111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008603506B2
`
`c12) United States Patent
`Ashley
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,603,506 B2
`*Dec. 10, 2013
`
`(54) METHODS OF TREATING ACNE
`
`FOREIGN PATENT DOCUMENTS
`
`(75)
`
`Inventar: Robert A. Ashley, Newtown, PA (US)
`
`(73) Assignee: Galderma Laboratories, Inc., Fort
`Worth, TX (US)
`
`("') Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 70 days.
`This patent is subject to a terminal dis-
`claimer.
`
`EP
`JP
`JP
`JP wo
`wo wo wo
`wo wo wo wo wo
`
`111991
`0 410 099 Al
`12/1993
`A-5-509288
`A-91-88617
`7/1997
`3/2001
`A-2001-72660
`wo 83/00628
`3/1983
`W092/03l33
`3/1992
`W098/05340
`2/1998
`W098/08480
`3/1998
`1111999
`W099/58l3l
`wo 00/15235
`3/2000
`W000/28983
`5/2000
`W000/07601
`2/2001
`4/2011
`W000/18230
`OTHER PUBLICATIONS
`
`(21) Appl. No.: 13/277,789
`
`(22) Filed:
`
`Oct. 20, 2011
`
`(65)
`
`Prior Publication Data
`US 2012/0108552A1
`May3, 2012
`
`Related U.S. Application Data
`(60) Continuation of application No. 11/876,478, filed on
`Oct. 22, 2007, now Pat. No. 8,052,983, which is a
`continuation of application No. 10/757,656, filed on
`Jan. 14, 2004, now abandoned, which is a division of
`application No. 10/117,709, filedonApr. 5, 2002, now
`Pat. No. 7,211,267.
`(60) Provisional application No. 60/325,489, filed on Sep.
`26, 2001, provisional application No. 60/281,916,
`filed onApr. 5, 2001.
`
`(51)
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 8102
`A61K 31174
`(52) U.S. Cl.
`USPC ........................................ 424/401; 424/78.05
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,704,383 A
`5,045,538 A
`5,122,519 A
`5,260,292 A
`5,300,304 A *
`5,532,227 A
`5,674,539 A
`5,827,840 A
`5,908,838 A
`5,998,390 A
`6,294,200 Bl
`6,365,623 Bl *
`6,455,583 BI*
`6,673,843 B2
`7,014,858 B2
`2002/0165220 Al*
`2003/0082120 Al
`2003/0148945 Al
`2005/0239723 Al
`
`1111987 McN amara et al.
`9/1991 Schneideret al.
`6/1992 Ritter
`11/1993 Robinson et al.
`4/1994 Sheth et al .................... 424/490
`7/1996 Golub et al.
`1011997 Tomas et al.
`10/1998 Ramamurthy et al.
`6/1999 Gans
`12/1999 Ramamurthy et al.
`9/200 l Conte et al.
`4/2002 Perricone ...................... 514/448
`9/2002 Pflugfelder et al ........... 514/528
`112004 Arbiser
`3/2006 Ashley
`11/2002 Heesch .................... 514/210.09
`5/2003 Milstein
`8/2003 McNico1 et al.
`10/2005 Amin et al.
`
`Akamatsu, et al. "Effect ofKeigai-Rengyo-To, a Japanese Kampo
`Medicine, on Neutorphil Functions: a Possible Mechanism ofAction
`ofKeigai-Rengyo-To inAcne," The Journal oflnternational Medical
`Research, 25: 255-265 (1997).
`Baer, et al. "High-Dose Tetracycline Therapy in Severe Acne," Arch
`Dermata!, 112:479-481 (Apr. 1976).
`Cheryl Guttman, "Emerging resistance changes face of antibiotic
`therapy for acne," Dermatology Times, Jan. 2001, p. 22.
`Hirohiko Akamatsu, Maki Asada, Jinro Komura, Yasuo Asada, and
`Yukie Niwa, "Effect of Doxycycline on the Generation of Reactive
`Oxygen Species: A Passihle Mechanism of Action of Acne Therapy
`with Doxycycline," Acta Derm Venereal (Stockh) 72:178-178
`(1992).
`Bodokh, Y. Jacomet, J. Ph. Lacour and J.P. Ortonne, "Minocycline
`Induces an lncrease in the Number of Excreting Pilosebaceous Fol-
`licles in Acne Vulgaris," Acta Derm Venereal (Stockh), 77:255-259
`(1997).
`W. J. Cunliffe, M.D., F.R.C.P., "Evolution of a Strategy for the
`Treatment of Acne," J AmAcad Dermata!, 16:591-9 (1987).
`E. Anne Eady, Eileen Ingham, Christina E. Walters, Jonathan H.
`Cove, and William J. Cunliffe, "Modulation of Comedonal Levels of
`Interleukin-1 in Acne Patients Treated with Tetracyclines," J. Invest
`Dermata!, 101:86-91 (1993).
`Boni E. Elewski, M.D., BethA.J. Lamb, W. Mitchell Sams, Jr., M.D.,
`and W. Ray Gammon, M.D., "In Vivo Suppression of Neutrophil
`Chemotaxis by Systemically and Topically Administered Tetracy-
`cline," J AmAcadDermatol, 8:807-812 (1983).
`Nancy B. Esterly, M.D., Nancy L. Furey, M.D., and Lillian E.
`Flanagan, B.S ., "The Effect of Antimicrobial Agents on Leukocyte
`Chemotaxis," The Journal oflnvestigative Dermatology, 70(1):51-55
`(1978).
`Sainte-Marie, I. Tenaud, 0. Jumbou and B. Drimo, "Minocycline
`Modulation of Alpha-MSH Production by Keratinocytes In vitro,"
`Acta Derm Venereal 79:265-267 (1999).
`Hoshiki Miyachi, M.D., Akira Yoshioka, M.D., Sadao Imamura,
`M.D., and Yukie Niwa, M.D., "Effect of Antibiotics on the Genera-
`tion ofReactive Oxygen Species," J luvest Dermato1, 86(4):449-453
`(1986).
`Gerd Plewig, M.D., and Erwin Schöpf, M.D., "Anti-Inflammatory
`Effects of Antimicrobial Agents: An In Vivo Study," The Journal of
`Investigative Dermatology, 65:532-536 (1975).
`(Continued)
`
`Primary Examiner- Susan Tran
`(74) Attorney, Agent, or Firm- Hoffmann & Baron, LLP
`
`(57)
`ABSTRACT
`A method of treating acne in a human in need thereof com-
`prising administering systemically to said human a tetracy-
`cline compound in an amount that is e
`Dr. Reddy's Laboratories, Ltd., et al.
`has substantially no antibiotic activitj
`V.
`a bisphosphorrate compound.
`Galderma Laboratories, lnc.
`IPR2015-__
`Exhibit 1001
`
`20 Claims, 1 Drawin
`
`

`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008603506B2
`
`c12) United States Patent
`Ashley
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,603,506 B2
`*Dec. 10, 2013
`
`(54) METHODS OF TREATING ACNE
`
`FOREIGN PATENT DOCUMENTS
`
`(75)
`
`Inventar: Robert A. Ashley, Newtown, PA (US)
`
`(73) Assignee: Galderma Laboratories, Inc., Fort
`Worth, TX (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 70 days.
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 13/277,789
`
`(22) Filed:
`
`Oct. 20, 2011
`
`(65)
`
`Prior Publication Data
`US 2012/0108552Al
`May 3, 2012
`
`Related U.S. Application Data
`(60) Continuation of application No. 11/876,478, filed on
`Oct. 22, 2007, now Pat. No. 8,052,983, which is a
`continuation of application No. 10/757,656, filed on
`Jan. 14, 2004, now abandoned, which is a division of
`application No. 10/117,709, filed onApr. 5, 2002, now
`Pat. No. 7,211,267.
`(60) Provisional application No. 60/325,489, filed on Sep.
`26, 2001, provisional application No. 60/281,916,
`filed onApr. 5, 2001.
`
`(51)
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 8102
`A61K 31174
`(52) U.S. Cl.
`USPC ........................................ 424/401; 424/78.05
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,704,383 A
`5,045,538 A
`5,122,519 A
`5,260,292 A
`5,300,304 A *
`5,532,227 A
`5,674,539 A
`5,827,840 A
`5,908,838 A
`5,998,390 A
`6,294,200 Bl
`6,365,623 Bl *
`6,455,583 Bl *
`6,673,843 B2
`7,014,858 B2
`2002/0165220 Al *
`2003/0082120 Al
`2003/0148945 Al
`2005/0239723 Al
`
`1111987
`9/1991
`6/1992
`1111993
`4/1994
`7/1996
`10/1997
`10/1998
`6/1999
`12/1999
`9/2001
`4/2002
`9/2002
`112004
`3/2006
`1112002
`5/2003
`8/2003
`10/2005
`
`McNamara et al.
`Schneideret al.
`Ritter
`Robinson et al.
`Sheth et al .................... 424/490
`Golub et al.
`Tomas et al.
`Ramamurthy et al.
`Gans
`Ramamurthy et al.
`Conte et al.
`Perricone .
`Pflugfelder et al.
`Arbiser
`Ashley
`Heesch
`Milstein
`McNicol et al.
`Amin et al.
`
`514/448
`514/528
`
`514/210.09
`
`EP
`JP
`JP
`JP
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`111991
`0 410 099 Al
`12/1993
`A-5-509288
`7/1997
`A-91-88617
`3/2001
`A-2001-72660
`wo 83/00628
`3/1983
`wo 92/03133
`3/1992
`wo 98/05340
`2/1998
`wo 98/08480
`3/1998
`wo 99/58131
`1111999
`wo 00/15235
`3/2000
`wo 00/28983
`5/2000
`wo 00/07601
`212001
`wo 00/18230
`4/2011
`OTHER PUBLICATIONS
`
`Akamatsu, et al. "Effect of Keigai-Rengyo-To, a Japanese Kampo
`Medicine, on Neutorphil Functions: a Possible Mechanism of Action
`ofKeigai-Rengyo-To in Acne," The Journal oflnternational Medical
`Research, 25: 255-265 (1997).
`Baer, et al. "High-Dose Tetracycline Therapy in Severe Acne," Arch
`Dermatol, 112:479-481 (Apr. 1976).
`Cheryl Guttman, "Emerging resistance changes face of antibiotic
`therapy for acne," Dermatology Times, Jan. 2001, p. 22.
`Hirohiko Akamatsu, Maki Asada, Jinro Komura, Yasuo Asada, and
`Yukie Niwa, "Effect of Doxycycline on the Generation of Reactive
`Oxygen Species: A Possible Mechanism of Action of Acne Therapy
`with Doxycycline," Acta Derm Venereol (Stockh) 72:178-178
`(1992).
`Bodokh, Y. Jacomet, J. Ph. Lacour and J.P. Ortonne, "Minocycline
`Induces an Increase in the Number ofExcreting Pilosebaceous Fol-
`licles in Acne Vulgaris," Acta Derm Venereol (Stockh), 77:255-259
`(1997).
`W. J. Cunliffe, M.D., F.R.C.P., "Evolution of a Strategy for the
`Treatment of Acne," J AmAcad Dermatol, 16:591-9 (1987).
`E. Anne Eady, Eileen Ingham, Christina E. Walters, Jonathan H.
`Cove, and William J. Cunliffe, "Modulation of Comedonal Levels of
`Interleukin-1 in Acne Patients Treated with Tetracyclines," J. Invest
`Dermatol, 101:86-91 (1993).
`Boni E. Elewski, M.D., BethA.J. Lamb, W. Mitchell Sams, Jr., M.D.,
`and W. Ray Ganunon, M.D., "In Vivo Suppression of Neutrophil
`Chemotaxis by Systemically and Topically Administered Tetracy-
`cline," J AmAcad Dermatol, 8:807-812 (1983).
`Nancy B. Esterly, M.D., Nancy L. Furey, M.D., and Lillian E.
`Flanagan, B.S., "The Effect of Antimicrobial Agents on Leukocyte
`Chemotaxis,"The Journal oflnvestigative Dermatology, 70(1):51-55
`(1978).
`Sainte-Marie, I. Tenaud, 0. Jumbou and B. Dreno, "Minocycline
`Modulation of Alpha-MSH Production by Keratinocytes In vitro,"
`Acta Derm Venereol 79:265-267 (1999).
`Hoshiki Miyachi, M.D., Akira Yoshioka, M.D., Sadao Imamura,
`M.D., and Yukie Niwa, M.D., "Effect of Antibiotics on the Genera-
`tion ofReactive Oxygen Species," J Invest Dermatol, 86(4):449-453
`(1986).
`Gerd Plewig, M.D., and Erwin Schöpf, M.D., "Anti-Inflanunatory
`Effects of Antimicrobial Agents: An In Vivo Study," The Journal of
`Investigative Dermatology, 65:532-536 (1975).
`(Continued)
`
`Primary Examiner- Susan Tran
`(74) Attorney, Agent, or Firm- Hoffmann & Baron, LLP
`
`ABSTRACT
`(57)
`A method of treating acne in a human in need thereof com-
`prising administering systemically to said human a tetracy-
`cline compound in an amount that is effective to treat acne but
`has substantially no antibiotic activity, without administering
`a bisphosphorrate compound.
`
`20 Claims, 1 Drawing Sheet
`
`Exh. 1001
`
`

`
`US 8,603,506 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`M. Toyoda and M. Morohashi, "An Overview of Topical Antibiotics
`for Acne Treatment," Dermatology, 196:130-134 (1998).
`Sheila E. Unkles, and Curtis G. Gemmell, "Effect of Clindamycin,
`Erythromycin, Lincomycin, and Tetracycline on Growth and
`Extracellular Lipase Production by Propionibacteria In Vitro," Anti-
`microbial Agentsand Chemotherapy, 21:39-43 (1982).
`G.F. Webster, K.J. McGinley, and J.J. Leyden, "Inhibition of Lipase
`Production in Propionibacterium acnes by Sub-Minimal-Inhibitory
`Concentrations ofTetracycline and Erythromycin," British Journal of
`Dermatology, 104:453-457 (1981).
`Guy F. Webster, M.D., Ph.D., Susan M. Toso, M.S., and Lutz
`Hegemann, M.D., Ph.D., "Inhibition of a Model of In Vitro Grann-
`Ioma Formation by Tetracyclines and Ciprofloxacin," Arch
`Dermatol., 130:748-752 (1994).
`Reynold C. Wong, M.D., Sewon Kang, M.P.H., Jan L. Heezen, L.P.
`N., John J. Voorhees, M.D., and Charles N. Ellis, M.D., "Oral
`Ibuprofen and Tetracycline for the Treatment of Acne Vulgaris," J Am
`Acad Dermatol, 11:1076-1081 ( 1984).
`Kenneth S. Kornman and Edward H. Kar!, "The Effect ofLong-Term
`Low-Dose Tetracycline Therapy on the Subgingival Microflora in
`Refractory Adult Periodontitis," J. Periodontol., 53(10):604-610
`(Oct. 1982).
`"Treatment of rosacea with doxycycline
`J.B.,
`Bikowski,
`monohydrate," Curtis. 2000 Aug., 66(2):149-152.
`Jimenez-Acosta, "Response to tetracycline oftelangiectasias in male
`hemophiliac with human immunodeficiency virus infection," J. Am.
`Acad. Dermatol. Aug. 1988, 19(2 Pt. 1):369-379.
`Torresani, C., "Clarithromycin versus doxycycline in the treatment of
`rosacea," Int. J. Clin. Dermatol. Dec. 1997, 36(12):942-946.
`McClellan, K.J., "Topical Metronidazole. A review of its use in
`rosaea," Am. J. Clin. Dermatol. May-Jun. 2000, 1(3):191-199.
`Quarterman, M.J., "Ocular Rosacea. Signs, symptoms and tear stud-
`ies before and after treatment with doxycycline," Arch. Dermatol.
`Jan. 1997, 133(1):49-54.
`Skidmore et al., "Effects of Subantimicrobial-Dose Doxycycline in
`the Treatment of Moderate Acne," Archives of Dermatology
`139:459-464 (Apr. 2003), XP009047590.
`
`Akamatsu, et al. "Effects of subminimal inhibitory concentrations of
`minocycline on neutrophil chemotactic factor production
`in
`comedonal bacteria, neutrophil phagocytosis and oxygen metabo-
`lism." Arch Dermatol Res 283:524-528 (1991).
`Bikowski, et al. "Treatment of rosacea with doxycycline
`monohydrate" Cutis, 66:149-152 (Aug 2000).
`Golub, et al. "Tetracyclines inhibit connective tissue breakdown:
`New therapeutic implications for an old family of drugs" Critical
`Reviews in Oral Biology and Medicine, 2(2):297-322 (1991).
`Illig "Positive side effects of antibiotic and antimicrobial substances
`in therapy" Infection 7 (Suppl. 6): S 584-588 ( 1979) (English trans-
`lation. Original document in German.).
`Knight, et al. "A follow-up of tetracycline-treated rosacea" British
`Journal ofDermatology 93:577-580 (1975).
`Marks, et al. "Comparative effectiveness oftetracycline and ampicil-
`lin in rosacea" The Lancet, 1049-1052 (Nov. 13, 1971).
`Miliar, et al. "A general practice study investigating the effect of
`minocycline (Minocin) 50 mg bd for 12 weeks in the treatment of
`acne vulgaris" The British Journal ofClinical Practice 41(8):882-886
`( Aug. 1987).
`Pi ewig, et al. Acne: Morphogenesis and Treatment, Springer-Verlag
`297-301 (1975).
`Webster, et al. "Suppression of Polymorphonuclear Leukocyte
`Chemotactic Factor Production in Propionibacterium acnes by Sub-
`minimal Inhibitory Concentrations of Tetracycline, Ampicillin,
`Minocycline, and Erythromycin" Antimicrobial Agentsand Chemo-
`therapy 21(5):770-772 (1982).
`The Research Foundation of State University ofN ew York; N ew York
`University; Galderma Laboratories, Inc; Galderma Laboratories, LP.;
`and Supemus Pharmaceuticals v. My/an Pharmaceuticals Inc. (Civ.
`No. 09-184-LPS) and Mylan Pharmaceuticals Inc. v. The Research
`Foundation of State University of New York; New York University;
`Ga/derma Laboratories, Inc; Ga/derma Laboratories, L.P; and
`Supemus Pharmaceuticals (Civ. No. 10-892-LPS), Opinion, U.S.
`District Court for the District ofDelaware, Case 1 :09-cv-00 184-LPS,
`Document 278, filedAug. 26, 2011, pp. 1-77.
`* cited by examiner
`
`Exh. 1001
`
`

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`~ = ~
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`·'
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`).
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`
`COL-808
`
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`COL-314
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`COL-302
`
`COL-303
`
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`
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`COL-306
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`PHOTOIRRITANCY
`
`FACTOR (PIF)
`
`PHOTOTOXICITY INDE~
`
`Exh. 1001
`
`

`
`1
`METHODS OF TREATING ACNE
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`US 8,603,506 B2
`
`2
`The numbering system of the multiple ring nucleus is as
`follows:
`
`Structure B
`
`This application is a continuation ofU.S. application Ser.
`No. 11/876,478, filed on Oct. 22, 2007 now U.S. Pat. No.
`8,052,983, allowed, which is a continuation ofU.S. applica-
`tion Ser. No. 10/757,656, filed on Jan. 14, 2004, abandoned,
`which is a divisional application ofU.S. application Ser. No. 10
`10/117,709, filed on Apr. 5, 2002, now U.S. Pat. No. 7,211,
`267, which claims the benefit ofU.S. Provisiona!Application
`No. 60/281,916, filed Apr. 5, 2001, and U.S. Provisional
`Application No. 60/325,489, filed Sep. 26, 2001. All ofthe
`aforementioned applications are incorporated herein by ref- 15
`erence in their entireties.
`
`BACKGROUND OF THE INVENTION
`
`Acne is a common disease characterized by various types
`of lesions. The areas affected typically are areas of the skin
`where sebaceous glands are largest, most numerous, and most
`active. The lesions associated with acne are usually catego-
`rized as either non-inflammatory or inflammatory.
`Non-inflammatory lesions include comedones. Come- 25
`dones appear in two forms, open and closed. Comedones are
`thought to arise from abnormal follicular differentiation.
`Instead of undergoing shedding and discharge through the
`follicular orifice, abnormal desquamated cells (kerati-
`nocytes) become unusually cohesive, forming a micro- 30
`comedo or a microscopic hyperkeratotic plug in the follicular
`canal. The progressive accumulation of these microcome-
`dones Iead to visible comedones.
`In its mildest form, acne is a more or less superficial dis-
`order characterized by slight, spotty skin irritations. In such
`cases, ordinary skin hygiene is typically a satisfactory treat-
`ment. In the more inflammatory types of acne, however, pus-
`tules; infected cysts; and in extreme cases, canalizing,
`inflamed and infected sacs appear. Without effective treat-
`ment, these lesions may become extensive and leave perma-
`nent, disfiguring scars.
`Microorganisms, especially Prapianibacterium acnes, are
`strongly implicated in the pathogenesis of acne. The micro-
`organisms are thought to release microbial mediators of
`inflammation into the dermis or trigger the release of cytok-
`ines from ductal keratinocytes.
`Accordingly, the efficacy of antibiotics in treating acne is
`thought to be due, in significant part, to the direct inhibitory
`effect ofthe antibiotics on the growth andmetabolism ofthese
`microorganisms. Systemically-administered
`tetracycline
`antibiotics, especially minocycline hydrochloride, are par-
`ticularly effective in treating acne.
`The tetracyclines are a class of compounds ofwhich tetra-
`cycline is the parent compound. Tetracycline has the follow-
`ing general structure:
`
`Structure A
`
`Tetracycline, as weil as the 5-hydroxy (oxytetracycline,
`e.g. Terramycin) and 7 -chloro ( chlorotetracycline, e.g.
`Aureomycin) derivatives, exist in nature, and are all weil
`known antibiotics. Semisynthetic derivatives such as 7-dim-
`ethylaminotetracycline (minocycline) and 6a-deoxy-5-hy-
`droxytetracycline ( doxycycline) are also known tetracycline
`antibiotics. Natural tetracyclines may be modified without
`losing their antibiotic properties, although certain elements of
`20 the structure must be retained to do so.
`In addition to the direct antibiotic activity oftetracyclines,
`further activities of antibiotic tetracyclines have been inves-
`tigated for possible therapeutic effects on acne.
`For example, a study by Elewski et al., J. Amer. Acad.
`Dermata!., 8:807-812 (1983) suggests that acne therapy, con-
`sisting of orally-administered tetracycline at a total daily dose
`of 1000 mg, may have therapeutic anti-inflammatory effects
`in addition to antibiotic effects. In particular, it was found that
`the anti-inflammatory effect of tetracycline was, at least in
`part, due to inhibition of neutrophil chemotaxis induced by
`bacterial chemotactic factors.
`A more recent study, performed by Eady et al., J. Invest.
`Dermata!., 101:86-91 (1993 ), evaluated the effects of oral
`minocycline or tetracycline therapy on the cytokine and
`35 microflora content of open comedones in acne patients. The
`total daily dose of minocycline administered was 100 mg. The
`total daily dose oftetracycline administered was 1000 mg.
`Eady et al. found that the therapies upregulated the produc-
`tion of bioactive IL-1 a-like material and immunochemical
`40 IL-1ß. IL-1 is considered tobe a pro-inflmatory cytokine.
`Accordingly to Eady et al., no overall decrease in the
`numbers of propionibacteria/mg of comedonal material was
`found. It is important to note, however, that the numbers of
`propionibacteria/mg of comedonal material arenot expected
`45 to decrease in response to antibiotic therapy. Since the bacte-
`ria within comedones are encapsulated by the follicle, they
`are not susceptible to antibiotic treatment.
`Another possible activity of tetracyclines in acne therapy
`was investigated by Bodokh, I., et al., Acta. Derm. Veneral.,
`so 77:255-259 (1997). Their study was designed to evaluate the
`action of minocycline on sebaceous excretion in acne
`patients. A 100 mg daily dose of minocycline was adminis-
`tered. A subclinical increase in seborrhoea was reported. The
`authors propose that minocycline induces an increase in seb-
`55 orrhoea via a reduction in ductal obstruction. The mechanism
`by which the ductal obstruction is reduced is proposed tobe a
`reduction in ductal irritation. The authors suggest that the
`reduction of ductal irritation is due to minocycline's direct
`effect on P. acnes, or minocycline's effect on the Iipase pro-
`60 duced by P. acnes.
`Bodokh et al. also found that during treatment no correla-
`tion exists between seborrhoea intensity and clinical severity
`of acne. The authors state that the Iack of correlation shows
`that seborrhoea is pathogenic because it is the "culture
`65 medium" of P. acnes. Thus, it can be concluded that the
`authors consider the antibiotic activity of minocycline to be
`therapeutically significant with respect to acne.
`
`Exh. 1001
`
`

`
`US 8,603,506 B2
`
`4
`
`COL
`
`308
`311
`306
`
`R7
`
`R8
`
`R9
`
`hydrogen
`hydrogen
`hydrogen
`
`hydrogen
`hydrogen
`hydrogen
`
`arnino
`palmitamide
`dimethylamino
`
`For structures L, M, N or 0 the compounds indicated are as
`follows:
`
`COL
`
`R7
`
`R8
`
`R9
`
`801
`802
`804
`805
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`acetarnido
`dimethylaminoacetamido
`nitro
`arnino
`
`For structure P, RS is hydrogen and R9 is nitro.
`
`DETAILED DESCRIPTION
`
`15
`
`20
`
`3
`Similarly, in a recent clinical study it was reported that
`tetracycline in sub-antibiotic doses had no clinical effect on
`acne. (Cunliffe et al., J. Am. Acad. Dermata!., 16:591-9
`(1987).) In particular, a 100 mg total daily dose ofminocy-
`cline and a 1.0 gtotal daily dose oftetracycline were found to
`be necessary to successfully treat acne.
`The antibiotic effects of antibiotics are generally directly
`proportional to the dose administered of the antibiotics.
`Accordingly, in moderate to severe (i.e. inflammatory) forms
`of acne, oral antibiotics are typically administered at high 10
`doses. For example, in conventional acne therapy, tetracy-
`cline is administered at an initial dose of500 to 2,000 mg/day,
`followed by a maintenance dose of 250-500 mg/day.
`Clearly, the state-of-the-art teaching is that the clinical
`efficacy of systemically-administered tetracyclines in the
`treatment of acne is due, at least in significant part, to the
`antibiotic effects of the tetracyclines. In addition to their
`antibiotic effects, it has been proposed that tetracyclines
`reduce the number of inflammatory lesions (papules, pustules
`and nodules) by a variety of non-antibiotic mechanisms. Such
`mechanisms include interfering with the chemotaxis of poly-
`morphonuclear leukocytes (PMN) into the inflmatory
`lesion, inhibition of PMN derived collagenase, and by scav-
`enging reactive oxidative species produced by resident
`inflammatory cells.
`There is no disclosure in the prior art of using either a
`sub-antibiotic dose of an antibiotic tetracycline compound, or
`of using a non-antibiotic tetracycline compound for the treat-
`ment of acne.
`The use of tetracycline antibiotics, however, can Iead to
`undesirable side effects. For example, the lang term admin-
`istration of antibiotic tetracyclines can reduce or eliminate
`healthy microbial flora, such as intestinal flora, and can Iead
`to the production of antibiotic resistant organisms or the
`overgrowth ofyeast and fungi.
`Accordingly, there is a need for an effective treatment of
`acne which causes fewer undesirable side effects produced by
`the systemically-administered antibiotics used in conven-
`tional acne therapy.
`
`The present invention provides methods of treating acne.
`25 As used herein, the term "acne" is a disorder of the skin
`characterized by papules, pustules, cysts, nodules, come-
`dones, and other blemishes or skin lesions. These blemishes
`and lesions are often accompanied by inflammation of the
`skin glands and pilosebaceous follicles, as weil as, microbial,
`30 especially bacterial, infection.
`For the purposes of this specification, acne includes all
`known types of acne. Same types of acne include, for
`example, acne vulgaris, cystic acne, acne atrophica, bromide
`acne, chlorirre acne, acne conglobata, acne cosmetica, acne
`35 detergicans, epidemic acne, acne estivalis, acne fulminans,
`halogen acne, acne indurata, iodide acne, acne keloid, acne
`mechanica, acne papulosa, pomade acne, premenstral acne,
`acne pustulosa, acne scorbutica, acne scrofulosorum, acne
`urticata, acne varioliformis, acne venenata, propionic acne,
`40 acne excoriee, gram negative acne, steroid acne, nodulocystic
`acne and acne rosacea. Acne rosacea is characterized by
`inflammatory lesions (erythema) and permanent dilation of
`blood vessels (telangectasia).
`The present invention is particularly effective in treating
`45 comedones, e.g., reducing the number of comedones. Both
`open and closed comedones can be treated in accordance with
`the methods ofthis invention.
`The present invention can also be used to treat certain other
`types of acneiform dermal disorders, e.g. perioral dermatitis,
`50 seborrheic dermatitis in the presence of acne, gram negative
`folliculitis, sebaceous gland dysfunction, hiddradenitis sup-
`purativa, pseudo-folliculitis barbae, or folliculitis.
`The method comprises the administration of a tetracycline
`compound to a human in an amount which is effective for its
`55 purpose e.g., the treatment of acne, including reducing the
`number of comedones, but which has substantially no antibi-
`otic activity.
`The tetracycline compound can be an antibiotic or non-
`antibiotic compound. The tetracycline compound has the
`60 general tetracycline structure indicated above, or a derivative
`thereof.
`Same examples of antibiotic (i.e. antimicrobial) tetracy-
`cline compounds include doxycycline, minocycline, tetracy-
`cline, oxytetracycline, chlortetracycline, demeclocycline,
`lymecycline and their pharmaceutically acceptable salts.
`Doxycycline is preferably administered as its hyclate salt or
`as a hydrate, preferably monohydrate.
`
`SUMMARY OF INVENTION
`
`The present invention provides a method oftreating acne in
`a human in need thereof. The method comprises administer-
`ing systemically to the human a tetracycline compound in an
`amount that is effective to treat acne but has substantially no
`antibiotic activity (i.e. substantially no antimicrobial activ-
`ity), without administering abisphosphorrate compound.
`Additionally, the present invention provides methods for
`reducing the number of comedones, inhibiting oxidation of
`melanin, andlor inhibiting lipid-associated abnormal follicu-
`lar differentiation in a human in need thereof. These methods
`comprise administering systemically to the human a tetracy-
`cline compound in an amount that is effective for its purpose,
`e.g., to reduce the number of comedones, to inhibit oxidation
`of melanin, andlor to inhibit lipid-associated abnormal folli-
`cular differentiation, but has substantially no antibiotic activ-
`ity.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the photoirritancy factor (PIF) for some 65
`tetracycline compounds. For structure K, the compounds
`indicated are as follows:
`
`Exh. 1001
`
`

`
`US 8,603,506 B2
`
`20
`
`5
`Non-antibiotic tetracycline compounds are structurally
`related to the antibiotic tetracyclines, but have had their anti-
`biotic activity substantially or completely eliminated by
`chemical modification. For example, non-antibiotic tetracy-
`cline compounds are capable of achieving antibiotic activity
`comparable tothat oftetracycline or doxycycline at concen-
`trations at least about ten times, preferably at least about
`twenty five tim es, greater than that of tetracycline or doxycy-
`cline, respectively.
`Examples of chemically modified non-antibiotic tetracy-
`clines ( CMTs)
`include 4-de( dimethy Iamina )tetracycline
`(CMT-1), tetracyclinonitrile (CMT-2), 6-demethyl-6-deoxy-
`4-de( dimethylamino )tetracycline (CMT-3), 7-chloro-4-de
`( dimethy Iamina )tetracycline ( CMT-4 ), tetracycline pyrazole
`(CMT-5),
`4-hydroxy-4-de( dimethylamino )tetracycline 15
`(CMT-6),
`4-de( dimethylamino-12a-deoxytetracycline
`(CMT-7), 6-deoxy-5a-hydroxy-4-de( dimethylamino )tetra-
`cycline
`(CMT-8), 4-de(dimethylamino)-12a-deoxyanhy-
`drotetracycline (CMT-9), 4-de( dimethylamino )minocycline
`(CMT-10).
`Further examples of chemically modified non-antibiotic
`tetracyclines include Structures C-Z. (See Index of Struc-
`tures.)
`Tetracycline derivatives, forpurposes ofthe invention, may
`be any tetracycline derivative, including those compounds 25
`disclosed generically or specifically in co-pending U.S.
`patent application Ser. No. 09/573,654 filed onMay 18, 2000,
`which are herein incorporated by reference.
`The minimal amount ofthe tetracycline compound admin-
`istered to a human is the lowest amount capable of providing 30
`effective treatment of acne. Effective treatment is a reduction
`or inhibition of the blemishes and lesions associated with
`acne. The amount ofthe tetracycline compound is suchthat it
`does not significantly prevent the growth of microbes, e.g.
`bacteria.
`Two ways in which to describe the administered amount of
`a tetracycline compound is by daily dose, and by serum Ievel.
`For example, tetracycline compounds that have significant
`antibiotic activity may be administered in a dose (i.e. amount)
`which is 10-80% of the antibiotic dose. More preferably, the
`antibiotic tetracycline compound is administered in a dose
`which is 40-70% ofthe antibiotic dose.
`Same examples of antibiotic doses of members of the
`tetracycline family include 50, 75, and 100 mg/day of doxy-
`cycline; 50, 75, 100, and 200 mg/day of minocycline; 250 mg
`of tetracycline one, two, three, or four times a day; 1000
`mg/day of oxytetracycline; 600 mg/day of demeclocycline;
`and 600 mg/day oflymecycline.
`Examples of the maximum non-antibiotic doses of tetra-
`cyclines based on steady-state pharmacokinetics are as fol-
`lows: 20 mg/twice a day for doxycycline; 38 mg of minocy-
`cline one, two, three or four times a day; and 60 mg of
`tetracycline one, two, three or four times a day.
`In a preferred embodiment, to reduce the number of come-
`dones, doxycycline is administered in a daily amount of from
`about 30 to about 60 milligrams, but maintains a concentra-
`tion in human plasma below the threshold for a significant
`antibiotic effect.
`In an especially preferred embodiment, doxycycline
`hyclate is administered at a 20 milligram dose twice daily.
`Such a formulation is sold for the treatment of periodontal
`disease by CollaGenex Pharmaceuticals, Inc. of Newtown,
`Pa. under the trademark Periostat®.
`Example 38 below sunmwrizes a clinical study using 20
`mg doxycycline hyclate tablets administered twice a day. A
`significant reduction in the number of comedones was
`observed. This reduction in the number of comedones is
`
`6
`unexpected. The reduction is particularly unexpected since,
`as can be seen from the microbiology results in Example 38,
`the treatment with doxycycline resulted in no reduction of
`skin microflora vis-a-vis a placebo control.
`The administered amount of a tetracycline compound
`described by serum Ievels follows.
`An antibiotic tetracycline compound is advantageously
`administered in an amount that results in a serum tetracycline
`concentration which is 10-80% of the minimum antibiotic
`10 serum concentration. The minimum antibiotic serum concen-
`tration is the lowest concentrationknown to exert a significant
`antibiotic effect.
`Same examples ofthe approximate antibiotic serum con-
`centrations ofmembers ofthe tetracycline family follow.
`For example, a single dose oftwo 100 mg minocycline HCI
`tablets administered to adult humans results in minocycline
`serum Ievels ranging from 0.74 to 4.45 flg/ml ov