Source: http://www.google.com/patents/US7914831?dq=7,177,838
Timestamp: 2017-02-21 03:57:15
Document Index: 623337719

Matched Legal Cases: ['Application No. 02737562', 'Application No. 02784313', 'Application No. 05723839', 'Application No. 05851567', 'Application No. 05723895', 'Application No. 05723895']

Patent US7914831 - Synergistic anti-inflammatory pharmaceutical compositions and related ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe invention provides compositions containing a fraction isolated or derived from hops and a methylxanthine. The invention additionally provides compositions containing a fraction derived from hops and a curcuminoid. The invention also provides methods of using such compositions to reduce inflammat...http://www.google.com/patents/US7914831?utm_source=gb-gplus-sharePatent US7914831 - Synergistic anti-inflammatory pharmaceutical compositions and related methods using curcuminoids or methylxanthinesAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS7914831 B2Publication typeGrantApplication numberUS 10/789,817Publication dateMar 29, 2011Filing dateFeb 27, 2004Priority dateFeb 27, 2004Fee statusPaidAlso published asCA2557643A1, CN1946409A, CN101690744A, EP1718312A2, EP1718312A4, EP1718312B1, EP2338481A2, EP2338481A3, US8092846, US8193201, US20050191375, US20070185213, US20110172253, WO2005084230A2, WO2005084230A3Publication number10789817, 789817, US 7914831 B2, US 7914831B2, US-B2-7914831, US7914831 B2, US7914831B2InventorsJohn G. Babish, Matthew L. Tripp, Jeffrey S. BlandOriginal AssigneeMetaproteomics, LlcExport CitationBiBTeX, EndNote, RefManPatent Citations (132), Non-Patent Citations (193), Classifications (29), Legal Events (6) External Links: USPTO, USPTO Assignment, EspacenetSynergistic anti-inflammatory pharmaceutical compositions and related methods using curcuminoids or methylxanthines
US 7914831 B2Abstract
1. A composition for treatment of inflammation comprising reduced isoalpha acid (RIAA) and methylxanthine in a synergistic ratio having a combination index (CI) of less than 1.
2. The composition of claim 1, wherein the RIAA is derived from hops.
3. The composition of claim 1, wherein said RIAA is a member of Genus A having the formula:
4. The composition of claim 1, wherein said RIAA is a member selected from the group consisting of dihydro-isohumulone, dihydro-isocohumulone, dihydro-adhumulone.
5. The composition of claim 1, wherein said methylxanthine is selected from caffeine; theobromine; theophylline; aminophylline; doxofylline; pentoxifylline; 8-oxopentoxifylline; 8-oxolisofylline; lisofylline; 1-proparagyl 3,7-dimethyl xanthine; 7-proparagyl 1,3-dimethyl xanthine; 3-proparagyl 1,7-dimethyl xanthine; 1,3,7-triproparagyl xanthine; 3-isobutyl-1-methylxanthine (IBMX); 1,3,7-tripropyl xanthine; 7-benzyl-IBMX; 1-propyl 3,7-dimethyl xanthine; 1,3-dipropyl 7-methyl xanthine; 1,3-dipropyl 7-proparagyl xanthine; 3,7-dimethyl 1-propyl xanthine; and 7-allyl 1,3-dimethyl xanthine.
6. The composition of claim 1, wherein the methylxanthine is caffeine.
7. The composition of claim 1, wherein the composition comprises about 50 to 7500 mg of the RIAA.
8. The composition of claim 1, wherein the composition comprises about 0.001 to 10 weight percent of the RIAA.
9. The composition of claim 8, wherein the composition comprises about 0.1 to 1 weight percent of the RIAA.
10. The composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier.
11. The composition of claim 1, wherein the composition is formulated for administration orally, topically, parenterally, or rectally.
12. The composition of claim 1, wherein the RIAA and the methylxanthine are in a ratio of about 100:1 to about 1:100.
13. The composition of claim 1, wherein the composition comprises about 0.5 to 10,000 mg of the RIAA. Description
†Adapted from Pairet, M. and van Ryn, J. Inflamm. Res. 47, Supplement: 2S93–S101 (1998) and incorporated herein by reference.
FIG. 3 illustrates exemplary fractions isolated or derived from hops. FIG. 3A shows the alpha-acid genus (AA) and representative species humulone (R═—CH2CH(CH3)2), cohumulone (R═, —CH(CH3)2), and adhumulone (R═—CH(CH3)CH2CH3); FIG. 3B shows the isoalpha acid genus (IAA) and representative species isohumulone (R═—CH2CH(CH3)2), isocohumulone (R═, —CH(CH3)2), and isoadhumulone (R═—CH(CH3)CH2CH3); FIG. 3C shows the reduced isomerized isoalpha acid genus (RIAA) and representative species dihydro-isohumulone (R═—CH2CH(CH3)2) dihydro-isocohumulone (R═, —CH(CH3)2), and dihydro-adhumulone (R═—CH(CH3)CH2CH3); FIG. 3D shows the tetra-hydroisoalpha acid genus (THIAA) and representative species tetra-hydro-isohumulone (R═—CH2CH(CH3)2), tetra-hydro-isocohumulone ((R═, —CH(CH3)2), and tetra-hydro-adhumulone (R═—CH(CH3)CH2CH3); FIG. 3E shows and the hexa-hydroisoalpha acid (HHIAA) genus with representative species hexa-hydro-isohumulone (R═—CH2CH(CH3)2) hexa-hydro-isocohumulone (R═, —CH(CH3)2), and hexa-hydro-adhumulone (R═—CH(CH3)CH2CH3).
0.5–5 0.1–5 None
Further in accordance with the present invention there are provided pharmaceutical formulations of oral dosage forms comprising an effective amount of hops derivatives for release of the active ingredient at a desired site in the gastrointestinal tract, for instance either in the stomach and/or duodenum according to known formulation techniques, for example, slow releasing tablets. Still further in accordance with the invention, there are provided pharmaceutical compositions comprising an effective tolerated amount of hops derivatives. Due to its low toxicity, high dosages of hops derivatives can be employed to produce useful results, depending upon the particular effect that is desired.
The invention additionally provides a method of reducing inflammation by administering an isoalpha acid or reduced isoalpha acid isolated from hops and a methylxanthine, such as caffeine (see Example 4). Other hops derivatives or a fraction isolated or derived from hops can also be administered with a methylxanthine such as caffeine to reduce inflammation. Methylxanthines such as caffeine and other methylated xanthine derivatives can be synthesized or isolated from natural sources such as coffee beans, tea leaves, guarana seeds, and the like. Guarana (Paullinia cupana) is a source of multiple methylxanthines, including caffeine and theophylline.
A yellow pigmented fraction isolated from the rhizomes of Curcuma longa contains curcuminoids belonging to the dicinnamoyl methane group. Curcuminoids are present to the extent of 3 to 5 percent. They are considered the most important active ingredients and are believed to be responsible for the biological activity of Curcuma longa. Though their major activity is anti-inflammatory, curcuminoids have been reported to possess antioxidant, anti-allergic, wound healing, antispasmodic, antibacterial, antifungal and antitumor activity as well. Curcumin (FIG. 4B) was isolated in 1815 and structurally defined in 1910. Other curcuminoids isolated from Curcuma longa include demethoxycurcumin (FIG. 4C), bisdemethoxycurcumin (FIG. 4D), a cis-trans geometrical isomer of curcumin (FIG. 4E), and cyclocurcumin (FIG. 4F). Curcuminoids may be found in other botanicals in addition to Curcuma longa, such as Curcuma xanthorrhiza and Curcuma zedoaria. Curcuminoids are well known for their anti-inflammatory activity. Tumeric is one of the oldest anti-inflammatory drugs used in Ayurvedic medicine. The anti-inflammatory activity of curcuminoids has been evaluated in inflammatory reaction models such as chemical or physical irritants like carrageenin, cotton pellets, formaldehyde and the granuloma pouch. Human, double-blinded, clinical trials have demonstrated efficacy in rheumatoid arthritis at a dose of 1200 mg curcuminoids/day for five to six weeks. At these doses, however, signs of gastrointestinal (GI) discomfort and stomach irritation are frequently reported. The GI upset and stomach irritation caused by high doses of curcuminoids may be due to the fact that curcuminoids act on prostaglandin production in a manner similar to that of aspirin and aspirin-like anti-inflammatory agents.
Equipment used in this example included: an OHAS Model #E01140 analytical balance, a Forma Model #F1214 biosafety cabinet (Marietta, Ohio), various pipettes to deliver 0.1 to 100 μL (VWR, Rochester, N.Y.), a cell hand tally counter (VWR Catalog #23609-102, Rochester, N.Y.), a Forma Model #F3210 CO2 incubator (Marietta, Ohio), a hemacytometer (Hausser Model #1492, Horsham, Pa., a Leica Model #DM IL inverted microscope (Wetzlar, Germany), a PURELAB Plus Water Polishing System (U.S. Filter, Lowell, Mass.), a 4° C. refrigerator (Forma Model #F3775, Marietta, Ohio), a vortex mixer (VWR Catalog #33994-306, Rochester, N.Y.), and a 37° C. water bath (Shel Lab Model #1203, Cornelius, Oreg.).
In the past, the classical COX-2 hypothesis has downplayed the role of COX-2 expression in the gastrointestinal mucosa. While in normal gastric mucosa COX-1 is the predominant COX isozyme, as demonstrated in this example and in the literature, there is increasing evidence that detectable amount of COX-2 mRNA and protein are both constitutively expressed and inducible in specific locations of the gastric mucosa in both animals and humans (Halter et al. Gut 49:443453 (2001)). Recent studies in rats have shown that whereas selective inhibition of COX-1 or COX-2 is not ulcerogenic, combined inhibition of both COX-1 and COX-2 induces severe lesions in the stomach and small intestine comparable with the effects of NSAID such as indomethacin. This observation suggests an important contribution of COX-2 to the maintenance of gastrointestinal mucosal integrity.
Summar—This example illustrates that hops fractions and derivatives inhibit COX-2 synthesis of PGE2 preferentially over COX-1 synthesis of PGE2 in the RAW 264.7 murine macrophage model.
For COX-2 associated PGE2 synthesis, 100 μL of medium were removed from each well of the cell plates prepared on day one and replaced with 100 μL of equilibrated 2× final concentration of the test compounds. Cells were then incubated for 90 minutes. Twenty μL of LPS were added to each well of cells to be stimulated to achieve a final concentration of 10 ng LPS/mL and the cells were incubated for 4 h. Following the LPS stimulation, the appearance of the cells was observed, and cell viability was assessed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-based calorimetric assay (Sigma, St. Louis, Mo.). The MTT solution was added directly to the wells after sampling for PGE2 determination. The absorbance of each well was read at 580 nm using an ELISA plate reader. No toxicity was observed at the highest concentrations tested for any of the compounds. Twenty-five μL of supernatant medium from each well was transferred to a clean microfuge tube for the determination of PGE2 released into the medium. PGE2 was assayed and reported as previously described in EXAMPLE 1.
For COX-1 associated PGE2 synthesis, 100 μL of medium were removed from each well of the cell plates prepared on day one and replaced with 100 μL of equilibrated 2× final concentration of the test compounds. Cells were then incubated for 90 minutes. Next, instead of LPS stimulation, the cells were incubated with 100 μM arachidonic acid for 15 minutes. Twenty-five μL of supernatant medium from each well was transferred to a clean microfuge tube for the determination of PGE2 released into the medium. The appearance of the cells was observed and viability was determined as described above. No toxicity was observed at the highest concentrations tested for any of the compounds. Twenty-five μL of supernatant medium from each well was transferred to a clean microfuge tube for the determination of PGE2 released into the medium. PGE2 was determined and reported as previously described in EXAMPLE 1. The median inhibitory concentrations (IC50) for PGE2 synthesis from both COX-2 and COX-1 were calculated as described below.
Summary—This example describes the effect of combinations of reduced isomerized alpha acids (RIAA) and curcumin on the inhibition of prostaglandin E2 (PGE2) production in the tumor necrosis factor-α (TNFα)-stimulated human aortic endothelial cell model of inflammation.
The standard equipment used in these experiments is described in Example 1. Chemicals and reagents were obtained as follows. TNFα was from Sigma (St. Louis, Mo.). Prostaglandin E2 monoclonal antibody kit was purchased from Cayman Chemical (Ann Arbor, Mich.). Heat inactivated Fetal Bovine Serum (FBS-HI Cat. #35-011CV) and Dulbecco's Modification of Eagle's Medium (DMEM Cat #10-1013CV) was purchased from Mediatech (Herndon, Va.). Unless otherwise noted, all standard reagents were obtained from Sigma (St. Louis, Mo.) and were the purest commercially available. Test substances included RIAA obtained from Betatech Hops Products (Redihop (rho-iso-alpha acids (RIAA), 29.5-30.5%, <0.2% iso-alpha acids)) (Washington, D.C.) and curcumin extract (06656) (Metagenics, Gig Harbor, Wash.). Other commercial sources of curcumin include Nutriscience Innovations (Fairfield Conn.).
On the day of the experiment, the EGM-2 growth medium was aspirated and replaced with 200 μL EGM-2 containing the test material. The EGM-2 growth medium containing test material was formulated by adding 4 μL of 250× stock test material in dimethylsulfoxide (DMSO) to 1 mL of EGM-2. Thus, each well contained the same amount of DMSO. Control wells received DMSO in growth media only. The final concentrations of test material were 5, 1, 0.1 and 0.01 μg/mL. The test material was added before stimulation with 100 ng/ml TNFα.
TNFα stimulation.
Fraction RIAA
Determination of PGE2—A commercial, non-radioactive procedure for quantification of PGE2 was employed (Caymen Chemical, Ann Arbor, Mich.) for the determination of PGE2, and the recommended procedure of the manufacturer was used without modification. Briefly, 50 μL of the supernatant culture medium were diluted with appropriate amounts of acetylcholinesterase-labeled tracer and PGE2 antiserum and incubated at room temperature for 18 h. Afterwards, the wells in the PGE2-assay microtiter plate were emptied and rinsed with wash buffer; two-hundred μL of Ellman's reagent containing substrate for acetylcholinesterase were then added. The reaction was maintained on a slow shaker at room temperature for 1 h and the absorbance at 415 nm was determined in a Bio-tek Instruments (Model #Elx800, Winooski, Vt.) enzyme-linked immunosorbent assay (ELISA) plate reader. The manufacturer's specifications for this assay include an intra-assay coefficient of variation of <10%, cross reactivity with PGD2 and PGF2α of less than 1% and linearity over the range of 10-1000 pg mL-1. The PGE2 concentration was computed as pg PGE2 per 105 cells, as described below.
Median inhibitory concentrations for RIAA, curcumin and RIAA:curcumin combinations for TNFα-stimulated HAEC are presented in Table 5, with the regions of synergy computed for each combination. Synergy was noted for all RIAA:curcumin combinations, albeit at different segments of the dose-response curves. Regions of synergy were seen at both the low and high ends of the dose response curve and with combinations in which RIAA>curcumin also when RIAA<curcumin (for example, RIAA:curcumin 100:1 to 1:100). Thus, it is reasonable to expect synergy to occur in vivo over a wide range of doses of both RIAA and curcumin regardless of the ratio of the components in the formulation dosed.
TABLE 5 Median inhibitory concentrations and regions of synergy for RIAA, curcumin and RIAA: curcumin combinations in TNFα-stimulated HAEC. Region of Synergy RIAA IC50 RIAA Test Material [%] [μg/mL] [μg/mL] RIAA 100 0.81 Curcumin 0 1.4 RIAA:Curcumin [100:1] 99 1.6 4.6–495 RIAA:Curcumin [10:1] 91 2.4 30–2266 RIAA:Curcumin [3:1] 75 1.3 0.000001–0.17 RIAA:Curcumin [3:2] 60 1.1 0.000004–0.36 RIAA:Curcumin [1:1] 50 1.7 0.00004–0.052 RIAA:Curcumin [2:3] 40 4.6 0.000026–0.013 RIAA:Curcumin [1:10] 9.1 2.9 0.000037–0.0018 RIAA:Curcumin [1:100] 1.0 2.0 0.0000082–0.000055 Region of synergy defined by CI < 1.0 HAEC were treated with test material 60 minutes prior to TNFα stimulation and incubated overnight. Eighteen hours post TNFα-stimulation, supernatant media was sampled for PGE2 determination. Median inhibitory concentrations were computed from a minimum of four concentrations over three independent experiments. The CIs were computed as described above.
These results show that RIAA and curcumin extract are potent inhibitors of PGE2 biosynthesis in TNFα-stimulated HAEC. Synergy between RIAA and curcumin for inhibition of PGE2 biosynthesis was observed at 100:1, 10:1 and 3:2 ratios of RIAA:curcumin. For the 100:1 and 10:1 combinations, this synergy occurred at the upper end of the dose-response curve and represented concentrations of RIAA greater than 3.4 and 30 μg/mL, respectively. Particularly effective synergy was observed at the 3:2 ratio of RIAA:curcumin, where the CI was less than 1 for concentrations of RIAA less than 0.36 μg/mL. Antagonism was more frequently observed than synergy for the RIAA:curcumin combinations tested. The most pronounced antagonism was noted at 40% RIAA with a significant increase in IC50 to 4.6 μg/mL and a mean CI for the IC50, IC75 and IC90 of 15.
Results—The IC50 of 1.3 μg/mL (95% confidence limit (CL) 0.41-3.9 μg/mL) obtained for RIAA in this study was consistent with previous results for RIAA in this laboratory using the LPS-RAW 264.7 overnight protocol. The median PGE2 inhibitory concentration for caffeine of 25 μg/mL (95% CL 4.6-138) in this study was consistent with the value of 8.2 μg/mL recently reported in the literature (Fiebich et al., Neurotpharmacology 39:2205-2213 (2000)). IC50 and CI values for RIAA, caffeine and RIAA:caffeine combinations are presented in Table 7.
TABLE 7 Median inhibitory concentrations and regions of synergy for RIAA, caffeine and RIAA: caffeine combinations in LPS-stimulated RAW264.7 cells. Region of Synergy RIAA IC50 RIAA Test Material [%] [μg/mL] [μg/mL] RIAA 100 1.3 Caffeine 0 25 RIAA:Caffeine [100:1] 99 2.3 3.1–1360 RIAA:Caffeine [10:1] 91 3.1 697–2.4 × 108 RIAA:Caffeine [3:1] 75 1.8 2.7–1.6 × 107 RIAA:Caffeine [3:2] 60 1.9 1.1–251 RIAA:Caffeine [1:1] 50 0.91 3.8 × 10−9–5.8 × 105 RIAA:Caffeine [2:3] 40 1 1.5 × 10−11–18 RIAA:Caffeine [1:10] 9.1 1.2 2.1 × 10−8–9.4 × 107 RIAA:Caffeine [1:100] 1.0 1.8 5.7 × 10−11–47705 Region of synergy defined by CI < 1.0 RAW 264.7 cells were treated with test material 60 minutes prior to LPS stimulation and incubated overnight. Eighteen hours post LPS-stimulation, supernatant media was sampled for PGE2 determination. Median inhibitory concentrations were computed from a minimum of four concentrations over two independent experiments. The CIs were computed as described.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS3451821Mar 1, 1965Jun 24, 1969Kalamazoo Spice Extract CoIncreasing the utilization of hops and improving flavor control of malt beverages and the likeUS3552975Jun 11, 1969Jan 5, 1971Kalamazoo Spice Extract CoHop flavors for malt beverages and the likeUS3720517Dec 21, 1970Mar 13, 1973Hamm T Brewing CoPreparation of a fermented malt champagneUS3932603May 28, 1971Jan 13, 1976General Foods CorporationOral preparations for reducing the incidence of dental cariesUS3933919Mar 4, 1974Jan 20, 1976Geoffrey WilkinsonHydroformylation of mono-α-olefins and mono-α-acetylenesUS3965188Jan 3, 1974Jun 22, 1976Miller Brewing CompanyHop extract process and productUS4123561Feb 1, 1977Oct 31, 1978S.S. Steiner, Inc.Method for processing hops for brewingUS4133903Dec 6, 1976Jan 9, 1979Siegfried AktiengesellschaftProcess for preparing bitter beveragesUS4148873Nov 5, 1976Apr 10, 1979S. S. Steiner, Inc.Method for treating the skin with extracts of hopsUS4154865Sep 8, 1977May 15, 1979S. S. Steiner, Inc.Method for processing hops for brewingUS4170638May 11, 1978Oct 9, 1979S. S. Steiner, Inc.Method for producing a deodorantUS4389421Oct 30, 1981Jun 21, 1983Busch Industrial Products CorporationMethod for controlling light stability in malt beverages and product thereofUS4401684Oct 1, 1981Aug 30, 1983Australian Hop Marketers Pty. Ltd.Preservation of hops utilizing ascorbic acidUS4473551Jun 9, 1983Sep 25, 1984Faxon Pharmaceuticals, Inc.Anti-inflammatory compositionUS4554170May 2, 1983Nov 19, 1985Hop Developments LimitedExtraction of plant material by using carbon dioxideUS4644084Feb 3, 1986Feb 17, 1987Miller Brewing CompanyPreparation of tetrahydroisohumulonesUS4692280Dec 1, 1986Sep 8, 1987The United States Of America As Represented By The Secretary Of CommercePurification of fish oilsUS4758445Mar 27, 1986Jul 19, 1988Hopstabil Hopfenverarbeitungs-Gesellschaft MbhProcess for the production of isohumulonesUS4767640Apr 11, 1987Aug 30, 1988Miller Brewing CompanyLight stable hop extracts and method of preparationUS4857554Aug 17, 1987Aug 15, 1989Georgios KallimanisMethod for the treatment of psoriasisUS5006337Apr 14, 1988Apr 9, 1991Marbert GmbhMedicinal compositions based on spent brewers' grains extract, a process for the preparation thereof, and the use of spent brewers' grains extract for the preparation of cosmetic compositions, and a special brewers' grains extractUS5013571Jan 31, 1990May 7, 1991Pfizer Inc.Methods for making tetrahydroisoalpha and hexahydroisoalpha acidsUS5041300 *Apr 30, 1990Aug 20, 1991Kalamazoo Holdings, Inc.Hop flavor which is odor forming impurity freeUS5073396May 11, 1989Dec 17, 1991Kalamazoo Holdings, Inc.Beer flavored with a non-acidic hop-flavor fractionUS5082975Feb 26, 1990Jan 21, 1992Kalamazoo Holdings, Inc.Synthesis of hexahydrolupulone, novel forms thereof, and its use as a selective inhibitor of cell growth and multiplicationUS5155276Sep 9, 1991Oct 13, 1992Hopstabil Hopfenverarbeitungs GmbhProcess for the isomerization of humulone in a carbon dioxide-hops extract and a process for the isolation of isohumulone from itUS5166449Jun 5, 1991Nov 24, 1992Kalamazoo Holdings, Inc.Synthesis of hexahydrolupulone, novel forms thereof, and its use as a selective inhibitor of cell growth and multiplicationUS5264236Oct 15, 1991Nov 23, 1993Sumitomo Seika Chemicals Co.Method for production of hop extracts and hop extracts obtained therebyUS5286506Oct 29, 1992Feb 15, 1994Bio-Technical ResourcesInhibition of food pathogens by hop acidsUS5296637Dec 31, 1992Mar 22, 1994Kalamazoo Holdings, Inc.Production of odor-free tetrahydroisohumulates from alpha acids via their tetrahydrohumulates and subsequent isomerizationUS5370863Dec 16, 1992Dec 6, 1994Miller Brewing CompanyOral care compositions containing hop acids and methodUS5387425Aug 13, 1993Feb 7, 1995Rhone-Poulenc Specialty Chemicals Co.Method and composition for enhancing foam properties of fermented malt beveragesUS5604263Apr 10, 1995Feb 18, 1997Hoechst Japan LimitedTreating osteoporosis with humulonesUS5641517Jul 22, 1993Jun 24, 1997Drymed AsComposition comprising fertilized shell eggsUS5827895Sep 20, 1996Oct 27, 1998Regents Of The University Of MinnesotaHexahydrolupulones useful as anticancer agentsUS5866162Apr 9, 1997Feb 2, 1999Smithkline Beecham P.L.C.Pharmaceutical composition containing a drug/β-cyclodextrin complex in combination with an acid-base coupleUS5919813Mar 13, 1998Jul 6, 1999Johns Hopkins University, School Of MedicineUse of a protein tyrosine kinase pathway inhibitor in the treatment of diabetic retinopathyUS5968539Jun 4, 1997Oct 19, 1999Procter & Gamble CompanyMild, rinse-off antimicrobial liquid cleansing compositions which provide residual benefit versus gram negative bacteriaUS6020019Mar 26, 1996Feb 1, 2000Miller Brewing CompanyHydrogenation of hop soft resins using CO2US6129907Aug 4, 1999Oct 10, 2000Colgate Palmolive CompanyStable hydrogenated lupulone antibacterial oral compositionsUS6200594Dec 29, 1999Mar 13, 2001Vital Dynamics, Inc.Breast-enhancing, herbal compositions and methods of using sameUS6210701Apr 30, 1999Apr 3, 2001Healthcomm International, Inc.Medical food for treating inflammation-related diseasesUS6224871Mar 11, 1998May 1, 2001Reliv International, Inc.Dietary supplement for nutritionally promoting healthy joint functionUS6264995Feb 25, 2000Jul 24, 2001Thomas NewmarkHerbal composition for reducing inflammation and methods of using sameUS6277396May 11, 2000Aug 21, 2001Maximum Human Performance, Inc.Dietary supplement containing a thermogenic substance and an adrenal support substanceUS6291483Feb 11, 1998Sep 18, 2001National Institute Of ImmunologyMethods for prevention and treatment of septic shockUS6383527Mar 4, 1999May 7, 2002Nps Pharmaceuticals, Inc.Compositions comprising valerian extracts, isovaleric acid or derivatives thereof with a NSAIDUS6391346Apr 5, 2001May 21, 2002Thomas NewmarkAnti-inflammatory, sleep-promoting herbal composition and method of useUS6440465May 1, 2000Aug 27, 2002Bioderm, Inc.Topical composition for the treatment of psoriasis and related skin disordersUS6447762Jan 20, 2000Sep 10, 2002Colomer Group Spain, S.L.Hair lotion useful for treatment of hair loss and stimulating hair growthUS6482456Jun 16, 2000Nov 19, 2002Suntory LimitedMethod for producing low acid beverageUS6492429Sep 14, 2000Dec 10, 2002N.V. NutriciaComposition for the treatment of osteoarthritisUS6583322Feb 25, 2000Jun 24, 2003Kalamazoo Holdings, Inc.Dihydro and hexahydro isoalpha acids having a high ratio of trans to cis isomers, production thereof, and products containing the sameUS6689388Oct 30, 2001Feb 10, 2004Lipoprotein Technologies, Inc.Microencapsulated delivery system for high viscosity fluidsUS6790459Nov 3, 2000Sep 14, 2004Andrx Labs, LlcMethods for treating diabetes via administration of controlled release metforminUS6801860Feb 15, 1999Oct 5, 2004Genetics Institute, LlcCrystal structure of cPLA2 and methods of identifying agonists and antagonists using sameUS7144590Jan 9, 2003Dec 5, 2006Lipoprotein Technologies, Inc.Bioactive compositions derived from humulus lupulusUS7195785Jun 20, 2002Mar 27, 2007Metaproteomics, LlcComplex mixtures exhibiting selective inhibition of cyclooxygenase-2US7205151Jun 20, 2001Apr 17, 2007Metaproteomics, LlcComplex mixtures exhibiting selective inhibition of cyclooxygenase-2US7270835Oct 20, 2003Sep 18, 2007Metaproteomics, LlcCompositions that treat or inhibit pathological conditions associated with inflammatory responseUS7279185Nov 13, 2004Oct 9, 2007Metaproteonics, LlcCurcuminoid compositions exhibiting synergistic inhibition of the expression and/or activity of cyclooxygenase-2US7332185Oct 24, 2002Feb 19, 2008Metaproteomics, LlcComplex mixtures exhibiting selective inhibition of cyclooxygenase-2US7431948Apr 12, 2006Oct 7, 2008Metaproteomics, LlcCompositions that treat or inhibit pathological conditions associated with inflammatory responseUS20020028852May 18, 2001Mar 7, 2002Geetha GhaiResveratrol analogs for prevention of diseaseUS20020076452Jul 31, 2001Jun 20, 2002Ashni Naturaceuticals, Inc.Combinations of sesquiterpene lactones and ditepene lactones or triterpenes for synergistic inhibition of cyclooxygenase-2US20020077299Jul 31, 2001Jun 20, 2002Babish John G.Combinations of sesquiterpene lactones and ditepene triepoxide lactones for synergistic inhibition of cyclooxygenase-2US20020086062Oct 30, 2001Jul 4, 2002Kuhrts Eric HauserMicroencapsulated delivery system for high viscosity fluidsUS20020086070Oct 17, 2001Jul 4, 2002Kuhrts Eric HauserAnti-inflammatory and connective tissue repair formulationsUS20020102345 *Jan 26, 2001Aug 1, 2002International Brewery Business IncorporatedNon-Alcoholic beer composition wih energy enhancing characteristics and method for making the sameUS20020156087Sep 6, 2001Oct 24, 2002Nuss John M.Inhibitors of glycogen synthase kinase 3US20030003212Jun 13, 2001Jan 2, 2003Givaudan SaTaste modifiersUS20030008021Jun 20, 2001Jan 9, 2003Ashni Naturaceuticals, Inc.Complex mixtures exhibiting selective inhibition of cyclooxygenase-2US20030035851Feb 8, 2002Feb 20, 2003Sophie ChenAnti-cancer agents and method of use thereofUS20030077313May 10, 2001Apr 24, 2003Robert SchwartzAnti-stress composition intended for incorporation mainly in nutritional vehiclesUS20030096027Oct 25, 2002May 22, 2003Babish John G.Curcuminoid compositions exhibiting synergistic inhibition of the expression and/or activity of cyclooxygenase-2US20030113393Oct 24, 2002Jun 19, 2003Babish John G.Complex mixtures exhibiting selective inhibition of cyclooxygenase-2US20030133958Sep 30, 2002Jul 17, 2003Noriyasu KunoExternal agent for the skin and whitening agentUS20030180402Mar 22, 2002Sep 25, 2003Unigen Pharmaceuticals, Inc.Isolation of a dual COX-2 and 5-lipoxygenase inhibitor from AcaciaUS20030228369May 6, 2002Dec 11, 2003Kuhrts Eric HauserProcess for conversion of high viscosity fluids and compositions thereofUS20040072900Jul 8, 2003Apr 15, 2004Nps PharmaceuticalsTreating a variety of pathological conditions, including spasticity and convulsions, by effecting a modulation of CNS activity with isovaleramide, isovaleric acid, or a related compoundUS20040086580Jun 18, 2003May 6, 2004Tripp Matthew L.Synergistic compositions that treat or inhibit pathological conditions associated with inflammatory responseUS20040115290Jun 18, 2003Jun 17, 2004Tripp Matthew L.Modulation of inflammation by hops fractions and derivativesUS20040137096Jan 9, 2003Jul 15, 2004Kuhrts Eric H.Anti-inflammatory cyclooxygenase-2 selective inhibitorsUS20040138199Dec 22, 2003Jul 15, 2004Gogliotti Rocco DeanBenzoxazines and derivatives thereof as therapeutic agentsUS20040151792Oct 20, 2003Aug 5, 2004Tripp Matthew L.Compositions that treat or inhibit pathological conditions associated with inflammatory responseUS20040219240Feb 5, 2004Nov 4, 2004Babish John G.Anti-inflammatory pharmaceutical compositions for reducing inflammation and the treatment or prevention of gastric toxicityUS20050042317Jun 20, 2002Feb 24, 2005Babish John GComplex mixtures exhibiting selective inhibition of cyclooxygenase-2US20050129791Nov 13, 2004Jun 16, 2005Babish John G.Curcuminoid compositions exhibiting synergistic inhibition of the expression and/or activity of cyclooxygenase-2US20050191375Feb 27, 2004Sep 1, 2005Babish John G.Synergistic anti-inflammatory pharmaceutical compositions and related methods using curcuminoids or methylxanthinesUS20050192356Feb 27, 2004Sep 1, 2005Babish John G.Synergistic anti-inflammatory pharmaceutical compositions and methods of useUS20060127511Jan 30, 2006Jun 15, 2006Tripp Matthew LModulation of inflammation by hops fractions and derivativesUS20060127512Jan 30, 2006Jun 15, 2006Tripp Matthew LModulation of inflammation by hops fractions and derivativesUS20060127513Jan 30, 2006Jun 15, 2006Tripp Matthew LSynergistic compositions that treat or inhibit pathological conditions associated with inflammatory responseUS20060127514Jan 30, 2006Jun 15, 2006Tripp Matthew LSynergistic compositions that treat or inhibit pathological conditions associated with inflammatory responseUS20060127515Jan 30, 2006Jun 15, 2006Tripp Matthew LSynergistic compositions that treat or inhibit pathological conditions associated with inflammatory responseUS20060127516Jan 30, 2006Jun 15, 2006Tripp Matthew LModulation of inflammation by hops fractions and derivativesUS20060127517Jan 30, 2006Jun 15, 2006Tripp Matthew LSynergistic compositions that treat or inhibit pathological conditions associated with inflammatory responseUS20060193933Apr 12, 2006Aug 31, 2006Tripp Matthew LModulation of inflammation by hops fractions and derivativesUS20060233902Feb 14, 2003Oct 19, 2006Kirin Beer Kabushiki KaishaCompositions and foods for improving lipid metabolismUS20070003646Jun 12, 2006Jan 4, 2007Kuhrts Eric HMethods of administering anti-inflammatory cyclooxygenase-2 selective inhibitorsUS20070020352Jan 6, 2006Jan 25, 2007Matthew TrippTreatment modalities for autoimmune diseasesUS20070160692Oct 20, 2003Jul 12, 2007Tripp Matthew LCompositions that treat or inhibit pathological conditions associated with inflammatory responseUS20070166418Jan 4, 2007Jul 19, 2007Metaproteomics, LlcTreatment modalities for autoimmune diseasesUS20070172532Jan 16, 2007Jul 26, 2007Metaproteomics, LlcComplex Mixtures Exhibiting Selective Inhibition of Cyclooxygenase-2US20070184133Mar 29, 2007Aug 9, 2007Metaproteomics, LlcCompositions that treat or inhibit pathological conditions associated with inflammatory responseUS20080127720Oct 22, 2007Jun 5, 2008Pauli Guido FSelection and rational development of solvent systems in counter-current chromatographUS20080248131Aug 9, 2006Oct 9, 2008Metaproteomics, LlcProtein Kinase Modulation by Hops and Acacia ProductsUS20090118373Jun 10, 2004May 7, 2009Tripp Matthew LInhibition of COX-2 and/or 5-LOX activity by fractions isolated or derived from hopsCN1203268CSep 17, 1998May 25, 2005本田技研工业株式会社Lock-up control deviceDE1901277UMay 25, 1964Sep 24, 1964Kuhlmann GebVorrichtung zur herstellung von durchbrechungen bei profilstangen.DE2212148A1Mar 14, 1972Sep 28, 1972 Title not availableDE3931147C2Sep 19, 1989Dec 24, 1992Weil, Walter, Dipl.-Biol., 7600 Offenburg, DeTitle not availableDE19841615A1Sep 11, 1998Mar 16, 2000Fritz Armin MuellerMedicinal wine for alleviating pain and other symptoms of premenstrual syndrome, comprising mixture of extracts of different plants in dry white wineEP0229022A3Jul 21, 1983Nov 8, 1989LASKA, Eugene M.Novel pharmaceutical compositions comprising analgesic agents or caffeineEP0606599A1Dec 15, 1993Jul 20, 1994Miller Brewing CompanyOral care compositions containing hop acidsEP1481671B1Feb 14, 2003Aug 31, 2011Kirin Beer Kabushiki KaishaCompositions and foods for improving lipid metabolismGB2330076B Title not availableJP6312924A Title not availableJP8073369A Title not availableJP9067245A Title not availableJP10152428A Title not availableJP10179129A Title not availableJP11246399A Title not availableJP11335231A Title not availableJP11513037A Title not availableJP52145509A Title not availableJP53009084B Title not availableJP59059623U Title not availableJP2001161338A Title not availableRU2045955C1 Title not availableSU1247011A1 Title not availableWO2003082249A1Mar 19, 2003Oct 9, 2003Alcon, Inc.Co-beadlet of dha and rosemary and methods of use* Cited by examinerNon-Patent CitationsReference1"Information on arthrotrimtm product", downloaded from Internet Aug. 30, 2002.2"Information on Hops and Beer Flavours", downloaded from internet Feb. 15, 2005.3"Information on Zyflamend and Zyflamend PM", downloaded from Internet Aug. 30, 2002.4Abdel-Salam, et al., "The Ant i-Inflammatory Effects of the Phosphodiesterase Inhibitor Pentoxifylline in the Rat", Pharmacological Research, England, vol. 47, No. 4, Apr. 2003, pp. 311-340.5Abel-salam et al., Pharmacological Research, England 47(4), pp. 311-340 (Apr. 2003).6Albal, MV., et al., "Clinical evaluation of berberine in mycotic infections." Indian J. Ophthalmol 34:91-2 (1986).7Anto, et al. Pharm. Pharmacol. Comm. 4:103-106 (1998).8Anto, et al., "Anti-inflammatory Activity of Natural and Synthetic Curcuminoids", Pharmacy and Pharmacology Communications, 4(2), pp. 103-106 (1998).9Arner, P., Insulin Resistance in Type 2 Diabetes—Role of the Adipokines. Curr. Mol. Med.; 5(3):333-339, (May 2005).10Baldermann et al., J. Chromatography A 1192(1):191-3 (May 23, 2008) (Epub Apr. 8, 2008); abstract only (1 page).11Berenbaum, M.C., What is Synergy?: Pharmacol Rev; 41(2):93-141 (1989).12Bermejo, et al. Rev. Esp. Enferm. Dig. 95: 621-624 and 625-628 (2003).13Boden, G., Role of Fatty Acids in the Pathogenesis of Insulin Resistance and NIDDM. Diabetes 46(1): 3-10, (1997).14Bolick D et al., Endocrinology 144(12), pp. 5227-5231 (Dec. 2003).15Bolick, et al., "Lisofylline, a Novel Anti-inflammatory Compound, Protects Mesangial Cells From Hyperglycemia-and Angiotensin 11-Mediated Extracellular Matrix Deposition", Endocrinology, vol. 144, No. 12, Dec. 2003, pp. 5227-5231.16Bolick, et al., "Lisofylline, a Novel Anti-inflammatory Compound, Protects Mesangial Cells From Hyperglycemia—and Angiotensin 11-Mediated Extracellular Matrix Deposition", Endocrinology, vol. 144, No. 12, Dec. 2003, pp. 5227-5231.17Brown, et al. J. Chem. Soc. 545 (1959).18Byrne, et al. J. Chem. Soc. (c):2810 (1971).19Carroccio, et al. Clin. Chem. 49(6):861-867 (2003).20Carroccio, et al. Clin. Chem. 49:861-867 (2003).21Carson, j. Am. Chem. Soc. 73:1850-1851 (1951).22Chandra, et al. Indian J. Medical Research 60(1):138-142 (1972).23Chandra, et al., "Anti-inflammatory and Anti-Arthritic Activity of Volatile Oil of Curcuma Longa (Haldi)", Indian Journal of Med. Research, vol. 60, No. 1, 1972, 138-142.24 *Chappel, C.I. et al. "Subchronic toxicity study of tetrahydroisohumulone and hexahydroisohumulone in the beagle dog" 1998, Food and Chemical Toxicology, vol. 36, p. 915.25Charlier, et al. Eur. J. Med. Chem. 38:645-659 (2003).26Chattopadhyay et al., Current Science, 87(1) (Jul. 10, 2004).27Chen Wei-Jen et al., Journal of Agricultural and Food Chemistry 52(1), pp. 55-64 (Jan. 1, 2004).28Cho et al., Akt1/PKBa Is Required for Normal Growth but Dispensable for Maintenance Glucose Homeostasis in Mice, J Biol Chem 276:38349-38352 (2001).29Cho et al., Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ), Science 292:1728-1731 (2001).30Chou et al. Eur. J. Biochem. 115:207-216 (1981).31Chou et al., TIPS, pp. 450-454, Nov. 1983.32Chou, et al. Adv enzyme regul 22:27-55 (1983).33Chou, et al. Adv enzyme regul 22:27-55 (1984).34Chou, et al. Eur. J. Biochem. 115:207-216 (1981).35Chou, et al. J. Biol. Chem. 252(18):6438-6442 (1977).36Chou, et al. J. Biol. Chem. 252:6438-6442 (1977).37Chou, et al. J. Theor. Biol. 35:285-297 (1972).38Chou, et al. Trends Pharm. Sci. 4:450-454 (1983).39Chou, J. Theor. Biol. 59:253-276 (1976).40Chou, T.C., et al., Quantitative Analysis of Dose-effect Relationships; The Combined Effects of Multiple Drugs or Enzyme Inhibitors; Adv Enzyme Regul 22:27-55, (1984).41Choy, et al., Cytokine Pathways and Joint Inflammation in Rheumatoid Arthritis; New England Jour. Med. 344:pp. 907-916, (2001).42Cohen, P., Perspectives, 2002 Nature Publishing Group, vol. 1, pp. 309-315.43Cohen, Protein Kinases-the major drug targets of the twenty-first century? Nature Reviews, 1: 309-315 (2002).44Cohen, Protein Kinases—the major drug targets of the twenty-first century? Nature Reviews, 1: 309-315 (2002).45Costa, et al. Digest. Liver Dis. 35:642-647 (2003).46Crowley, et al., A Critical Role for Syk in Signal Transduction and Phagocytosis Mediated by Fcγ Receptors on Macrophages; J. Exp. Med. 186:1027-1039, (1997).47Davies, WL. Abstract—Fertiliser, Feeding stuffs and Farm Supplies J. 11:694 (1926).48De Keukeleire "Fundamentals of Beer and Hop Chemistry" Quimica Nova, 23(1) pp. 108-112 (2000).49Dignam, et al., Accurate Transcription Initiation by RNA Polymerase II in a Soluble Extract From Isolated Mammalian Nuclei; Nucl Acids Res 11:1475-1489, (1983).50Ding, et al. Biochem. Biophy. Res. Comm. 261:218-223 (1999).51El-Toumy et al., Polyphenois from Acacia Nilotica Leaves and Evaluation of Antihyperglycemic Effect of Aqueous Extract, Bulletin of the Faculty of Pharmacy (2004), 42 (2), 317-325.52EP Search Report for EP App. No. 07809709.4, (2010).53European Search Report EP 05 723 839.6, (2010).54European Search Report for corresponding EP Application No. 02737562.5 (4 pages), (2004).55European Search Report for related European Application No. 02784313.5, (2006).56Examination Report from related EP Application No. 05723839.6, dated Jan. 22, 2010, 6 pages.57Exercise as Treatment for Arthritis, Rheumatic and Immunologic Diseases, Cleveland Clinic, www.clevelandclinic.org, Mar. 14, 2000.58Extended European Search Report EP 07717798.8, (2010).59Extended European Search Report EP 07809708.6, (2010).60Fasshauer, M., et al., Hormonal Regulation of Adiponectin Gene Expression in 3T3-L1 Adipocytes; Biochem Biophys Res Commun, 290:1084-1089, (2002).61Foucault et al., J. Chromatography A 808(1-2):3-22 (May 29, 1998); abstract only (3 pages).62Friedman, et al. J Cutan Med. Surg. 6(5):449-459 (2002).63Gerhauser, Beer Constituents as Potential Cancer Chemopreventive Agents, EP Journal of Cancer 41; 1941-1954: (2005).64Gerhäuser, C., European Journal of Cancer 41 (2005), pp. 1941-1954.65Germany, "The Absolutely German Drink," contents of beer, 2004, 5 pages.66Gilani, "Studies on Antihypertensive and Antispasmodic Activities of Methanol Extract of Acacia nilotica Pods", Phytotherapy Research 13: 665-669 (1999).67Gilani, A.H., Phytotherapy Research, 13 (1999), pp. 665-669.68Goldstein, et al. Am. J. Gastroenterol. 96(4):1019-1027 (2001).69Goldstein, et al. Am. J. Gastroenterol. 96:1019-1027 (2001).70Halter, et al. Gut 49:443-453 (2001).71Hamberg, et al. J. Bio. Chem. 246(22):6713-6721 (1971).72Hamberg, et al. J. Bio. Chem. 246:6713-6721 (1971).73Hibi, M., et al., IL-6 Cytokine Family and Signal Transduction: A Model of the Cytokine System. J Mol Med. 74(1):1-12, (Jan. 1996).74Hofstee, B.H., Non-inverted Versus Inverted Plots in Enzyme Kinetics; Nature 184:1296-1298, (1959).75Huang, et al. Cancer Res. 51:813-819 (1991).76Hutchcroft, J. E., et al., Association of the 72-kDa Protein-tyrosine Kinase Ptk72 with the B-cell Antigen Receptor; J. Biol. Chem. 267:8613-8619, (1992).77Information on "Hops and Beer Flavours", IOB Technical Symposium, Apr. 2001, pp. 1-9.78Information on "Zyflamend and Zyflamend PM", downloaded from Internet Aug. 30, 2002.79Information on ArthroTrimTM product, downloaded from Internet Aug. 30, 2002.80International Search Report for Corresponding PCT Application No. PCT/US05/41018; 2pp.81International Search Report for PCT /US06/30920, Aug. 3, 2007, 3 pages.82International Search Report for PCT/US02/19617.83International Search Report for PCT/US04/16043.84International Search Report for PCT/US06/47196.85International Search Report for PCT/US2005/039483.86International Search Report for related PCT Application No. PCT/US06/30920, (2007).87International Search Report for related PCT Application No. PCT/US06/47196.88Jiang, K., et al., Regulation of Akt-dependent Cell Survival by Syk and Rac; Blood 101, pp. 236-244, (2003).89Kaltner, Investigation of Formation of Hops Aroma and Technological Measures for Production of Hops-Aromatic Beers, Technical University of Munich, Approved Dissertation, (2000).90Kaltner, Investigation of formation of Hops Aroma and technological Measures for Products of Hops-Aromatic Beers, Technical University of Munich, 7 pp, corresponding to Kaltner, D., Technische Universitat Munchen, (Nov. 30, 2000), pp. 1-193, plus Tabs. AH1-AH31.91Kanematsu, et al. J Bone Miner Res 12(11):1789-1796 (1997).92Kasturi, R., et al., Hormonal Regulation of Stearoyl Coenzyme a Desaturase Activity and Lipogenesis During Adipose Conversion of 3T3-L1 Cells; J Biol Chem, 257:12224-12230, 1982.93Konda, et al., Arthritis & Rheumatism 62(6): 1683-1692, (2010).94Lamy Virginie et al., Apoptosis, an Int'l Journal on Programmed Cell Death,13(10), pp. 1232-1242 (Aug. 25, 2008).95Lamy Virginie et al., Carcinogenesis, 28(7), pp. 1575-1581 (Jul. 2007).96Li, Y., et al., Differential Gene Regulation by PPARgamma Agonist and Constitutively Active PPARgamma2; Mol. Endocrinol., 16:1040-1048, (2002).97Lopes, Curr. Med Res Opin. 8(3):145-149 (1982).98Lopes, Curr. Med Res Opin. 8:145-149 (1982).99Mannering et al., Food, Nutrition and Chemical Toxicity, pp. 311-323 (Jan. 1, 1993).100Martin, G., et al. PPARgamma Activators Improve Glucose Homeostasis by Stimulating Fatty Acid Uptake in the Adipocytes; Atherosclerosis 137 Suppl:S75-S80, (1998).101Meling, et al. Scand. J. Gastroenterol. 31:339-344 (1996).102Moon KD, et al., Molecular Basis for a Direct Interaction between the Syk Protein-tyrosine Kinase and Phosphoinositide 3-Kinase; J. Biol. Chem. 280, No. 2, Issue of Jan. 14, pp. 1543-1551, (2005).103Newark, et al., "Beyond Aspirin", pp. 147-150, Hohm Press (2000).104Noreen, et al. J. Nat. Prod 61:2-7 (1998).105Oakes, N. D., et al., Thiazolidinediones Increase Plasma-Adipose Tissue FFA Exchange Capacity and Enhance Insulin-Mediated Control of Systemic FFA Availability; Diabetes 50(5):1158-1165, (2001).106Office Action issued for U.S. Appl. No. 11/667,614 mailed Apr. 16, 2010.107Office Action issued for U.S. Appl. No. 11/667,615 mailed Mar. 16, 2010.108Office Action issued for U.S. Appl. No. 11/701,583 mailed Feb. 8, 2008.109Office Action issued for U.S. Appl. No. 11/701,583 mailed Jul. 6, 2009.110Office Action issued for U.S. Appl. No. 11/701,583 mailed Nov. 26, 2008.111Office Action issued in U.S. Appl. No. 10/464,834 on Aug. 3, 2010.112Office Action issued in U.S. Appl. No. 10/532,388 on Mar. 26, 2010.113Office Action issued in U.S. Appl. No. 10/590,301 on Aug. 19, 2010.114Office Action issued in U.S. Appl. No. 10/590,424 on Jun. 29, 2010.115Office Action issued in U.S. Appl. No. 10/789,814 on Jun. 11, 2010.116Office Action issued in U.S. Appl. No. 11/344,556 on Dec. 16, 2009.117Office Action issued in U.S. Appl. No. 11/344,556 on Mar. 27, 2009.118Office Action issued in U.S. Appl. No. 11/344,556 on Sep. 3, 2010.119Office Action issued in U.S. Appl. No. 11/344,557 on Apr. 21, 2008.120Office Action issued in U.S. Appl. No. 11/344,557 on Aug. 28, 2009.121Office Action issued in U.S. Appl. No. 11/344,557 on Jan. 10, 2007.122Office Action issued in U.S. Appl. No. 11/344,557 on Mar. 25, 2010.123Office Action issued in U.S. Appl. No. 11/344,557 on Sep. 26, 2007.124Office Action issued in U.S. Appl. No. 11/649,584 on Mar. 3, 2010.125Office Action issued in U.S. Appl. No. 11/729,696 on Mar. 25, 2010.126Pairet, et al. Inflamm. Res 47(2), s93-s101 (1998).127Pairet, et al. Inflamm. Res 47, Supplement 2s93-s101 (1998).128Parker, P. J., et al., Glycogen Synthase from Rabbit Skeletal Muscle; Effect of Insulin on the State of Phosphorylation of the Seven Phosphoserine Residues in vivo; (1983) Eur. J. Biochem. 130:227-234.129Parts per Milliion, 1 page, 2004.130Pippa, et al. Scand. J. Gastroenterol. Suppl. 167:32-35 (1989).131Plewig, et al. J Invest. Dermatol. 65(6):532-536 (1975).132Poullis ,et al. J. Gastroenterol. Hepatol. 18:756-762 (2003).133Poullis, et al. J. Gastroenterol. Hepatol. 18:756-762 (2003).134Provital Group, Rosemary-eco Botany, 2007, 9 pages.135Q & A, (what does ppm or ppb mean?) 3 pages, 2004.136Raeder, E. M., et al., Syk Activation Initiates Downstream Signaling Events During Human Polymorphonuclear Leukocyte Phagocytosis, J. Immunol. 163: 6785-6793, (1999).137Rahman, M.M., et al., "Conjugated linoleic acid inhibits osteoclast differentiation of RA W264.7 cells by modulating RANKL signaling" J. Lipid Res., 47(8): 1739-1748, (2006).138Raz, I, et al.; Diabetes: insulin resistance and derangements in lipid metabolism. Cure Through intervention in fat transport and storage; Diabetes Metab. Res. Rev.; 21: 3-14 (2005).139Ringbom, et al. J. Nat Prod 61:1212-1215 (1998).140Røseth, digest. Liver Dis. 35:607-609 (2003).141Schjerven, et al. Br. J. Dermatol. 149:484-491 (2003).142Shah, et al. Gut 48:339-346 (2001).143Shimamura, et al. Biochem. Biophys. Res. Comm. 289:220-224 (2001).144Shimamura, et al. Biochem. Biophys. Res. Comm. 289:220-224, (2001).145Shureiqi, et al. Cancer res. 61:6307-6312 (2001).146Sivri, fundam. Clinic. Pharmacol. 18:23-31 (2004).147Smith, et al., Natural Foam Stabilizing and Bittering Compounds Derived From Hops, Journal of the American Society of Brewing Chemists, vol. 56, No. 2, 1998, pp. 52-57.148Stephan T E et al., Biochemical Pharmacology, 55(4), pp. 505-514, (Feb. 15, 1998).149Stevens, et al., Xanthohumol and Related Prenylflavonoids from Hops and Beer: To your Good Health!, Sciencedirect, Nov. 2007, 2 pp (abstract).150Stevens, Xanthohumol and related Prenylflavonoids from Hops and Beer: To Your Good Health, Science Direct, 2pp (2004).151Stumvoll, M., et al., Glitazones: clinical effects and molecular mechanisms. Ann Med 34(3): 217-224, (2002).152Subbaramaiah, et al. Cancer Res. 60:2399-2404 (2000).153Suh, et al. Cancer Res 58:717-723 (1988).154Suh, et al. Cancer Res. 58:717-723 (1988).155Supplemental European Search Report for EP 07845228, (2010).156Supplementary European Search Report from related EP Application No. 05851567, 8PP, (2008).157Supplementary Partial European Search Report for EP Application No. 05723895.8 (5 pages), (2007).158Supplementary Partial European Search Report for related European Patent Application No. 05723895.8, 5 pages, (2007).159Tagashira M et al., Bioscience, Biotechnology, and Biochemistry, 59(4), pp. 740-742 (Apr. 1995).160Tagashira, et al., Biosci. Biotech. Biochem. 59(4):740-742 (1996).161The national. 3 pages (1999).162Thomas m. Newmark and paul schulick, Beyond Aspirin nature's answer to arthritis, cancer & alzheimer's disease, hohm press (2000) release 7; pp. 147-151, 248.163Thomas m. Newmark and paul schulick, Beyond Aspirin nature's answer to arthritis, cancer & alzheimer's disease, hohm press (2000) release 7; pp. 147-151.164Tibble, et al. Drugs Today 37(2):85-96 (2001).165Tibble, et al. Drugs Today 37:85-96 (2001).166Tibble, et al. Gut 45:362-366 (1999).167Tobe, et al. Biosci. Biotech. Biochem 61(1):158-159 (1997).168Turmeric: The Ayurvedic Spice of Life, published at www.bioponic.com/pdfs/TurmericAyurveda.pdf (2003).169US News and world report, 10 pages (2008).170van der Kraan P.M., et al., Anabolic and destructive mediators in osteoarthritis. Curr Opin Clin Nutr Metab Care,3:205-211, 2000.171Van Montfrans et al. Inflammatory Signal Transduction in Crohn's Disease and Novel Therapeutic Approaches. Science Direct, Jun. 2, 2002, 20 pages. Biochemical Pharmacology, vol. 64, issues 5-6.172Vanhoenacker, et al., Analysis of iso-alpha-acids and reduced iso-alpha-acids in beer by direct injection and liquid chromatography with ultraviolet absorbance detection or with mass spectrometry, Journal of Chromatography, vol. 1035, No. 1, (Apr. 30, 2004), pp. 53-61.173Vanhoenacker, et al., Journal of Chromatography, vol. 1035, No. 1, (Apr. 30, 2004), pp. 53-61.174Verdu et al., Cell-autonomous regulation of cell and organ growth in Drosopholia by Akt/PKB; Nat cell Biol 1:500-505 (1999).175Verzele and De Keukeleire (eds.) Chemistry and Analysis of Hop and Beer Bitter Acids; Elsevier, Chapters 5, 20 pages (1991).176Verzele and De Keukeleire (eds.) Chemistry and Analysis of Hop and Beer Bitter Acids; Elsevier, Chapters 6, 8 pages (1991).177Verzele, et al. Chemistry and analysis of hop and beer bitter acids, Developments in food science, 27, pp. 44-51, 88-139 (1991).178Wang, et al. Free Radical Biology & Medicine 27:612-616 (1999).179Ward, et al., Therapeutic Potential of Phosphoinositide 3-Kinase Inhibitors, Chemistry & Biology, vol. 10, 207-210, Mar. 2003.180Ward, et al., Therapeutic Potential of Phosphoinositide 3-Kinase Inhibitors, Chemistry & Biology, vol. 10, 207-213, Mar. 2003.181Ward, S.G., et al., Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Curr Opin Pharmacol. Aug;3(4):426-434, (2003).182Warner, et al. Proc Natl Acad Sci USA 96:7563-7568 (1999).183Warner, T.D. et al. Nonsteroidal drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis. Proc. Natl. Acad. Sci. USA 96:7563-7568, (1999).184Wong B.R., et al., Targeting Syk as a treatment for allergic and autoimmune disorders. Expert Opin Investig Drugs 13:743-762, 2004.185Yajima, H., et al., Isohumulones, Bitter Acids Derived From Hops, Activate Both Peroxisome Proliferator-Activated Receptor Alpha and Gamma and Reduce Insulin Resistance. J Biol Chem, 279: 33456-33462, (2004).186Yamada, T., et al., Association with B-cell antigen cell antigen receptor with protein-tyrosine kinase-P72(Syk) and activation by engagement of membrane IgM; Eur. J. Biochem. 213: 455-459, (1993).187Yamamoto, et al. Abstract—Prostaglandins & Other Lipid Mediators 59:1-235 (1999).188Yamamoto, FEBS Letters 465:103-106 (2000).189Yamauchi, T., et al., The mechanisms by Which Both Heterozygous Peroxisome Proliferator-activated Receptor gamma (PPARgamma) Deficiency and PPARgamma Agonist Improve Insulin Resistance; J Biol Chem 276(44): 41245-41254, (2001).190Yang, W. S., et al., Weight Reduction Increases Plasma Levels of an Adipose-Derived Anti-Inflammatory Protein, Adiponectin; J Clin Endocrinol Metab 86(8): 3815-3819, (2001).191Yui, et al. Biol. Pharm. Bull. 26(6):753-760 (2003).192Yui, et al. Biol. Pharm. Bull. 26:753-760 (2003).193Zhao Feng et al., Biological and Pharmaceutical Bulletin, 26(1), pp. 61-65 (Jan. 2003).* Cited by examinerClassifications U.S. Classification424/778, 514/690, 514/574, 514/263.31International ClassificationA61K31/52, A01N35/00, A01N43/90, A01N65/00, A61K31/557, A61K36/9066, A61K36/00, A01N37/00, A61K36/185, A61K31/12, A61K45/06, A61K31/19, A61K31/522Cooperative ClassificationA61K36/9066, A61K36/185, A61K45/06, A61K31/19, A61K31/522, A61K31/12European ClassificationA61K45/06, A61K31/19, A61K31/12, A61K31/522, A61K36/185, A61K36/9066Legal EventsDateCodeEventDescriptionJun 14, 2004ASAssignmentOwner name: METAPROTEOMICS, LLC, CALIFORNIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BABISH, JOHN G.;BLAND, JEFFREY S.;TRIPP, MATTHEW L.;REEL/FRAME:014728/0597;SIGNING DATES FROM 20040330 TO 20040405Owner name: METAPROTEOMICS, LLC, CALIFORNIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BABISH, JOHN G.;BLAND, JEFFREY S.;TRIPP, MATTHEW L.;SIGNING DATES FROM 20040330 TO 20040405;REEL/FRAME:014728/0597Jun 2, 2006ASAssignmentOwner name: COMERICA BANK, CALIFORNIAFree format text: SECURITY AGREEMENT;ASSIGNORS:METAGENICS, INC.;METAGENICS FAR EAST, INC.;META PROTEOMICS, L.L.C.;REEL/FRAME:017706/0815;SIGNING DATES FROM 20050531 TO 20060531Owner name: COMERICA BANK, CALIFORNIAFree format text: SECURITY AGREEMENT;ASSIGNORS:METAGENICS, INC.;METAGENICS FAR EAST, INC.;META PROTEOMICS, L.L.C.;SIGNING DATES FROM 20050531 TO 20060531;REEL/FRAME:017706/0815Oct 15, 2009ASAssignmentOwner name: BANK OF AMERICA, N.A., CALIFORNIAFree format text: SECURITY AGREEMENT;ASSIGNOR:META PROTEOMICS, LLC;REEL/FRAME:023373/0684Effective date: 20091014Owner name: BANK OF AMERICA, N.A.,CALIFORNIAFree format text: SECURITY AGREEMENT;ASSIGNOR:META PROTEOMICS, LLC;REEL/FRAME:023373/0684Effective date: 20091014Oct 26, 2009ASAssignmentOwner name: META PROTEOMICS, LLC, CALIFORNIAFree format text: RELEASE BY SECURED PARTY;ASSIGNOR:COMERICA BANK;REEL/FRAME:023424/0038Effective date: 20091014Owner name: METAGENICS FAR EAST, INC., CALIFORNIAFree format text: RELEASE BY SECURED PARTY;ASSIGNOR:COMERICA BANK;REEL/FRAME:023424/0038Effective date: 20091014Owner name: METAGENICS, INC., CALIFORNIAFree format text: RELEASE BY SECURED PARTY;ASSIGNOR:COMERICA BANK;REEL/FRAME:023424/0038Effective date: 20091014Feb 7, 2012CCCertificate of correctionSep 3, 2014FPAYFee paymentYear of fee payment: 4RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services