muscle, presumably to preserve
`
`the blood glucose at a concentration adequate to ensure a
`
`well functioning central nervous system.
`
`Pyruvate in combination with dihydroxyacetone increases the
`
`muscle uptake of glucose both at rest and during exertion
`
`(Stanko RT et al, J Appl Physiol 69(5), 1651-1656, 1990)
`resulting in an improved leg exercise endurance.
`In practice,
`the combination of pyruvate and dihydroxyacetone is not
`
`satisfactory due to poor chemical stability.
`
`5
`
`10
`
`15
`
`,1
`
`fig
`q(%7%
`
`20
`
`A typical beVerage designed to support energy status during
`phasical exertion is an isotonic aqueous solution which
`includes traditional food ingredients such as glucose,
`fructose and galactose and salts. Because of a limited trans-
`port of these sugars into the muscle during physical exer-
`tion,
`they are not optimally utilized as energy substrates.
`
`Further, even small amounts of sugar tend to delay the water
`absorption due to decreased water passage through the
`
`25
`
`pylorus. Even a limited loss of water, corresponding to four
`to five percent of the body weight, results in a marked
`
`decrease in muscular work and a concomitant loss of body
`protein.
`
`M‘
`
`{A
`
`SUBSWTUTESHEET
`
`

`

`, W0 95/12991
`
`PCT/SE94/01048
`
`Description of the invention
`
`The present invention provides a beverage, or a dry composi—
`tion therefor, useful as an energy source in situations with
`
`demand of large and rapid energy supply to'a healthy mammal
`including man, comprising an effective amount of
`
`a—ketoglutaric acid or a water-soluble innocuous salt thereof
`
`together with a nutritionally acceptable water—soluble
`carrier.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`According to another aspect,
`
`the invention is related to a
`
`method of large and rapid_energy supply to a healthy mammal
`including man, comprising providing to said animal, a'
`
`beverage, or a dry composition therefor, comprising an
`effective amount of a-ketoglutaric acid or a water-soluble
`
`innocuous salt thereof together with a nutritionally
`acceptable water-soluble carrier.
`
`the invention is related to
`According to a further aspect,
`the use of an effectiVe amount of a—ketoglutaric acid or a
`
`water-soluble innocuous salt thereof together with an accepw
`table water-soluble carrier, for preparation of a beverage,
`or a dry composition therefor, for use as an energy source in
`situations with demand of large and rapid energy supply to a
`healthy mammal including man.
`
`the beverage of the
`In contrast to sugars such as glucose,
`invention provides energy with only a minimal increase of
`
`water retention in the stomach and will thus counteract the
`
`loss of water from the body during physical exertion more
`efficiently than conventional sugar containing beverages. The
`enhanced water balance minimizes the loss of body protein
`during exercise.
`
`Preferred embodiments of the invention will be evident from
`
`the following descriptions and claims.
`
`SUBSWTUTESHEET
`
`

`

`WO 95112991
`
`'
`
`PCTISE94/01048
`
`7
`
`The nutritionally acceptable water~soluble carrier preferably
`
`includes one or more of the components: minerals, vitamins,
`
`carbohydrates, fat and protein, and is in dry form if the
`
`beverage is provided as an extract for dilution. If the
`
`beverage is provided ready for consumption it further
`
`comprises water. From the stated purpose with the beverage of
`
`the invention it will be apparent that the beverage is
`
`preferably not
`
`intended to fulfil to any substantial degree
`
`the requirements of said individual of several free,
`
`in
`
`particular several essential free, amino acids. The final
`
`beverage may have controlled tonicity and acidity, e.gn as a
`buffered solution. Among further ingredients may be mentioned
`
`malic acid, which enhances the rate of energy generating
`
`oxidation of a—ketoglutaric acid. Accordingly,
`
`the
`
`combination of a—ketoglutaric acid and malic acid is one
`preferred embodiment of the invention)/\
`
`Two particularly preferred beverages of the invention are as
`fOIIOWS:
`
`10
`
`15
`
`”We W
`
`20
`
`SUBSHTUTESHEET
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`

`

`W0 95.! 12991
`
`PCT/SE94IOIO48
`
`8
`
`WW
`1.
`
`' Ingredient
`
`Preferred range of
`
`content per 100 ml
`
`a—ketoglutaric acid
`.
`Malic acid*
`Glucose or a di— or polysaccharide
`
`0.5 — 2 g
`0,3 - 3 g
`
`containing glucose
`Fructose*
`Sodium, Potassium and Calcium
`Aroma, such as citric acid
`
`and/or lime concentrate
`Water
`
`'
`
`1 - 8 g
`0.5 - 1.5 g
`0.1 - 0.5 g
`
`0.5 - 2.5 g
`A
`
`Mrs/g 77
`W
`
`5
`
`10
`
`’ ( [TICK
`
`15
`
`'
`
`10 - 50 kcal
`
`Preferred range of
`,content per 100 ml
`
`adv/«7g
`46:0L=_l*5_g‘~
`0,3.- 3 g
`
`2 — 6 g
`0.5 - 1,5 g
`0.1 - 0,5 g
`
`0.5 — 2.5 g
`
`10 — 50 kcal
`
`Energy
`
`2.
`
`Ingredient
`
`2 0
`
`2 5
`
`.
`
`a-ketoglutaric acid
`Malic acid‘
`Glucose or a di— or polysaccharide
`containing glucose*
`Fructose*
`Sodium, Potassium and Calcium
`Aroma, such as citric acid
`
`3 o
`
`and/or lime concentrate
`Water
`'
`
`at?
`If! 5’?)
`
`M L
`
`"
`,,qe
`TM
`
`W
`
`Energy
`
`* optional
`
`3 5
`
`W‘
`
`SUBSHTUTESHEET
`
`

`

`wo 95112991
`
`'
`
`PCTISE94101048
`
`9
`
`Beverage for energy replenishment
`
`In order to provide a nutritiously more complete replenish-
`
`ment after physical exertion the following ingredients may be
`
`added to the formula of above described beverages:
`
`Ingredient
`
`Preferred range of
`
`content per 100 ml
`
`ML’ 7
`
`10
`
`Lipids and fatty acids*
`
`0,1 - 1,0 g
`
`Water—soluble protein, e.g. whey protein 1 — 5 g
`Essential minerals according tO'WHO**
`0,1 — 0,3 g
`
`Vitamins according to WHO**
`
`0,01 — 0,1 g
`
`Energy
`
`15
`
`* optional
`
`'
`
`5 — 25 kcal
`
`** Handbook on Human Nutritional Requirements, Geneva, WHO,
`
`Monogr. Serial No 61 (1974), and Nutr. Metab. 21, p 210
`
`20
`
`(1977).
`M
`
`25
`
`30
`
`35
`
`In contrast to other keto acids a-ketoglutaric acid is
`
`stable, and hence suitable for use in beverages. The pH of
`
`the beverages is preferably in the range of about
`
`2 - 5, an in particular about 2 - 4,
`
`to prevent bacterial and
`
`fungal growth. Due to the stability of a-ketoglutaric acid
`
`the production of a sterilised beverage at a pH of about 6 —
`
`8 is also possible.
`
`The beverage of the present invention provides energy accor-
`
`ding to the principle of rapid energy recruitment within the
`
`organelles of the mammalian cell. An organelle is a sub—
`
`cellular compartment representing specialized metabolic
`
`function, such as the mitochondria were the formation of
`
`energy by oxidative reaction in the citric acid cycle takes
`
`place.
`
`(See citric acid cycle, fig 2). The main energy
`
`substrate of the said beverage, a-ketoglutaric acid,
`
`is
`
`SUBSNTUTESHEET
`
`

`

`WO 95112991
`
`.
`
`PCT/SE94IOIO48
`
`10
`
`rapidly converted to energy or other metabolites, such as
`
`glucose, and a minimum of metabolic waste products. Further,
`
`a—ketoglutaric acid stimulates the transport of glucose from
`
`the blood into the muscle. The invention will thereby enhance
`
`the performance of muscle fibres and save or replenish the
`
`indigenous energy depot resulting in an enhanced physical and
`
`mental endurance. Also, q—ketoglutaric acid, a constituent in
`the gluconeogenesis,
`increases the glycogen deposition when
`administered before exertion,
`leading to improved exercise
`endurance.
`
`a-ketoglutaric acid is formed in each cell that is active in
`
`terms of oxidative metabolism and/or amino acid deamination
`
`reactions, and is therefore not considered as an essential
`
`nutrient. The cells of the intestinal mucosa utilize a-keto-
`
`glutaric acid, derived from glutamine, as an energy
`substrate. This reaction has not, until now, been considered
`
`to be limiting for an optimal intestinal function in healthy
`individuals. Athletes consuming two to four times as much
`
`calories as the untrained person, have not been thoroughly
`studied from such aspect. A further advantage is provided by
`the invention on the intestinal function exemplified by a
`sustained absorption efficiency during periods of large food
`intake, which permits a rapid build-up of the body’s stored
`energy levels upon rest.
`
`the improved muscle energy and water supply
`Taken together,
`during physical exertion and the sustained intestinal absorp—
`tion during periods of large food intake, make the invention
`facilitate the accretion of muscle tissue as a result of
`
`physical training.
`
`The following examples and tests are provided by way of
`illustration and not by way of limitation.
`
`SUBSWTUTESHEET
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`,1 ,/
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`

`

`W0 95/1299]
`
`PCT/SE94IOIO48
`
`Content per 100 ml
`
`1,2 g
`
`2,5 g
`1,0 g
`0,3 g
`1.5 g
`
`19 kcal
`
`‘
`
`Content per 100 ml
`
`11
`
`Examples of preferred beverages
`Example 1
`
`Ingredient
`
`a-ketoglutaric acid
`Glucose or.a di~ or polysaccharide
`
`of glucose
`Fructose
`Sodium, Potassium and Calcium
`Citric acid and/or lime concentrate
`Water
`
`‘
`
`( Leif.
`«
`
`5
`
`W L
`
`L’M-
`#7
`
`1 0
`
`Energy
`
`15
`
`Example 2
`
`Ingredient
`
`'tV
`lbfl? 7
`
`20
`
`25
`
`a—ketoglutaric acid
`Glucose or a di- or polysaccharide
`of glucose
`Fructose
`Lipids and fatty acids
`Water-soluble protein
`Sodium, Potassium and Calcium
`Essential minerals according to WHO*
`Vitamins according to WHO*
`Citric acid and/or lime concentrate
`Water
`
`30
`
`Energy
`
`1.5 g
`
`4,0 g
`1.0 g
`0.1 g
`3.0 g
`0.3 g
`0.2 g
`0.05 g
`1.5 9
`
`39 kcal
`
`* Handbook on Human Nutritional Requirements, Geneva, WHO,
`Monogr. Serial No 61 (1974), and Nutr. Metab. 21, p 210
`(1977).
`
`35
`
`__mm_#_ml_l
`
`SUBSflTUTESHEET
`
`

`

`WO 95/12991
`
`PCT/SE94I01043
`
`Stabilit
`
`test
`
`12
`
`Two beVerages, A and B, were prepared according to the compo—
`
`sitions in example 1 and 2, respectivelyQBeverage A and B
`
`were each divided into four samples and treated as follows:
`
`Sample one: Stored at room temperature for 24 hours.
`
`Sample two: Autoclaved at 120°C for 25 minutes.
`
`Sample three: sterilized by heating to 140°C for 5 seconds
`
`(ultra high temperature sterilization, UHT)
`
`10
`
`Sample four: sterilized according to sample 3 and then stored
`
`at room temperature for 6 months.
`
`The samples were then analyzed for the content|of a-ketoglut-
`
`aric acid, by glutamate dehydrogenase specific NADH oxida-
`tion.
`
`15
`
`Results
`
`After treatment of the samples one,
`
`two and three, more than
`
`95 percent of the a—ketoglutaric acid added was recovered
`
`20
`
`from both beverage A and B. When stored for six months
`
`(sample four) the content of a—ketoglutaric acid in the two
`
`beverages was more than 90 percent of the added amount. The
`
`biological value of other ingredients of the beverages were
`
`not negatively affected by the presence of a—ketoglutaric
`acid.
`
`25
`
`Physical Tests
`
`Physical Exertion Program:
`
`30
`
`-
`
`-
`
`Running 6 kilometres three times a week at a speed corre~
`
`sponding to 60 - 70 % of maximal capacity.
`
`50 - 60 sit-ups and 30 - 4o arm push-ups four times a
`week.
`
`SUBSTITUTE SHEET
`
`

`

`W0 95l1299l
`
`PCT/5394101048
`
`13
`
`ems—1cm
`
`Study group
`
`Six healthy men, who on a regular base, practised physical
`
`exercise according to the training program above during at
`
`least one year prior the onset of the study.
`
`10
`
`15
`
`The study were divided into two periods:
`
`I. The test persons practised physical exercise, as
`
`described, for one month. During this month they consumed
`
`three times 200 ml per day of an energy rich conventional
`
`beverage for sportsmen, containing salts and 7.5 g of glucose
`per 100 ml.
`
`II. The test persons continued their physical exercise
`
`according to the protocol for a second month. At the start of
`
`this month,
`
`they changed from a conventional beverage to
`
`consumption of three times 200 ml per day of a beverage
`
`according to the present invention (see Example 1)
`
`20
`
`Results
`
`During study period (I), when provided the conventional
`
`beverage,
`
`the healthy men did not improve their physical
`
`performance. A change to the beverage according to the inven—
`
`25
`
`tion (study period II), was concomitant with an increased
`physical performance corresponding 10 to 20 percent of aver-
`
`age running speed and number of situps and push-ups before
`exhaustion.
`
`30
`
`35
`
`Further, when consuming a beverage according to the inven—
`
`tion,
`
`the oxygen debt was less pronounced during the day to
`
`day intensive short term physical exertion.
`
`As the conventional sugar containing beverage was consumed,
`
`close to and during physical exertion, a heavy stomach
`
`revealed a slow absorption of the liquid. In contrast,
`
`the
`
`beverage composed according to the present invention was
`
`effectively absorbed when used closed to and during exertion.
`
`SUBSTITUTE SHEET
`
`

`

`WO 95112991
`
`PCTISE94/01048
`
`Ph sical Test 2
`
`14
`
`Six healthy men performing a weekly physical exercise as
`described in Physical Test 1 Were provided with a beverage
`according to the present invention during a period of six
`months. The beverage was composed according to Example 1,
`except from a varying content of a-ketoglutaric acid betWeen _
`0,01 and 3.5 gram per 109 ml and malic acid in relation
`thereto. The different beverages were kept isocaloric by
`compensating the varying content of organic acids with a
`proportional amount of glucose.
`
`-Results
`
`The test persons reported an enhanced endurance during physi—
`cal exertion when consuming a beverage including 0.1 to 2.5 g
`of a-ketoglutaric acid per 100 ml.
`Immediately after exer—
`cise,
`the consumption of a beverage containing a combination
`of a—ketoglutaric acid and malic acid, resulted in a signifi-
`cantly faster energy boost as compared to a beverage contain-
`ing a-ketoglutaric acid alone.
`
`Ph sical Test 3
`
`Study group
`Six well trained long distance runners joined the study
`during a training period according to the Physical Exertion
`Program above. The athletes were provided a beverage of the
`invention according to Example 2. During a study period of
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Results
`
`The athletes recorded an increased training tolerance the day
`after heavy exercise, as a retained endurance. The onset of
`muscle fatigue_during physical exercise was postponed and
`correlated to a decreased accumulation of lactic acid. Fur—
`ther,
`the athletes interpreted part of the impact of the
`beverage on physical performance, as a rapid build—up of the
`body's stored energy levels upon rest. The increased training
`
`35
`
`~ "I...
`/v
`I
`\_
`
`SUBSWTUTESHEET
`
`k
`
`-.
`
`

`

`WO 95112991
`s
`
`PCT/SE94101048
`
`15
`
`tolerance in combination with a high level of stored energy
`
`minimize the combustion of amino acids and thus facilitates
`
`accretion of muscle protein and development of muscle per—
`formance.
`
`SUBSNTUTESHEET
`
`

`

`wo 95112991
`
`CLAIMS
`
`/
`
`PCT/SE94I01048 '
`
`16
`
`A beverage, or a dry composition therefor, providing an
`energy source in situations with demand of large and
`ra 1
`ener
`su
`1
`t
`a healt
`al
`pd
`.\ Ppsigerceagcyogkee. 3&3?»
`fof a—
`og utaric ac
`comprising
`or a water-soluble innocuous salt thereof together with
`a nutritionally acceptable water--soluble carrier.
`
`'
`
`or a dry composition therefor, according to
`the content of a—ketoglutaric acid is
`
`
`ent of the wetweight.
`
`I-_ 5
`
`A beVerag
`or a dry composition therefor, according to
`claim rer'Zy wherein a—ketoglutaric acid is combined
`
`with malic acid.
`
`2.
`A beverage according to c 1m“, wherein the ratio a-
`ketoglutaric acid:malic acid is 1:0.5 to 1:1.5.
`
`A b vera 9,
`qrna
`
`or a dry com
`
`ition therefor,
`
`according to
`, comprising an acid
`
`and heat stable whey protein concentrate making up a 1
`'on.
`
`to 20 percent visually clear water solu
`5/qu /
` A beverage according to
`
`3O
`
`-ciaims~wherein the nutritionally acceptable water—
`soluble carrier includes at least one of the
`components: water, minerals, vitamins, organic acids,
`carbohydrates, fat and protein in a water—sol ble form.
`
`
`ge acc
`auemqu%rt?
`éflfiumaa whereinA
`millimoles of monosaccharides per litre.
`
`A b ve
`
`
`
`A method of large and rapid energy supply to a healthy
`mammal innsludiag—man, comprising providing to said
`
`SUBSTITUTE SHEET
`
`

`

`WO 95112991
`
`PCT/SE941‘01048
`
`17
`
`i
`therefor
`cm
`animal
`a beve a e, or
`big“,
`Mopfb'i
`.1 . D a
`9
`us.
`“at"? H
`.
`a—ke oglutaric acid
`comprlsing
`or a water—soluble innocuous salt thereof together with
`a nut