Dry Powder Drug Delivery System And Methods

  *US09802012B2*
  US009802012B2                                 
(12)United States Patent(10)Patent No.: US 9,802,012 B2
  et al. (45) Date of Patent:Oct.  31, 2017

(54)Dry powder drug delivery system and methods 
    
(75)Inventor: Mannkind Corporation,  Valencia, CA (US) 
(73)Assignee:MannKind Corporation,  Westlake Village, CA (US), Type: US Company 
(*)Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 366 days. 
(21)Appl. No.: 13/941,365 
(22)Filed: Jul.  12, 2013 
(65)Prior Publication Data 
 US 2014/0014106 A1 Jan.  16, 2014 
 Related U.S. Patent Documents 
(60)Provisional application No. 61/671,041, filed on Jul.  12, 2012.
 
Jan.  1, 2013 A 61 M 15 00 F I Oct.  31, 2017 US B H C Feb.  4, 2014 A 61 M 11 001 L I Oct.  31, 2017 US B H C Feb.  4, 2014 A 61 M 15 002 L I Oct.  31, 2017 US B H C Feb.  4, 2014 A 61 M 15 0005 L I Oct.  31, 2017 US B H C Feb.  4, 2014 A 61 M 15 0021 L I Oct.  31, 2017 US B H C Jan.  1, 2013 A 61 M 15 0028 L I Oct.  31, 2017 US B H C Feb.  4, 2014 A 61 M 15 0025 L A Oct.  31, 2017 US B H C Jan.  1, 2013 A 61 M 15 0065 L A Oct.  31, 2017 US B H C Jan.  1, 2013 A 61 M 2016 0027 L A Oct.  31, 2017 US B H C Jan.  1, 2013 A 61 M 2202 064 L A Oct.  31, 2017 US B H C Jan.  1, 2013 A 61 M 2205 076 L A Oct.  31, 2017 US B H C Jan.  1, 2013 A 61 M 2206 14 L A Oct.  31, 2017 US B H C Jan.  1, 2013 A 61 M 2206 16 L A Oct.  31, 2017 US B H C Jan.  1, 2013 A 61 M 2206 20 L A Oct.  31, 2017 US B H C
(51)Int. Cl. A61M 015/00 (20060101); A61M 011/00 (20060101); A61M 016/00 (20060101)
(58)Field of Search  128/203.12, 203.15, 203.19, 203.21, 203.23

 
(56)References Cited
 
 U.S. PATENT DOCUMENTS
 2,549,303  A  4/1951    Friden     
 2,754,276  A  7/1956    Joseph et al.     
 D189,076  S  10/1960    Altman     
 3,337,740  A  8/1967    Gray et al.     
 3,407,203  A  10/1968    Buijle     
 3,518,340  A  6/1970    Raper     
 3,622,053  A  11/1971    Ryden     
 3,669,113  A  6/1972    Altounyan et al.     
 3,673,698  A  7/1972    Guerard     
 3,823,816  A  7/1974    Controullis et al.     
 3,823,843  A  7/1974    Stephens et al.     
 3,856,142  A  12/1974    Vessalo     
 3,873,651  A  3/1975    Mosley, Jr. et al.     
 3,906,950  A  9/1975    Cocozza     
 3,921,637  A  11/1975    Bennie et al.     
 3,976,773  A  8/1976    Curran et al.     
 3,980,074  A  9/1976    Watt et al.     
 3,998,226  A  12/1976    Harris     
 4,013,075  A  3/1977    Cocozza     
 4,018,619  A  4/1977    Webster et al.     
 4,022,749  A  5/1977    Kuechler     
 4,040,536  A  8/1977    Schwarz     
 4,047,525  A  9/1977    Kulessa et al.     
 4,066,756  A  1/1978    Orr et al.     
 4,078,128  A  3/1978    Hoyt et al.     
 4,091,077  A  5/1978    Smith et al.     
 4,098,273  A  7/1978    Glenn     
 4,102,953  A  7/1978    Johnson et al.     
 4,110,240  A  8/1978    Leo et al.     
 4,148,308  A  4/1979    Sayer     
 4,153,689  A  5/1979    Hirai     
 D252,707  S  8/1979    Besnard     
 4,168,002  A  9/1979    Crosby     
 4,171,000  A  10/1979    Uhle     
 4,175,556  A  11/1979    Freezer     
 4,187,129  A  2/1980    Bost et al.     
 4,196,196  A  4/1980    Tiholiz     
 4,206,758  A  6/1980    Hallworth et al.     
 4,210,140  A  7/1980    James et al.     
 4,211,769  A  7/1980    Okada     
 4,268,460  A  5/1981    Boiarski et al.     
 4,272,398  A  6/1981    Jaffe     
 4,275,820  A  6/1981    LeBlond     
 4,289,759  A  9/1981    Heavener     
 4,294,829  A  10/1981    Suzuki     
 4,300,546  A  11/1981    Kruber     
 4,356,167  A  10/1982    Kelly     
 D269,463  S  6/1983    Young et al.     
 4,407,525  A  10/1983    Hoppe     
 4,456,007  A  6/1984    Nakao et al.     
 4,481,139  A  11/1984    Folkers et al.     
 4,483,922  A  11/1984    Carpenter     
 D276,654  S  12/1984    Snellman-Wasenius et al.     
 4,487,327  A  12/1984    Grayson     
 4,524,769  A  6/1985    Wetterlin     
 4,526,804  A  7/1985    Escallon     
 4,534,345  A  8/1985    Wetterlin     
 D282,209  S  1/1986    Newell et al.     
 4,581,020  A  4/1986    Mittleman     
 4,592,348  A  6/1986    Waters, IV et al.     
 4,613,500  A  9/1986    Suzuki     
 4,615,817  A  10/1986    McCoy     
 4,624,861  A  11/1986    Yale et al.     
 4,637,996  A  1/1987    Konishi     
 D288,852  S  3/1987    Miyoshi     
 4,659,696  A  4/1987    Hirai et al.     
 4,668,218  A  5/1987    Virtanen     
 4,671,954  A  6/1987    Goldberg et al.     
 4,681,752  A  7/1987    Melillo     
 D295,321  S  4/1988    Hallworth     
 4,742,156  A  5/1988    Wright     
 4,757,066  A  7/1988    Shiokari et al.     
 4,792,451  A  12/1988    Kim     
 4,811,731  A  3/1989    Newell et al.     
 D301,273  S  5/1989    Leonard     
 4,835,312  A  5/1989    Itoh et al.     
 4,841,964  A  6/1989    Hurka et al.     
 4,847,091  A  7/1989    Illum     
 4,849,227  A  7/1989    Cho     
 4,861,627  A  8/1989    Mathiowitz     
 4,866,051  A  9/1989    Hunt et al.     
 4,873,087  A  10/1989    Morishita et al.     
 4,887,722  A  12/1989    Greenward, Sr.     
 4,900,730  A  2/1990    Miyauchi     
 4,907,583  A  3/1990    Wetterlin     
 4,925,673  A  5/1990    Steiner     
 4,926,852  A  5/1990    Zoltan et al.     
 4,927,555  A  5/1990    Colarusso, Jr.     
 4,927,928  A  5/1990    Shroot et al.     
 4,946,828  A  8/1990    Markussen     
 4,981,295  A  1/1991    Belman et al.     
 4,981,625  A  1/1991    Rhim et al.     
 4,983,402  A  1/1991    Steiner et al.     
 4,984,158  A  1/1991    Hillsman     
 4,991,605  A  2/1991    Keritsis     
 4,998,624  A  3/1991    Capes et al.     
 5,006,343  A  4/1991    Benson     
 D316,902  S  5/1991    Hoefling     
 5,017,383  A  5/1991    Ozawa et al.     
 5,019,400  A  5/1991    Gombotz et al.     
 5,021,376  A  6/1991    Nienburg et al.     
 5,027,806  A  7/1991    Zoltan et al.     
 5,042,975  A  8/1991    Chien     
 D321,570  S  11/1991    Blasdell et al.     
 5,067,500  A  11/1991    Keritsis     
 5,069,204  A  12/1991    Smith et al.     
 5,074,418  A  12/1991    Buan et al.     
 5,075,027  A  12/1991    Dixit et al.     
 5,098,590  A  3/1992    Dixit et al.     
 5,105,291  A  4/1992    Matsumoto et al.     
 D326,517  S  5/1992    Funai et al.     
 5,110,007  A  5/1992    Law et al.     
 5,110,823  A  5/1992    Hamaguchi et al.     
 5,118,666  A  6/1992    Habener     
 5,120,712  A  6/1992    Habener     
 5,124,291  A  6/1992    Bremer et al.     
 5,131,539  A  7/1992    Karita et al.     
 5,139,878  A  8/1992    Kim     
 5,145,684  A  9/1992    Liversidge et al.     
 5,152,284  A  10/1992    Valentini et al.     
 D331,106  S  11/1992    Fuchs     
 5,167,506  A  12/1992    Kilis et al.     
 5,170,801  A  12/1992    Casper et al.     
 5,188,837  A  2/1993    Domb     
 5,196,049  A  3/1993    Coombs et al.     
 5,201,308  A  4/1993    Newhouse     
 5,203,768  A  4/1993    Haak et al.     
 5,204,108  A  4/1993    Illum     
 5,208,998  A  5/1993    Dyler, Jr.     
 5,215,739  A  6/1993    Kamishita et al.     
 D337,636  S  7/1993    Kocinski     
 D338,062  S  8/1993    Yair     
 D338,268  S  8/1993    Kobayashi et al.     
 5,239,992  A  8/1993    Bougamont et al.     
 5,239,993  A  8/1993    Evans     
 5,244,653  A  9/1993    Berke et al.     
 5,250,287  A  10/1993    Cocozza     
 D340,975  S  11/1993    Sladek     
 5,260,306  A  11/1993    Boardman et al.     
 5,270,305  A  12/1993    Palmer     
 5,287,850  A  2/1994    Haber et al.     
 D344,796  S  3/1994    Sochon et al.     
 D344,797  S  3/1994    Sochon et al.     
 D345,013  S  3/1994    Huck et al.     
 5,301,666  A  4/1994    Lerk et al.     
 5,306,453  A  4/1994    Shulman     
 D347,057  S  5/1994    Yair     
 D348,100  S  6/1994    Clarke     
 5,320,094  A  6/1994    Laube et al.     
 D348,928  S  7/1994    Ashley et al.     
 D348,929  S  7/1994    Paton     
 5,327,883  A  7/1994    Williams et al.     
 5,328,464  A  7/1994    Kriesel et al.     
 5,331,953  A  7/1994    Andersson et al.     
 5,333,106  A  7/1994    Lanpher et al.     
 D349,572  S  8/1994    Jagnandan et al.     
 D350,193  S  8/1994    Huck et al.     
 5,337,740  A  8/1994    Armstrong et al.     
 D350,602  S  9/1994    Hobbs     
 D350,821  S  9/1994    Wright et al.     
 5,351,683  A  10/1994    Chiesi et al.     
 5,352,461  A  10/1994    Feldstein et al.     
 5,354,562  A  10/1994    Platz     
 5,358,734  A  10/1994    Lenox et al.     
 D352,107  S  11/1994    Meier et al.     
 5,360,614  A  11/1994    Fox et al.     
 5,363,842  A  11/1994    Mishelevich et al.     
 5,364,838  A  11/1994    Rubsamen     
 5,372,128  A  12/1994    Haber et al.     
 D355,029  S  1/1995    Kinneir et al.     
 5,385,904  A  1/1995    Andersson et al.     
 5,394,868  A  3/1995    Ambrosio et al.     
 5,401,516  A  3/1995    Milstein et al.     
 D357,603  S  4/1995    Wolff     
 5,404,871  A  4/1995    Goodman et al.     
 D358,880  S  5/1995    Mulhauser et al.     
 5,413,804  A  5/1995    Rhodes     
 5,415,162  A  5/1995    Casper et al.     
 D359,153  S  6/1995    Viggiano     
 D359,555  S  6/1995    Funai et al.     
 5,424,286  A  6/1995    Eng     
 5,437,271  A  8/1995    Hodson et al.     
 5,443,841  A  8/1995    Milstein et al.     
 D362,500  S  9/1995    Cook et al.     
 5,447,150  A  9/1995    Bacon     
 5,447,151  A  9/1995    Bruna et al.     
 5,447,728  A  9/1995    Milstein et al.     
 5,451,410  A  9/1995    Milstein et al.     
 D363,775  S  10/1995    Hobbs     
 5,454,871  A  10/1995    Liaw et al.     
 5,455,335  A  10/1995    Kahne et al.     
 5,458,135  A  10/1995    Patton et al.     
 5,466,971  A  11/1995    Higuchi     
 5,469,750  A  11/1995    Lloyd et al.     
 5,469,971  A  11/1995    Chilton et al.     
 5,476,093  A  12/1995    Laniken     
 5,477,285  A  12/1995    Riddle et al.     
 D365,876  S  1/1996    Chawla     
 5,482,032  A  1/1996    Smith et al.     
 5,482,927  A  1/1996    Maniar et al.     
 5,483,954  A  1/1996    Mecikalski     
 5,484,606  A  1/1996    Dhaber et al.     
 5,487,378  A  1/1996    Robertson et al.     
 5,492,112  A  2/1996    Mecikalski et al.     
 D368,364  S  4/1996    Reitano et al.     
 5,503,144  A  4/1996    Bacon     
 5,503,852  A  4/1996    Steiner et al.     
 5,505,194  A  4/1996    Adjei et al.     
 5,506,203  A  4/1996    Backstrom et al.     
 D370,255  S  5/1996    Yamamoto et al.     
 5,514,646  A  5/1996    Chance et al.     
 5,518,998  A  5/1996    Backstrom et al.     
 5,524,613  A  6/1996    Haber et al.     
 5,532,461  A  7/1996    Crummenauer et al.     
 5,533,502  A  7/1996    Piper     
 5,533,505  A  7/1996    Kallstrand et al.     
 5,541,155  A  7/1996    Leone-Bay     
 5,542,411  A  8/1996    Rex     
 5,542,539  A  8/1996    Early     
 5,545,618  A  8/1996    Buckley et al.     
 5,547,929  A  8/1996    Andersson, Jr. et al.     
 5,562,909  A  10/1996    Allcock et al.     
 5,562,918  A  10/1996    Stimpson     
 5,568,884  A  10/1996    Bruna     
 5,570,810  A  11/1996    Lambelet, Jr. et al.     
 5,571,795  A  11/1996    Kahne et al.     
 5,574,008  A  11/1996    Johnson et al.     
 5,577,497  A  11/1996    Mecikalski et al.     
 5,578,323  A  11/1996    Milstein et al.     
 5,584,417  A  12/1996    Graf et al.     
 D377,215  S  1/1997    Rand     
 D377,686  S  1/1997    Waldeck et al.     
 5,595,175  A  1/1997    Malcher et al.     
 5,596,701  A  1/1997    Augusteijn et al.     
 D377,861  S  2/1997    Jacober     
 5,598,835  A  2/1997    von Schrader     
 5,601,846  A  2/1997    Milstein et al.     
 5,610,271  A  3/1997    Dooley et al.     
 5,614,492  A  3/1997    Habener     
 5,615,670  A  4/1997    Rhodes et al.     
 5,617,844  A  4/1997    King     
 5,619,984  A  4/1997    Hodson et al.     
 5,622,164  A  4/1997    Kilis et al.     
 5,622,166  A  4/1997    Eisele et al.     
 5,623,724  A  4/1997    Gurkovich et al.     
 5,623,920  A  4/1997    Bryant     
 D379,506  S  5/1997    Maher     
 5,629,020  A  5/1997    Leone-Bay     
 5,631,224  A  5/1997    Efendic et al.     
 5,632,971  A  5/1997    Yang     
 5,634,900  A  6/1997    Makino et al.     
 5,639,441  A  6/1997    Sievers et al.     
 5,641,861  A  6/1997    Dooley et al.     
 D381,416  S  7/1997    Hansson et al.     
 5,642,727  A  7/1997    Datta et al.     
 5,642,728  A  7/1997    Andersson et al.     
 5,643,957  A  7/1997    Leone-Bay et al.     
 5,645,051  A  7/1997    Schultz     
 5,651,359  A  7/1997    Bougamont et al.     
 5,653,961  A  8/1997    McNally et al.     
 5,655,516  A  8/1997    Goodman et al.     
 5,655,523  A  8/1997    Hodson et al.     
 5,657,748  A  8/1997    Braithwaite     
 5,658,878  A  8/1997    Backstrom et al.     
 5,660,169  A  8/1997    Kallstrand et al.     
 5,672,581  A  9/1997    Rubsamen et al.     
 5,673,686  A  10/1997    Villax et al.     
 5,679,377  A  10/1997    Bernstein et al.     
 5,687,710  A  11/1997    Ambrosio et al.     
 5,690,910  A  11/1997    Ahmed et al.     
 5,693,338  A  12/1997    Milstein     
 5,699,789  A  12/1997    Hendricks     
 D389,238  S  1/1998    Kirk, III et al.     
 D389,570  S  1/1998    Savolainen     
 5,705,483  A  1/1998    Galloway et al.     
 D390,651  S  2/1998    Smith et al.     
 D390,653  S  2/1998    Blasdell et al.     
 5,714,007  A  2/1998    Pletcher et al.     
 5,714,167  A  2/1998    Milstein et al.     
 5,715,811  A  2/1998    Ohki et al.     
 5,727,333  A  3/1998    Folan     
 5,727,546  A  3/1998    Clarke et al.     
 5,740,793  A  4/1998    Hodson et al.     
 5,740,794  A  4/1998    Smith et al.     
 5,746,197  A  5/1998    Williams     
 5,746,227  A  5/1998    Rose et al.     
 5,747,445  A  5/1998    Backstrom et al.     
 5,752,505  A  5/1998    Ohki et al.     
 5,755,218  A  5/1998    Johansson et al.     
 D395,147  S  6/1998    Vidgren et al.     
 D395,499  S  6/1998    Eisele et al.     
 5,758,638  A  6/1998    Kreamer     
 5,763,396  A  6/1998    Weiner et al.     
 5,766,620  A  6/1998    Heiber et al.     
 5,766,633  A  6/1998    Milstein et al.     
 5,769,073  A  6/1998    Eason et al.     
 5,772,085  A  6/1998    Bryant et al.     
 RE35,862  E  7/1998    Steiner et al.     
 5,775,320  A  7/1998    Patton et al.     
 5,785,049  A  7/1998    Smith et al.     
 5,785,989  A  7/1998    Stanley et al.     
 D397,435  S  8/1998    Naumann     
 5,792,451  A  8/1998    Sarubbi et al.     
 5,794,613  A  8/1998    Piskorski     
 5,797,391  A  8/1998    Cook et al.     
 D398,992  S  9/1998    Feret     
 5,799,821  A  9/1998    Lambelet, Jr. et al.     
 5,807,315  A  9/1998    Va Antwerp et al.     
 5,809,997  A  9/1998    Wolf     
 5,811,127  A  9/1998    Milstein et al.     
 5,813,397  A  9/1998    Goodman et al.     
 5,817,343  A  10/1998    Burke     
 5,824,345  A  10/1998    Milstein et al.     
 5,839,429  A  11/1998    Marnfeldt et al.     
 5,840,279  A  11/1998    Narodylo et al.     
 5,840,340  A  11/1998    Milstein et al.     
 5,846,447  A  12/1998    Beatty     
 5,848,589  A  12/1998    Welnetz     
 5,849,322  A  12/1998    Ebert et al.     
 5,857,457  A  1/1999    Hyppola     
 5,858,099  A  1/1999    Sun et al.     
 5,865,012  A  2/1999    Hansson et al.     
 5,868,774  A  2/1999    Reil     
 5,874,064  A  2/1999    Edwards et al.     
 5,875,776  A  3/1999    Vaghefi     
 5,877,174  A  3/1999    Ono et al.     
 5,881,719  A  3/1999    Gottenauer et al.     
 5,881,721  A  3/1999    Bunce et al.     
 5,884,620  A  3/1999    Gonda et al.     
 5,888,477  A  3/1999    Gonda et al.     
 5,896,855  A  4/1999    Hobbs et al.     
 5,901,703  A  5/1999    Ohki et al.     
 5,904,139  A  5/1999    Hauser     
 D410,541  S  6/1999    Moulin     
 D411,005  S  6/1999    Coe     
 5,908,639  A  6/1999    Simpkin et al.     
 5,912,011  A  6/1999    Makino et al.     
 5,918,594  A  7/1999    Asking et al.     
 5,919,897  A  7/1999    Dooley et al.     
 5,921,237  A  7/1999    Eisele et al.     
 5,922,253  A  7/1999    Herbert et al.     
 5,924,419  A  7/1999    Kotliar     
 5,929,027  A  7/1999    Takama et al.     
 D412,572  S  8/1999    Gray     
 D412,744  S  8/1999    Braithwaite     
 D412,978  S  8/1999    Cameron     
 D412,979  S  8/1999    Weinstein et al.     
 5,934,273  A  8/1999    Andersson et al.     
 5,942,242  A  8/1999    Mizushima et al.     
 5,948,749  A  9/1999    Igarashi et al.     
 5,952,008  A  9/1999    Backstrom et al.     
 5,954,047  A  9/1999    Armer et al.     
 5,965,701  A  10/1999    Junien     
 5,971,951  A  10/1999    Ruskewicz     
 D416,085  S  11/1999    Forssell et al.     
 D416,621  S  11/1999    Forssell et al.     
 D416,998  S  11/1999    Hodson et al.     
 D417,271  S  11/1999    Denyer et al.     
 5,975,347  A  11/1999    Lambelet, Jr. et al.     
 5,976,569  A  11/1999    Milstein     
 5,976,574  A  11/1999    Gordon     
 5,977,071  A  11/1999    Galloway et al.     
 5,980,865  A  11/1999    Ahmed et al.     
 5,981,488  A  11/1999    Hoffman     
 5,983,893  A  11/1999    Wetterlin     
 5,985,248  A  11/1999    Gordon et al.     
 5,985,309  A  11/1999    Edwards et al.     
 5,990,077  A  11/1999    Drucker     
 D417,732  S  12/1999    Dagsland et al.     
 D417,912  S  12/1999    Dagsland et al.     
 5,996,577  A  12/1999    Ohki et al.     
 5,997,848  A*12/1999    Patton 424/43
 6,001,336  A  12/1999    Gordon     
 6,006,747  A  12/1999    Eisele et al.     
 6,006,753  A  12/1999    Efendic     
 D418,600  S  1/2000    Haerle     
 D420,736  S  2/2000    Moulin     
 6,026,809  A  2/2000    Abrams et al.     
 6,029,663  A  2/2000    Eisele et al.     
 D421,800  S  3/2000    Doat     
 6,039,208  A  3/2000    Lambelet et al.     
 6,043,214  A  3/2000    Jensen et al.     
 6,045,828  A  4/2000    Bystrom et al.     
 6,051,256  A  4/2000    Platz et al.     
 6,051,551  A  4/2000    Hughes et al.     
 6,055,980  A  5/2000    Mecikalski et al.     
 6,056,169  A  5/2000    Bruna et al.     
 6,060,069  A  5/2000    Hill et al.     
 6,063,910  A  5/2000    Debenedetti et al.     
 6,071,497  A  6/2000    Steiner et al.     
 6,073,629  A  6/2000    Hardy et al.     
 6,076,521  A  6/2000    Lindahl et al.     
 6,077,543  A  6/2000    Gordon et al.     
 6,080,762  A  6/2000    Allen et al.     
 D428,486  S  7/2000    Schuckmann     
 6,085,745  A  7/2000    Levander et al.     
 6,087,334  A  7/2000    Beeley et al.     
 6,087,351  A  7/2000    Nye     
 6,089,228  A  7/2000    Smith et al.     
 6,095,136  A  8/2000    Virtanen     
 6,098,618  A  8/2000    Jennings et al.     
 6,098,619  A  8/2000    Britto et al.     
 6,099,517  A  8/2000    Daugherty     
 6,102,035  A  8/2000    Asking et al.     
 6,105,571  A  8/2000    Coffee     
 6,105,574  A  8/2000    Jahnsson     
 6,109,261  A  8/2000    Clarke et al.     
 6,109,481  A  8/2000    Alexander et al.     
 6,116,237  A  9/2000    Schultz     
 6,116,238  A  9/2000    Jackson et al.     
 6,116,239  A  9/2000    Volgyesi     
 6,119,684  A  9/2000    Nohl et al.     
 6,119,688  A  9/2000    Whaley et al.     
 6,131,567  A  10/2000    Gonda et al.     
 6,132,766  A  10/2000    Sankaram et al.     
 6,133,235  A  10/2000    Galloway et al.     
 6,142,145  A  11/2000    Dagsland     
 6,152,130  A  11/2000    Abrams     
 6,153,613  A  11/2000    Ono et al.     
 6,155,423  A  12/2000    Katzne et al.     
 6,156,114  A  12/2000    Bell et al.     
 6,158,431  A  12/2000    Poole     
 6,159,360  A  12/2000    Gerteis et al.     
 RE37,053  E  2/2001    Hanes et al.     
 6,182,655  B1  2/2001    Keller et al.     
 6,187,291  B1  2/2001    Weinstein et al.     
 6,191,102  B1  2/2001    DiMarchi et al.     
 6,192,876  B1  2/2001    Denyer et al.     
 6,193,844  B1  2/2001    McLaughlin et al.     
 6,193,957  B1  2/2001    Ahmed     
 D438,612  S  3/2001    Suh     
 D439,325  S  3/2001    Frost     
 D439,656  S  3/2001    Andersson et al.     
 6,198,847  B1  3/2001    Washizawa     
 D441,446  S  5/2001    Dagsland et al.     
 D441,859  S  5/2001    Pera     
 D442,685  S  5/2001    Sladek     
 6,235,725  B1  5/2001    Ahmed     
 D444,226  S  6/2001    Geert-Jensen et al.     
 6,250,300  B1  6/2001    Andersson et al.     
 6,254,854  B1  7/2001    Edwards et al.     
 6,257,232  B1  7/2001    Andersson et al.     
 6,258,816  B1  7/2001    Singh et al.     
 6,263,871  B1  7/2001    Brown et al.     
 6,269,952  B1  8/2001    Watt et al.     
 6,273,084  B1  8/2001    Frid     
 6,273,085  B1  8/2001    Eisele et al.     
 6,273,086  B1  8/2001    Ohki et al.     
 6,277,819  B1  8/2001    Efendic     
 6,279,511  B1  8/2001    Loughnane     
 D448,076  S  9/2001    von Schuckmann     
 6,286,506  B1  9/2001    MacAndrew et al.     
 6,286,507  B1  9/2001    Jahnsson     
 6,294,204  B1  9/2001    Rossling et al.     
 D449,684  S  10/2001    Christrup et al.     
 6,298,846  B1  10/2001    Ohki et al.     
 6,298,847  B1  10/2001    Datta et al.     
 D450,117  S  11/2001    Braithwaite et al.     
 D451,597  S  12/2001    Suh     
 6,328,034  B1  12/2001    Eisele et al.     
 6,331,318  B1  12/2001    Milstein     
 D452,910  S  1/2002    Braithwaite et al.     
 6,335,316  B1  1/2002    Hughes et al.     
 D453,264  S  2/2002    Acevedo, Jr.     
 6,347,629  B1  2/2002    Braithwaite     
 6,348,447  B1  2/2002    Hellstrom et al.     
 6,357,442  B1  3/2002    Casper et al.     
 6,358,058  B1  3/2002    Strupat et al.     
 6,358,924  B1  3/2002    Hoffman     
 6,360,743  B1  3/2002    Andersson et al.     
 6,360,929  B1  3/2002    McCarthy     
 D455,208  S  4/2002    Bacon et al.     
 6,363,932  B1  4/2002    Forchione et al.     
 6,365,190  B1  4/2002    Gordon et al.     
 6,372,258  B1  4/2002    Platz et al.     
 6,375,975  B1  4/2002    Modi     
 6,380,357  B2  4/2002    Hermeling et al.     
 6,386,195  B1  5/2002    Coffee     
 6,388,053  B1  5/2002    Galloway et al.     
 6,394,085  B1  5/2002    Hardy et al.     
 6,395,300  B1  5/2002    Straub et al.     
 6,395,774  B1  5/2002    Milstein     
 6,410,513  B1  6/2002    Galloway et al.     
 D460,173  S  7/2002    Harrison et al.     
 6,415,784  B1  7/2002    Christrup et al.     
 6,418,926  B1  7/2002    Chawla     
 6,423,344  B1  7/2002    Platz et al.     
 D461,239  S  8/2002    Cassidy     
 6,427,688  B1  8/2002    Ligotke et al.     
 6,428,771  B1  8/2002    Steiner et al.     
 6,428,805  B1  8/2002    Dohi et al.     
 6,432,383  B1  8/2002    Modi     
 6,436,443  B2  8/2002    Edwards et al.     
 6,439,227  B1  8/2002    Myrman et al.     
 6,440,463  B1  8/2002    Feldstein et al.     
 6,441,172  B1  8/2002    Nefzi et al.     
 D463,544  S  9/2002    Engelbreth et al.     
 6,443,143  B1  9/2002    Ishida et al.     
 6,444,226  B1  9/2002    Steiner et al.     
 6,446,626  B1  9/2002    Virtanen     
 6,446,627  B1  9/2002    Bowman et al.     
 6,447,750  B1  9/2002    Cutie et al.     
 6,447,751  B1  9/2002    Weinstein et al.     
 6,447,753  B2  9/2002    Edwards et al.     
 6,451,337  B1  9/2002    Smith et al.     
 6,457,470  B1  10/2002    Coffee     
 6,468,507  B1  10/2002    Cutie et al.     
 6,470,884  B2  10/2002    Horlin     
 6,479,049  B1  11/2002    Platz et al.     
 6,484,715  B1  11/2002    Ritsche et al.     
 6,484,717  B1  11/2002    Dagsland et al.     
 D469,527  S  1/2003    Keller et al.     
 6,503,480  B1  1/2003    Edwards et al.     
 6,509,006  B1  1/2003    Platz et al.     
 6,509,313  B1  1/2003    Smith     
 D469,866  S  2/2003    Albulet et al.     
 6,514,482  B1  2/2003    Bartus et al.     
 6,518,239  B1  2/2003    Kuo et al.     
 6,523,536  B2  2/2003    Fugelsang et al.     
 D471,273  S  3/2003    Albulet et al.     
 6,528,096  B1  3/2003    Musa et al.     
 6,532,437  B1  3/2003    Clardy et al.     
 6,536,427  B2  3/2003    Davies et al.     
 D473,298  S  4/2003    Bowman et al.     
 D473,640  S  4/2003    Cuffaro et al.     
 6,540,672  B1  4/2003    Simonsen et al.     
 6,540,982  B1  4/2003    Adjei et al.     
 6,540,983  B1  4/2003    Adjei et al.     
 6,543,448  B1  4/2003    Smith et al.     
 6,546,929  B2  4/2003    Burr et al.     
 6,555,127  B2  4/2003    Steiner     
 6,555,521  B2  4/2003    Hermeling et al.     
 D474,536  S  5/2003    Albulet et al.     
 D475,133  S  5/2003    McLuckie     
 6,557,549  B2  5/2003    Schmidt et al.     
 6,561,186  B2  5/2003    Casper et al.     
 6,567,686  B2  5/2003    Sexton     
 6,568,390  B2  5/2003    Nichols et al.     
 6,569,406  B2  5/2003    Stevenson et al.     
 6,571,793  B1  6/2003    Nilsson et al.     
 6,572,893  B2  6/2003    Gordon et al.     
 6,575,160  B1  6/2003    Volgyesi     
 6,575,162  B1  6/2003    Rand     
 6,578,571  B1  6/2003    Watt     
 6,582,728  B1  6/2003    Platz et al.     
 6,583,111  B1  6/2003    DiMarchi et al.     
 D477,665  S  7/2003    Myrman et al.     
 6,589,560  B2  7/2003    Foster et al.     
 6,591,832  B1  7/2003    DeJonge     
 6,592,904  B2  7/2003    Platz et al.     
 6,595,205  B2  7/2003    Andersson et al.     
 6,595,208  B1  7/2003    Coffee et al.     
 D478,983  S  8/2003    Whitehall et al.     
 6,606,992  B1  8/2003    Smith et al.     
 D479,745  S  9/2003    Albulet et al.     
 6,613,308  B2  9/2003    Bartus et al.     
 6,615,987  B1  9/2003    Greenhill et al.     
 6,620,910  B1  9/2003    Calas et al.     
 6,626,173  B2  9/2003    Genova et al.     
 D480,806  S  10/2003    Engelbreth et al.     
 6,630,169  B1  10/2003    Bot et al.     
 6,632,258  B1  10/2003    Wheelock et al.     
 6,632,456  B1  10/2003    Backstrom et al.     
 6,635,283  B2  10/2003    Edwards et al.     
 6,637,431  B2  10/2003    Ekelius et al.     
 6,640,050  B2  10/2003    Nichols et al.     
 6,644,309  B2  11/2003    Casper et al.     
 6,645,468  B2  11/2003    Cutie et al.     
 6,645,504  B1  11/2003    Weiner et al.     
 6,652,838  B2  11/2003    Weinstein et al.     
 6,652,885  B2  11/2003    Steiner et al.     
 D483,860  S  12/2003    Knoch     
 6,655,379  B2  12/2003    Clark et al.     
 6,655,380  B1  12/2003    Andersson et al.     
 6,655,381  B2  12/2003    Keane et al.     
 6,660,716  B1  12/2003    Yakubu-Madus et al.     
 6,663,898  B2  12/2003    Milstein     
 6,668,826  B1  12/2003    Myrman et al.     
 6,672,304  B1  1/2004    Casper et al.     
 6,676,931  B2  1/2004    Dugger, III     
 6,679,255  B2  1/2004    Pera     
 6,681,767  B1  1/2004    Patton et al.     
 6,681,768  B2  1/2004    Haaije de Boer et al.     
 6,685,967  B1  2/2004    Patton et al.     
 6,696,090  B1  2/2004    Nilsson et al.     
 6,698,421  B2  3/2004    Attolini     
 6,698,422  B2  3/2004    Fugelsang et al.     
 6,698,425  B1  3/2004    Widerstorm     
 6,701,917  B2  3/2004    O'Leary     
 6,703,361  B2  3/2004    Weiner et al.     
 6,703,365  B2  3/2004    Galloway et al.     
 6,703,381  B1  3/2004    Ekwuribe et al.     
 6,705,313  B2  3/2004    Niccolai     
 6,715,486  B2  4/2004    Gieschen et al.     
 6,715,487  B2  4/2004    Nichols et al.     
 6,718,972  B2  4/2004    O'Leary     
 6,720,407  B1  4/2004    Hughes et al.     
 6,722,363  B1  4/2004    von Schuckmann     
 D489,448  S  5/2004    Shayan     
 6,729,324  B2  5/2004    Casper et al.     
 6,729,328  B2  5/2004    Goldemann     
 6,737,045  B2  5/2004    Patton     
 6,745,761  B2  6/2004    Christrup et al.     
 6,747,006  B2  6/2004    Efendic     
 6,748,946  B1  6/2004    Rand et al.     
 6,748,947  B2  6/2004    Keane et al.     
 6,752,145  B1  6/2004    Bonney et al.     
 6,755,190  B2  6/2004    Rasmussen     
 D492,769  S  7/2004    Hatanaka     
 D493,220  S  7/2004    Burge et al.     
 D493,519  S  7/2004    Jonsson et al.     
 6,774,112  B2  8/2004    Gougoutas     
 6,787,152  B2  9/2004    Kirby et al.     
 6,790,496  B1  9/2004    Levander et al.     
 6,792,945  B2  9/2004    Davies et al.     
 6,797,258  B2  9/2004    Platz et al.     
 6,799,572  B2  10/2004    Nichols et al.     
 6,800,643  B2  10/2004    Cuenoud et al.     
 6,803,044  B1  10/2004    Catania et al.     
 6,821,949  B2  11/2004    Bridon et al.     
 6,823,863  B2  11/2004    Huxham et al.     
 D499,802  S  12/2004    Pinon et al.     
 6,830,046  B2  12/2004    Blakley et al.     
 6,838,075  B2  1/2005    Stevenson et al.     
 6,838,076  B2  1/2005    Platton et al.     
 6,847,595  B2  1/2005    Tanaka     
 6,848,443  B2  2/2005    Schmidt et al.     
 6,849,708  B1  2/2005    Habener     
 6,852,690  B1  2/2005    Nauck et al.     
 6,858,199  B1  2/2005    Edwards et al.     
 6,860,262  B2  3/2005    Christrup et al.     
 6,866,037  B1  3/2005    Aslin et al.     
 6,871,646  B2  3/2005    Keane et al.     
 6,871,647  B2  3/2005    Allan et al.     
 6,880,554  B1  4/2005    Coffee     
 6,881,423  B2  4/2005    Dohi et al.     
 6,884,435  B1  4/2005    O'Hagan et al.     
 6,887,459  B1  5/2005    Haeberlin     
 6,887,849  B2  5/2005    Bridon et al.     
 6,889,687  B1  5/2005    Olsson     
 6,892,728  B2  5/2005    Helgesson et al.     
 6,896,906  B2  5/2005    Hastedt et al.     
 D506,680  S  6/2005    Saelzer     
 6,904,907  B2  6/2005    Speldrich et al.     
 6,906,030  B2  6/2005    Milstein     
 6,916,354  B2  7/2005    Elliott     
 6,918,991  B2  7/2005    Chickering, III et al.     
 6,921,458  B2  7/2005    Chickering, III et al.     
 6,921,528  B2  7/2005    Edwards et al.     
 6,923,175  B2  8/2005    Poole     
 D509,296  S  9/2005    Minshull et al.     
 D509,898  S  9/2005    Bunce et al.     
 6,948,496  B2  9/2005    Eason et al.     
 6,949,258  B2  9/2005    Zhang     
 6,951,215  B1  10/2005    Hoffman     
 6,953,812  B2  10/2005    Joregenson et al.     
 D511,208  S  11/2005    Pardonge et al.     
 D511,977  S  11/2005    Saelzer     
 6,962,006  B2  11/2005    Chickering, III et al.     
 D512,777  S  12/2005    Beisner et al.     
 6,979,437  B2  12/2005    Bartus et al.     
 D514,222  S  1/2006    Anderson et al.     
 6,981,499  B2  1/2006    Andersson et al.     
 6,989,155  B1  1/2006    Ganderton et al.     
 6,991,779  B2  1/2006    Steiner et al.     
 D515,696  S  2/2006    Lucking et al.     
 D515,924  S  2/2006    Grant     
 D516,211  S  2/2006    Minshull et al.     
 6,998,387  B1  2/2006    Goke et al.     
 D518,170  S  3/2006    Clarke et al.     
 D518,171  S  3/2006    Anderson et al.     
 7,022,674  B2  4/2006    DeFelippis et al.     
 7,025,056  B2  4/2006    Eason et al.     
 7,028,686  B2  4/2006    Gonda et al.     
 7,030,084  B2  4/2006    Ekwuribe et al.     
 7,032,593  B2  4/2006    Johnston et al.     
 7,035,294  B2  4/2006    Dove et al.     
 7,047,967  B2  5/2006    Knudsen     
 7,048,908  B2  5/2006    Basu et al.     
 7,060,274  B2  6/2006    Blumberg et al.     
 7,067,129  B2  6/2006    Blumberg et al.     
 7,077,130  B2  7/2006    Nichols et al.     
 7,080,642  B2  7/2006    Hodson et al.     
 7,084,243  B2  8/2006    Glaesner et al.     
 7,093,594  B2  8/2006    Harrison et al.     
 7,093,595  B2  8/2006    Nesbitt     
 D527,817  S  9/2006    Ziegler et al.     
 7,101,843  B2  9/2006    Glaesner et al.     
 7,101,866  B2  9/2006    Biggadike et al.     
 7,105,489  B2  9/2006    Hathaway     
 7,107,988  B2  9/2006    Pinon et al.     
 7,109,161  B1  9/2006    Gayed     
 D529,604  S  10/2006    Young et al.     
 7,125,566  B2  10/2006    Etter     
 7,128,067  B2  10/2006    Byron et al.     
 7,131,441  B1  11/2006    Keller et al.     
 7,132,115  B2  11/2006    Musa et al.     
 7,140,365  B2  11/2006    Poole et al.     
 D533,268  S  12/2006    Olfati     
 7,143,764  B1  12/2006    Dagsland et al.     
 7,143,765  B2  12/2006    Asking et al.     
 7,144,863  B2  12/2006    DeFelippis et al.     
 7,146,978  B2  12/2006    Edwards et al.     
 7,151,456  B2  12/2006    Godfrey     
 7,163,014  B2  1/2007    Nichols et al.     
 D537,522  S  2/2007    Cox et al.     
 7,171,965  B2  2/2007    Young et al.     
 7,172,768  B2  2/2007    Hastedt et al.     
 7,179,788  B2  2/2007    DeFelippis et al.     
 D537,936  S  3/2007    Cox et al.     
 D538,423  S  3/2007    Berube et al.     
 7,185,650  B2  3/2007    Huber et al.     
 D540,671  S  4/2007    Born     
 D541,151  S  4/2007    Born     
 7,198,806  B2  4/2007    Berndt     
 7,211,557  B2  5/2007    DiMarchi et al.     
 7,219,664  B2  5/2007    Ruckdeschel et al.     
 7,223,728  B2  5/2007    Yakubu-Madus et al.     
 D544,093  S  6/2007    Eriksen     
 7,231,919  B2  6/2007    Giroux     
 7,232,897  B2  6/2007    Hotamisligil et al.     
 7,234,459  B2  6/2007    Del Bon     
 7,234,460  B2  6/2007    Greenleaf et al.     
 7,234,464  B2  6/2007    Goede et al.     
 7,238,663  B2  7/2007    DeFelippis et al.     
 7,246,617  B1  7/2007    Hammer et al.     
 D548,330  S  8/2007    Cox et al.     
 D548,618  S  8/2007    Ferguson et al.     
 D548,619  S  8/2007    Ferguson et al.     
 D548,833  S  8/2007    Young et al.     
 D549,111  S  8/2007    Ferguson et al.     
 7,258,118  B2  8/2007    Goede et al.     
 7,259,233  B2  8/2007    Dodd et al.     
 D550,835  S  9/2007    Tanaka et al.     
 7,265,087  B1  9/2007    Goke et al.     
 7,270,124  B2  9/2007    Rasmussen     
 D552,729  S  10/2007    Cox et al.     
 7,276,534  B2  10/2007    Milstein     
 7,278,419  B2  10/2007    Gonda     
 7,278,426  B2  10/2007    Myrman et al.     
 7,278,843  B2  10/2007    Feldstein et al.     
 7,279,457  B2  10/2007    Pohl et al.     
 7,284,553  B2  10/2007    Hochrainer     
 D557,799  S  12/2007    Greenhalgh et al.     
 7,305,986  B1  12/2007    Steiner et al.     
 7,306,787  B2  12/2007    Tarara et al.     
 D560,793  S  1/2008    Pearl et al.     
 7,314,859  B2  1/2008    Green et al.     
 7,316,748  B2  1/2008    Li et al.     
 7,331,340  B2  2/2008    Barney     
 7,334,577  B2  2/2008    Gumaste et al.     
 7,344,734  B2  3/2008    Heijerman et al.     
 D566,549  S  4/2008    Russell et al.     
 7,368,102  B2  5/2008    Tarara et al.     
 7,373,938  B2  5/2008    Nichols et al.     
 7,377,277  B2  5/2008    Hickey et al.     
 7,387,122  B2  6/2008    Nishibayashi et al.     
 7,399,528  B2  7/2008    Caponetti et al.     
 7,401,712  B2  7/2008    Kaye et al.     
 7,401,713  B2  7/2008    Ede et al.     
 7,402,564  B1  7/2008    Schteingart et al.     
 7,414,720  B2  8/2008    Wachtel et al.     
 D577,815  S  9/2008    Gokhale et al.     
 7,422,013  B2  9/2008    Burr et al.     
 D579,549  S  10/2008    Birath et al.     
 7,448,375  B2  11/2008    Gonda et al.     
 7,448,379  B2  11/2008    Yamashita et al.     
 7,451,761  B2  11/2008    Hickey et al.     
 7,453,556  B2  11/2008    Hochrainer et al.     
 D583,463  S  12/2008    Wood et al.     
 7,461,653  B2  12/2008    Oliva     
 7,462,367  B2  12/2008    Schmidt et al.     
 7,464,706  B2  12/2008    Steiner et al.     
 7,469,696  B2  12/2008    Yang et al.     
 7,500,479  B2  3/2009    Nichols et al.     
 7,503,324  B2  3/2009    Barney et al.     
 7,504,538  B2  3/2009    Chang et al.     
 7,517,874  B2  4/2009    Beckett et al.     
 7,520,278  B2  4/2009    Crowder et al.     
 7,521,069  B2  4/2009    Patton et al.     
 7,533,668  B1  5/2009    Widerstrom     
 D594,753  S  6/2009    Eadicicco et al.     
 7,556,798  B2  7/2009    Edwards et al.     
 7,559,322  B2  7/2009    Foley et al.     
 D597,418  S  8/2009    Stojek     
 D597,657  S  8/2009    Kinsey et al.     
 D598,785  S  8/2009    Stojek     
 7,584,846  B2  9/2009    Senter     
 7,598,222  B2  10/2009    Prouty, Jr. et al.     
 D604,832  S  11/2009    Smutney et al.     
 D604,833  S  11/2009    Polidoro     
 D605,752  S  12/2009    Polidoro     
 D605,753  S  12/2009    Smutney     
 7,625,865  B2  12/2009    Colombo     
 7,648,960  B2  1/2010    Steiner et al.     
 D613,849  S  4/2010    Smutney     
 D614,045  S  4/2010    Gaudenzi et al.     
 D614,760  S  4/2010    Smutney et al.     
 7,694,676  B2  4/2010    Wachtel     
 7,709,639  B2  5/2010    Stevenson     
 7,713,937  B2  5/2010    Schteingart et al.     
 7,727,963  B2  6/2010    Schteingart et al.     
 D620,812  S  8/2010    Gaudenzi et al.     
 7,794,754  B2  9/2010    Feldstein et al.     
 7,799,344  B2  9/2010    Oberg     
 7,803,404  B2  9/2010    Hokenson     
 7,820,676  B2  10/2010    Leone-Bay et al.     
 D626,836  S  11/2010    Lien     
 D628,090  S  11/2010    Stuiber et al.     
 7,833,549  B2  11/2010    Steiner et al.     
 7,833,550  B2  11/2010    Steiner et al.     
 7,842,662  B2  11/2010    Schteingart et al.     
 D629,505  S  12/2010    Adamo     
 D629,506  S  12/2010    Adamo     
 D629,886  S  12/2010    Adamo     
 D629,887  S  12/2010    Adamo     
 D629,888  S  12/2010    Adamo     
 D635,241  S  3/2011    McLean     
 D635,242  S  3/2011    Adamo     
 D635,243  S  3/2011    Kinsey     
 7,913,688  B2  3/2011    Cross     
 D636,867  S  4/2011    Polidoro et al.     
 D636,868  S  4/2011    Kinsey et al.     
 D636,869  S  4/2011    Laurenzi et al.     
 7,919,119  B2  4/2011    Straub et al.     
 7,943,178  B2  5/2011    Steiner et al.     
 7,943,572  B2  5/2011    Cheatham et al.     
 7,954,491  B2  6/2011    Hrkach     
 7,959,609  B2  6/2011    Gaydos et al.     
 D641,076  S  7/2011    Grunstad et al.     
 D643,308  S  8/2011    Bergey     
 D645,954  S  9/2011    Hately     
 D647,195  S  10/2011    Clarke et al.     
 D647,196  S  10/2011    Clarke et al.     
 8,037,880  B2  10/2011    Zhu et al.     
 8,037,881  B2  10/2011    Pentafragas     
 8,039,431  B2  10/2011    Wilson et al.     
 8,047,203  B2  11/2011    Young et al.     
 D652,322  S  1/2012    Stuiber et al.     
 8,109,267  B2  2/2012    Villax et al.     
 8,119,593  B2  2/2012    Richardson     
 D655,622  S  3/2012    Sadler et al.     
 8,133,514  B2  3/2012    Milstein     
 8,146,588  B2  4/2012    Steiner et al.     
 8,156,936  B2  4/2012    Steiner et al.     
 D659,020  S  5/2012    Kemner     
 D659,022  S  5/2012    Kemner     
 D660,956  S  5/2012    Zuyderhoudt     
 8,166,970  B2  5/2012    Poole et al.     
 8,172,817  B2  5/2012    Michaels et al.     
 8,196,576  B2  6/2012    Kriksunov     
 8,201,555  B2  6/2012    Chawla     
 8,202,992  B2  6/2012    Stevenson     
 D663,830  S  7/2012    Sears     
 D664,640  S  7/2012    Smutney et al.     
 8,217,007  B1  7/2012    Schteingart     
 8,227,409  B2  7/2012    Kraft     
 8,236,766  B2  8/2012    Schteingart     
 8,252,916  B2  8/2012    Simard et al.     
 8,258,095  B2  9/2012    Boss et al.     
 8,278,308  B2  10/2012    Leone-Bay et al.     
 8,293,869  B2  10/2012    Bossard     
 8,314,106  B2  11/2012    Kraft     
 D671,842  S  12/2012    Bergey     
 D674,893  S  1/2013    Kinsey et al.     
 8,372,804  B2  2/2013    Richardson     
 8,389,470  B2  3/2013    Steiner     
 8,394,414  B2  3/2013    Steiner et al.     
 8,408,200  B2  4/2013    Clark et al.     
 8,420,604  B2  4/2013    Hokenson     
 8,424,518  B2  4/2013    Smutney     
 8,485,180  B2  7/2013    Smutney     
 8,486,894  B2  7/2013    Schteingart et al.     
 8,499,757  B2  8/2013    Smutney     
 8,512,932  B2  8/2013    Wilson et al.     
 8,522,775  B2  9/2013    Malhotra et al.     
 8,536,131  B2  9/2013    Schteingart et al.     
 8,538,707  B2  9/2013    Adamo et al.     
 8,539,946  B2  9/2013    Esteve et al.     
 8,551,528  B2  10/2013    Grant et al.     
 8,563,101  B2  10/2013    Spallek     
 8,636,001  B2  1/2014    Smutney     
 8,642,548  B2  2/2014    Richardson et al.     
 8,671,937  B2  3/2014    Steiner et al.     
 8,677,992  B2  3/2014    Villax     
 8,763,606  B2  7/2014    Mosier et al.     
 8,778,403  B2  7/2014    Grant et al.     
 8,783,249  B2  7/2014    Trent et al.     
 D711,740  S  8/2014    Lien     
 8,808,786  B2  8/2014    Jinks et al.     
 8,820,324  B2  9/2014    Smith et al.     
 8,909,487  B2  12/2014    Adamo et al.     
 8,925,726  B2  1/2015    Bergey     
 9,041,925  B2  5/2015    Adamo et al.     
 9,138,407  B2  9/2015    Caponetti et al.     
 9,283,337  B2*3/2016    Lastow     
 D771,237  S  11/2016    Smutney et al.     
 2001//0020147  A1  9/2001    Staniforth et al.     
 2001//0039442  A1  11/2001    Gorge et al.     
 2002//0000225  A1  1/2002    Schuler et al.     
 2002//0015737  A1  2/2002    Shih et al.     
 2002//0033177  A1  3/2002    Ohki et al.     
 2002//0052381  A1  5/2002    Bar-Or et al.     
 2002//0053344  A1  5/2002    Davies et al.     
 2002//0053347  A1  5/2002    Ziaee     
 2002//0065239  A1  5/2002    Caplan et al.     
 2002//0088462  A1  7/2002    Genova et al.     
 2002//0101590  A1  8/2002    Shimaoka     
 2002//0144680  A1  10/2002    Nilsson et al.     
 2002//0161001  A1  10/2002    Kanstrup et al.     
 2003//0000524  A1  1/2003    Andersson et al.     
 2003//0010794  A1  1/2003    Herdtle et al.     
 2003//0013641  A1  1/2003    Steiner et al.     
 2003//0017211  A1  1/2003    Steiner     
 2003//0053960  A1  3/2003    Heijerman et al.     
 2003//0064097  A1  4/2003    Patel et al.     
 2003//0068378  A1  4/2003    Chen et al.     
 2003//0099636  A1  5/2003    Epshtein et al.     
 2003//0136405  A1  7/2003    Goede et al.     
 2003//0168370  A1  9/2003    Merboth et al.     
 2003//0194420  A1  10/2003    Holl et al.     
 2003//0235538  A1  12/2003    Zierenberg     
 2004//0022861  A1  2/2004    Williams et al.     
 2004//0024180  A1  2/2004    Drauz     
 2004//0025875  A1  2/2004    Reber et al.     
 2004//0034014  A1  2/2004    Kanstrup et al.     
 2004//0038865  A1  2/2004    Gelber et al.     
 2004//0053819  A1  3/2004    Dodd et al.     
 2004//0062722  A1  4/2004    Gonda et al.     
 2004//0076588  A1  4/2004    Batycky et al.     
 2004//0077528  A1  4/2004    Steiner et al.     
 2004//0096403  A1  5/2004    Steiner     
 2004//0107963  A1  6/2004    Finlay et al.     
 2004//0121964  A1  6/2004    Madar et al.     
 2004//0138099  A1  7/2004    Draeger     
 2004//0151059  A1  8/2004    Roberts, II et al.     
 2004//0151774  A1  8/2004    Pauletti et al.     
 2004//0157928  A1  8/2004    Kim et al.     
 2004//0163648  A1  8/2004    Burton     
 2004//0182387  A1  9/2004    Steiner et al.     
 2004//0187869  A1  9/2004    Bjorndal et al.     
 2004//0204439  A1  10/2004    Staniforth et al.     
 2004//0204440  A1  10/2004    Staniforth et al.     
 2004//0211419  A1  10/2004    Eason et al.     
 2004//0211420  A1  10/2004    Minshull     
 2004//0234615  A1  11/2004    Sabetsky     
 2004//0234616  A1  11/2004    Sabetsky     
 2004//0235956  A1  11/2004    Quay     
 2004//0241232  A1  12/2004    Brown et al.     
 2004//0247628  A1  12/2004    Lintz et al.     
 2004//0250812  A1  12/2004    Davies et al.     
 2005//0000518  A1  1/2005    Dunkley et al.     
 2005//0039743  A1  2/2005    Taylor     
 2005//0043228  A1  2/2005    DeFelippis et al.     
 2005//0043247  A1  2/2005    Trunk et al.     
 2005//0056281  A1  3/2005    Snow     
 2005//0070469  A1  3/2005    Bloom     
 2005//0080000  A1  4/2005    Thurow et al.     
 2005//0119604  A1  6/2005    Bonney et al.     
 2005//0124644  A1  6/2005    Nilsson et al.     
 2005//0147581  A1  7/2005    Zamiri et al.     
 2005//0153874  A1  7/2005    Cheatham et al.     
 2005//0155601  A1  7/2005    Steiner et al.     
 2005//0183723  A1  8/2005    Pinon et al.     
 2005//0187749  A1  8/2005    Singley     
 2005//0203002  A1  9/2005    Tzannis et al.     
 2005//0214251  A1  9/2005    Pohl et al.     
 2005//0252508  A1  11/2005    Koerner     
 2005//0265927  A1  12/2005    Lee     
 2005//0274378  A1  12/2005    Bonney et al.     
 2006//0000469  A1  1/2006    Tseng     
 2006//0003316  A1  1/2006    Simard et al.     
 2006//0040953  A1  2/2006    Leone-Bay et al.     
 2006//0041133  A1  2/2006    Stevenson et al.     
 2006//0060194  A1  3/2006    Oliva     
 2006//0062740  A1  3/2006    Rand     
 2006//0073105  A1  4/2006    Yamashita et al.     
 2006//0099269  A1  5/2006    Cheatham et al.     
 2006//0102511  A1  5/2006    Pasbrig et al.     
 2006//0120969  A1  6/2006    Nilsson et al.     
 2006//0153778  A1  7/2006    Gelber     
 2006//0160722  A1  7/2006    Green et al.     
 2006//0165756  A1  7/2006    Catani et al.     
 2006//0169280  A1  8/2006    Yamashita et al.     
 2006//0219242  A1  10/2006    Zierenberg     
 2006//0239933  A1  10/2006    Nilsson et al.     
 2006//0239934  A1  10/2006    Cheatham     
 2006//0243275  A1  11/2006    Ruckdeschel et al.     
 2006//0249419  A1  11/2006    Taylor et al.     
 2006//0260777  A1  11/2006    Rashba-Step et al.     
 2006//0283758  A1  12/2006    Pasbrig et al.     
 2007//0006876  A1  1/2007    Finlay et al.     
 2007//0017506  A1  1/2007    Bell et al.     
 2007//0020191  A1  1/2007    Boss et al.     
 2007//0027063  A1  2/2007    Boss et al.     
 2007//0044793  A1  3/2007    Kleinstreuer et al.     
 2007//0049576  A1  3/2007    Barlow et al.     
 2007//0059373  A1  3/2007    Oberg     
 2007//0059374  A1  3/2007    Hokenson et al.     
 2007//0074989  A1  4/2007    Merboth et al.     
 2007//0077219  A1  4/2007    Fahl et al.     
 2007//0086952  A1  4/2007    Steiner     
 2007//0099454  A1  5/2007    Gordon     
 2007//0125375  A1  6/2007    Finlay et al.     
 2007//0128193  A1  6/2007    O'Neil et al.     
 2007//0151562  A1  7/2007    Jones     
 2007//0160789  A1  7/2007    Merical et al.     
 2007//0175314  A1  8/2007    Wanne     
 2007//0190163  A1  8/2007    Malakhov et al.     
 2007//0191462  A1  8/2007    Hettiarachchi     
 2007//0196503  A1  8/2007    Wilson     
 2007//0207958  A1  9/2007    Bridon et al.     
 2007//0225587  A1  9/2007    Burnell et al.     
 2007//0235029  A1  10/2007    Zhu et al.     
 2007//0240708  A1  10/2007    Schuckmann     
 2007//0272763  A1  11/2007    Dunne et al.     
 2007//0277820  A1  12/2007    Crowder et al.     
 2007//0277821  A1  12/2007    Oliva et al.     
 2007//0295332  A1  12/2007    Ziegler     
 2007//0299074  A1  12/2007    Netz et al.     
 2008//0008764  A1  1/2008    Milstein     
 2008//0015457  A1  1/2008    Silva     
 2008//0039368  A1  2/2008    Steiner et al.     
 2008//0039402  A1  2/2008    Mossalayi et al.     
 2008//0047550  A2  2/2008    Steiner et al.     
 2008//0066739  A1  3/2008    LeMahieu et al.     
 2008//0108554  A1  5/2008    Jackson et al.     
 2008//0108574  A1  5/2008    Barlow et al.     
 2008//0115785  A1  5/2008    Eason et al.     
 2008//0127970  A1  6/2008    Steiner et al.     
 2008//0127971  A1  6/2008    King et al.     
 2008//0127974  A1  6/2008    Lastow     
 2008//0168987  A1  7/2008    Denny et al.     
 2008//0190424  A1  8/2008    Lucking et al.     
 2008//0190425  A1  8/2008    Steiner et al.     
 2008//0197044  A1  8/2008    Hickey et al.     
 2008//0216824  A1  9/2008    Ooida     
 2008//0217199  A1  9/2008    Burress et al.     
 2008//0255468  A1  10/2008    Derchak et al.     
 2008//0260838  A1  10/2008    Hokenson et al.     
 2008//0260840  A1  10/2008    Alessi     
 2008//0295833  A1  12/2008    Rohrschneider et al.     
 2008//0312155  A1  12/2008    Kitada et al.     
 2008//0314384  A1  12/2008    Harris et al.     
 2008//0319333  A1  12/2008    Gavish et al.     
 2009//0025720  A1  1/2009    Chen     
 2009//0068274  A1  3/2009    Edwards et al.     
 2009//0084379  A1  4/2009    Goeckner et al.     
 2009//0084380  A1  4/2009    Gieschen et al.     
 2009//0110647  A1  4/2009    Richardson     
 2009//0134051  A1  5/2009    Rapp et al.     
 2009//0149727  A1  6/2009    Truitt et al.     
 2009//0151720  A1  6/2009    Inoue et al.     
 2009//0178676  A1  7/2009    Villax et al.     
 2009//0205657  A1  8/2009    Barney et al.     
 2009//0209502  A1  8/2009    Haeberlin et al.     
 2009//0232891  A1  9/2009    Gelber et al.     
 2009//0241949  A1  10/2009    Smutney     
 2009//0250058  A1  10/2009    Lastow     
 2009//0258818  A1  10/2009    Surolia et al.     
 2009//0308390  A1  12/2009    Smutney     
 2009//0308391  A1*12/2009    Smutney 128/203.15
 2009//0314291  A1  12/2009    Anderson et al.     
 2009//0314292  A1  12/2009    Overfield     
 2009//0320837  A1  12/2009    Smith et al.     
 2010//0012120  A1  1/2010    Herder     
 2010//0051027  A1  3/2010    Remmelgas et al.     
 2010//0065048  A1  3/2010    Mueller-Walz et al.     
 2010//0086609  A1  4/2010    Steiner et al.     
 2010//0113363  A1  5/2010    Holst et al.     
 2010//0163042  A1  7/2010    Bhowmick et al.     
 2010//0180894  A1  7/2010    Jones et al.     
 2010//0181225  A1  7/2010    Spallek et al.     
 2010//0190701  A1  7/2010    Day et al.     
 2010//0193380  A1  8/2010    Sullivan et al.     
 2010//0197565  A1  8/2010    Smutney et al.     
 2010//0212667  A1  8/2010    Smith et al.     
 2010//0235116  A1  9/2010    Adamo et al.     
 2010//0238457  A1  9/2010    Adamo et al.     
 2010//0278924  A1  11/2010    Oberg     
 2010//0288276  A1  11/2010    Ganderton et al.     
 2010//0326438  A1  12/2010    Dunne     
 2011//0000482  A1  1/2011    Gumaste et al.     
 2011//0003004  A1  1/2011    Hokenson     
 2011//0011394  A1  1/2011    Edwards et al.     
 2011//0023876  A1  2/2011    Vehring et al.     
 2011//0083667  A1  4/2011    Briant     
 2011//0155129  A1  6/2011    Stedman et al.     
 2011//0158935  A1  6/2011    Kraft     
 2011//0183901  A1  7/2011    Cheatham     
 2012//0014999  A1  1/2012    Grant et al.     
 2012//0040899  A1  2/2012    Costello     
 2012//0071515  A1  3/2012    Lu     
 2012//0094905  A1  4/2012    Costello     
 2012//0115777  A1  5/2012    Richardson     
 2012//0122775  A1  5/2012    Boss et al.     
 2012//0160241  A1  6/2012    Oliva     
 2012//0164186  A1  6/2012    Grant et al.     
 2012//0178935  A1  7/2012    Stevenson     
 2012//0192865  A1  8/2012    Steiner et al.     
 2012//0207913  A1  8/2012    Smyth     
 2012//0240929  A1  9/2012    Steiner et al.     
 2012//0247235  A1  10/2012    Adamo et al.     
 2012//0247465  A1  10/2012    Wachtel     
 2012//0328676  A1  12/2012    Leone-Bay et al.     
 2013//0012710  A1  1/2013    Freeman et al.     
 2013//0053309  A1  2/2013    Kraft     
 2013//0104887  A1  5/2013    Smutney     
 2013//0118491  A1  5/2013    Richardson et al.     
 2013//0125886  A1  5/2013    Richardson et al.     
 2013//0143801  A1  6/2013    Steiner et al.     
 2013//0189365  A1  7/2013    Hokenson     
 2013//0199527  A1  8/2013    Smutney     
 2013//0289278  A1  10/2013    Kraft     
 2013//0291866  A1  11/2013    Smutney     
 2013//0291867  A1  11/2013    Smutney     
 2013//0303445  A1  11/2013    Wilson et al.     
 2013//0338065  A1  12/2013    Smutney     
 2014//0007873  A1  1/2014    Smutney     
 2014//0014106  A1  1/2014    Smutney     
 2014//0083421  A1  3/2014    Smutney     
 2014//0096771  A1  4/2014    Remmelgas et al.     
 2014//0100158  A1  4/2014    Richardson et al.     
 2014//0187490  A1  7/2014    Richardson et al.     
 2014//0199398  A1  7/2014    Grant et al.     
 2014//0227359  A1  8/2014    Leone-Bay et al.     
 2014//0243530  A1  8/2014    Stevenson et al.     
 2014//0271888  A1  9/2014    Grant et al.     
 2014//0290654  A1  10/2014    Poole et al.     
 2014//0302151  A1  10/2014    Leone-Bay et al.     
 2014//0308358  A1  10/2014    Oberg et al.     
 2014//0315953  A1  10/2014    Leone-Bay et al.     
 2015//0031609  A1  1/2015    Steiner et al.     
 2015//0045295  A1  2/2015    Smutney et al.     
 2015//0052977  A1  2/2015    Adamo et al.     
 2015//0065422  A1  3/2015    Kraft     
 2015//0080298  A1  3/2015    Costello et al.     
 2015//0108023  A1  4/2015    Bergey     
 2015//0122258  A1  5/2015    Steiner et al.     
 2015//0150980  A1  6/2015    Leone-Bay et al.     
 2015//0174210  A1  6/2015    Boss et al.     
 2015//0196724  A1  7/2015    Adamo et al.     
 2015//0226656  A1  8/2015    Adamo et al.     
 2015//0231067  A1  8/2015    Mann     
 2015//0246188  A1  9/2015    Steiner et al.     
 2015//0283069  A1  10/2015    Smutney et al.     
 2015//0283213  A1  10/2015    Costello et al.     
 2015//0290132  A1  10/2015    Gelber et al.     
 2015//0359744  A1  12/2015    Hokenson et al.     
 2016//0008557  A1  1/2016    Smutney et al.     
 2016//0031833  A1  2/2016    Wilson et al.     
 2016//0067183  A1  3/2016    Kraft     
 2016//0095990  A1  4/2016    Smutney et al.     
 2016//0101049  A1  4/2016    Wilson et al.     
 2016//0151287  A1  6/2016    Oberg et al.     
 2016//0158156  A1  6/2016    Fabio et al.     
 2016//0175079  A1  6/2016    Adamo et al.     
 2016//0193432  A1  7/2016    Harris et al.     
 2016//0221967  A1  8/2016    Stevenson et al.     
 2016//0228659  A1  8/2016    Smutney et al.     
 2016//0243322  A1  8/2016    Smutney et al.     
 2016//0250297  A1  9/2016    Leone-Bay et al.     
 2016//0256640  A1  9/2016    Overfield et al.     
 2016//0287820  A1  10/2016    Smutney et al.     
 2016//0346212  A1  12/2016    Hokenson et al.     
 2016//0346394  A1  12/2016    Grant et al.     

 
 FOREIGN PATENT DOCUMENTS 
 
       CA       2536047       A1                3/2005      
       CA       2551182       C                8/2010      
       CN       101290219       A                10/2008      
       CN       101851213                         10/2010      
       CN       102436238       A                5/2012      
       DE       2840442       C2                2/1982      
       DE       3639836       A1                6/1988      
       DE       19519840       A1                12/1996      
       EP       0069715                         1/1983      
       EP       0122036                         10/1984      
       EP       0143524                         6/1985      
       EP       0180543                         5/1986      
       EP       220958                         5/1987      
       EP       0237507                         8/1987      
       EP       0257915                         2/1988      
       EP       0308637       A1                3/1989      
       EP       0360340                         3/1990      
       EP       0364235                         4/1990      
       EP       0387222       A1                9/1990      
       EP       0388621       A                9/1990      
       EP       00606486                         12/1993      
       EP       00581473       A1                2/1994      
       EP       0655237                         5/1995      
       EP       0666085       A1                8/1995      
       EP       0748213                         12/1996      
       EP       0558879       B1                5/1997      
       EP       0844007                         12/1998      
       EP       1060741       A1                12/2000      
       EP       1114644                         7/2001      
       EP       0837710       B1                11/2001      
       EP       0640354       B1                12/2001      
       EP       1348428       A1                10/2003      
       EP       1364967                         11/2003      
       EP       0825885       B1                3/2004      
       EP       96911738                         6/2004      
       EP       1598066                         11/2005      
       EP       0833652       B1                2/2008      
       EP       1923087       A2                5/2008      
       EP       2060268       A1                5/2009      
       EP       2314298       A1                4/2011      
       GB       475440       A                11/1937      
       GB       716815                         10/1954      
       GB       2072536       A                10/1981      
       GB       2148841       A                6/1985      
       GB       2240337                         7/1991      
       GB       2253200       A                9/1992      
       GB       2262452                         6/1993      
       GB       2398065       A                8/2004      
       JP       S55-156085       U                11/1980      
       JP       63-020301                         1/1988      
       JP       2115154       A                4/1990      
       JP       2-149545                         2/1992      
       JP       H07-041428                         2/1995      
       JP       09-208485                         8/1997      
       JP       10234827       A                9/1998      
       JP       2002322294                         11/2002      
       JP       2003-503420                         1/2003      
       JP       2004-121061                         4/2004      
       JP       2006-280620       A                10/2006      
       JP       2007-061281                         3/2007      
       TW       200505517       A                2/2005      
       WO       90/13285                         11/1990      
       WO       91/04011                         4/1991      
       WO       91/06287                         5/1991      
       WO       91/16038                         10/1991      
       WO       91/16882                         11/1991      
       WO       91/19524                         12/1991      
       WO       92/04069                         3/1992      
       WO       92/08509                         5/1992      
       WO       93/02712                         2/1993      
       WO       93/14110                         7/1993      
       WO       93/17728                         9/1993      
       WO       93/18754                         9/1993      
       WO       94/00291                         1/1994      
       WO       94/08552                         4/1994      
       WO       94/08599                         4/1994      
       WO       94/19041                         9/1994      
       WO       94/23702                         10/1994      
       WO       94/25005       A1                11/1994      
       WO       95/00127                         1/1995      
       WO       95/05208                         2/1995      
       WO       95/11666                         5/1995      
       WO       95/24183                         9/1995      
       WO       95/31979                         11/1995      
       WO       95/34294                         12/1995      
       WO       96/01105                         1/1996      
       WO       96/05810                         2/1996      
       WO       96/13250                         5/1996      
       WO       96/22802       A                8/1996      
       WO       96/27386       A1                9/1996      
       WO       96/32149                         10/1996      
       WO       96/36314                         11/1996      
       WO       96/36317       A1                11/1996      
       WO       96/40206       A1                12/1996      
       WO       97/01365                         1/1997      
       WO       97/04747                         2/1997      
       WO       97/25086       A2                7/1997      
       WO       97/30743                         8/1997      
       WO       97/35562       A1                10/1997      
       WO       97/46206                         12/1997      
       WO       97/49386                         12/1997      
       WO       98/26827       A1                6/1998      
       WO       98/34661       A1                8/1998      
       WO       98/39043                         9/1998      
       WO       98/41255       A2                9/1998      
       WO       98/43615                         10/1998      
       WO       99/14239       A1                3/1999      
       WO       99/18939       A1                4/1999      
       WO       99/32510       A1                7/1999      
       WO       99/33862                         7/1999      
       WO       99/52506                         10/1999      
       WO       00/12116                         3/2000      
       WO       00/33811       A2                6/2000      
       WO       00/59476       A1                10/2000      
       WO       00/71154       A2                11/2000      
       WO       01/00654                         1/2001      
       WO       01/81321       A                1/2001      
       WO       01/07107                         2/2001      
       WO       01/49274       A2                7/2001      
       WO       01/51071                         7/2001      
       WO       01/52813       A1                7/2001      
       WO       01/66064                         9/2001      
       WO       01/68169                         9/2001      
       WO       01/97886       A1                12/2001      
       WO       02/11676                         2/2002      
       WO       02/12201       A1                2/2002      
       WO       02/04769       A2                6/2002      
       WO       02/058735                         8/2002      
       WO       02/059574       A1                8/2002      
       WO       02/067995       A1                9/2002      
       WO       02/085281                         10/2002      
       WO       02/098348                         12/2002      
       WO       02/102444                         12/2002      
       WO       03/000202                         1/2003      
       WO       03/015857       A1                2/2003      
       WO       03/018059       A2                3/2003      
       WO       03/022304       A1                3/2003      
       WO       03/055547       A1                7/2003      
       WO       03/057170                         7/2003      
       WO       03/061578       A2                7/2003      
       WO       03/072195       A2                9/2003      
       WO       03/080149       A2                10/2003      
       WO       03/084502       A1                10/2003      
       WO       03/086345                         10/2003      
       WO       03/094951                         11/2003      
       WO       2004/012672                         2/2004      
       WO       2004/012720                         2/2004      
       WO       2004/033010                         4/2004      
       WO       2004/035121                         4/2004      
       WO       2004/041338                         5/2004      
       WO       2004/050152                         6/2004      
       WO       2004/054647       A1                7/2004      
       WO       2004/056314                         7/2004      
       WO       2004/060458                         7/2004      
       WO       2004/064862                         8/2004      
       WO       2004/075919                         9/2004      
       WO       2004/080401                         9/2004      
       WO       2004/080482                         9/2004      
       WO       2004/103304       A2                12/2004      
       WO       2005/002654       A2                1/2005      
       WO       2005/020964                         3/2005      
       WO       2005/023348       A                3/2005      
       WO       2005/028699       A1                3/2005      
       WO       2005/067964                         7/2005      
       WO       2005/081977       A2                9/2005      
       WO       2005/089722                         9/2005      
       WO       2005/089843                         9/2005      
       WO       2005/102428       A1                11/2005      
       WO       2005/102429                         11/2005      
       WO       2005/113042       A1                12/2005      
       WO       2005/113043                         12/2005      
       WO       2005/120616                         12/2005      
       WO       2006/010248                         2/2006      
       WO       2006/017688       A2                2/2006      
       WO       2006/023849                         3/2006      
       WO       2006/023943                         3/2006      
       WO       2006/023944                         3/2006      
       WO       2006/037636                         4/2006      
       WO       2006/059939                         6/2006      
       WO       2006/061637       A2                6/2006      
       WO       2006/086107                         8/2006      
       WO       2006/090149                         8/2006      
       WO       2006/105501                         10/2006      
       WO       2007/007110       A1                1/2007      
       WO       2007/016600       A2                2/2007      
       WO       2007/019229                         2/2007      
       WO       2007/024953       A1                3/2007      
       WO       2007/030706                         3/2007      
       WO       2007/033316                         3/2007      
       WO       2007/033372       A2                3/2007      
       WO       2007/042822                         4/2007      
       WO       2007/068896                         6/2007      
       WO       2007/075534       A2                7/2007      
       WO       2007/093310                         8/2007      
       WO       2007/098500                         8/2007      
       WO       2007/100535                         9/2007      
       WO       2007/118342                         10/2007      
       WO       2007/118343       A1                10/2007      
       WO       2007/121411                         10/2007      
       WO       2007/132217                         11/2007      
       WO       2007/144607                         12/2007      
       WO       2007/144614                         12/2007      
       WO       2008/001744                         1/2008      
       WO       2008/008021                         1/2008      
       WO       2008/014613       A1                2/2008      
       WO       2008/020217                         2/2008      
       WO       2008/060484       A2                5/2008      
       WO       2008/092864                         8/2008      
       WO       2008/110809                         9/2008      
       WO       2009/005546       A1                1/2009      
       WO       2009/008001       A2                1/2009      
       WO       2009/009013       A2                1/2009      
       WO       2009/047281       A1                4/2009      
       WO       2009/055030                         4/2009      
       WO       2009/055740                         4/2009      
       WO       2009/055742                         4/2009      
       WO       2009/095684       A1                8/2009      
       WO       2009/121020       A1                10/2009      
       WO       2009/140587       A1                11/2009      
       WO       2009/047281                         12/2009      
       WO       2009/152477       A2                12/2009      
       WO       2009/155581       A1                12/2009      
       WO       2010/021879       A2                2/2010      
       WO       2010/078373       A1                7/2010      
       WO       2010/080964                         7/2010      
       WO       2010/102148                         9/2010      
       WO       2010/105094       A1                9/2010      
       WO       2010/108046       A1                9/2010      
       WO       2010/125103       A1                11/2010      
       WO       2010/144785       A2                12/2010      
       WO       2010/144789                         12/2010      
       WO       2011/017554       A2                2/2011      
       WO       2011/056889       A1                5/2011      
       WO       2011/082328       A1                7/2011      
       WO       2011/163272                         12/2011      
       WO       2012/064892       A1                5/2012      
       WO       2012/135765                         10/2012      
       WO       2012/174472       A1                12/2012      
       WO       2012/174556       A1                12/2012      
       WO       2013/016754       A1                2/2013      
       WO       2013/063160       A1                5/2013      
       WO       2014/012069       A2                1/2014      
       WO       2014/036323       A1                3/2014      
       WO       2014/066856       A1                5/2014      
       WO       2014/144895       A1                9/2014      
       WO       2015/010092       A1                1/2015      
       WO       2015/021064       A1                2/2015      
       WO       2015/063100       A1                5/2015      
       WO       2015/148905       A1                10/2015      

 OTHER PUBLICATIONS
  
  Leahy et al. Beta-cell dysfunction in type II diabetes mellitus. Curr Opin Endocrinol Diabetes 2:300-306, 1995.
  Leiner et al. “Particles facilitate the absorption of insulin in a primary cell culture model of alveolar epithelium without evidence of cytotoxicity.” Presented at the American Diabetes Association 64th Scientific Sessions, Jun. 2004, abstract 467-P.
  Leiner et al. “The pharmacokinetic profile of insulin administered by inhalation in the rat.” Diabetes 53 Supplement, Jun. 2004, A111.
  Lian et al. A self-complementary self-assembling microsphere system: application for intravenous delivery of the antiepileptic andneuroprotectant compound felbanate. J Pharm Sci 89:867-875, 2000.
  Lindner et al. “Increase in serum insulin levels is correlated with lung distribution after pulmonary delivery of Technosphere/Insulin.” Diabetologia 46:A277, 2003.
  Mandal “Inhaled insulin for diabetes mellitus.” Am J Health Sys Pharm 62:1359-64, 2005.
  Mann “Pulmonary insulin—the future of prandial insulin therapy.” Presented at the 5th Annual Meeting of the Diabetes Technology Society, Nov. 2005, abstract A94.
  Monnier et al. “Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes.” JAMA 295:1681-7, 2006.
  Nathan et al. “Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.” N Engl J Med 353:2643-53, 2005.
  Nemmar et al., Passage of inhaled particles into the blood circulation in humans. Circulation pp. 411-414 (2002).
  Newman, Principles of metered-dose inhaler design. Respiratory Care, vol. 50, No. 9, pp. 1177-1190 (2005).
  Next Generation Inhaler Nears Market, Manufacturing Chemist, Cambridge Consultants, Polygon Media Ltd. (2006).
  Non-covalent interactions from UCDavis ChemWiki, pp. 1-5. Accessed by Examiner on Jul. 23, 2013 and cited in Office Action issued on Jul. 26, 2013 in U.S. Appl. No. 12/830,557.
  Oberdorster et al., Correlation between particle size, in vivo particle persistence, and lung injury. Environ Health Perspect 102 Suppl 5, pp. 173-179 (1994).
  Oberdorster et al.,Pulmonary effects of inhaled ultrafine particles. International Archives of Occupational and Environmental Health, vol. 74, pp. 1-8 (2001).
  O'Neill, Air pollution and inflammation in type 2 diabetes: a mechanism for susceptibility. Occup Environ Med. vol. 64, pp. 373-379 (2007).
  Owens et al. “Alternative routes of insulin delivery.” Diabetic Medicine 20:886-898, 2003.
  Patton et al. “Clinical pharmacokinetics and pharmacodynamics of inhaled insulin.” Clin Pharmacokinet 43:781-801, 2004.
  Pesic, Inhaler delivers more drug to the deep lung, says Cambridge Consultants. in-Pharma Technologist.com, http://www/in-pharmatechnologist.com/content/view/print/344335, Dec. 1, 2010.
  Peyrot et al. “Resistance to insulin therapy among patients and providers.” Diabetes Care 28:2673-2679, 2005.
  Pfeiffer et al. Insulin secretion in diabetes mellitus. Am J Med 70:579-88, 1981.
  Pfützner A et al. “Lung distribution of radiolabeled Technosphere™/Insulin.” Diabetes 52 Supplement, Jun. 2003, A107.
  Pfützner A et al. Pilot study with Technosphere/PTH(1-34)—a new approach for effective pulmonary delivery of parathyroid hormone (1-34). Horm Metab Res 35:319-323, 2003.
  Pfützner A et al. “Variability of insulin absorption after subcutaneous and pulmonary application in patients with type 2 diabetes.” Diabetes 51 Supplement, Jun. 2002, A47-48.
  Pfützner A. et al. “Influence of small dose i.v., s.c. and pulmonary insulin treatment on prandial glucose control in patients with Type 2 diabetes.” 37th Annual Meeting of the EASD, Sep. 9-13, 2001, abstract 812.
  Pfutzner et al. “Inhaled Technosphere/Insulin Shows a Low Variability in Metabolic Action in Type 2 Diabetic Patients.” Diabetes 49 Supplement, May 2000, A121.
  Pfutzner et al. “Pulmonary Insulin Delivery by Means of the Technosphere Drug Carrier Mechanism.” Expert Opin Drug Deliv 2:1097-1106, 2005.
  Pfutzner, Technosphere/Insulin—A new approach for effective delivery of human insulin via the pulmonary route. Diabetes Technology & Therapeutics, vol. 4, No. 5, pp. 589-594 (2002).
  Polonsky et al. “Abnormal Patterns of Insulin Secretion in Non-insulin-Dependent Diabetes Mellitus.” N Eng J Med 318:1231-39, 1988.
  Raskin et al. “Continuous Subcutaneous Insulin Infusion and Multiple Daily Injection Therapy are Equally Effective in Type 2 Diabetes.” Diabetes Care 26:2598-2603, 2003.
  Rave et al. “Dose Response of Inhaled Dry-Powder Insulin and Dose Equivalence to Subcutaneous Insulin Lispro.” Diabetes Care 28:2400-2405, 2005.
  Rave et al. “Results of a Dose-Response Study with a New Pulmonary Insulin Formulation and Inhaler.” Diabetes 49, Supplement, May 2000, A75.
  Raz et al. “Pharmacodynamics and Pharmacokinetics of Dose Ranging Effects of Oralin Versis S.S. Regular Insulin in Type 1 Diabetic Subjects.” Fourth Annual Diabetes Technology Meeting, Philadelphia, 2004.
  Rhodes et al. “Technosphere: Microspherical Particles from Substituted Diketopiperazines for Use in Oral Drug Delivery.” 208th ACS National Meeting, Aug. 1994.
  Rosenstock et al. “Inhaled Insulin Improves Glycemic Control when Substituted for or Added to Oral Combination Therapy in Type 2 Diabetes.” Ann Intern Med 143:549-558, 2005.
  Roumeliotis, New inhaler launched with a bag, in-Pharma Technologist.com, Decision News Media SAS (2006).
  Rousseau et al. “Drug delivery by fumaryl diketopiperazine particles: evidence for passive transport.” Presented at the American Diabetes Association 64th Scientific Sessions, Jun. 2004, abstract 484-P.
  Sakagami et al. “Respirable microspheres for inhalation: the potential of manipulating pulmonary disposition for improved therapeutic efficacy.” Clin Pharmacokinet 44:263-77, 2005.
  Shimada et al. Translocation pathway of the intertracheally instilled ultrafine particles from the lung into the blood circulationin the mouse. Toxicologic Pathology pp. 949-957 (2006).
  Skyler JS et al. “Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects.” Diabetes Care 28:1630-1635, 2005.
  Steiner et al. “A novel glucagon delivery system for the management of hyperinsulinemia.” Diabetes 49 Supplement, May 2000, A368.
  Steiner et al. “Bioavailability and pharmacokinetic properties of inhaled dry powder Technosphere®/Insulin.” Diabetes 49 Supplement, May 2000, A126.
  Steiner et al. “Technosphere®, a novel drug delivery system for oral administration of calcitonin.” Pharmaceutical Res 11:S299, 1994.
  Steiner et al. Technosphere(TM)/Insulin—proof of concept study with a new insulin formulation for pulmonary delivery. Exp Clin Endocrinol Diabetes 110:17-21, 2002.
  Svartengren et al., Added External Resistance Reduces Oropharyngeal Deposition and Increases Lung Deposition of Aerosol Particles in Asthmatics. Am. J. Respir. Crit. Care Med., vol. 152, pp. 32-27, 1995.
  Taylor et al. “Aerosols for macromolecule delivery. Design challenges and solutions.” Am J Drug Deliv 2:143-155, 2004.
  Telko et al., Dry Powder Inhaler Formulation. Respiratory Care, Sep. 2005, vol. 50, No. 9, 1209-1227.
  Vaczek, Accelerating drug delivery firms exploring new drug-delivery routes and devices intently awaiting the commercial launch of Exubera. Pharmaceutical & Medical Packaging News, vol. 14, No. 6 (2006).
  Warren et al. “Postprandial versus prandial dosing of biphasic insulin aspart in elderly type 2 diabetes patients.” Diabetes Res Clin Pract 66:23-29, 2004.
  White JR et al. “Inhaled insulin: an overview.” Clinical Diabetes 19:13-16, 2001.
  “An inhaled insulin formulation (Technosphere Insulin) effectively improves glycaemic control in patients with type 2 diabetes mellitus.” Inpharma Weekly, vol. 1522, Jan. 28, 2006, p. 8.
  Baso A et al. “Effects of a change in the pattern of insulin delivery on carbohydrate tolerance in diabetic and nondiabetic humans in the presence of differing degrees of insulin resistance.” J Clin Invest 97:2351-2361, 1996.
  Bayés M et al. “Gateways to clinical trials” Methods Find Exp Clin Pharmacol 24:431-455, 2002.
  Belmin J et al. “Novel drug delivery systems for insulin. Clinical potential for use in the elderly.” Drugs Aging 20:303-12, 2003.
  Boss AH et al. “Inhaled Technosphere®/Insulin: Glucose elimination at the right time?” Poster presented at the American Diabetes Association 65th Scientific Sessions, Jun. 2005, abstract 443-P.
  Boss AH et al. “Insulin bio-effect is limited by speed of absorption and elimination: similarities between an inhaled insulin formulation that mimics first-phase kinetics and i.v. insulin.” Diabetologia 47:A314, 2004.
  Boss AH et al. “Mimicry of the early phase insulin response in humans with rapidly available inhaled insulin accelerates post prandial glucose disposal compared to slower bioavailable insulin.” Presented at the American Diabetes Association 65th Scientific Sessions, Jun. 2005, abstract 1373-P.
  Boss AH et al. “Does kinetics matter? Physiological consequences of the ability of Technosphere®/Insulin inhalation to mimic first phase insulin release.” Presented at the 5th Annual Meeting of the Diabetes Technology Society, Nov. 2005, abstract A14.
  Boss AH et al. “Markedly reduced post prandial glucose excursions through inhaled Technosphere®/Insulin in comparison to SC injected regular insulin in subjects with type 2 diabetes.” 1st Annual Meeting of the European Association for the Study of Diabetes, Sep. 2005, abstract 816.
  Boss AH et al. “The variability and time-action profile of inhaled Technosphere®/Insulin compares favorably to that of subcutaneous human regular insulin.” Presented at the American Diabetes Association 65th Scientific Sessions, Jun. 2005, abstract 358-OR.
  Brownlee M et al. “Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications.” JAMA 295:1707-8, 2006.
  Caumo et al. “First-phase insulin secretion: does it exist in real life” Considerations on shape and function. Am J Physiol Endocrinol Metab 287:E371-E385, 2004.
  Cefalu “Concept, strategies and feasibility of noninvasive insulin delivery.” Diabetes Care 27:239-246, 2004.
  Cefalu “Novel routes of insulin delivery for patients with type 1 or type 2 diabetes.” Ann Med 33:579-586, 2001.
  Cerasi et al. Decreased sensitivity of the pancreatic beta cells to glucose in prediabetic and diabetic subjects. A glucose dose-response study. Diabetes 21(4):224-34, 1972.
  Cernea et al. “Dose-response relationship of oral insulin spray in healthy subjects.” Diabetes Care 28:1353-1357, 2005.
  Cheatham et al. “Desirable dynamics and performance of inhaled insulin compared to subcutaneous insulin given at mealtime in type 2 diabetes: A report from the Technosphere®/Insulin study group.” Diabetes Tech Ther 6:234-235, 2004.
  Cheatham et al. “A novel pulmonary insulin formulation replicates first phase insulin release and reduces s-proinsulin levels.” Presented at the American Diabetes Association 64th Scientific Sessions, Jun. 2004, abstract 457-P.
  Cheatham et al. “Prandial Technosphere®/Insulin inhalation provides significantly better control of meal-related glucose excursions than prandial subcutaneous insulin.” Presented at the Diabetes Technology Society meeting, Oct. 2004.
  CN Office Action cited in application No. 200880122670.3 mailed on Nov. 23, 2011.
  Coors et al., Polysorbate 80 in medical products and nonimmunologic anaphylactoid reactions. Ann. Allergy Asthma Immunol., 95(6): 593-599 (2005). Abstract only. Accessed by Examiner on Jul. 22, 2013 and cited in Office Action issued on Jul. 26, 2013 in U.S. Appl. No. 12/830,557.
  Definition of analog from http://cancerweb.ncl.ac.uk/omd/about.html, pp. 1-5. Accessed by Examiner on Jul. 7, 2005 and cited in Office Action issued on Jul. 26, 2013 in U.S. Appl. No. 12/830,557.
  Del Prato “Unlocking the opportunity of tight glycaemic control. Far from goal.” Diabetes Obesity Metabolism 7:S1-S4, 2005.
  Drug Delivery, Easing the drug delivery route, Jun. 2006, Pharmaceutical & Medical Packaging News, Canon Communications.
  Edelman SV Type II diabetes mellitus. Adv Int Med 43:449-500, 1998.
  Edwards et al., Recent advances in pulmonary drug delivery using large, porous inhaled particles. Journal of Applied Physiology, pp. 379-385 (1998).
  English tranaslation of Chinese Office Action for Chinese Patent application No. 201080026117.7.
  Exubera indications, dosage, storage, stability. Http://www.rxlist.com/cgi/generic4/exuberaids.htm.
  Exubera package insert, p. 1.
  Ferrin et al, Pulmonary retention of ultrafine and fine particles in rats. Am. J. Repir. Cell Mol. Biol., pp. 535-542 (1992).
  File History of Related U.S. Appl. No. 13/921,104, filed Jun. 18, 2013.
  File History of Related U.S. Appl. No. 13/941,365, filed Jul. 12, 2013.
  File History of Related U.S. Appl. No. 14/092,810, filed Nov. 27, 2013.
  Gates BJ “Update on advances in alternative insulin therapy.” Advances in Pharmacy 1:159-168, 2003.
  Grant et al “Both insulin sensitivity and maximal glucose elimination rate are reduced in type 2 diabetes.” Presented at the American Diabetes Association 65th Scientific Sessions, Jun. 2005, abstract 2202-PO.
  Grant et al. “The distribution of 14C-labeled particles following intra-tracheal liquid installation in the Sprague-Dawley rat.” Presented at the American Diabetes Association 64th Scientific Sessions, Jun. 2004, abstract 461-P.
  Gupta et al. Contemporary approaches in aerosolized drug delivery to the lung. J Controlled Resease 17:129-148, 1991.
  Harsch IA “Inhaled Insulins: Their potential in the treatment of diabetes mellitus.” Treat Endocrinol 4:131-138, 2005.
  Heinemann, L., et al., “Current status of the development of inhaled insulin” Br. Diabetes Vasc Dis 4:295-301, 2004.
  Hirsch IB “Insulin analogues.” N Engl J Med 352:174-83, 2005.
  Insulin inhalation NN 1998, Drugs R & D, 2004, pp. 46-49, Adis Data Information BV.
  International Search Report for PCT/US2010/038287.
  Kapitza et al. “Dose-response characteristics for a new pulmonary insulin formulation and inhaler.” Presented at the 35th Annual Meeting of the EASD, Sep. 2000, abstract OP29 184.
  Katchalski, Ephraim, “Synthesis of Lysine Anhydride”, J. Amer. Chem. Soc., vol. 68, 1946, pp. 879-880.
  Kaur et al., A delineation of diketopiperazine self-assembly processes: understanding the molecular events involved in NΛe-(Fumaroyl) diketopiperazine of L-Lys (FDKP) Ineractions. Molecular Pharmaceutics, vol. 5, No. 2, pp. 294-315 (2008).
  Klinger et al., Insulin-micro and nanoparticles for pulmonary delivery. International Journal of Pharmaceutics, vol. 377, pp. 173-179 (2009).
  Kohler et al. Non-radioactive approach for measuring lung permeability: inhalation of insulin. Atemw Lungenkrkh 13:230-232, 1987.
  Kopple, Kenneth D., “A Convenient Synthesis of 2.,5-Piperazinediones”, J. Org. Chem., vol. 33, No. 2, 1968, pp. 862-864.
  Krueger et al. “Toxicological profile of pulmonary drug delivery agent.” Presented at the American Diabetes Association 64th Scientific Sessions, Jun. 2004, abstract 465-P.
  Laureano et al. “Rapid absorption and elimination of insulin from the lung following pulmonary administration of Technosphere®/Insulin: A pharmacokinetic study in a rat model.” Presented at the American Diabetes Association 65th Scientific Sessions, Jun. 2005, abstract 445-P.
  Pfuetzner A, Rave K, Heise T, et al. Inhaled Technosphere™/insulin results in low variability in metabolic action in type 2 diabetic patients. Exp Clin Endocrinol Diabetes 2000; 108:S161.
  Pfuetzner A, Rave K, Heise T, et al. Low variability in metabolic action in type 2 diabetic patients with inhaled Technosphere/insulin. Diabetologia 2000; 43:Abstract 774.
  Phillips M, Amin N, Boss AH, et al. Pulmonary functions (over 2 years) in diabetic subjects treated with Technosphere® insulin or usual antidiabetic treatment. Diabetologia 2009; 52 (suppl 1).
  Pohl R, Muggenberg BA, Wilson BR, et al. A dog model as predictor of the temporal properties of pulmonary Technosphere/insulin in humans. Respiratory Drug Delivery 2000; VII: 463-465.
  Potocka E, Amin N, Cassidy J, et al. Insulin pharmacokinetics following dosing with Technosphere® insulin in subjects with chronic obstructive pulmonary disease. Current Medical Research and Opinion 2010; 26:2347-2353.
  Potocka E, Baughman R A, Derendorf H. Population pharmacokinetic model of human insulin following different routes of administration. Journal of Clinical Pharmacology 2011;51:1015-1024.
  Potocka E, Baughman R, Derendorf H. Population Pharmacokinetic Model of Regular Human Insulin Following Different Routes of Administration. AAPS Journal. 2009; 11(S1). Available from: http://www.aapsj.org. Presented at the 2009 AAPS (American Association of Pharmaceutical Scientists) National Biotechnology Conference, Jun. 21-24, Seattle, WA.
  Potocka E, Baughman RA, Derendorf J. A population PK/PD model of Technosphere® insulin administered to healthy and type 2 diabetics. ADA 2010; Poster 624.
  Potocka E, Baughman RA, Schwartz SL, et al. Pharmacokinetics of AFRESA® unchanged in patients with chronic obstructive pulmonary function ADA 2009; Poster 437.
  Potocka E, Cassidy J P, Haworth P, et al. Pharmacokinetic characterization of the novel pulmonary delivery excipient fumaryl diketopiperazine. Journal of diabetes science and technology 2010;4:1164-1173.
  Potocka E, Cassidy JP, Haworth P, et al. Pharmacokinetic characterization of fumaryl diketopiperazine. Third International Conference on Advanced Technologies and Treatments for Diabetes 2010; Poster 291.
  Potocka E, Hovorka R, Baughman R, et al. Characterization of metabolism parameters following Technosphere® insulin and insulin Lispro. ADA 2010; Poster 1561.
  Potocka E, Hovorka R, Baughman RA, et al. AFRESA™ supresses endogenous glucose production earlier than a rapid-acting analog (Lispro) and inhaled Exubera® ADA 2009; Oral 232.
  Potocka E, Hovorka R, Baughman RA, et al. Technosphere® insulin suppresses endogenous glucose production earlier than a rapid-acting analog (lispro) and an inhaled insulin (exubera). Diabetologia 2009; 52 (suppl 1).
  Prabhu et al. “A study of factors controlling dissolution kinetic of zinc complexed protein suspensions in various ionic species”, Int. J. Pharm. 217(1-2):71-8 (2001).
  Laube et al., The lung as an alternative route for delivery for insulin in controlling postrprandial glucose levels in patients with diabetes. Chest, Preliminary Report 114 (6) : 1734-1739 (1998).
  Quattrin et al. “Efficacy and Safety of Inhaled Insulin (Exubera) Compared with Subcutaneous Insulin Therapy in Patients with Type 1 Diabetes.” Diabetes Care, vol. 27, No. 11, Nov. 2004, p. 2622-2627.
  Quddusi et al. “Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans.” Diabetes Care 26:791, 2003.
  Rachman et al. “Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36) amide in patients with NIDDM.” Diabetes 45:1524, 1996.
  Raju et al., Naseseazines A and B: a new dimeric diketopiperazine framework from a marine-derived actinomycete, Streptomyces sp. Organic letters, vol. 11, No. 17, pp. 3862-3865 (2009).
  Raskin P, Heller S, Honka M, et al. Pulmonary function over 2 years in diabetic patients treated with prandial inhaled Technosphere® Insulin or usual antidiabetes treatment: A randomized trial. Diabetes, Obesity and Metabolism 2012;14:163-173.
  Raskin P, Phillips M, Amin N, et al. Hypoglycemia in patients with type 1 diabetes incorporating prandial inhaled Technosphere® insulin into their usual diabetes treatment regimen vs continuing their usual diabetes management. AACE 2010; Poster 283.
  Raskin P, Phillips MD, Rossiter A, et al. A1C and hypoglycemia in patients with type 2 diabetes mellitus incorporating prandial inhaled Technosphere® insulin into their usual antihyperglycemic regimen vs continuing their usual antihyperglycemic regimen. ADA 2010; Abstract 359-OR.
  Raufman et al., Exendin-3, a novel peptdie from Heloderma horridum venom, interacts with vasoactive intestinal peptide receptors and a newly described receptor on dispersed aciin from guinea pig pancreas. J. Biol. Chem. 266(5) : 2897-2902 (1991).
  Raufman et al., Truncated glucagon-like peptide-1 interacts with exendin receptors on dispersed acini from guina pig pancreas. J. Biol. Chem. 267(30) : 21432-21437 (1992).
  Raun et al. “Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, where as a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not.” Diabetes 56:8, 2007.
  Rave et al. “Coverage of Postprandial Blood Glucose Excursions with Inhaled Technosphere Insulin in Comparison to Subcutaneously Injected Regular Human Insulin in Subjects with Type 2 Diabetes.” Diabetes Care, vol. 30, No. 9, pp. 2307-2308, Sep. 2007.
  Rave et al. “Inhaled Technosphere Insulin in Comparison to Subcutaneous Regular Human Insulin: Time Action Profile and Variability in Subjects with Type 2 Diabetes.” Journal of Diabetes Science and Technology, vol. 2, Issue 2, pp. 205-212, Mar. 2008.
  Rave et al. “Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin.” Diabetes Care 28:1077, 2005.
  Rave K, Heise T, Pfuetzner A, et al. Assessment of dose-response characteristics for a new pulmonary insulin formulation and inhaler. Exp Clin Endocrinol Diabetes 2000; 108:S161.
  Rave K, Potocka E, Boss AH, et al. Pharmacokinetics and linear exposure of AFRESA™ compared with the subcutaneous injection of regular human insulin Diabetes, Obesity and Metabolism 2009; 11:715-720.
  Razavi et al. “TRPVI+ sensory neurons control beta cell stress and islet inflammation in autoimmune disease.” Cell 127:1123, 2006.
  Retrieved from website: http://groups.molbiosci.northwestern.edu/holmgren/Glossary/Definitions/Def-P/placebo.html, 1 page, Retrieved on Mar. 12, 2013.
  Richardson et al. “Technosphere Insulin Technology.” Diabetes Technology & Therapeutics, vol. 9, Supplement 1, pp. S65-S72, 2007.
  Richardson PC, Potocka E, Baughman RA, et al. Pharmacokinetics of Technosphere® insulin unchanged in patients with chronic obstructive pulmonary disease. Diabetologia 2009; 52 (suppl 1).
  Richter et al. “Characterization of glucagon-like peptide-1(7-36)amide receptors of rat membranes by covalent cross-linking.” FEBS Letters 280:247, 1991.
  Richter et al. “Characterization of receptors for glucagon-like peptide-1 (7-36)amide on rat lung membranes.” FEBS Letters 267:78, 1990.
  Riddle “Combining Sulfonylureas and Other Oral Agents.” Am J Med, 2000, vol. 108(6A), pp. 15S-22S.
  Riddle et al. “Emerging therapies mimicking the effects of amylin and glucagon-like peptide 1.” Diabetes Care 29:435, 2006.
  Ritzel et al. “Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 (7-36 amide) after subcutaneous injection in healthy volunteers. Dose-response-relationships.” Diabetologia 38:720, 1995.
  Rosen et al., Substance P microinjected into the periaqueductal gray matter induces antinociception and is released folloing morphine administration. Brain Research, 1001: 87-94 (2004).
  Rosenmund et al., Diketopiperazines from Leuchs Anhydrides. Angew Chem Intern. Edit. vol. , No. 2 (1970).
  Rosenstock “Dual therapy with inhaled human insulin (Exubera(R)) as add-on to metformin (with stopping sulfonurea) is better than triple therapy with rosiglitazone add-on to combination metformin and sulfonurea in poorly controlled Type 2 diabetes.” Diabetes 57:supplement 1:A557, Abstract 2018-PO, 2008.
  Exubera package insert, p. 1, 2008.
  Fadl et al., Effects of MDI spray angle on aerosol penetration efficiency through an oral airway cast. Journal of Aerosol Science, vol. 38, No. 8, pp. 853-864 (2007).
  Falsone et al., The Biginelli dihydropyrimidone synthesis using polyphosphate ester as a mild and efficient cyclocondensation/dehydration reagent. Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University, pp. 122-134 (2001).
  Farr, S.J. et al., Pulmonary insulin administration using the AERx® system:physiological and physiochemical factors influencing insulin effectiveness in healthy fasting subjects. Diabetes Tech. Ther. 2:185-197, 2000.
  Fehmann et al. “Cell and molecular biology of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulin releasing polypeptide.” Endocrine Reviews 16:390, 1995.
  Festa et al., “LDL particle size in relation to insulin, proinsulin, and insulin sensitivity” Diabetes Care, 22 (10):1688-1693 (1999).
  Forst et al., “Metabolic Effects of Mealtime Insulin Lispro in Comparison to Glibenclamide in Early Type 2 Diabetes”, Exp. Clin. Endocrinol. Diabetes, 2003, 111, 97-103.
  Fritsche et al. “Glimepiride Combined with Morning Insulin Glargine, Bedtime Neutral Protamine Hagedorm Insulin, or Bedtime Insulin Glargine in Patients with Type 2 Diabetes.” American College of Physicians 2003.
  Galinsky et al., A synthesis of diketopiperazine's using polyphosphoric acid. Journal of the American Pharmaceutical Association, vol. 46, No. 7, pp. 391-393 (1957).
  Garber, “Premixed insulin analogues for the treatment of diabetes mellitus”, Drugs, 66(1):31-49 (2006).
  Garg et al. “Improved glycemic control without an increase in severe hypoglycemic episodes in intensively treated patients with type 1 diabetes receiving morning, evening, or split dose insulin glargine.” Diabetes Research and Clinical Practice 66 (2004) 49-56.
  Garg SK, Kelly W, Freson B, et al. Treat-to-target Technosphere® insulin in patients with type 1 diabetes. ADA 2011; Abstract 941-P.
  Garg SK, McGill JB, Rosenstock J, et al. Technosphere® insulin vs insulin lispro in patients with type 1 diabetes using multiple daily injections. ADA, Abstract 917-P (2011).
  Glucagon for Injection (1999) glucagon for injection (rDNA origin), pp. 1-7.
  Glucagon-like peptide-1; http://en.wikipedia.org/wiki/Glucagon-like peptide-1 (accessed Apr. 24, 2015).
  GLUCOPHAGE Product Insert. Jan. 2009.
  GLUCOTROL Product Insert. Sep. 2006.
  Gnudi L, Lorber D, Rosenstock J, et al. Basal/bolus with prandial inhaled Technosphere® insulin (TI) plus insulin glargine qd vs biaspart 70/30 insulin bid in type T2 diabetes mellitus inadequately controlled on insulin with/without oral agents. Diabetologia 2009; 52 (suppl 1).
  Goke et al., Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J. Biol. Chem. 268(26):19650-19655 (1993).
  Golpon et al. “Vasorelaxant effect of glucagon-like peptide-(7-36) amide and amylin on the pulmonary circulation of the rat.” Regulatory Peptides 102:81, 2001.
  Gonzalez et al., Actualizacion del tratamiento farmacologico de la diabetes mellitus tipo 2. Del Sistema Nacional de Salud. Volumen 32, No. 1, pp. 3-16 (2008)—full article in Spanish with English abstract.
  Gotfried M, Cassidy JP, Marino MT, et al. Lung deposition and absorption of insulin from Technosphere® insulin. Diabetologia 2009; 52 (suppl 1).
  Grant M, Harris E, Leone-Bay A, Rousseau K. Technosphere®/insulin: Method of action. Diabetes Technology Meeting 2006; Poster.
  Grant ML, Greene S, Stowell GW, et al. Mimicking endogenous peptide secretion by inhalation APS 2009; poster.
  Greene et al. “Effects of GLP-1 Technosphere(TM) powder: administered by pulmonary insufflation in male obese Zucker diabetic fat (ZDF) rats.” Diabetes Technology Meeting, San Francisco, Oct. 2007.
  Greene et al., Greene's protective groups in organic synthesis. 4th ed., pp. 781-783 (2007).
  Gurrieri et al., Thermal condensation of some alpha-aminoacids with phatalic acid. Thermochimica Acta, 7 (1973) 231-239.
  Gutniak et al. “Antidiabetogenic action of glucagon-like peptide-1 related to administration relative to meal intake in subjects with type 2 diabetes.” J Int Med 250:81, 2001.
  Gutniak et al. “Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus.” NEJM 326:1316, 1992.
  Gutniak et al. “GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions.” Diabetes Care 20:1874, 1997.
  Gutniak et al. “Potential therapeutic levels of glucagon-like peptide I achieved in humans by a buccal tablet.” Diabetes Care 19:843, 1996.
  Gutniak et al. “Subcutaneious injection of the incretin hormone glucagon-like peptide 1 abolishes postprandial glycemia in NIDDM.” Diabetes Care 17:1039, 1994.
  Guyton et al., “Acute Control of Llocal Blood Flow”, Textbook of Medical Physiology, Chapter 17, 10th Edition, W.B. Saunders Company, pp. 176-177, 2000.
  Gyore et al., Thermal Analysis, vol. 2—Proceedding Fourth ICTA Budapest 1974; 387-394.
  Haak “New developments in the treatment of type 1 diabetes mellitus.” Exp Clin Endocrinol Diabetes 107:Suppl 3: S108, 1999.
  Haffner et al., “Proinsulin and insulin concentrations I relation to carotid wall thickness”, Strock 29:1498-1503 (1998).
  Hagedorn et al. “Protamine Insulin”, JAMA, 106:177-180 (1936).
  Haino, Takeharu et al. “On-beads Screening of Solid-Attached Diketopiperzines for Calix[5]Arene-Based Receptor.” Tetrahedron Letters, 40(20), 3889-3892, 2003.
  Halozyme Press Release. Jun. 6, 2009.
  Hanley et al., “Cross-sectional and prospective associations between proinsulin and cardovascular disease risk factors in a population experiencing rapid cultural transition” Diabetes Care 24(7): 1240-1247 (2001).
  Hassan et al. “A Randomized, Controlled Trial Comparing Twice-a-Day Insulin Glargine Mixed with Rapid-Acting Insulin Analogs Versus Standard Neutral Protamine Hagedom (NPH) Therapy in Newly Diagnosed Type 1 Diabetes.” Pediatrics, 121(3), e466-e472, 2008.
  Hassan et al. “In vivo dynamic distribution of 131I-glucagonOlike peptide-1 (7-36) amide in the rat studied by gamma camera.” Nucl Med Biol 26:413, 1999.
  Hausmann et al. “Inhaled insulin as adjunctive therapy in subjects with type 2 diabetes failing oral agents: a controlled proof of concept study.” Diabetes Obesity and Metabolism 8:574, 2006.
  Hayasaka et al. “Proliferation of type II pneumocytes and alteration in their apical surface membrane antigenicity in pulmonary sarcoidosis.” Chest 116:477, 1999.
  Chelikani et al., Intravenous infusion of glucagon-like peptide-1 potently inhibits food intake, sham feeding, and gastric emptying in rats. Am J Physiol. Regul. Integr. Comp. Physiol., 288(6):R1695-706, 2005.
  Chemical Abstracts, vol. No. 114(22), Abstract No. 214519x (1990).
  Chemicaland21.com. Solvents. Dec. 12, 2008. Available from: <http://web.archive.org/web20081212035748/http://www.chemicalland21.com/info/SOLVENTS.htm.
  Chow et al., Particle Engineering for Pulmonary Drug Delivery. Pharmaceutical Research, vol. 24, No. 3, pp. 411-437 (2007).
  Glee et al. Nature Genetics 38:688-693, 2006.
  Cobble “Initiating and Intensifying Insulin Therapy for Type 2 Diabetes: Why, When, and How.” Am J Ther. Jan. 8, 2009.
  Coffey et al. “Valuing heath-related quality of life in diabetes.” Diabetes Care 25:2238, 2002.
  Colagiuri et al., Are lower fasting plasma glucose levels at diagnosis of type 2 diabetes associated with improved outcomes? Diabetes Care, vol. 25, pp. 1410-1417 (2002).
  Combettes and Kargar, C, Newly Approved and Promising Antidiabetic Agents. Therapie, Jul.-Aug. 2007: 62 (4): 293-310.
  Costello et al., “Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism in prostate epithelial cells”, Journ. Biol. Chem. 272(46):28875-28881 (1997).
  Cricket TM Single-Use Inhalers [on-line]. MannKind Technologies Website, posted in 2011, [retrieved on Jul. 30, 2012]. Retrieved from the Internet. <URL:mannkindtechnologies,com/DeviceTechnology/CricketSingleUseInhalers.aspx>.
  Crosby, J. “Dog Normals”, <http://vetmedicine.about.com/od/diseasesconditionsfaqs/tp/TPdogfacts.htm>, copyright 2013.
  Cruetzfeldt et al. “Glucagonostatic actions and reduction of fasting hyerglycemia by exogenous glucagon-like peptide i(7-36) amide in type 1 diabetic patients.” Diabetes Care 19:580, 1996.
  D'Alessio et al., Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons. J. Clin. Invest., 97:133-38 (1996).
  Database adisinsight, “Gucagon-like peptide-1 inhalation—MannKind Corporation”, Database accession No. 2009:1048 Abstract.
  Davis “Postprandial Physiology and the Pathogenesis of Type 2 Diabetes Mellitus.” Insulin, vol. 3, Apr. 1, 2008, pp. 132-140.
  De Heer et al. “Sulfonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like peptide-1.” Diabetes 56:438, 2007.
  Deacon “Therapeutic strategies based on glucagon-like peptide 1.” Diabetes. Sep;53(9):2181-9, 2004.
  Deacon et al., “Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig”, Am. J. Physiol. 271 (Endocrino. Metab. 34): E458-E464, 1996.
  DECODE study group. “Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.” Lancet. Aug. 21, 1999;354(9179):617-21.
  DedicatedPhase, “Preclinical Trials and Research”, <http://www.dedicatedphase1.com/preclinical-research.html>, copyright 2006-2011, p. 1.
  Delgado-Aros et al. “Effect of GLP-1 on gastric volume, emptying, maximum volume ingested and postprandial symptoms in humans.” Am J Physiol Gastrointest Liver Physiol 282:G424, 2002.
  Diabetes: Counting Carbs if You Use Insulin, WedMD, http://diabetes.webmd.com/carbohydrate-counting-for-people-who-use-insulin#m Oct. 1, 2010.
  Diez et al. “Inhaled insulin—a new therapeutic option in the treatment of diabetes mellitus” Expert Opin. Pharmacother, 2003, 4, 191-200.
  Dorwald, F.A. Side reactions in organic synthesis. Wiley, (2005).
  Doyle et al. “Glucagon-like peptide-1.” Recent Prog Horm Res. 2001;56:377-99.
  Dreamboat TM Reusable Inhalers [on-line]. MannKind Technologies Website, posted in 2011, Retrieved from the Internet: <URL: mannkindtechnologies.com/Device Technology/Dream Boat Reuseable Inhalers.aspx>.
  Drucker “Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes.” Curr Pharma Design 7:1399, 2001.
  Drucker et al., “The incretin system:glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes”, www.thelancet.com, vol. 368, pp. 1696-1705, Nov. 11, 2006.
  Dungan et al., Glucagon-like peptide 1-based therapies for type 2 diabetes: a focus on exntadtide. Clinical Diabetes, 23: 56-62 (2005).
  Dunn, “Zinc-ligand interactions modulate assembly and stability of the insulin hexamer”, Biometals, 18(4):295-303 (2005).
  Edited by Fukushima, Masanori, “Arterial Sclerosis,” Merck Manual 17th, Japanese Edition, NIKKEI BP Corp., p. 1659-1663, 1999.
  Edwards CMB et al. “Cardiovascular and pancreatic endocrine response to glucagon-like peptide-1(7-36) amide in the conscious calf.” Exp Physiol 82:709, 1997.
  Edwards CMB et al. “Subcutaneous glucagon-like peptide-1(7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects.” Clinical Science 96:719, 1998.
  Eggers et al., Molecular confinement influences protein structure and enhances thermal protein stability. Protein Sci., 10:250-261 (2001).
  Ehlers et al. “Recombinant glucagon-like peptide-1 (7-36 amide) lowers fasting serum glucose in a broad spectrum of patients with type 2 diabetes.” Horm Metab Res 35:611, 2003.
  Eissele et al., Rat gastric somatostatin and gastrin relase: interactions of exendin-4 and truncated glucagon-like peptide-1 (GLP-1) amide. Life Sci., 55(8):629-634 (1994).
  Elliot et al., Parenteral absorption of insulin from the lung in diabetic children. Austr. Paediatr. J. 23: 293-297 (1987).
  Elrick et al. “Plasma insulin response to oral and intravenous glucose administration.” J Clin Endocr 24:1076, 1964.
  Engelgau MM “Screening for type 2 diabetes.” Diabetes Care 23:1563-1580, 2000.
  Engwerda et al., Improved pharmackinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology. Diabetes Care, vol. 34, Aug. 2011, pp. 1804-1808.
  Erlanger et al., Phosphorous pentoxide as a reagent in peptide synthesis. College of Physicians and Surgeons—Columbia Univeristy, vol. 26, pp. 2534-2536 (1960).
  Exubera indications, dosage, storage, stability. Http://www.rxlist.com/cgi/generic4/exuberaids.htm, 2008.
  Bilheimer DW, Ren H, Boss AH. Analysis of cardiovascular adverse events in patients with type 1 or type 2 diabetes enrolled in selected therapeutic trials in the phase 2/3 Technosphere® insulin development program. ADA 2011. Poster 922-P.
  Billings CC, Smutney CC, Howard CP, et al. Handleability and characterization of inhalation profiles using the Gen2 delivery system in a pediatric population. Diabetes Technology Meeting 2010; poster.
  Biodel's Intellecutal Property position strengthened for ultra-rapid-acting insulin programs by notice of intent to grant from European Patent Office. Newswire Feed, published May 2, 2012.
  Blazquez E et al. “Glucagon-like peptide-1 (7-36) amide as a novel neuropeptide.” Mol Neurobio 18:157, 1998.
  Bloomgarden “Gut-derived incretin hormones and new therapeutic approaches.” Diabetes Care 27:2554, 2004.
  Boer et al., Design and application of a new modular adapter for laser diffraction characterization of inhalation aerosols. International Jornal of Pharmaceutics 249, pp. 233-245 (2002).
  Boer et al., Inhalation characteristics and their effects on in vitro drug delivery from dry powder inhalers. Part 1. Inhalation characteristics, work of breathing and volunteers' preference in dependence of the inhaler resistance. Int. J. Pharm. 130 (1996) 231-244.
  Bojanowska “Physiology and pathophysiology of glucagon-like peptide-1 (GLP-1): the role of GLP-1 in the pathogenesis of diabetes mellitus, obesity and stress.” Med Sci Monit 11:RA271, 2005.
  Bonner-Weir S et al. “New sources of pancreatic beta-cells.” Nat Biotechnol 23:857-61, 2005.
  Boss et al. “Prandial Insulin: Is Inhaled Enough?” Drug Development Research 69(3):138-142 (2008).
  Boss A H, Petrucci R, Lorber D. Coverage of prandial insulin requirements by means of an ultra-rapid-acting inhaled insulin. Journal of diabetes science and technology 2012;6:773-779.
  Boss AH, Baughman RA, Evans SH, et al. A 3 month comparison in type 1 diabetes of inhaled Technosphere®/Insulin (TI) to Sc administered rapid-acting insulin analogue (RAA) as prandial insulin in a basal/prandial regimen. Diabetes 2006; 55:A97.
  Boss AH, Evans SH, Firsov I, et al. Technosphere® insulin as effective as sc rapid acting insulin analogue in providing glycemic control in a 6-month study of patients with type 2 diabetes. Diabetes Technology Meeting 2006; poster.
  Boss AH, Evans, SH, Ren, H, et al. Superior post prandial glucose control in patients with type 1 diabetes when using prandial technosphere insulin compared to NovoLog. Diabetologia 2006; Abstract 181.
  Boss AH, Marino MT, Cassidy JP, et al. C-peptide correction method to determine exogenous insulin levels in pharmacokinetic studies using Technosphere® insulin. Diabetologia 2009; 52 (suppl 1).
  Boss AH, Raskin P, Philips M, et al. Glycosylated hemoglobin and hypoglycaemia in patients with Type 2 diabetes mellitus: Technosphere® insulin and usual antihyperglycaemic regimen vs usual antihyperglycaemic regimen. Diabetologia 2010;53(suppl 1).
  Brandt D, Boss AH. The next generation insulin therapy. OndrugDelivery 2006 (published online).
  Brange et al., “Insulin Structure and Stability”, Pharm Biotechnol, 5:315-50 (1993).
  Bray “Exanatide” Am J Health—Sys Pharm 63:411, 2006.
  Bruce, D.G., et al. “Physiological importance of deficiency of early prandial insulin secretion in non-insulin-dependent diabetes.” Diabetes 37:736-44, 1988.
  Bullock BP et al. “Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor” Endocrinology 137:2968, 1996.
  Burcelin et al. “Encapsulated, genetically engineered cells, secreting glucagon-like peptide-1 for the treatment of non-insulin-dependent diabetes mellitus.” Ann N Y Acad Sci. Jun. 18, 1999;875:277-85.
  Calles-Escandon, J. and Robbins, D.C. “Loss of early phase insulin release in humans impairs glucose tolerance and blunts thermic effect of glucose.” Diabetes 36:1167-72, 1987.
  Camilleri, Clinical Practice: Diabetic Gastroparesis. The New England Journal of Medicine, 356: 820-829 (2007).
  Campos et al. “Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon0like peptide-1 in the mouse.” Endocrinology 134:2156, 1994.
  Cassidy J P, Amin N, Marino M, et al. Insulin lung deposition and clearance following Technosphere® insulin inhalation powder administration. Pharmaceutical Research 2011; 28:2157-2164.
  Cassidy J, Amin N, Baughman R, et al. Insulin kinetics following Technosphere® insulin inhalation powder administration unchanged in albuterol-treated asthmatics. ADA 2010; Poster 522.
  Cassidy J, Baughman RA, Tonelli G, et al. Use of rapid acting insulin analog as the baseline infusion during glucose clamping improves pharmacokinetic evaluation. ADA 2007; 56: Abstract 602-P.
  Cassidy JP, Baughman RA, Schwartz SL, et al. AFRESA® (Technosphere® insulin) dosage strengths are interchangeable ADA 2009; Poster 433.
  Cassidy JP, Marino MT, Amin N, et al. Lung deposition and absorption of insulin from AFRESA® (Technosphere® insulin) ADA 2009; Poster 425.
  Cassidy JP, Potocka E, Baughman RA, et al. Pharmacokinetic characterization of the Technosphere® inhalation platform Diabetes Technology Meeting 2009. poster.
  Cefalu et al., Inhaled human insulin treatment in patients with type 2 diabetes mellitus. Ann. Int. Med., 2001, 134(3): 203-207.
  Ceglia et al. “Meta-analysis: efficacy and safety of inhaled insulin therapy in adults with diabetes mellitus.” Ann Intern Med 145:665, 2006.
  Cernea et al. “Noninjectable Methods of Insulin Administration.” Drugs of Today 2006, 42 (6): 405-424.
  Chan et al., “Pharmacological Management of Type 2 Diabetes Mellitus: Rationale for Rational Use of Insulin”, Mayo Clin Proc, 2003, 78, 459-467.
  Chase et al., “Redefining the clinical remission period in children with type 1 diabetes”, Pediatric Diabetes, 2004, 5, 16-19.
  Fabio et al., Heat-stable dry powder oxytocin formulations or delivery by oral inhalation. AAPS PharmSciTech, (2015).
  ACTOS Product Insert. Aug. 2008.
  Adjusting Mealtime Insulin Doses. BD Diabetes. http://www.bd.com/diabetes/page.aspx?cat=7001&id=7280 (2014).
  Ahren “GLP-1 and extra-islet effects.” Horm. Med Res 36:842, 2004.
  Ahren B et al. “Characterization of GLP-1 effects on b-cell function after meal ingestion in humans.” Diabetes Care 26:2860, 2003.
  Ahren B., Glucagon-like peptide-1 (GLP-1): a gut hormone of potential interest in the treatment of diabetes. BioEssays, V. 20, pp. 642-651 (1998).
  Akerlund et al., Diketopiperazine-based polymers from common acids. Journal of Applied Polymer Science (2000), 78(12), 2213-2218.
  Alabraba et al. Diabetes Technology & Therapeutics. Jul. 2009, 11(7): 427-430.
  Alcohols limited. Alcohol speciality solvents—Go green! Jul. 24, 2010. Available from: <http://webarchive.org/web/20100724193725/http://www.alcohols.co.uk/specialitysolvents.php>.
  Aljada et al. “Insulin inhibits the pro-inflammatroy transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations.” The Journal of Clinical Endocrinology and Metabolism, vol. 87, No. 3, p. 1419-1422, 2002.
  Al-Showair et al., Can all patients with COPD use the correct inhalation flow with all inhalers and does training help? Respiratory Medicine, vol. 101, No. 11, p. 2395-2401 (2007).
  American Diabetes Association, “Standards of medical care in diabetes—2009”, Diabetes Care, Jan. 2009, 32 Suppl 1: S13-61.
  Amin N, Boss AH, Petrucci R, et al. Pulmonary functions (over 2 years) in diabetic subjects treated with AFRESA® or usual antidiabetic treatment ADA 2009; Poster 570.
  Amin N, et al. Long-term sustained safety and efficacy of continued use of Technosphere insulin in subjects with type 2 diabetes. Abstract—Oral Presentation 215, 48th EASD Annual Meeting, Sep. 29-Oct. 2, 2009, Vienna Austria.
  Amin N, Marino MT, Cassidy JP, et al. Acute pulmonary effects of Technosphere® insulin inhalation powder administered using a Gen2B inhaler compared to MedTone® C inhaler. Diabetes Technology Meeting 2010; poster.
  Amin N, Phillips M, Boss AH, et al. Pulmonary functions (over 2 years) in diabetic patients treated with Technosphere® insulin (TI) or usual antidiabetic treatment. Third International Conference on Advanced Technologies and Treatments for Diabetes. 2010; Poster 290.
  Angelo et al., Technosphere Insulin: Defining the Role of Technosphere Particles at the Celluar Level. J. Diabetes Sci. Technol., vol. 3, Issue 3, pp. 545-554 (2009).
  Angelo et al. Technosphere® insulin inhalation powder: Defining the mechanism of action. ADA 2008; 57: Poster 428-P.
  Antosiewiez et al., Prediction of pH-dependent properties of proteins. J Mol. Biol., 238:415-436 (1994).
  Arakawa et al., Preferential interactions determine protein solubility in three-component solutions: the MgCl2 system. Biochemistry, 29:1914-1923 (1990).
  Ashwell et al. “Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.” 2006 Diabetes UK, Diabetic Medicine, 23, 879-886.
  Ashwell et al., “Optimal timing of injection of once-daily insulin gargine in people with Type 1 diabetes using insulin ispro at meal-times” 2005 Diabetes UK, Diabetic Medicine, 23, 46-52.
  Atherton, F. et al. “Synthesis of 2(R)-A3(S)-Acylamino-2-OXO-1-Azetidinyloxy U-Acetic Acids.” Tetrahedron, vol. 40, No. 6, Jan. 1, 1984, pp. 1039-1046.
  AVANDIA Product Insert, Oct. 2008.
  Baggio et al. “A recombinant human glucagon-like peptide (GLP)-1-albumin protein (Albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostatsis.” Diabetes 53:2492, 2004.
  Baggio et al. “Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, regulates fasting glycemia and noneneteral glucose clearance in mice.” Endocrinology 141:3703, 2000.
  Baggio et al. “Harnessing the therapeutic potential of glucagon-like peptide-t” Treat Endocrinol 1:117, 2002.
  Drucker et al., Minireview: The glucagon-like peptides. Endocrinology, vol. 142, No. 2, pp. 521-527 (2001).
  Balkan B et al. “Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms.” Am J. Physiol Regulatory Integrative Comp Physiol 279:R1449, 2000.
  Barnett AH et al. “An open, randomized, parallel-group study to compare the efficacy and safety profile of inhaled human insulin (Exubera) with glibenclamide as adjunctive therapy in patients with Type 2 diabetes poorly controlled on metformin.” Diabetes Care 29(8):1818-1825, 2006.
  Barnett et al., An open, randomized, parallel-group study to compare the efficacy and safety profile of inhaled human insulin (Exubera) with metformin as adjunctive therapy in patients with type 2 diabetes poorly controlled on a sulfonylurea. Diabetes Care, 29(6): 1282-1287 (2006).
  Barragan et al. “Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7-36) amide in rats.” Am J. Physiol 266 (Endocrinol Metab 29):E459, 1994.
  Bauer et al., “Assessment o beta-adrenergic receptor blockade after isamoitane, a 5-HT1-receptor active compound, in healthy volunteer”, Clin. Pharmacol Ther 53:76-83 (1993).
  Bauer et al., “Pharmacodynamic effects of inhaled dry powder formulations of fenterol and colforsin in asthma”, Clin Pharmacol Ther 53:76-83, 1993.
  Baughman R, Cassidy J, Amin N, et al. A phase I, open-label study of the effect of albuterol or fluticasone on the pharmacokinetics of inhaled Technosphere® insulin inhalation powder in healthy subjects. ADA 2010; Poster 528.
  Baughman R, Cassidy J, Levy B, et al. Technosphere® insulin inhalation powder pharmacokinetics unchanged in subjects who smoke. Diabetes 2008; 57: A128.
  Baughman R, Haworth P, Litwin J, et al. No cardiac effects found with therapeutic and suprtherapeutic doses of Technosphere® inhalation powder: results from a thorough QTc clinical study. ADA 2011. Poster 933-P.
  Baughman, RA, Evans, SH, Boss, AH, et al. Technosphere insulin does not affect pulmonary function in a 6 month study of patients with type 2 diabetes. Diabetologia 2006;49:177-118.
  Beers et al., Section 2—Chapter 13—Diabetes Mellitus, The Merck Manual of Diagnosis and Therapy, Merck Research Laboratories, pp. 165-177 (1999).
  Behme et al. “Glucagon-like peptide-1 improved glycemic control in type 1 diabetes.” BMC Endocrine Disorders 3:3, 2003.
  Bellary et al. “Inhaled insulin:new technology, new possibilities.” Int J Clin Pract 60:728, 2006.
  Benita, Charaterization of Drug-Loaded Poly(d,I-lactide) Microspheres. J. Pharm. Sci., 73: 1721-1724 (1984).
  Benito E et al. “Glucagon-like peptide-1-(7-36) amide increases pulmonary surfactant secretion through a cyclic adenosine 3′,5′-monophosphate-dependent protein kinase mechanism in rat type II pneumocytes.” Endocrinology 139:2363, 1998.
  Bensch et al., Absorption of intact protein molecules across the pulmonary air-tissue barrier, Science 156: 1204-1206 (1967).
  Berge et al., “Pharmaceutical Salts”, J. Pharmaceutical Sciences, Review Article, 66(1):1-19 (1977).
  Bergenstal R, Kapsner P, Rendell M, et al., Comparative efficacy and safety of AFRESA® and a rapid-acting analog both given with glargine in subjects with T1 DM in a 52-week study ADA 2009; Poster 479.
  Bergeron et al. “Macromolecular Self-Assembly of Diketopiperazine Tetrapeptides.” J. Am. Chem. Soc. 116, 8479-8484, 1994.
  Lee et al., Intrapulmonary potential of polyethylene glycol-modified glucagon-like peptide-1s as a type 2 anti-diabetic agent. Regulatory Peptides, 152:101-107 (2009).
  Selam, Jean-Louis. Inhaled Insulin: Promises and Concerns. Journal of Diabetes Science and Technology, vol. 2, Issue 2, pp. 311-315 (2008).
  Shields, Irritable bowel syndrome, archived Jun. 21, 2009, available at: https://web.archive.org/web/200906211 00502/http://www.gastroenterologistpaloalto.com/conditions-diseases-irritable-bowelsyndrome-palo-alto-ca. html; Aug. 26, 2015 is U.S. Appl. No. 14/139,714.
  Smith et al., Evaluation of novel aerosol formulations designed for mucosal vaccination against infleunza virus. Vacine, vol. 21, pp. 2805-2812 (2003).
  U.S. Appl. No. 14/873,041, filed Oct. 1, 2015.
  Design U.S. Appl. No. 29/504,212, filed Oct. 2, 2014.
  U.S. Appl. No. 15/017,153, filed Feb. 5, 2016.
  Young et al., Encapsulation of lysozyme in a biodegradable polymer by preparation with a vapor-over-liquid antisolvent. Journal of Pharmaceutical Sciences, 88:640-650 (1999).
  Hazard Prevention and Control in the Work Environment: Airborne Dust WHO/SDE/OEH/99. 14 Chapter 1—Dust: Definitions and Concepts [retrieved from internet by Examiner in European case on Sep. 22, 2015]. <URL: http://www.who.int/occupationalhealth/publications/airdust/en/> published on Oct. 29, 2004 as per Wayback Machine.
  Owens et al., Blood glucose self-monitoring in type 1 and type 2 diabetes: reaching a multidisciplinary consensus. Diabetes and Primary Care, vol. 6, No. 1, pp. 8-16 (2004).
  U.S. Appl. No. 14/905,236, filed Jan. 14, 2016.
  U.S. Appl. No. 14/991,777, filed Jan. 8, 2016.
  U.S. Appl. No. 14/971,785, filed Dec. 16, 2015.
  U.S. Appl. No. 14/910,235, filed Feb. 4, 2016.
  Amodeo et al., Pain peptides. Solution structure of orphanin FQ2. FEBS Letters, vol. 473, Issue 2, pp. 157-160 (2000).
  Vanderah et al., FE200041 (D-Phe-D-Phe-D-Nle-D-Arg-NH2): A peripheral efficacious k opioid agonist with unprecedented selectivity. The Journal of Pharmacology and Experimental Therapeutics, vol. 310, No. 1, pp. 326-333 (2004).
  Krondahl et al., Regional differences in bioavailability of an opioid tetrapeptide in vivo rats after administration to the respiratory tract. Peptides, vol. 23, No. 3, pp. 479-488 (2002).
  Design U.S. Appl. No. 29/553,303, filed Jan. 29, 2016.
  Design U.S. Appl. No. 29/553,302, filed Jan. 29, 2016.
  Design U.S. Appl. No. 29/553,305, filed Jan. 29, 2016.
  Design U.S. Appl. No. 29/553,300, filed Jan. 29, 2016.
  Nathan DM et al. “Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.” Diabetes Care 29:1963-1972, 2006.
  Nathan DM et al. “Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.” Diabetes Care 31:173-175, 2008.
  Nathan DM et al. “Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.” Diabetes Care 32:193-203, 2009.
  Nathan, “Initial Management of Glycemia in Type 2 Diabetes Melllitus” N. Eng. J. Med., 2002, 347, 1342-9.
  Nauck “Is glucagon-like peptide 1 an incretin hormone?” Diabetologia 42:373-379, 1999.
  Nauck et al. “Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans.” Am J Physiol 273 (Endocrinol Metabl 36):E981, 1997.
  Nauck et al. “Reduced incretin effect in type 2 (non-insulin-dependent) diabetes.” Diabetologia 29:46-52, 1986.
  Nauck et al., Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab., 87:1239-1246, 2002.
  Nauck et al., Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. Diabetologia, 39:1546-1553, 1996.
  Nauck et al., Normalization of fasting hyperglycemia by exogenous GLP-1 (7-36 amide) in type 2 diabetic patients. Diabetologia, 36:741-744, 1993.
  NHS Clinical Guidelines, “Type 1 diabetes diagnosis and mangement of type 1 diabetes in children and young people”, National Collaborating Centre for Women's and Children's Health Commissioned by the National Institute for Clinical Excellence, Sep. 2004, p. 1-217.
  Nystrom et al. “Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetic patients with stable coronary artery disease.” Am J Physiol Endocrinol Metabl 287:E1209, 2004.
  Okumura et al., Intratracheal delivery of insulin: absorption from solution and aerosol by rat lung. Int. J. Pharmaceuticals 88: 63-73 (1992).
  Orgsoltab et al., Division of Organic Chemistry. Ohio Northern University. Nov. 24, 2009. Available from: <http://www.2.onu.edu/˜b-meyers/organicsolvents.html>.
  Oshima et al. “Comparison of half-disappearance times, distribution volumes and metabolic clearance rates of exogenous glucagon-like peptide 1 and glucagon in rats.” Regulatory Peptides 21:85, 1988.
  Ostrovsky, Gene. Mannkind Inhalation Insulin Going to FDA to Seek Approval [on-line]. MedGadget.com, posted on Mar. 17, 2009, Retrieved from the Internet: <URL:http://medgadget.com/2009/03mannkindinhalationinsulingoingtofdatoseekapproval.html>.
  Owens et al. “Inhaled human insulin.” Nature Reviews, Drug Discovery, vol. 5, No. 5, pp. 371-372, May 2006.
  Ozyazgan et al. “Effect of glucagon-like peptide-1)7-36) and exendin-4 on the vascular reactivity in streptozotocin/nicotinamide-induced diabetic rats.” Pharmacology 74:119, 2005.
  Pacini P, Marino MT. Evaluation of endogenous and exogenous components to peripheral insulin concentration during administration of inhaled insulin. ADA 2010; Abstract 2094-PO.
  Patton “Mechanisms of macromolecule absorption by the lungs.” Advanced Drug Delivery Reviews 19:3, 1996.
  Patton “Unlocking the opportunity of tight glycaemic control. Innovative delivery of insulin via the lung.” Diabetes Obesity and Metabolism 7:S5, 2005.
  Patton & Platz, Routes of Delivery: Case Studies: pulmonary delivery of peptides and proteins for systemic action. Adv. Drug. Del. Rev. 8: 179-196 (1992).
  Patton et al. “The lungs as a portal of entry for systemic drug delivery.” Proc Am Thorac Soc 1:338, 2004.
  Patton et al., “Inhaled Insulin”, Advanced Drug Delivery Reviews, 35, Feb. 1999, p. 235-247.
  Onoue et al., Dry powder inhalation systems for pulmonary delivery of therapeutic peptides and proteins. Expert Opin. Ther. Patents 18(4):429-442 (2008).
  Pearson et al., Systematically Initiating Insulin, supplemental to vol. 32, No. 1, 19S-28S, 2006.
  Perera et al. “Absorption and Metabolic Effect of Inhaled Insulin.” Diabetes Care, vol. 25, No. 12, Dec. 2002, p. 2276-2281.
  Petkowicz et al., “Hypoglycemic effect of liposome-entrapped insulin adminstered by various routes into normal rats”, Pol. J. Pharmacol. Pharm. 41:299-304 (1989).
  Petrucci R, Amin N, Lovertin P. et al. Pulmonary function tests remain similar in patients who received Technosphere® insulin and in patients currently receiving standard antidiabetic therapy. Diabetologia 2009; 52 (suppl 1).
  Peyrot M, Rubin RR, Otterbach K. Effect of Technosphere® inhaled insulin on treatment satisfaction, glycemic control and quality of life. Diabetes 2006; 55:Abstract 423-P.
  Pezron et al., Insulin aggregation and asymmetric transport across human bronchial epithelial cell monolayers (Calu-3). J. Pharmaceutical Sci. 91: 1135-1146 (2002).
  Li et al. “GLP-1; a novel zinc finger protein required in somatic cells of the gonad for germ cell development.” Dev Biol 301:106, 2007.
  Li, Jun. Chapter 15: Drug Therapy of Metabolic Diseases. Clinical Pharmacotherapy, People's Medical Publishing House, 1st Edition, pp. 333-335 (2007).
  Lim, “Microencapsulation of Living Cells and Tissues”, J. Pharm. Sci., 70: 351-354 (1981).
  Liu et al., “Pulmonary delivery of free and liposomal insulin”, Pharmaceuticals Res. 10:228-232, 1993.
  Lorber D, Howard CP, Ren H, et al. Reduced incidence and frequency of hypoglycemia in an integrated analysis of pooled data from clinical trials of subjects with type 2 diabetes using prandial inhaled Technosphere® insulin. AACE 2010; Poster 270.
  Luque et al. “Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes.” J. Endocrinol 173:465, 2002.
  Luzi, L. and DeFronzo, R.A. “Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans” Am. J. Physiol. 257 (Endocrinol. Metab. 20):E241-E246, 1989.
  Luzio, S.D., et al. “Intravenous insulin simulates early insulin peak and reduces post-prandial hyperglycaemia/hyperinsulinaemia in type 2 (non-insulin-dependent) diabetes mellitus.” Diabetes Res. 16:63-67, 1991.
  Malhotra et al., Exendin-4, a new peptide from Heloderma suspectum venom, potentiates cholecystokinin-induced amylase release from rat pancreatic acini. Regulatory Peptides, 41:149-56, 1992.
  MannKind Corporation “Postprandial hyperglycemia: clinical significance, pathogenesis and treatment.” MannKind Corporation Monograph. 2009.
  MannKind Corporation, Pulmonary Delivery: Innovative Technologies Breathing New Life into Inhalable Therapeutics, www.ondrugdelivery.com, 2006.
  Burcelin et al., Long-lasting antidiabetic effect of a dipeptidyl peptidase IV-resistant analong of glucagon-like peptide-1. Metabolism, vol. 48, No. 2, pp. 252-258 (1999).
  Marino MT, Cassidy JP, Smutney CC, et al. Bioequivalence and dose proportionality of Afrezza® inhalation powder administered using a Gen2 inhaler compared to the MedTone® inhaler. Diabetes Technology Meeting 2010; poster.
  Marino MT, Cassidy JP, Smutney CC, et al. Improvement in bioavailability of FDKP with the NexGen2A device: Implications for delivery of pulmonary insulin. Third International Conference on Advanced Technologies and Treatments for Diabetes 2010; Poster 108.
  Marino MT, Cassidy JP, Smutney CC, et al. Improvement in bioavailability of FDKP and insulin with the NGDSB device. Third International Conference on Advanced Technologies and Treatments for Diabetes 2010; Poster 107.
  Marino MT. A pharmacokinetic/pharmacodynamic model of inhaled insulin with application to clinical trial simulation. ADA 2010; Abstract 2105-PO.
  Marino MT. Cassidy JP, Baughman RA, et al. C-peptide correction method to determine exogenous insulin levels in pk studies using AFRESA® (Technosphere® insulin [TI]) ADA 2009; Poster 1451.
  Marshall “Preventing and detecting complications of diabetes.” BMJ 333:455, 2006.
  Mastrandrea “A breath of life for inhaled insulin: severe subcutaneous insulin resistance as an indication.” Pediatric Diabetes 2010: 11: 377-379.
  Mathiowitz, Morphology of Polyanhydride Microsphere Delivery Systems, Scanning Microscopy, 4: 329-340 (1990).
  Mathiowitz, Novel microcapsules for delivery systems. Reactive Polymers, 6: 275-283 (1987).
  Mathiowitz, Polyanhydride microspheres as drug carriers I, hot-melt microencapsulation. J. Controlled Medicine, 5: 13-22 (1987).
  Mathiowitz, Polyanhydride microspheres as drug carriers II, microencapsulation by solvent removal. J. Appl. Polymer Sci., 35: 755-774 (1988).
  Mathiowitz, Polyanhydride microspheres IV, morphology and characterization systems made by spray drying. J. App. Polymer Sci., 45: 125-134 (1992).
  Matsui et al. “Hyperplasia of type II pheumocytes in pulmonary lymphangioleiomyomatosis. Immunohistochemical and electron microscope study.” Arch Pathol Lab Med 124:1642, 2000.
  Matthews DR et al. “Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.” Diabetologia. Jul. 1985;28(7):412-9.
  McElduff A et al. “Influence of acute upper respiratory tract infection on the absorption of inhaled insulin using the AERx(R) insulin diabetes management system.” Br J Clin Pharmacol 59:546, 2005.
  McMahon et al., “Effects of basal insulin supplementation on disposition of mixed meal in obese patients with NIDDM”, Diabetes, vol. 38, pp. 291-303 (1989).
  Meier et al. “Absence of a memory effect for the insulinotropic action of glucagon-like peptide-1 (GLP-1) in healthy volunteers.” Horm Metab Res 35:551, 2003.
  Meier et al. “Secretion, degradation, and elimination of glucagon-like peptide-1 and gastric inhibitor polypeptide in patients with chronic renal insufficiency and healthy control subjects.” Diabetes 53:654, 2004.
  Meier et al. “The glucagon-like peptide-1 metabolite GLP-1-(9-36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans.” Am J Physiol Endocrinol Metab 290:E1118, 2006.
  Mendes et al., A non-dimensional functional relationship for the fine particle fraction produced by dry powder inhalers, Aerosol Science 38, pp. 612-624 (2007).
  Mentlein et al., Dipeptidyl peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1 (7-36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem., 214:829-835, 1993.
  Merck Manual 17th, Japanese Edition, NIKKEI BP Corp., 1999, p. 167-179.
  Mitchell et al. “Intranasal Insulin: PK Profile Designed Specifically for Prandial Treatment of Type 2 Diabetes.” Drug Development Research 69(3):143-152 (2008).
  Montrose-Rafizadeh et al., Diabetes, 45(Suppl. 2):152A, 1996.
  Moren, Aerosols in Medicine (2nd Ed.), Elsevier, pp. 321-350 (1993).
  Mudaliar et al., Insulin Therapy in Type 2 Diabetes. Endocrinology and Metabolism Clinics, vol. 30, No. 4, pp. 1-32 (2001).
  Nagai et al., “Powder Dosage Form of Insulin for Nasal Administration”, J. Control Ref., 1:15-22 (1984).
  Narayan et al. “Impact of recent increase in incidence on future diabetes burden.” Diabetes Care 29:2114, 2006.
  Naslund E et al. “GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans.” Am J Physiol (Regulatory Integrative Comp Physiol 46):R910, 1999.
  Naslund E et al. “Prandial subcutaneous injections of glucagon-like petide-1 cause weight loss in obese human subjects.” Br J Nutrition 91:439, 2004.
  International Search Report mailed on Nov. 21, 2013 for International Application No. PCT/US2013/057397 filed on Aug. 29, 2013.
  Eavarone et al., A voxel-based monte carlo model of drug release from bulk eroding nanoparticles. Journal of Nanoscience and Nanotechnology, vol. 10, pp. 5903-5907 (2010).
  Marino MT, Cassidy JP, Smutney CC, et al. Improvement in bioavailability of FDKP with the NexGen2A device: Implications for delivery of pulmonary insulin. Diabetes Technology Meeting 2009; poster.
  Heine “Unlocking the opportunity of tight glycaemic control. Promise ahead: the role of inhaled insulin in clinical practice.” Diabetes, Obesity and Metabolism 7:S19, 2005.
  Heinemann “Variability of Insulin Absorption and Insulin Action.” Diabetes Technology & Therapeutics, vol. 4, No. 5, pp. 673-682. 2002.
  Heinemann L et al. “Time-action profile of inhaled insulin.” Diabetic Med 14:63-72, 1997.
  Heinemann, L. “Intra-individual Variability of the Metabolic Effect of Inhales Insulin Together with an Absorption Enhancer”, Diabetes Care, vol. 23, No. 9, Sep. 2000, p. 1343-1347.
  Heise et al. “The effect of insulin antibodies on the metabolic action of inhaled and subcutaneous insulin.” Diabetes Care 28:2161, 2005.
  Herbst et al., Insulin Strategies for Primary Care Providers. Clinical Diabetes, vol. 20, No. 1, pp. 11-17 (2002).
  Heubner et al. “On inhalation of insulin” Klinische Wochenschrift 16:2342, 1924. (Original and English translation provided in one document).
  Heyder “Particle Transport onto Human Airway Surfaces”, Eur. J. Respir. Dis, Suppl. 119, 29-50 (1982).
  Heyder, “Alveolar deposition of inhaled particles in humans”, Am. Ind. Hyg. Assoc. J. 43(11): 864-866 (1982).
  Hirsch, “Type 1 Diabetes Mellitus and the Use of Flexible Insulin Regimens” American Family Phyician, Nov. 15, 1999, p. 1-16.
  Hirshberg B et al. “Islet transplantation: where do we stand now?” Diabetes Metab Res Rev 19:175-8, 2003.
  Hite et al. “Exhuberance over Exubera.” Clin Diabetes 24(3):110-114, 2006.
  Hoet et al., Review: Nanoparticles—known and unknown health risks. Journal of Nanobiotechnology, vol. 2, No. 12, (15 pages) (2004).
  Hollander et al. “Efficacy and Safety of Inhaled Insulin (Exubera) Compared with Subcutaneous Insulin Therapy in Patients with Type 2 Diabetes.” Diabetes Care, vol. 27, No. 10, Oct. 2004, p. 2356-2362.
  Holst “Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1.” Diabetes Metab Res Rev 18:430, 2002.
  Holst et al. “On the effects of glucagon-like peptide-1 on blood glucose regulation in normal and diabetic subjects.” Ann N Y Acad Sci. Dec. 26, 1996;805:729-36.
  Howard C, Ren H, Rossiter A, et al. Reduced incidence and frequency of hypoglycemia in an integrated analysis of pooled data from clinical trials of subjects with type 1 diabetes using prandial inhaled Technosphere® insulin. Diabetologia 2009; 52 (suppl 1).
  Howard CP, Gnudi L, Loiter D, et al. Prandial inhaled Technosphere® insulin plus insulin glargine vs. biaspart 70/30 insulin in type 2 diabetes inadequately controlled with/without oral agents. Third International Conference on Advanced Technologies and Treatments for Diabetes. 2010; Poster 300.
  Howard CP, Loiter D, Ren H, et al. Reduced incidence and frequency of hypoglycemia in pooled data from trials of type 2 diabetics using prandial inhaled Technosphere® insulin. Third International Conference on Advanced Technologies and Treatments for Diabetes 2010; Poster 304.
  Howard CP, Petrucci R,Amin N, et al. Pulmonary function test remain similar in patients who received Technosphere® insulin and in patients currently receiving standard antidiabetic therapy. AACE 2010; Poster 267.
  Howard CP, Ren H, Rossiter A, Boss AH. Reduced incidence and frequency of hypoglycemia in pooled data from trials of type 1 diabetics using prandial inhaled Technosphere® insulin. Third International Conference on Advanced Technologies and Treatments for Diabetes. 2010; Poster 302.
  Howard CP, Ren H, Rossiter A, et al. Reduced incidence and frequency of hypoglycemia in an integrated analysis of pooled data from clinical trials of subjects with type 1 diabetes using prandial inhaled Technosphere® insulin. AACE 2010; Poster 269.
  Howard CP, Rubin RR, Peyrot. M. Patient reported outcomes in adults with type 2 diabetes using mealtime AFRESA® (inhaled Technosphere® insulin) and basal insulin versus premixed insulin ADA 2009; Poster 551.
  http://www.bilcaresolutions.com/en/products/pharma-packaging-innovations-pvc-aclar-films <URL:http://web.archive.org/web/20110127102552/http://www.bilcaresolutions.com/en/products/pharma-packaging-innovations-pvc-aclar-films> published on Jan. 27, 2011 as per “Wayback Engine”.
  http://www.pmpnews.com/article/blister-packaging-materials (May 26, 2009).
  Huda et al. “Gut peptides and the regulation of appetite.” Obesity Reviews 7:163, 2006.
  Hui et al., The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects. European Journal of Endocrinology, 146: 863-869 (2002).
  Hussain et al. “State of insulin self-association does not affects its absorption from the pulmonary route.” Eur. J. Pharm. Sciences 25:289-298, 2005.
  Ikeda, Kuniki et al. “Peptide Antibiotics. XXVI. Syntheses of Cyclodipeptides Containing N. delta.-p-aminobenzenesulfonyl Ornithine Residue.” Chemical & Pharmaceutical Bulletin, 20(9), 1849-55, 1972.
  Imeryuz et al. “Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms.” Am J Physiol 273 (Gastrointest Liver Physiol 36):G920, 1997.
  Insulin is a natural product from http://www.levemir.com/startingoninsulin/whatisinulin.aspx, pp. 1-3. Accessed by Examiner on Apr. 30, 2014 and in Non-Final Offfice Action dated May 22, 2014 for U.S. Appl. No. 13/797,657 and in Non-Final Office Action dated May 22, 2014 for U.S. Appl. No. 12/883,369.
  International Search Report for PCT International Application No. PCT/US2010/055323 filed on Nov. 3, 2010.
  Written Opinion mailed on Jul. 1, 2013 for International Application No. PCT/US2013/032162 filed on Mar. 15, 2013.
  International Search Report mailed on Jun. 21, 2010 for International Application No. PCT/US2010/027038 filed on Mar. 11, 2010.
  Written Opinion for International Application No. PCT/US2011/060057 filed on Nov. 9, 2011.
  International Search Report mailed Mar. 18, 2013 for International Application No. PCT/US2012/061749 filed on Oct. 24, 2012.
  International Search Report mailed on Jun. 20, 2012 for International Applicaion No. PCT/US2012/031695 filed on Mar. 30, 2012.
  International Search Report mailed on Nov. 19, 2014 for International Application No. PCT/US2014/049817 filed on Aug. 5, 2014.
  International Search Report for International Application No. PCT/US2010/020448 filed on Jan. 8, 2010.
  International Search Report mailed on Mar. 11, 2010 for International Application No. PCT/US2009/069745 filed on Dec. 29, 2009.
  International Search Report mailed on Oct. 17, 2011 for International Application No. PCT/US2010/026271 filed on Mar. 4, 2010.
  International Search Report for International Application No. PCT/US2010/038287 filed on Jun. 11, 2010.
  Ishibashi, Norio et al. “Studies on Flavord Peptides. Part V. A Mechanism for Bitter Taste Sensibility in Peptides.” Agricultural and Biological Chemistry, 52(3), 819-27, 1988.
  Iwanij et al., Characterization of the Glucagon Receptor and its Functional Domains Using Monoclonal Antibodies. The Journal of Biological Chemistry, vol. 265, No. 34, pp. 21302-21308, 1990.
  Jain et al. “Insulin Therapy in Type 2 Diabetic Subjects Suppresses Plasminogen Activator Inhibitor (PAI-1) Activity and Proinsulin-like Molecules Independently of Glycaemic Control.” Diabetic Medicine, vol. 10, No. 1, p. 27-32, 1993.
  Johnson et al., Peptide turn mimetics. Biotechnology and Pharmacy, p. 366-378 (1993).
  International Search Report for International Application No. PCT/US2013/050392 filed on Jul. 12, 2013.
  Rosenstock et al. “Efficacy and Safety of Technosphere Inhaled Insulin Compared With Technosphere Powder Placebo in Insulin-Naive Type 2 Diabetes Suboptimally Controlled with Oral Agents.” Diabetes Care, vol. 31, No. 11, pp. 2177-2182, 2008.
  Rosenstock et al., “Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes”, Diabetes Care, 28(4):950-5 (2005).
  Rosenstock J, Baughman RA, Ribera-Schaub T, et Al. A randomized, double-blind, placebo controlled study of the efficacy and safety of inhaled Technosphere® insulin in patients with type 2 diabetes (T2DM). Diabetes 2005;54: 4bstract 357-OR.
  Rosenstock J, Lorber D, Petrucci R, et al. Basal/bolus with prandial inhaled Technosphere® insulin (TI) plus insulin glargine qd vs biaspart 70/30 insulin bid in T2 DM inadequately controlled on insulin with/without oral agents ADA 2009; Poster 466.
  Rosenstock J, Lorger DL. Gnudi L, et al.Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial. Lancet 2010;375:2244-2253.
  Rossiter A, Amin N, Harris R, et al. Pulmonary safety of inhaled Technosphere® insulin therapy in adults with diabetes using high-resolution computerized tomography of the chest. Diabetologia 2009; 52 (suppl 1).
  Rossiter A, Howard C, Amin N, et al. Technosphere® insulin: Safety in type 2 diabetes mellitus. ADA 2010; Poster 523.
  Rubin RR, Peyrot M. Psychometric properties of an instrument for assessing the experience of patients treated with inhaled insulin: The inhaled insulin treatment questionnaire (INTQ) Health & Quality of Life Outcomes 2010.8:32.
  Rubin RR, Peyrot M; Patient reported outcomes in adults with type 1 diabetes using mealtime AFRESA® (inhaled Technosphere® insulin) or rapid acting insulin with basal insulin ADA 2009; Poster 1881.
  Ryan EA et al. “Successful islet transplantation. Continued insulin reserve provides long-term glycemic control.” Diabetes 51:2148-2157, 2002.
  Sajeesh et al., Cyclodextrin-insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery. International Journal of Pharmaceuticals, 2006, 325, pp. 147-154.
  Sakr, A new approach for insulin delivery via the pulmonary route: design and pharmacokinetics in non-diabetic rabbits. International Journal of Pharmaceutics, 86: 1-7 (1992).
  Salib, Utilization of sodium alginate in drug microencapsulation. Pharazeutische Industrie, 40(11a): 1230-1234 (1978).
  Saraceni C et al. “Effects of glucagon-like peptide-1 and long-acting analogues on cardiovascular and metabolic function.” Drugs R D 8:145, 2007.
  Sarrach et al., “Binding and entrapment of insulin by liposomes made of lecithin-phosphotidix acid in acid solution” Pharmazie 40:642-645, 1985 (German and English Abstract).
  Savage et al., “Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying healthy volunteers”, Gut, vol. 28, pp. 166-170, 1987.
  Sawhney et al., Bioerodible hydrogels based on photopolymerized poly(ethylene glycol)-co-poly(a-hydroxy acid) diacrylate macromere. Macromolecules, 26: 581-587 (1993).
  Schaffer et al. “Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks.” PNAS 100:4435-4439, 2003.
  Schepp et al., Eur. J. Pharmacol., 269:183-91, 1994.
  Scherbaum “Unlocking the opportunity of tight glycaemic control. Inhaled insulin: clinical efficacy.” Diabetes Obesity and Metabolism 7:S9-S13, 2005.
  Schirra et al. “Gastric emptying and release of incretin hormones after glucose ingestion in humans.” J Clin Invest 97:92-103, 1996.
  Schluter et al., “Pulmonary Administration of Human Insulin in volunteers and Type I Diabetics”, Diabetes, 33, (Suppl) 298 (1984).
  Schneider et al., “Stimulation by proinsulin of expression of plasminogen activator inhibitor type 1 in endothelial cells”, Diabetes 41(7):890-895 (1992).
  Schon, Istvan et al. “Formation of Aminosuccinyl Peptides During Acidolytic Deprotection Followed by their Tranformation to Piperazine-2, 5-dione Derivatives in Neutral Media.” International Journal of Peptide & Protein Research, 14(5), 485-494, 1979.
  Schroder, “Crystallized carbohydrate spheres as a slow release matrix for biologically active substances”, Biomaterials 5:100-104, 1984.
  Scrocchi et al. “Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene.” Nature Medicine 2:1254-1258, 1996.
  Seshiah & Balaji, “Early Insulin Therapy in Type 2 Diabetics”, Int. J. Diabetes in Developing Countries, 2003, 23, 90-93.
  Seville, P.C. et al., Preparation of dry powder dispersions for non-viral gene delivery by freeze-drying and spray dying. J. Gene Medicine 2002; 4:428-437.
  Shah et al. “Lack of suprression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus.” J Clin Indocrinol Metab 85:4053, 2000.
  Shelly et al. “Polysorbate 80 hypersensitivity.” The Lancet 345:1312, 1995.
  Shojania et al. “Effect of quality improvement strategies for type 2 diabetes on glycemic control.” JAMA 296:427, 2006.
  Silverstein et al., “Care of Children and Adolescens with Type 1 Diabetes, A Statement of the American Diabetes Association”, Diabetes Care, Jan. 2005, vol. 28, p. 186-212.
  Singh et al., Use of 125I-[Y39]exendin-4 to characterize exendin receptors on dispersed pancreatic acini and gastric chief cells from guinea pig. Regul. Pept. 53 : 47-59 (1994).
  Simms JR, Carballo I, Auge CR, et al. Assessment of immunotoxic effects on humoral and cellular immune parameters following repeated inhalation of Technosphere insulin in the rat. Diabetes 2005;54:Abstract 2078-PO.
  Skyler, Pulmonary insulin: current status. Diabetes Voice, vol. 51, Issue I, p. 23-25, 2006.
  Skyler “Pulmonary Insulin Delivery—State of the Art 2007.” Diabetes Tecnology & Therapeutics, vol. 9, Supplement 1, pp. S1-S3. 2007.
  Smith et al. “New-onset diabetes and risk of all-cause and cardiovascular mortality.” Diabetes Care 29:2012, 2006.
  Smutney CC, Friedman EM, Amin N. Inspiratory efforts achieved in use of the Technosphere® insulin inhalation system. Diabetes Technology Meeting 2008; Poster SMUT8052.
  Smutney CC, Friedman EM, Amin N. Inspiratory efforts achieved in use of the Technosphere® insulin inhalation system. Journal of Diabetes Science and Technology 2009 3(5):1175-1189.
  Smutney CC, Polidoro JM, Adamo B, et al. In-vitro performance improvement realized in a next generation dry powder delivery system. Diabetes Technology Meeting 2009; poster.
  Smutney CC, Polidoro JM, Adamo B, Shah S. In vitro performance improvement realized in a next generation dry powder delivery system. Third International Conference on Advanced Technologies and Treatments for Diabetes 2010; Poster 122.
  Smutney CC, Polidoro JM. Easy-to-use next-generation pulmonary insulin delivery system. ADA 2010; Abstract 2093.
  Smutney CC, Polidoro JM. Improvements realized in a next-generation pulmonary insulin delivery system. ADA 2010; Abstract 2097.
  Sodium chloride is a natural product from http://www.wqpmag.com/potassium-chloride-vs-sodium-chloride, pp. 1-3. Accessed by Examiner on May 16, 2014 and in Non-Final Ofthce Action dated May 22, 2014 for U.S. Appl. No. 13/797,657 and in Non-Final Office Action dated May 22, 2014 for U.S. Appl. No. 12/883,369.
  Standl et al. “Good Glycemic Control With Flexibility in Timing of Basal Insulin Supply.” Diabetes Care, vol. 28, No. 2, Feb. 2005.
  Stanley et al. “Gastrointestinal satiety signals III. Glucagon-like peptide 1, oxyntomodulin, peptide YY and pacretic peptide.” Am J Physiol Gastrointest Liver Physiol 286:G693, 2004.
  Steinberg et al. “A new approach to the safety assessment of pharmaceutical excipients.” Reg Toxicol Pharmacol 24:149, 1996.
  Steiner, K et al. “The relative importance of first- and second-phase insulin secretion in countering the action of glucagon on glucose turnover in the conscious dog.” Diabetes 31:964-972, 1982.
  Steiner S, Rave K, Heise T, et al. Pharmacokinetic properties and bioavailablility of inhaled drug powder Technosphere™/insulin. Exp Clin Endocrinol Diabetes 2000; 108:S161.
  Steiner S, Rave K, Heise T, et al. Technosphere™/insulin: Bioavailability and pharmacokinetic properties in healthy volunteers. Diabetologia 2000;43:Abstract 511-P.
  Steiner SS, Burrell BB, Feldstein R, et Al Pulmonary delivery of Technosphere™/insulin: Increased bioefficacy and bioavailability in clinical trials using the PDC Medtone™ inhaler. Proceed Int'l Symp Control Rel Bioact Mater 2000; 27: 1000-1001.
  Stowell et al. “Development of GLP-1 Technosphere(TM) powder: an inhaled GLP-1 product.” Diabetes Technology Meeting, San Francisco, Oct. 2007.
  Strack “Inhaled Human Insulin.” Drugs of Today 2006, 42 (4): 207-221.
  Sturis et al., GLP-1 deriative liraglutide in rats with beta-cell deficiences: influence of metabolic state on beta-cell mass dynamics. British Journal of Pharmacology, 140: 123-132 (2003).
  Sympatecs. Dry Dispersion for Laser Diffraction and Image Analysis, 2011. XP-002586530.
  Leone-Bay et al., Innovation in drug delivery by inhalation. Ondrugdelivery, No. 7, pp. 4-8 (2010).
  Tack CJ, Boss AH, Baughman RA, et al. A randomized, double blind, placebo controlled study of the forced titration of prandial Technosphere®/Insulin in patients with type 2 diabetes mellitus. Diabetes 2006;55:Abstract 428-P.
  Tack CJ, Christov V, deGalan BE, et al. Randomized forced titration to different doses of Technosphere® insulin demonstrates reduction in postprandial glucose excursions and hemoglobin A1c in patients with type 2 diabetes. J Diabetes Sci Technol 2008; 2(1) :47-57.
  Tang-Christensen et al. “Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats.” Am J Physiol 271 (Regulatory Integrative Comp Physiol 40):R848, 1996.
  Teeter et al. “Dissociation of lung function changes with humoral immunity during inhaled human insulin therapy.” Am J Resp Crit Care Med 173:1194, 2006.
  The American Diabetes Association “Insulin Administration” Diabetes Care, vol. 27, Supplement 1, S106-S109 (2004).
  Gerber et al., Treatment satisfaction with inhaled insulin in patients with type 1 diabetes. Diabetes Care 24:1556-1559 (2001).
  The Lancet. 1989, vol. 333, p. 1235-1236.
  Thorens “Expression cloning of the pancreatic b-cell receptor for the gluco-incretin hormone glucagon-like peptide-1.” PNAS 89:8641, 1992.
  Thorens B et al. “Cloning and function expression of the human islet GLP-1 receptor: demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.” Diabetes 42:1678, 1993.
  Todd et al. “Glucagon-like peptide-1 (GLP-1: a trial of treatment in non-insulin-dependent diabetes mellitus.” Eur J Clin Invest 27:533, 1997.
  Todd et al. Subcutaneous glucagon-like peptide-1 improves postprandial glucaemic control over a 3-week period in patients with early type 2 diabetes. Clinical Science 95:325, 1998.
  Toft-Nielson et al. “Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes.” J Clin Endocrinol Metab 86:3853, 2001.
  Toft-Nielson et al. “Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglcaemia.” Diabetologia 41:1180, 1998.
  Toft-Nielson et al. “The effect of glucagon-like peptide-1 (GLP-1) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones” Diabetes 45:552, 1996.
  Tornusciolo D.R. et al., Biotechniques 19(5):800-805, 1995. Simultaneous detection of TDT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive cells and multiple immunohistochemical markers in single tissue sections.
  Triantafyllidis et al., Structural, compositional and acidic characteristics of nanosized amorphous or partially crystalline ZSM-5 zeolite based materials. Microporous and Mesoporous Materials, 75:89-100 (2004).
  Tu N, Kramer DA, Baughman RA. Inhaled Technosphere® Insulin improves glycemic control without weight gain. Diabetes 2007;56:Abstract 471-P.
  Tuley et al., Experimental observations of dry powder inhaler dose fluidisation. International Journal of Pharmaceutics, 358, pp. 238-247 (2007).
  Utah Valley University. Saponification. © 2009. Available from: <http://science.uvu.edu/ochem/index.php/alphabetical/s-t/saponification/printpage/>.
  Vahl et al. “Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1-(9-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans.” J Clin Endocrinol Metabol 88:1772, 2003.
  Van Alfen-Van Der Velden et al. “Successful treatment of severe subcutaneou insulin resistance with inhaled insulin therapy”, Pediatric Diabetes 2010: 11:380-382.
  Vara E et al. “Glucagon-like peptide-1 (7-36) amide stimulates surfactant secretion in human type II pneumocytes.” Am J Resp Crit Care Med 163:840-846, 2001.
  Vella A et al. “Effect of glucagon-like peptide 1(7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes.” Diabetes 49:611, 2000.
  Vella A et al. “The gastrointestinal tract and glucose tolerance.” Curr Opin Clin Nutr Metab Care 7:479, 2004.
  Vendrame et al. “Prediabetes: prediction and prevention trials.” Endocrinol Metab Clin N Am, 2004, vol. 33, pp. 75-92.
  Verdich C, et al., A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab., 86:4382-4389, 2001.
  Vilsboll et al. “Reduced postprandial concentrations of intact biologically active glucagon-like peptide-1 in type 2 diabetic patients.” Diabetes 50:609, 2001.
  Vilsboll et al. “Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects.” J Clin Endocrinol Metab 88:220, 2003.
  Vilsboll et al., “Evaluation of β-Cell Secretary Capacity Using Glucagon-Like Peptide 1”, Diabetes Care, vol. 23, No. 6, pp. 807-812, Jun. 2000.
  Vilsboll et al., “Incretin secretion in Relation to Meal Size and Body Weight in Healthy Subjects and People with Type 1 and Type 2 diabetes Mellitus”, The Journal of Clinical Endrocronology & Metabolism, vol. 88, No. 6, pp. 2706-2713, 2003.
  Amorij et al., Development of stable infleunza vaccine powder formulations challenges and possibilities. Pharmaceutical Research, vol. 25, No. 6, pp. 1256-1273 (2008).
  Audouy et al., Development of a dried influenza whole inactivated virus vaccine for pulmonary immunization. Vaccine, vol. 29, pp. 4345-4352 (2011).
  Volund “Conversion of insulin units to SI units.” American Journal of Clinical Nutrition, Nov. 1993, 58(5), pp. 714-715.
  Wachters-Hagedoorn et al. “The rate of intestinal glucose absorption is correlated with plasma glucose-dependent insulinotropic polypeptide concentrations in healthy men.” J Nutr 136:1511, 2006.
  Wang et al., Glucagon-like peptide-1 is a physiological incretin in rat. J. Clin. Invest., 95 : 417-421 (1995).
  Wang et al., Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells. Diabetologia, 47:478-487, 2004.
  Wareham et al., “Fasting Proinsulin Concentrations Predict the Development of Type 2 Diabetes”, Diabetes Care, 1999, 22, 262-70.
  Waterhouse et al., “Comparatie assessment of a new breath-actuated inhaler in patients with reversible airways obstruction”, Respiration 59:155-158 (1992).
  WebMD (retrieved from http://www.webmd.com/pain-management/tc/pain-management-side-effects-of-pain-medicines in 2012, 4 pages).
  Wei et al. “Tissue-specific expression of the human receptor for glucagon-like peptide-1: brain and pancreatic forms have the same deduced amino acid sequence.” FEBS Letters 358:219, 1995.
  Neir et al. “Glucagonlike peptide 1 (7-37) actions on endocrine pancreas.” Diabetes 38:338, 1989.
  Weiss, SR et al. “Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents.” Arch Intern Med 163:2277-2282, 2003.
  Weissberger, “Mannkind: Overlooked Biotech with Excellent Prospects (Part V),” http://www.investorvillage.com/smbd.asp?mb=2885&mn=45817&pt=msg&mid=5021385 (posted on Jun. 19, 2008, accessed on Oct. 18, 2012).
  West, Solid State Chemistry and its Applications, Chp 10, Solid Solutions. Wiley, New York, 358 (1998).
  Wettergren A et al. “Truncated GLP-1 (proglucagon 78-107-Amide) inhibits gastric and pancreatic functions in man.” Digestive Diseases and Sciences 38:665, 1993.
  Wigley et al., Insulin across respiratory mucosae by aerosol delivery. Diabetes 20(8): 552-556 (1971).
  Willms B et al. “Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients.” J. Clin Endocrinol Metab 81:327, 1996.
  Wilson BR et al. “Technospheres(TM) for pulmonary and nasal applications.” Respiratory Drug Delivery VIII, 2002,p. 545.
  Wilson et al., Spray-drying, a viable technosphere formulation process option to lyophilization, http://www.aapsj.org/abstracts/AM2004/AAPS2004-002724.PDF, 1 page, 2004.
  Witchert, Low molecular weight PLA: A suitable polymer for pulmonary administered microparticles. J. Microencapsulation, 10(2): 195-207 (1993).
  Wright et al., Inhaled Insulin: Breathing new life into diabetes therapy. Nursing, vol. 37, No. 1, p. 46-48 (2007).
  Wong et al. “From cradle to grave: pancreatic b-cell mass and glucagon-like peptide-1.” Minerva Endocrinologica 31:107, 2006.
  Wuts et al. “The Role of Protective Groups in Organic Synthesis,” John Wiley, New York, 2nd Ed. 1991.
  Yan et al., Analgesic action of microinjection of neurokinin A into the lateral reticular nucleus and nucleus raphe magnus in rats. Acta Physiologica Sinica, vol. 48, No. 5, pp. 493-496 (1996)—abstract.
  Yang et al., Division and differentiation of natural antibody-producing cells in mouse spleen. PNAS, 104(11): 1542-4546 (2007).
  Yoshida et al., Absorption of insulin delivered to rabbit trachea using aerosol dosage form. J. Pharm. Sci. 68(5): 670-671 (1979).
  Yoshioka et al., “Serum proinsulin levels at fasting and after oral glucose load in patients with Type 2 (non-insulin dependent) diabetes mellitus”, Diabetogia, 1988, 31, 355-60.
  Yu W, Marino MT, Cassidy JP, et al. Insulin antibodies associated with Technosphere® insulin. ADA 2010; Abstract 216-OR.
  Yusta B et al. “GLP-1 receptor activation improves b-cell function and survival following induction of endoplasmic reticulum stress.” Cell Metabolism 4:391, 2006.
  Zander et al., Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet, 359:824-830, 2002.
  Zethellius et al., “Proinsulin is an Independent Predictor of Coronary Heart Disease”, Circulation 105:2153-2158 (2002).
  Zimmerman, K., “Respiratory System: Fats, Function, and Diseases”, <www.livescience.com/22616-respiratory-system.html>, copyright 2013, p. 1.
  Zisser et al. “In Patients Using Technospere Insulin. Variation in PPG Stayed Within ADA-recommended Targets Despite Large Variations in Glucose Load.” Mannkind Corporation (2010), ADA 2010; Poster 554.
  Zisser H, Jovanovic L, Markova K, et al. Technosphere® insulin effectively controls postprandial glycemia in patients with type 2 diabetes mellitus. Diabetes Technology and Therapeutics 2012;14:997-1001.
  Wasada, Glucagon-like peptide-1 (GLP-1). Nihon Rinsho, vol. 62, No. 6, pp. 1175-1180 (2004) (full Japanese article with English abstract).
  Bosquillon et al., Pulmonary delivery of growth hormone using dry powders and visualization of its local fate in rates. Journal of Controlled Release 96: 233-244 (2004).
  Cho et al., Targeting the glucagon receptor family for diabetes and obesity therapy. Pharmacology & Therapeutics 135: 247-278 (2012).
  Definition of medicament from http://medical-dictionary.thefreedictionary.com/medicament, retrieved by the Examiner on Mar. 20, 2015 and cited in Office Action issued on Mar. 26, 2015 in U.S. Appl. No. 13/942,482.
  Definition of matrix from http://medical-dictionary.thefreedictionary.com/matrix, retrieved by the Examiner on Mar. 5, 2015 and cited in Office Action issued on Mar. 26, 2015 in U.S. Appl. No. 12/471,260.
  Diabetes Frontier, vol. 10, No. 5, p. 647-657 (1999) (full Japanese article with translated English portion provided in separate attachment, portion translated in English is the bottom of p. 655 and the left column of p. 656).
  Ely et al., Effervescent dry powder for respiratory drug delivery. European Journal of Pharmaceutics and Biopharmaceutics 65: 346-353 (2007).
  European Search report for European Application 14192154.4 mailed on Mar. 19, 2015.
  Extended European Search report for European Application 14187552.6 mailed on Mar. 2, 2015.
  Gillespie et al., Using carbohydrate counting in diabetes clinical practice. Journal of the American Diabetic Association, vol. 98, No. 8, p. 897-905 (1998).
  Yamamoto et al., Engineering of Poly (DL-lactic-co-glycolic acid) Nano-composite particle for dry powder inhalation dosage forms of insulin with spray fludized bed granulating system. J. Soc. Powder Technol., Japan, 41: 514-521 (2004).
  Johnson et al., “Turbuhaler a new device for dry powder terbutaline inhalation”, Allergy 43(5):392-395 (1988).
  Johnson et al: RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets. J Biol Chem., 279 (23):24794-802, 2004.
  Johnson, Keith A., Preparation of peptide and protein powders for inhalation. Advanced Drug Delivery Reviews 1997; 26:3-15.
  Jones et al., An investigation of the pulmonary absorption of insulin in the rat. Third European Congress of Biopharmaceutics and Pharmacokinetics, (1987).
  Joseph et al. “Oral delivery of glucagon-like peptide-1 in a modified polymer preparation normalizes basal glycaemia in diabetic db/db mice.” Diabetologia 43:1319-1328, 2000.
  Joy et al. “Incretin mimetics as emerging treatments for type 2 diabetes.” Annal Pharmacother 39:110, 2005.
  Juntti-Berggren et al. “The antidiabetogenic effect of GLP-1 is maintained during a 7-day treatment period and improves diabetic dyslipoproteinemia in NIDDM patients.” Diabetes Care 19:1200-1206, 1996.
  Kanse et al. “Identification and characterization of glucagon-like peptide-1 7-36 amide-binding sites in the rat brain and lung.” FEBS Letters 241:209, 1988.
  Kapitza C et al. “Impact of particle size and aerosolization time on the metabolic effect of an inhaled insulin aerosol.” Diabetes Tech Ther 6:119, 2004.
  Kapsner P, Bergenstal RM, Rendell M, et al. Comparative efficacy and safety of Technosphere® insulin and a rapid-acting analog both given with glargine in subjects with type 1 diabetes in a 52-week study. Diabetologia 2009; 52 (suppl 1).
  Katz et al. “Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.” J. Clin. Endocrinol. Metab. 85:5402-2410, 2000.
  Kawai et al. “Evidence that glucagon stimulates insulin secretion through its own receptor in rats.” Diabetologia 38:274, 1995.
  Kawamori et al. “Does hyperinsulinemia accelerate atherosclerosis?” Department of Medicine, Juntendo University School, vol. 13, No. 12, p. 954-960, 1994.
  Kelley, D. et al. “Impaired postprandial glucose utilization in non-insulin dependent diabetes mellitus.” Metabolism 43:1549-1557, 1994.
  Kenny AJ et al. “Dipeptidyl peptidase IV, a kidney brush-border serin peptidase.” Biochem J. 155:169, 1976.
  Kim et al. “Development and characterization of a glucagon-like peptide 1-albumin conjugate. The ability to activate the glucagon-like peptide 1 receptor in vivo.” Diabetes 52:751, 2003.
  Kinzig et al. “The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness.” J Neurosci 22:10470, 2002.
  Kirk et al. “Disparities in HbA1c levels between African-American and non-hispanic white adults with diabetes.” Diabetes Care 29:2130, 2006.
  Kitabchi, Proinsulin and C-peptide:a review. May 26, 1977 (5):547-87, http://www/ncbi.nlm.nih.gov/pubmed/403392.
  Knop et al. “No hypoglycemia after subcutaneous administration of glucagon-like peptide-1 in lean type 2 diabetic patients and in patients with diabetes secondary to chronic pancreatitis.” Diabetes Care 26:2581, 2003.
  Knop et al. “Reduced incretin effect in type 2 diabetes. Cause or consequence of the diabetic state?” Diabetes 56:1951, 2007.
  Kohler, “Aerosols for Systemic Treatment”, Lung (Suppl.) 677-684 (1990).
  Komada et al., Intratracheal delivery of peptide and protein agents: absorption from solution and dry powder by rat lung. J. Pharm. Sci. 83(6): 863-867 (1994).
  Komatsu et al. “Glucagonostatic and insulinotropic action of glucagon-like peptide-1 (7-36)-amide.” Diabetes 38:902, 1989.
  Koning et al., Relationship between inspiratory flow through simulated dry powder inhalers and peak maximal inspiratory pressure. Flow Through a Simulated DPI, Chapter 3, pp. 43-56 (2001).
  Labiris et al., Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. British Journal of Clinical Pharmocology 56: 588-599 (2003).
  Kontny et al., Issues Surrounding MDI Formulation Development with Non-CFC Propellants), J. Aerosol Med 4(3), 181-187 (1991).
  Kraft KS, Grant M. Preparation of macromolecule-containing drug powders for pulmonary delivery Methods in Molecular Biology 2009;480:165-174.
  Kreymann B et al. “Glucagon-like peptide-1 7-36: a physiological incretin in man.” The Lancet, Dec. 5, 1987, p. 1300.
  Krssak, M. et al. “Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes.” Diabetes 53:3048-3056, 2004.
  Kwon et al. “Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets.” Diabetes 53:S225, 2004.
  Lankat-Buttgereit B et al. “Molecular cloning of a cDNA encoding for the GLP-1 receptor expressed in rat lung.” Exp Clin Endocrinol 102:241, 1994.
  Lebovitz “Therapeutic options in development for management of diabetes: pharmacologic agents and new technologies.” Endocr Pract 12:142, 2006.
  Lee et al. “Synthesis, characterization and pharmacokinetic studies of PEGylated glucagon-like peptide-1.” Bioconjugate Chem 16:377, 2005.
  Lee et al., “Development of an Aerosol Dosage Form Containing Insulin”, J. Pharm. Sci. 65(4), 567-572 (1976).
  Leone-Bay et al. “Evaluation of novel particles as an inhalation system for GLP-1.” Diabetes, Obesity and Metabolism. 11:1050-1059, 2009.
  Leone-Bay A, Grant M. Technosphere® Technology: A Platform for inhaled protein therapeutics. OndrugDelivery 2006 (published online).
  Leone-Bay A, Grant M. Technosphere®/insulin: mimicking endogenous insulin release. In: Rathbone M, Hadgraft J, Roberts M, et al, eds. Modified Release Drug Delivery, 2e. New York, NY: Informa Healthcare USA, Inc; 2008.
  Kieffer et al. “The glucagon-like peptides.” Endocrine Reviews 20:876, 1999.
  Kim et al., Dose-response relationships of inhaled insulin delivered via the aerodose insulin inhaler and subcutaneously injected insulin in patients with type 2 diabetes. Diabetes Care, 26:2842-2847 (2003).
  Klonoff, David C. M.D., Afrezza inahled insulin: the fastest-acting FDA-approved insulin on the market has favorable properties. Journal of Diabetes Science and Technology, vol. 8(6): 10-71-1073 (2014).
  U.S. Appl. No. 15/377,641, filed Dec. 13, 2016.
  U.S. Appl. No. 15/418,388, filed Jan. 27, 2017.
  U.S. Appl. No. 15/421,743, filed Feb. 1, 2017.
  Chan et al., Physical stability of salmon calcitonin spray-dried powders for inhalation. Journal of Pharmaceutical Sciences, vol. 93, No. 3, pp. 792-804 (2004).
  Mumenthaler et al., Feasibility study on spray-drying protein pharmaceuticals: recombinant human growth hormone and tissue-type plasminogen activator. Pharm Res., 11(1):12-20 (1994).
  Sarala et al., Technosphere: New drug delivery system for inhaled insulin. Future Prescriber, vol. 13, No. 1, pp. 14-16 (2012).
  U.S. Appl. No. 15/233,794, filed Aug. 10, 2016.
  U.S. Appl. No. 15/300,239, filed Sep. 28, 2016.
  Uwaifo et al., Novel pharmacologic agents for type 2 diabetes. Endocrinology and Metabolism Clinics of North America, vol. 34, No. 1, pp. 155-197 (2005).
  Xi-de Tu, et al. Pharmaceutics. Oct. 2002, 3rd edition, second printing, p. 905.
  Lane et al., Influence of post-emulsification drying processes on the microencapsulation of Human Serum Albumin. International Journal of Pharmaceutics, 307: 16-22 (2006).
  U.S. Appl. No. 15/152,355, filed May 11, 2016.
  U.S. Appl. No. 15/182,503, filed Jun. 14, 2016.
 
 
     * cited by examiner
 
     Primary Examiner —Todd J Scherbel
     Assistant Examiner —Elliot S Ruddie
     Art Unit — 3778
     Exemplary claim number — 1
 
(74)Attorney, Agent, or Firm — K&L Gates LLP; Louis C. Cullman; Brian J. Novak

(57)

Abstract

A pulmonary drug delivery system is disclosed, including a breath-powered, dry powder inhaler, with or without a cartridge for delivering a dry powder formulation. The inhaler and cartridge can be provided with a drug delivery formulation comprising, for example, a diketopiperazine and an active ingredient, including, small organic molecules, peptides and proteins, including, hormones such as insulin and glucagon-like peptide 1 for the treatment of disease and disorders, for example, diseases and disorders, including endocrine disease such as diabetes and/or obesity.
19 Claims, 38 Drawing Sheets, and 57 Figures


[0001] This application claims the benefit under 35 U.S.C. §119(e) from U.S. Provisional Patent Application Ser. No. 61/671,041, filed on Jul. 12, 2012, the contents of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

[0002] The present disclosure relates to dry powder inhalation systems including dry powder inhalers, cartridges and pharmaceutical compositions for delivering one or more drugs to the pulmonary tract and pulmonary circulation for the treatment of local and/or systemic diseases or disorders.

BACKGROUND

[0003] Drug delivery systems for disease treatment which introduce active ingredients into the circulation are numerous and include oral, transdermal, inhalation, subcutaneous and intravenous administration. Drugs delivered by inhalation are typically delivered using positive pressure relative to atmospheric pressure in air with propellants. Such drug delivery systems deliver drugs as aerosols, nebulized or vaporized. More recently, drug delivery to lung tissue has been achieved with dry powder inhalers. Dry powder inhalers can be breath activated or breath-powered and can deliver drugs by converting drug particles in a carrier into a fine dry powder which is entrained into an air flow and inhaled by the patient. Drugs delivered with the use of a dry powder inhaler are no longer only intended to treat pulmonary disease, but can also be absorbed into the systemic circulation so they can be used to treat many conditions, including, but not limited to diabetes and obesity.
[0004] Dry powder inhalers, used to deliver medicaments to the lungs, contain a dose system of a powder formulation usually either in bulk supply or quantified into individual doses stored in unit dose compartments, like hard gelatin capsules or blister packs. Bulk containers are equipped with a measuring system operated by the patient in order to isolate a single dose from the powder immediately before inhalation. Dosing reproducibility requires that the drug formulation is uniform and that the dose can be delivered to the patient with consistent and reproducible results. Therefore, the dosing system ideally operates to completely discharge all of the formulation effectively during an inspiratory maneuver when the patient is taking his/her dose. However, complete discharge is not generally required as long as reproducible dosing can be achieved. Flow properties of the powder formulation, and long term physical and mechanical stability in this respect, are more critical for bulk containers than they are for single unit dose compartments. Good moisture protection can be achieved more easily for unit dose compartments such as blisters. However, materials used to manufacture blisters allow air into the drug compartment and subsequently formulations can lose viability with long storage. Additionally, dry powder inhalers which use blisters to deliver a medicament by inhalation can suffer with inconsistency of dose delivery to the lungs due to variations in the air conduit architecture resulting from puncturing films or peeling films of the blisters.
[0005] Dry powder inhalers in the art can generate drug particles or suitable inhalation plumes during an inspiratory maneuver by deagglomerating the powder formulation within a cartridge or capsule. The amount of fine powder discharged from the inhaler's mouthpiece during inhalation is largely dependent on, for example, interparticulate forces in the powder formulation and efficiency of the inhaler to separate those particles so that they are suitable for inhalation. One important inhaler characteristic is the ability of the inhaler to discharge effectively and repeatedly all of its powder content in order to deliver an accurate dose. Also the inhaler should be designed with internal conduits that avoid retaining powder and thus induce costly loss of the active agent to be delivered, which can be typical of, for example, amorphous and/or cohesive powders, and/or crystalline powders. Thus, the inhaler structural design must provide air conduits which effectively deliver the powder from its reservoir during use. The benefits of delivering drugs via the pulmonary circulation are numerous and can include rapid entry into the arterial circulation, avoidance of drug degradation by liver metabolism, ease of use, i.e., lack of discomfort of administration by other routes of administration.
[0006] Dry powder inhaler products developed for pulmonary delivery have met with limited success to date, due to lack of practicality and/or cost of manufacture. Some of the persistent problems observed with prior art inhalers, include lack of ruggedness, inconsistency in dosing, inconvenience of the equipment, poor deagglomeration, problems with delivery in light of divorce from propellant use, reduced powder discharge or loss of the powder due to powder retention within an inhaler, and/or lack of patient compliance. In some cases, efficient powder delivery from an inhaler is also dependent on the type of powder, i.e., crystalline versus amorphous powder. Certain types of amorphous powders tend to cake and smear while tumbling, which leads to a decrease inhaler emptying or deagglomeration efficiency and ultimately in drug delivery to a user. Therefore, an inhaler has been designed and manufactured with consistent powder delivery properties, which is easy to use without discomfort, and has discrete inhaler configurations which can allow for better patient compliance.

SUMMARY

[0007] Described herein generally are dry powder inhalation systems for pulmonary delivery, wherein the systems include dry powder inhalers and containers including cartridges for dry powder inhalers for rapid and effective delivery of dry powder formulations to the pulmonary tract. The dry powder formulations of the inhalation systems comprise active agents for the treatment of one or more diseases. These diseases can include, but are not limited to local or systemic diseases or disorders, including, but not limited to diabetes, obesity, pain, headaches such as migraines, central or peripheral nervous system and immune disorders and the like, as well as for delivery of a vaccine formulation. The dry powder inhalers can be breath-powered, compact, reusable or disposable systems, which can have various shapes and sizes, and comprise a system of airflow conduit pathways for the effective and rapid delivery of dry powder medicaments.
[0008] In one embodiment, the inhaler can be a unit dose, reusable or disposable inhaler that can be used with or without a cartridge. By use without a cartridge we refer to systems in which cartridge-like structures are provided that are integral to the inhaler and the inhaler is for a single use and disposable. Alternatively, in some embodiments, the systems comprise a cartridge which is provided separately and installed in the inhaler for use by, for example, the user. In this embodiment, the inhaler can be a reusable inhaler and a new cartridge is installed in the inhaler at every use. In another embodiment, the inhaler can be a multidose inhaler, disposable or reusable, that can be used with single unit dose cartridges installed in the inhaler or cartridge-like structures built-in or structurally configured as part of the inhaler.
[0009] In further embodiments, the dry powder inhalation system comprises a dry powder inhalation device or inhaler with or without a cartridge, and a pharmaceutical formulation comprising an active ingredient or active agent for pulmonary delivery. In some embodiments, powder delivery is to the deep lung, including, to the alveolar region, and in some of these embodiments, one or more active agents are delivered to the lungs and absorbed into the pulmonary circulation for systemic delivery. The system can also comprise a dry powder inhaler with or without a unit dose cartridge, and a drug delivery formulation comprising, for example, a pharmaceutically acceptable carrier or substance, for example, a diketopiperazine and an active ingredient such as small molecules, peptides, polypeptides and proteins, including insulin, oxyntomodulin, oxytocin, peptide YY, parathyroid hormone, glucagon-like peptide 1 and the like. In alternate embodiments, the pharmaceutically acceptable carriers and/or excipients, including polyethylene glycol, polyvinylpyrrolidone, saccharides, oligosaccharides, polysaccharides, including lactose, trehalose, mannose, mannitol, sorbitol, and the like; amino acids including, leucine, lysine, isoleucine, trileucine, arginine, cysteine, cystine, histidine and methionine; and/or derivatives thereof.
[0010] In one exemplary embodiment, a dry powder inhaler is provided comprising: a) a first element comprising a mouthpiece; b) a second element comprising a container; and c) at least two rigid air conduits; wherein one of the at least two rigid air conduits in use is configured to have a deflector or stem to direct powder movement within a powder container in a substantially U-shaped configuration from an air intake port through a container void and through a dispensing or air exit port to reach a second airflow conduit in the mouthpiece of the inhaler prior to delivery to a user. In this an other embodiments herewith the dry powder inhaler comprises a predetermined air flow balance distribution in use through the air conduit through the powder container and through the air conduit in the mouth piece. The inhaler system also comprises high resistance air flow pathways as described below.
[0011] In one embodiment, the dry powder inhaler comprises a housing, a moveable member, and a mouthpiece, wherein the moveable member is operably configured to move a container from a powder containment position to a powder dosing position. In this and other embodiments, the moveable member can be a sled, a slide tray, or a carriage which is moveable by various mechanisms.
[0012] In another embodiment, the dry powder inhaler comprises a housing and a mouthpiece, structurally configured to have an open position and a closed position, and a mechanism operably configured to receive, hold, and reconfigure a cartridge from a containment position to a dispensing, dosing or dose delivery position upon movement of the inhaler from the open position to the closed position. In versions of this embodiment, the mechanism can also reconfigure a cartridge installed in the inhaler from the dosing position to an alternate position after use when the inhaler is opened to unload a used cartridge, thereby indicating to a user that the cartridge has been spent. In one embodiment, the mechanism can reconfigure a cartridge to a disposable or discarding configuration after use. In such embodiments, the housing is structurally configured to be moveably attached to the mouthpiece by various mechanisms including, a hinge. The mechanism can be configured to receive and reconfigure a cartridge installed in the inhaler from a containment position to the dosing position and can be designed to operate manually or automatically upon movement of the inhaler components, for example, by closing the device from an open configuration. In one embodiment, the mechanism for reconfiguring a cartridge comprises a slide tray or sled attached to the mouthpiece and movably attached to the housing. In another embodiment, the mechanism is mounted or adapted to the inhaler and comprises a geared mechanism integrally mounted within, for example, a hinge of the inhaler device. In yet another embodiment, the mechanism operably configured to receive and reconfigure the cartridge from a containment position to a dosing position comprises a cam that can reconfigure the cartridge upon rotation of, for example, the housing or the mouthpiece.
[0013] In an alternate embodiment, the dry powder inhaler can be made as a single use, unit dose disposable inhaler, which can be provided with a container configured to hold a powder medicament and the container is moveable from a containment configuration to a dosing configuration by a user, wherein the inhaler can have a first and a second configuration in which the first configuration is a containment configuration and the second configuration is a dosing of dispensing configuration. In this embodiment, the inhaler can be provided with or without a mechanism for reconfiguring the powder container. According to aspects of the latter embodiment, the container can be reconfigured directly by the user. In some aspects of this embodiment, the inhaler and container can be manufactured as a two piece inhalation system wherein the powder medicament is provided to the container prior to assembling the device in a containment configuration. In this embodiment, the container is attached or inserted into to the inhaler body and is moveable from the containment configuration to a dosing configuration, for example, by sliding relative to the top portion of the inhaler comprising a mouthpiece.
[0014] In yet another embodiment, an inhaler is described comprising a container mounting area configured to receive a container, and a mouthpiece having at least two inlet apertures and at least one exit aperture. In one embodiment, one inlet aperture of the at least two inlet apertures is in fluid communication with the container area, and the other of the at least two inlet apertures is in fluid communication with the at least one exit aperture via a flow path configured to bypass the container area.
[0015] In one embodiment, the inhaler has opposing ends such as a proximal end for contacting a user's lips or mouth and a distal end, and comprises a mouthpiece and a medicament container; wherein the mouthpiece comprises a top surface and a bottom or undersurface. The mouthpiece undersurface has a first area configured relatively flat to maintain a container in a sealed or containment configuration, and a second area adjacent to the first area which is raised relative to the first area. In this embodiment, the container is movable from the containment configuration to the dosing configuration and vice versa, and in the dosing configuration, the second raised area of the mouthpiece undersurface and the container form or define an air inlet passageway to allow ambient air to enter the internal volume of the container or expose the interior of the container to ambient air. In one embodiment, the mouthpiece can have a plurality of openings, for example, an inlet port, an outlet port and at least one port for communicating with a medicament container in a dispensing or dosing position, and can be configured to have integrally attached panels extending from the bottom surface sides of the inhaler and having flanges protruding towards the center of the inhaler mouthpiece, which serve as tracks and support for the container on the mouthpiece so that the container can move along the tracks from the containment position to a dispensing or dosing position and back to containment if desired. In one embodiment, the medicament container is configured with wing-like projections or winglets extending from its top border to adapt to the flanges on the mouthpiece panels. In one embodiment, the medicament container can be moved manually by a user from containment position to a dosing position and back to the containment position after dosing, or by way of a sled, a slide tray, or a carriage.
[0016] In another embodiment, a single use, unit dose, disposable inhaler can be constructed to have a sled incorporated and operably configured to the mouthpiece. In this embodiment, a bridge on the sled can abut or rest on an area of the medicament container to move the container along the mouthpiece panel tracks from the containment position to the dispensing or dosing position. In this embodiment, the sled can be operated manually to move the container on the mouthpiece tracks.
[0017] In a particular embodiment, a single use, unit dose disposable inhaler is structurally configured to have a powder containment configuration and a powder dosing configuration, the inhaler comprises two elements and has a top surface, bottom surface, a proximal end and a distal end; a first element and a second element; the first element has at least three openings and comprises a mouthpiece at the proximal end; a body, an undersurface configured to adapt to the second element and has a protruding structure or stem configured to extending downwardly into the second element; the first element further configured to have a first flow pathway having an air inlet, and an air outlet for delivering an airstream into a subject's mouth during an inhalation; and a third opening configured to form an air conduit and a second flow pathway with the second element in the powder dosing configuration; the second element is configured to adapt to the undersurface of the first element and is moveable relative to the first element to form an inhaler containment configuration or a dosing configuration; the second element comprises a container or reservoir, has an opening configured to receive and retain a powder and form an air inlet and an air conduit or a second flow pathway with the first element in the dosing configuration; wherein in the powder dispensing configuration a powder is exposed to ambient air to be dispensed or discharged during an inhalation. In this and other embodiments, a dry powder inhaler in a dosing configuration comprises a stem-like or protruding structure extending downwardly into the container void or chamber and serves to deflect powder. In this embodiment, airflow entering the container or powder reservoir travels primarily in a pathway closely related to the shape of the container which is structurally configured in the shape substantially of the letter U having the portion of the air conduit extending from the air inlet in the form of an open letter s on its side, and powder is lifted and translated or transported from this second airstream to the first airstream into a subject's mouth and airways.
[0018] In one embodiment, the dry powder inhaler comprises one or more air inlets and one or more air outlets. When the inhaler is closed, at least one air inlet can permit flow to enter the inhaler and at least one air inlet allows flow to enter a cartridge compartment or the interior of the cartridge or container adapted for inhalation. In one embodiment, the inhaler has an opening structurally configured to communicate with the cartridge placement area and with a cartridge inlet port when the cartridge container is in a dosing position. Flow entering the cartridge interior can exit the cartridge through an exit or dispensing port or ports; or flow entering the container of an inhaler can exit through at least one of the dispensing apertures. In this embodiment, the cartridge inlet port or ports is/are structurally configured so that all, or a portion of the air flow entering the interior of the cartridge is directed at the exit or dispensing port or ports.
[0019] The medicament container or powder reservoir can be structurally configured to have two opposing, relatively curvilinear sides which can direct airflow. In one embodiment, flow entering the air inlet during an inhalation enters the container or powder reservoir and can circulate within the interior of the container about an axis relatively perpendicular to the axis of the dispensing ports, and thereby, flow can lift, tumble and effectively fluidize a powder medicament contained in the cartridge or reservoir prior to exiting through dispensing ports or outlets. In another embodiment, flow entering the air inlet during an inhalation can lift powder from the container of powder reservoir and translate or transport the powder particles entrained in the airstream into a second stream in the inhaler. In this and other embodiments, fluidized powder in the air conduit can be further deagglomerated into finer powder particles by a change in direction or velocity, i.e., acceleration or deceleration of the particles in the flow pathway. In certain embodiments, the change in acceleration or deceleration can be accomplished by changing the angle and geometries of, for example, the dispensing port or ports, the mouthpiece conduit and/or its interfaces. In the inhalers described herewith, the mechanism of fluidization and acceleration of particles as they travel through the inhaler are methods by which deagglomeration and delivery of a dry powder formulation is effectuated.
[0020] In particular embodiments, a method for deagglomerating and dispersing a dry powder formulation comprises one or more steps such as tumbling within a primary container region started and enhanced by flow entering the container; a rapid acceleration of powder in the flow through the dispensing ports leaving the container; further accelerating the powder induced by a change in direction or velocity as the powder exits the dispensing port; shearing of powder particles caught within a flow gradient, wherein the flow on the top of the particle is faster than flow on bottom of the particle; deceleration of flow due to expansion of cross-sectional area within the mouthpiece air conduit; expansion of air trapped within a particle due to the particle moving from a higher pressure region to a lower pressure region, or collisions between particles and flow conduit walls at any point in the flow passageways.
[0021] In another embodiment, a dry powder inhaler comprises a mouthpiece; a sled, slide tray, or a carriage; a housing, a hinge, and a gear mechanism configured to effectuate movement of the sled or slide tray; wherein the mouthpiece and the housing are moveably attached by the hinge.
[0022] Cartridges for use with the dry powder inhaler can be manufactured to contain any dry powder medicament for inhalation. In one embodiment, the cartridge is structurally configured to be adaptable to a particular dry powder inhaler and can be made of any size and shape, depending on the size and shape of the inhaler to be used with, for example, if the inhaler has a mechanism which allows for translational movement or for rotational movement. In one embodiment, the cartridge can be configured with a securing mechanism, for example, having a beveled edge on the cartridge top corresponding to a matching beveled edge in an inhaler so that the cartridge is secured in use. In one embodiment, the cartridge comprises a container and a lid or cover, wherein the container can be adapted to a surface of the lid and can be movable relative to the lid or the lid can be movable on the container and can attain various configurations depending on its position, for example, a containment configuration, a dosing configuration or after use configuration. Alternatively, the lid can be removable.
[0023] An exemplary embodiment can comprise an enclosure to hold medicament configured having at least one inlet aperture to allow flow into the enclosure; at least one dispensing aperture to allow flow out of the enclosure; the inlet aperture configured to direct at least a portion of the flow at the dispensing aperture or at the particles approaching the dispensing aperture within the enclosure in response to a pressure gradient. The dispensing aperture or apertures and the intake gas aperture each independently can have a shape such as oblong, rectangular, circular, triangular, square and oval-shaped and can be in close proximity to one another. In one embodiment and during inhalation, a cartridge adapted to the inhaler in a dosing position allows airflow to enter the enclosure and mix with the powder to fluidize the medicament. The fluidized medicament can move within the enclosure such that medicament gradually exits the enclosure through the dispensing aperture, wherein the fluidized medicament exiting the dispensing aperture is sheared and diluted by a secondary flow not originating from within the enclosure. In one embodiment, the flow of air in the internal volume rotates in a circular manner so as to lift a powder medicament in the container or enclosure and recirculate the entrained powder particles or powder mass in the internal volume of the container promoting the flow to tumble prior to the particles exiting dispensing ports of the container or one or more of the inhaler inlet ports or air outlet or dispensing apertures, and wherein the recirculating flow, can cause tumbling, or non-vortical flow of air in the internal volume acts to deagglomerate the medicament. In one embodiment, the axis of rotation is mostly perpendicular to gravity. In another embodiment the axis of rotation is mostly parallel to gravity. The secondary flow not originating from within the enclosure further acts to de-agglomerate the medicament. In this embodiment, the pressure differential is created by the user's inspiration. A cartridge for a dry powder inhaler, comprising: an enclosure configured to hold a medicament; at least one inlet port to allow flow into the enclosure, and at least one dispensing port to allow flow out of the enclosure; the at least one inlet port is configured to direct at least a portion of the flow entering the at least one inlet port at the at least one dispensing port within the enclosure in response to a pressure differential.
[0024] A unit dose cartridge for an inhaler is described comprising: a substantially flat cartridge top, arrow-like in configuration, having one or more inlet apertures, one or more dispensing apertures, two side panels extending downwardly and each of the two side panels having a track; and a container moveably engaged to the track of the side panels of the cartridge top, and comprising a chamber configured to have a relatively cup-like shape with two relatively flat and parallel sides and a relatively rounded bottom, and interior surface defining an internal volume; the container configurable to attain a containment position and a dosing position with the cartridge top; wherein in use with a dry powder inhaler during an inhalation a flow entering the internal volume diverges as it enters the internal volume with a portion of the flow exiting through the one or more dispensing apertures and a portion of the flow rotating inside the internal volume and lifting a powder in the internal volume before exiting through the dispensing apertures.
[0025] In one embodiment, an inhalation system for pulmonary drug delivery is provided, comprising: a dry powder inhaler comprising a housing and a mouthpiece having an inlet and an outlet port, an air conduit between the inlet and the outlet, and an opening structurally configured to receive a cartridge; a cartridge mounting mechanism such as a sled; a cartridge configured to be adapted to the dry powder inhaler and containing a dry powder medicament for inhalation; wherein the cartridge comprises a container and a lid having one or more inlet ports or one or more dispensing ports; the dry powder inhaler system in use has a predetermined airflow balance distribution through the cartridge relative to total flow delivered to the patient.
[0026] In embodiments disclosed herewith, the dry powder inhaler system comprises a predetermined mass flow balance within the inhaler. For example, a flow balance of approximately 20% to 70% of the total flow exiting the inhaler and into the patient is delivered by the dispensing ports or passed through the cartridge, whereas approximately 30% to 80% is generated from other conduits of the inhaler. Moreover, bypass flow or flow not entering and exiting the cartridge can recombine with the flow exiting the dispensing port of the cartridge within the inhaler to dilute, accelerate and ultimately deagglomerate the fluidized powder prior to exiting the mouthpiece.
[0027] In embodiments described herein, the dry powder inhaler is provided with relatively rigid air conduits or a plumbing system and high flow resistance levels to maximize deagglomeration of powder medicament and facilitate delivery. Inhalation systems disclosed herein comprise conduits which exhibit resistance to flow in use maintaining low flow rates which minimize high inertial forces on powder particles discharged from the inhaler, preventing throat deposition or impaction of the powder particles in the upper respiratory tract, and thereby, maximizing powder particle deposition in the lungs. Accordingly, the present inhalation systems provide effective and consistent powder medicament discharge from the inhalers after repeated use since the inhalers are provided with air conduit geometries which remain the constant and cannot be altered. In some embodiments, the dry powder medicament is dispensed with consistency from an inhaler in less than about 3 seconds, or generally less than 1 second. In some embodiments, the inhaler system can have a high resistance value of, for example, approximately 0.065 to about 0.200 (√kPa)/liter per minute. Therefore, in the inhalation systems, peak inhalation pressures drop offs between 2 and 20 kPa produce resultant peak flow rates of about between 7 and 70 liters per minute. These flow rates result in greater than 75% of the cartridge contents dispensed in fill masses between 1 and 30 mg or greater. In some embodiments, these performance characteristics are achieved by end users within a single inhalation maneuver to produce cartridge dispense percentages greater than 90%. In certain embodiments, the inhaler and cartridge system are configured to provide a single dose by discharging powder from the inhaler as a continuous flow of powder delivered to a patient.
[0028] In one embodiment, a method for effectively deagglomerating a dry powder formulation during an inhalation in a dry powder inhaler is provided. The method can comprise the steps of providing a dry powder inhaler comprising a container having an air inlet, dispensing ports communicating with a mouthpiece air conduit and containing and delivering a formulation to a subject in need of the formulation; generating an airflow in the inhaler by the subject's inspiration so that about 20 to about 70% of the airflow entering the inhaler enters and exits the container; allowing the airflow to enter the container inlet, circulate and tumble the formulation in an axis perpendicular to the dispensing ports to fluidize the formulation so as to yield a fluidized formulation; accelerating metered amounts of fluidized formulation through the dispensing ports and in the air conduit, and decelerating the airflow containing fluidized formulation in the mouthpiece air conduit of the inhaler prior to reaching the subject. In some specific embodiments, 20% to 60% of the total flow through the inhaler goes through the cartridge during dose delivery.
[0029] In another embodiment, a method for deagglomerating and dispersing a dry powder formulation for inhalation is provided, comprising the steps of: generating an airflow in a dry powder inhaler comprising a mouthpiece and a container having at least one inlet port and at least one dispensing port and containing a dry powder formulation; the container forming an air passage between at least one inlet port and at least one dispensing port and the inlet port directs a portion of the airflow entering the container to at least one dispensing port; allowing airflow to tumble powder within the container in a substantially perpendicular axis to the at least one dispensing port so as to lift and mix the dry powder medicament in the container to form an airflow medicament mixture; and accelerating the airflow exiting the container through at least one dispensing port. In one embodiment, the inhaler mouthpiece is configured to have a gradual expanding cross-section to decelerate flow and minimize powder deposition inside the inhaler and promote maximal delivery of powder to the patient. In one embodiment, for example, the cross-sectional area of the oral placement region of an inhaler can be from about 0.05 cm2 to about 0.25 cm2 over an approximate length of about 3 cm. These dimensions depend on the type of powder used with the inhaler and the dimensions of the inhaler itself.
[0030] In one embodiment, a cartridge for a dry powder inhaler is provided, comprising: a cartridge top and a container defining an internal volume; wherein the cartridge top has an undersurface that extends over the container; the undersurface configured to engage the container, and comprising an area to contain the internal volume and an area to expose the internal volume to ambient air. In one aspect of this embodiment, the container can optionally have one or more protrusions, or stems extending from the undersurface or inner surface of the top into void of the container. The protrusions can be of any shape or size as long as they can direct or deflect flow, particularly downwardly in the container in use. In particular embodiments, the protrusion can be configured in the lid of a cartridge extending from the surface facing the internal volume of the container in proximity to an air inlet in the dosing configuration. Alternatively, the protrusion can be designed in the surface of the mouthpiece for contacting the internal volume of a container and in proximity to the air inlet formed by the container in the dosing configuration.
[0031] In an alternate embodiment, a method for particle delivery through a dry powder delivery device is provided, comprising: inserting into the delivery device a cartridge for the containment and dispensing of particles comprising an enclosure enclosing the particles, a dispensing aperture and an intake gas aperture; wherein the enclosure, the dispensing aperture, and the intake gas aperture are oriented such that when an intake gas enters the intake gas aperture, the particles are deagglomerated by at least one mode of deagglomeration as described herein to separate the particles, and the particles along with a portion of intake gas are dispensed through the dispensing aperture; concurrently forcing a gas through a delivery conduit in communication with the dispensing aperture thereby causing the intake gas to enter the intake gas aperture, deagglomerate the particles, and dispense the particles along with a portion of intake gas through the dispensing aperture; and, delivering the particles through a delivery conduit of the device, for example, in an inhaler mouthpiece. In embodiments described herein, to effectuate powder deagglomeration, the dry powder inhaler can be structurally configured and provided with one or more zones of powder deagglomeration, wherein the zones of deagglomeration during an inhalation maneuver can facilitate tumbling of a powder by air flow entering the inhaler, acceleration of the air flow containing a powder, deceleration of the flow containing a powder, shearing of a powder particles, expansion of air trapped in the powder particles, and/or combinations thereof.
[0032] In another embodiment, the inhalation system comprises a breath-powered dry powder inhaler, a cartridge containing a medicament, wherein the medicament can comprise, for example, a drug formulation for pulmonary delivery such as a composition comprising a carrier, for example, a saccharide, oligosaccharide, polysaccharide, or a diketopiperazine and an active agent. In some embodiments, the active agent comprises peptides and proteins, such as insulin, glucagon-like peptide 1, oxyntomodulin, peptide YY, exendin, parathyroid hormone, analogs thereof, vaccines, small molecules, including anti-asmatics, vasodilators, vasoconstrictors, muscle relaxants, neurotransmitter agonist or antagonists, and the like.
[0033] The inhalation system can be used, for example, in methods for treating conditions requiring localized or systemic delivery of a medicament, for example, in methods for treating diabetes, pre-diabetes conditions, respiratory track infection, osteoporosis, pulmonary disease, pain including headaches including, migraines, obesity, central and peripheral nervous system conditions and disorders and prophalactic use such as vaccinations. In one embodiment, the inhalation system comprises a kit comprising at least one of each of the components of the inhalation system for treating the disease or disorder.
[0034] In one embodiment, there is provided a method for the effective delivery of a formulation to the blood stream of a subject, comprising an inhalation system comprising an inhaler including a cartridge containing a formulation comprising a diketopiperazine, wherein the inhalation system delivers a powder plume comprising diketopiperazine microparticles having a volumetric median geometric diameter (VMGD) ranging from about 2.5 μm to 10 μm. In an example embodiment, the VMGD of the microparticles can range from about 2 μm to 8 μm. In an example embodiment, the VMGD of the powder particles can be from 4 μm to about 7 μm in a single inhalation of the formulation of fill mass ranging between 3.5 mg and 10 mg of powder. In this and other embodiments, the inhalation system delivers greater than about 90% of the dry powder formulation from the cartridge.
[0035] In another embodiment, there is provided a dry powder inhaler comprising: a) a mouthpiece configured to deliver a dry powder to a subject by oral inhalation; b) a container housing, and c) rigid air conduits extending between the container housing and the mouthpiece and configured to communicate with ambient air; wherein the dry powder inhaler is configured to emit greater than 75% of a dry powder as powder particles from a container oriented in the container housing in a single inhalation and the powder particles emitted have a volumetric median geometric diameter (VMGD) of less than about 5 microns, when a user inhales through the mouthpiece to generate a peak inspiratory pressure of about 2 kPa within two seconds and an area under the curve (AUC) within 1 second for a pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec. In another embodiment, the AUC within 1 second for a pressure versus time curve is between about 1.0 and about 15 kPa*sec.
[0036] In some embodiments, there is also provided a method of delivering a dose of a dry powder medication using a high resistance dry powder inhaler comprising, providing a high resistance dry powder inhaler containing a dose of a dry powder medicament and inhaling from the inhaler with sufficient force (or effort) to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and generating an area under the curve in the first second (AUC0-1sec) of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec; wherein greater than 75% of the dry powder dose is discharged or emitted from the inhaler as powder particles. In some embodiments the VMGD of the emitted particles is less than about 5 microns.
[0037] In another embodiment, a method of delivering an adequately de-agglomerated dose of a dry powder medication using a high resistance dry powder inhaler comprising, providing a high resistance dry powder inhaler containing a dose of a dry powder medicament; inhaling from the inhaler with sufficient force to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and generating an area under the curve in the first second (AUC0-1sec) of a inspiratory pressure-time curve of at least about 1.0, 1.1, or 1.2 kPa*second; wherein VMGD (×50) of the emitted powder is less than about 5 um. In an alternative embodiment, the dry powder is composed of microparticles with a median particle size and the VMGD (×50) of the emitted powder particles is not greater than 1.33 times the median particle size when the inhaler is used optimally, for example, at about 6 kPa.
[0038] In another embodiment, described is a use of a high resistance dry powder inhaler for the delivery of a dry powder wherein the dry powder inhaler having an airflow resistance value ranging from about 0.065 (√kPa)/liter per minute to about 0.200 (√kPa)/liter per minute, and containing the dose of the dry powder, wherein sufficient force is applied to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and wherein an area under the curve in the first second (AUC0-1sec) of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec is generated; and wherein greater than 75% of the dose of the dry powder is discharged or emitted from the inhaler as powder particles.
[0039] In some embodiments the inhalation systems described herein are used to treat patients in need of treatment of a disease or disorder described herein using a medicament as described.
[0040] In still another embodiment, a high resistance dry powder inhaler for use to deliver a dry powder medicament to a patient is described, characterized in that the dry powder inhaler is provided having an airflow resistance value ranging from about 0.065 (√kPa)/liter per minute to about 0.200 (√kPa)/liter per minute, and containing a dose of the dry powder medicament, wherein in use sufficient force is applied to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and an area under the curve is generated in the first second (AUC0-1sec) of an inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec; and wherein greater than 75% of the dose of the dry powder is discharged or emitted from the inhaler as powder particles.
[0041] In another embodiment, an inhalation system is provided comprising an inhaler, a cartridge containing a dry powder formulation for delivery to the systemic circulation comprising diketopiperazine microparticles; wherein the diketopiperazine microparticles deliver a plasma level (exposure) of diketopiperazine having an AUC0-2 hr between 1,300 ng*min/mL and 3,200 ng*min/mL per mg of diketopiperazine emitted in a single inhalation. In another exemplary embodiment, an inhalation system is provided comprising an inhaler, a cartridge containing a dry powder formulation for delivery to the systemic circulation comprising diketopiperazine microparticles; wherein the diketopiperazine microparticles deliver a plasma level (exposure) of diketopiperazine having an AUC0-∞ greater than 2,300 ng*min/mL per mg of powder emitted in a single inhalation. In an aspect of such embodiments the DKP is FDKP. In this and other embodiments, the diketopiperazine microparticles do not cause a reduction in lung function as assessed by pulmonary function tests and measured as forced expiratory volume in one second (FEV1). In certain embodiments, the measured plasma exposure of FDKP in a subject can be greater than 2,500 ng*min/mL per mg of FDKP powder emitted in a single inhalation. In alternate embodiments, the measured plasma exposure, AUC0-∞ of FDKP of a subject can be greater than 3,000 ng*min/mL per mg of FDKP powder emitted in a single inhalation. In yet another embodiment, the measured plasma exposure of FDKP AUC0-∞ in a subject can be less than or about 5,500 ng*min/mL per mg of FDKP emitted in a single inhalation of a dry powder composition comprising FDKP. In some embodiments, the stated level of exposure represents an individual exposure. In alternate embodiments, the stated level of exposure represents a mean exposure. Active agent quantities, including contents and exposures may be express alternatively in units of activity or mass.
[0042] In these and other embodiments, the microparticles can further comprise an active ingredient. In particular embodiments, the active ingredient is insulin. In another exemplary embodiment, an inhalation system is provided comprising an inhaler, a cartridge containing a dry powder formulation for delivery to the systemic circulation comprising diketopiperazine microparticles containing insulin; wherein the diketopiperazine microparticles deliver a plasma level (exposure) of insulin with an AUC0-2 hr greater than 160 μU*min/mL per units of insulin in the powder formulation emitted in a single inhalation. In an aspect of this embodiment, the inhalation system is configured to deliver and attain an insulin plasma level or exposure wherein the measured insulin AUC0-2 hr ranges from about 100 to 1,000 μU*min/mL per units of insulin in the powder formulation emitted in a single inhalation. In some embodiments, the stated level of exposure represents an individual exposure. In alternate embodiments, the stated level of exposure represents a mean exposure.
[0043] In another exemplary embodiment, an inhalation system is provided comprising an inhaler, a cartridge containing a dry powder formulation for delivery to the systemic circulation comprising diketopiperazine microparticles comprising insulin; wherein the diketopiperazine microparticles deliver a plasma level (exposure) of insulin with an AUC0-4 hr greater than 100 μU*min/mL per U of insulin filled emitted in a single inhalation. In an aspect of this embodiment, the inhalation system is configured to deliver to a patient a formulation of insulin and fumaryl diketopiperazine which attains a plasma exposure of insulin having measured AUC0-4 hr in the range of 100 to 250 μU*min/mL per U of insulin filled dose, emitted in a single inhalation. In aspects of these embodiments, the AUC0-4 hr can be greater than 110, 125, 150 or 175 μU*min/mL per U of insulin filled, emitted in a single inhalation. In this and other embodiments, the insulin content of the formulation comprises from about 10 to about 20% (w/w) of the formulation
[0044] In still another exemplary embodiment, an inhalation system is provided comprising an inhaler, a cartridge containing a dry powder formulation for delivery to the systemic circulation comprising diketopiperazine microparticles containing insulin; wherein the diketopiperazine microparticles deliver a plasma level of insulin with a Cmax over 10 μU/mL per mg of powder emitted in a single inhalation, within 30 minutes of administration. In an aspect of this embodiment, the insulin formulation administered generates a Cmax ranging from about 10 to 20 μU/mL per mg of powder emitted in a single inhalation, and within 30 minutes after administration. In further aspects of this embodiment, insulin Cmax can be attained within 25, 20, or 15 minutes of administration. In alternatives of these Cmax embodiments, the Cmax attained after pulmonary inhalation of the formulation is greater than 3 μU/mL per U of insulin filled into a cartridge, or in the range of 3 U to 6 U, or 4 U to 6 μU/mL per U of insulin in a cartridge dose.
[0045] In another embodiment, an inhalation system, comprising: a dry powder inhaler; and a dry powder formulation comprising a plurality of powder particles of a diketopiperazine is provided, wherein the inhalation system is configured to deliver the diketopiperazine to the pulmonary circulation of a subject, and the diketopiperazine can be measured in the subject's plasma having a mean exposure or AUC0-∞ greater than 2,300 ng*min/mL per mg of diketopiperazine content in the dry powder formulation administered in a single inhalation. In one embodiment, the inhalation system further comprises a cartridge configured to adapt to a breath powered dry powder inhaler. In this and other embodiments, the diketopiperazine in the formulation is 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine (FDKP).
[0046] In embodiments wherein FDKP is used in the formulation, the system can deliver the FDKP into the systemic circulation at a Tmax of less than 1 hour. In some embodiments, the Tmax for FDKP can be less than 15 or 30 minutes after administration of the FDKP in a single inhalation. In this an other embodiments, the AUC is measured from 0 to 2 hours, 0 to 4 hrs or 0 to ∞.
[0047] In another embodiment, an inhalation system, comprising: a breath-powered dry powder inhaler, and a dry powder formulation comprising a plurality of diketopiperazine particles is provided; wherein the inhalation system is operably configured to emit a powder plume comprising the diketopiperazine microparticles having a volumetric median geometric diameter ranging from 2 μm to 8 μm and a geometric standard deviation of less than 4 μm.
[0048] In yet another embodiment, an inhalation system for pulmonary delivery of a drug, comprising: a breath-powered dry powder inhaler, and a dry powder formulation comprising a plurality of diketopiperazine particles is provided; wherein the inhalation system is operably configured to emit more than 90% of the powder particles that dissolve and are absorbed into the blood in less than 30 minutes or less than 25 minutes yield a peak concentration of the diketopiperazine after a single inhalation of the dry powder formulation. In some embodiments, the system emits more than 95% of the powder particles in a single inhalation, which particles are absorbed into the circulation.
[0049] In one embodiment, an inhalation system, comprising: a dry powder inhaler; and a dry powder formulation comprising a plurality of dry powder particles comprising insulin is provided; wherein the inhalation system is configured to deliver the insulin to the pulmonary circulation of a subject, and the insulin can be measured in a subject's plasma at an exposure having a mean AUC0-2 hr greater than 160 uU*min/mL per unit of insulin emitted in the dry powder formulation administered in a single inhalation.
[0050] In one embodiment, the inhalation system, the dry powder formulation is administered to a subject by oral inhalation and the formulation comprises powder particles of insulin which can deliver the insulin to the subject systemic circulation, wherein a Cmax for insulin is measured in less than 30 minutes after administration to a patient in a single inhalation.
[0051] In an embodiment, there is provided an inhalation system, comprising: a breath-powered dry powder inhaler, and a powder formulation comprising a plurality of diketopiperazine particles; wherein the inhalation system is operably configured to emit a powder plume comprising the diketopiperazine microparticles having a volumetric median geometric diameter ranging from 2 μm to 8 μm and a geometric standard deviation of less than 4 μm.
[0052] In yet another embodiment, an inhalation system for pulmonary delivery of a drug is provided, comprising: a breath-powered dry powder inhaler, and a powder formulation comprising a plurality of diketopiperazine particles; wherein the inhalation system is operably configured to emit powder particles that are absorbed into the blood to yield a peak concentration of the drug in less than or equal to 30, 25, 20, or 15 minutes.
[0053] In one embodiment, a dry powder inhaler comprising a mouthpiece configured to deliver a dry powder to a subject by oral inhalation, a container configured to hold a dry powder, and air conduits extending between the container and the mouthpiece and configured to communicate with ambient air, wherein the dry powder inhaler is configured to emit greater than 75% of the dry powder as powder particles in a single inhalation and the powder particles emitted have a volumetric median geometric diameter of less than 5 microns, when a user inhales through the mouthpiece to generate a peak inspiratory pressure of about 2 kPa within two seconds, and an AUC0-1sec of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec; wherein greater than 75% of the dry powder dose is discharged or emitted from the inhaler as powder particles.
[0054] In yet another embodiment, a method of delivering a dose of a dry powder medication to a subject is disclosed using a high resistance dry powder inhaler comprising the steps of providing a dry powder inhaler having a resistance value to airflow ranging from about 0.065 (√kPa)/liter per minute to about 0.200 (√kPa)/liter per minute and containing a dose of a dry powder medicament; inhaling from the inhaler with sufficient force to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and generating an AUC0-1sec of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec; wherein greater than 75% of the dry powder dose is discharged or emitted from the inhaler as powder particles.

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1 depicts an example embodiment of the inhaler used in the inhalation system, showing an isometric view of the inhaler in a closed configuration.
[0056] FIGS. 2, 3, 4, 5, and 6 depict side, top, bottom, proximal and distal views, respectively, of the inhaler of FIG. 1.
[0057] FIG. 7 depicts a perspective view of an embodiment of the inhalation system comprising the inhaler of in FIG. 1 in an open configuration showing a corresponding cartridge and a mouthpiece covering.
[0058] FIG. 8 depicts an isometric view of the inhaler of FIG. 6 in an open configuration with a cartridge installed in the holder in cross-section through the mid-longitudinal axis with