Trademark Trial and Appeal Board Electronic Filing System. http://estta.uspto.gov
`ESTTA461398
`ESTTA Tracking number:
`03/13/2012
`
`Filing date:
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`BEFORE THE TRADEMARK TRIAL AND APPEAL BOARD
`92053495
`Plaintiff
`Isotonic OPC Antioxidants, Inc.
`SENGEN SUN PHD
`ISOTONIC OPC ANTIOXIDANT INC
`8838 LA CAMESA STREET
`SAN DIEGO, CA 92129
`UNITED STATES
`info@amerinutra.net
`Motion for Summary Judgment
`Sengen Sun, PhD
`info@amerinutra.net
`/Sengen Sun/
`03/13/2012
`EXHIBIT PET-002 Label.pdf ( 1 page )(1327 bytes )
`EXHIBIT PET-002.pdf ( 5 pages )(430678 bytes )
`
`Proceeding
`Party
`
`Correspondence
`Address
`
`Submission
`Filer's Name
`Filer's e-mail
`Signature
`Date
`Attachments
`
`

`
`EXHIBIT PET-002
`EXHIBIT PET—OO2
`
`
`
`

`
`IIIEIIIIIIIIIIII
`
`US005720956A
`
`Umted States Patent
`
`[191
`
`[11] Patent Number:
`
`5,720,956
`
`Rohdewald
`
`[45] Date of Patent:
`
`Feb. 24, 1998
`
`[54] METHOD or CONTROLLING THE
`REACTIVITY or HUMAN spoon
`PLATELETS BY ORAL ADMIINISTRATION
`OF THE EXTIIACT OF THE MA
`"NE (PYCNOGENOL)
`Inventor: Peter nohdewala. Schulz:-Isforsir. 4,
`D-48341 Altcnbcrgc. Germany
`
`[76]
`
`5"” A991’ N°" 63””
`[22] Filed:
`Apr. 10, 1996
`
`6
`
`......................................... AGIK 35f78
`Int. Cl.
`[51]
`42¢Ul95.1; 51413156: 5141322
`[52] US. Cl.
`[58] Field of Search ..................... 424.’195.l; 514I456,
`5l4I822
`
`[56]
`
`References Cited
`
`"'5' “VENT DOCUMENTS
`4,698,360 lCIl'l937
`.......................... 514M-55
`Primary Emnu'ner=--Jolm w. Rollins
`""”""3‘ "9"" "’ F‘””‘Ni"““° M“"“°‘5‘°i" Mm“? &
`0”“ 1”’
`[57]
`
`ABSTRACT
`
`A method of inhibiting platelet aggregation with an agent
`which is able to normalize and enhance platelet reactivity’
`without adversely affecting the blceding time. The method
`additionally P1-evcms am-ena1me_induoed P133313; 33311333.
`fiom
`
`5 Claims, 2 Drawing Sheets
`
`

`
`US. Patent
`
`Feb. 24, 1993
`
`Sheet 1 of 2
`
`5,720,956
`
`A PF’
`
`0.4
`
`WITHOUT
`
`
`
`PYCNOGENOL
`
`fi5A
`
`WITHOUT
`
`SEC
`
`250
`
`I50
`
`50
`
`

`
`U.S. Patent
`
`Feb. 24, 1993
`
`Sheet 2 of 2
`
`5,720,956
`
`40
`
`(96)
`
`(pg/mi)
`
`Fig.3
`
`

`
`1
`METHOD OF CONTROLLING THE
`REACTIVITY OF HUMAN BLOOD
`PLATELETS BY ORAL ADMINISTRATION
`OF THE EXTRACT OF THE MARITIME
`PINE (PYCNOGENOL)
`
`10
`
`35
`
`S5
`
`The present invention relates to a method of controlling
`human blood platelets reactivity.
`Platelet aggregation is a major contributing factor to a
`great variety of cardiovascular diseases In the pathogenesis
`of arteriosclerosis, besides lesions of the endothelium, the
`activation of platelet aggregation leading to the adhesion of
`platelet aggregates to the vascular wall is one of the tits!
`steps in thrombus formation.
`Consequently.
`inhibition of platelet aggregation is
`applied in stroke prophylaxis. Therefore. aoetylsalicylic acid
`(ASA). a well-known inhibitor of platelet aggregation has
`been successfully tested in clinical trials for the prevention
`of arteric-thrombotic, cerebral or myocardial infarction.
`ASA was found to reduce the number of infarclions in
`volunteas and in high~risk patients. too. In a subpopulation
`of patients platelet aggregation could not be prevented by
`ASA. One reason for the lack of the anti-thrombotic effect
`of ASA in those patients might be the fact that adrenaline is
`able to induce platelet aggregation even in presence of ASA.
`Since adrenaline is produced under stress, non-responders to
`ASA anti-thrombotic prophylaxis may be under: greater
`continuous stress than responders.
`A high risk factor for cmdiovascular diseases is smoking.
`Smoking increases platelet reactivity, and it has been dem-
`onstrated that nicotine induces thrombus formation. Besides
`nicotine or. additionally. the tar fraction of smoke may also
`produce increased platelet reactivity.
`Ithas been demonstratedtbatASAis able to reduce the
`enhanced platelet aggregation following smoking. However.
`in this case as well ASA could not prevent the smoking-
`indnced enhancement of platelet function in men with
`coronary heart diseases.
`Therefore. it seems that the action mechanism of ASA,
`i.e. the irreversible acetylation of cyclooxygenase. cannot
`inhibit platelet aggregation in each case.
`Besides these cases of lacking prevention the side clfects
`of regular intake of ASA are not totally insignificant. even
`when relatively low doses are applied. Gastric bleedings and
`allergic reactions like ASA-induced asthma or even serious
`derrnatological reactions like Lyell’s syndrome must be
`taken into consideration.
`If it were possible to inhibit platelet aggregation by a
`substance preventing increased platelet reactivity. however.
`without producing bleedings or allergic asthma. the benefit-
`risk ratio in the prophylaxis of infarctions would be
`improved. An additional advantage would be achieved by a
`substance inhibiting adrenaline-induced platelet aggrega-
`tion.
`It is therefore an object of the present invention to
`provide an agent which is able to normalize an enhanced
`platelet reactivity without adversely affecting the bleeding
`time as a measure of bleeding tendency. A further object of
`the invention is to provide an agent which does not only
`normalize platelet reactivity to the same extent as ASA—-
`tested on the model of smoking-induced platelet reactivity--
`but. additionally, prevents adrenaline-induced platelet
`aggregation.
`Still another object is to provide a method of controlling
`human blood platelet reactivity, especially by inhibition of
`adrenaline-induced platelet aggregation. These objeas are
`achieved by the method of administering an extract of the
`
`5 ,720,956
`
`2
`
`bark of the maritime pine. Pinus may-itima, to a human being
`for controlling platelet aggregation. Said extract of the bark
`of the maritime pine is in the following referred to as
`Pycnogenolm.
`Pycnogenolm contains procyanidines consisting of cat-
`echin and epicatechin units linked by C-C bonds to form
`dimers. trirners and other oligomers up to a chain length of
`6-? molecules and phenolic acids and its glucose derivatives
`(1). Pycnogenolm is produced according to U.S. Pat. No.
`4.698360 which is incorporated herein for reference. The
`extract used according to the invention may be prepared
`essentially by exnacting maritime pine bark in comminuted
`form with boiling water. saturating the filtered extract with
`sodium chloride or. alternatively. adding ammonium sulfate
`to 20% wfv. separating the precipitate formed. repeatedly
`extracting the supernatant with Vin volume of ethyl acetate.
`drying the collected ethyl acetate extracts. concentrating the
`dried extract. potuing it into 3 volumes of chloroform with
`stirring and collecting the precipitate which may be purified
`by repeating the dissolution in ethyl acetate and precipitation
`with chloroform. Other extraction methods leading to the
`same composition of the extract may also be used to prepare
`this extract.
`
`Procyanidins normalize in vitro platelet aggregation, the
`etfecls are comparable with ASA. The inhibitory elfect on
`platelet aggregation might be explained by the fact that
`thnomboxane biosynthesis is inhibited by procyanidins in
`cell free systems and in intact platelets (2). Pycnogenoln‘
`can be used as an agent in animals or humans to tighten
`capillaries so that edema formation is prevented (3.4).
`Ftnthermore. Pycnogenolm is known to have radical
`scavenging activity and anti-inflammatory properties in ani-
`mals (1). An inhibition of platelet reactivity in humans
`cannot be deduced from these properties.
`The invention is based on the finding that Pycnogenol“'.
`after oral intake. inhibits the smoking-induced enhanced
`platelet reactivity in humans and that Pycnogenolm also
`normalizes in vitro the adrenaline-induced aggregation of
`human platelets.
`It is known that Pycnogenolm produces only minor side
`efiects, such as gastro-intestinal troubles. when the extract is
`taleen on an empty stomach. No such side elfects had been
`reported after intake together with the meals.
`The new method of use according to the present inven-
`tion thus allows normalizatcion of enhanced platelet reactiv-
`ity without producing the adverse elfects related to the intake
`of ASA, especially without atfecting bleeding time. because
`Pycnogenolm causes no increase in bleeding time in
`humans. in contrast to ASA. In contrast to the dosage of
`Pycnogenolm used as a radical scavenger and anti-
`ittflammatory agent of 100 mg daily. the dosage for the
`normalisation of enhanced platelet reactivity is 200-500 mg
`daily, preferably about 250-350 mg daily. with the single
`dose being about 50-150 mg. The maritime pine bark extract
`may be administered in dry form. e.g. tablets. coated pills.
`pellets. capsules. cachets or solutions prepared with com-
`mon pharmaceutical solvents. Usual pharmaceutically
`acceptable excipients. diluents and carriers may also be
`used.
`The invention is illustrated by the following examples in
`conjunction with the figures of the accompanying drawing.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph showing the increase in platelet reac-
`tivity after smoking without intake of ASA and following
`intake of 500 mg ASA or 100 mg Pycnogenolfll demon-
`strating the etfect of ASA as well as Pycnogenolm by
`
`

`
`5,720,956
`
`3
`providing APR difference in platelet reactivity index to the
`value before smelcing. FIG. 2 is a graph showing the
`bleeding time following the administration of 500 mg ASA
`and Pycaogenolm and without medication. FIG. 3 is a graph
`showing the decrease of adrenaline-induced platelet reac-
`tivity following addltion of pine bark extract in vitro.
` l
`
`Experiments were performed with 22 male healthy smok-
`ers; written consent and approval of the local ethical com-
`mittee was obtained. 500 mg ASA or 100 mg Pycnogenolm
`(extract from the bark of the maritime pine) were given as
`tablets 2-3 hrs before the first blood sampling at an interval
`of 2 weeks. Ablanlt experiment to obtain a basic value was
`performed before. Immediateiy after a first blood sampling
`volunteas smoked 3 cigarettes within 30 min. Thereafter,
`blood sampling was repeated. 300 pl blood were suspended
`in both a syringe fllledwith E-2DTAbufl’erandin another one
`filled with EIIFA-formaldehyde buifer. Red blood cells were
`counted in both samples. Whereas in the EDTA sample the
`activated platelets attached to each other or tored blood cells
`were dissolved.
`they remained fixed in the EDTA-
`forrnaldehyde medimn. Centrifugation caused only single
`platelets to remain in the supernatant. Platelets were counted
`in both supernatant; by means of a platelet counter. The
`platelet reactivity index (PR) was calculated as follows:
`
`Platelets inED1'A X IledB1oodCel1s inFotm.ttIin-EDTA
`in
`Ax
`Ill
`
`Zn‘
`
`The PR increases linearly with the number of aggregated
`platelets.
`FIG. 1 shows the expected increase in platelet reactivity
`after smolcing with standard deviations. Smoking-induced
`platelet aggregation was significantly normalized by ASA
`(p=0.06) and by the pine bark extract (p=0.08).
`Hence it follows that a single dose of 100 mg Pyeno-
`genolm is able to normalize smoking-induced platelet
`aggregation to the same extent as 500 mg ASA; the slight
`difference between both treatments is not significant
`Bleeding time was determined following puncture of the
`earlobe before smoking. FIG. 2 shows that bleeding times
`without medication and following intake of pine bark extract
`are not significantly different, however. following intake of
`ASA the bleeding time is signifitatntly longer (p=0.0D2). The
`
`4
`bleeding time following intake of 100 mg Pycnogenolm is
`significantly shorter than after intake of 500 mg ASA
`(p=D.02).
`The example demonstrates that Pycnogenolm normalizes
`platelet aggregation in lower dose as compared to ASA.
`however. without alfectiag the bleeding time.
`
`EXAMPLE2
`
`10
`
`The following experiment was carried out to detarnine
`whether Pycnogenolm can be used in suitable concentra-
`tions to inhibit adrenaline-induced platelet aggregation.
`Blood samples were collected from healthy volunteers and
`thrornhocyte-etrrichetl plasma was obtained by repeated
`centrifugation. The aggregation rate was measured by tur-
`bidimetry with and without preincubation with Pycno-
`genoln‘ in dilferent concentrations following addition of
`adrenalin. The inhibition rate was calculated as given below.
`
`The example (FIG. 3) shows that Pycnogenolnl signifi-
`cantly inhibits platelct aggregation even in the presence of
`adrenaline.
`I claim:
`1. Method of controlling blood platelet aggregation
`induced by smoking or adrenaline in a human being com-
`prising administering to a patient in need thereof 200 to 500
`mgofexhactofthebarkofthemaritimcjincper day.
`2. Method according to claim 1 wherein about 250 to 350
`
`35
`
`3. Method according to claim 1 wherein oral administra-
`tion is used.
`4. Method according of claim 1 wherein single dose units
`of 50-150 mg are administered
`5. A method for reducing blood platelet aggregation
`induced by smoking or adrenaline in a human being com-
`prising administering to a patient in need thereof a throm-
`boxane biosynthesis inhibiting amount of extratx of the bark
`of the maritime pine.