111111111111111111111111111111111111111111111111111111111111111111111111111
`US007232572B2
`
`c12) United States Patent
`Ashley
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,232,572 B2
`*Jun.19,2007
`
`(54) METHODS OF TREATING ROSACEA
`
`(75)
`
`Inventor: Robert A. Ashley, Tucson, AZ (US)
`
`(73) Assignee: CollaGenex Pharmaceuticals, Inc.,
`Newtown, PA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 11/061,866
`
`(22) Filed:
`
`Feb. 18, 2005
`
`(65)
`
`Prior Publication Data
`US 2005/0209202 Al
`Sep. 22, 2005
`
`Related U.S. Application Data
`(63) Continuation of application No. 10/272,499, filed on
`Oct. 15, 2002, now Pat. No. 7,014,858, which is a
`continuation of application No. 10/117,709, filed on
`Apr. 5, 2002.
`(60) Provisional application No. 60/281,916, filed on Apr.
`5, 2001, provisional application No. 60/325,489, filed
`on Sep. 26, 2001.
`
`(56)
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 9120
`(2006.01)
`A61K 9/48
`(2006.01)
`A61K 9168
`AOJN 37118
`(2006.01)
`(52) U.S. Cl ....................... 424/401; 424/440; 424/451;
`424/464; 514/152
`(58) Field of Classification Search ..................... None
`See application file for complete search history.
`References Cited
`U.S. PATENT DOCUMENTS
`5,122,519 A
`6/1992 Ritter
`10/1992 Van Wauwe et al.
`5,157,046 A
`5,260,292 A •
`11/1993 Robinson et al. ........... 514/198
`5,505,949 A
`4/1996 Benitez
`5,674,539 A
`10/1997 Tomas et al.
`5,827,840 A
`10/1998 Ramamurthy et al.
`5,908,838 A
`6/1999 Gans
`5,998,390 A
`12/1999 Ramamurthy et al.
`6,015,803 A
`1/2000 Wirostko
`10/2000 Parks
`6,133,310 A
`6,455,583 B1 •
`9/2002 Pflugfelder et al. ......... 514/528
`6,664,287 B2
`12/2003 Avery et al.
`6,673,843 B2
`1/2004 Arbiser ....................... 514/679
`7,008,631 B2 •
`3/2006 Ashley ....................... 424/401
`7,014,858 B2 •
`3/2006 Ashley ....................... 424/401
`2003/0082120 AI
`5/2003 Milstein ...................... 424/59
`2003/0139380 A1
`7/2003 Ashley
`
`FOREIGN PATENT DOCUMENTS
`0 410 099 AI
`1/1991
`1/1990
`02006437 A
`
`EP
`JP
`
`wo
`wo
`
`wo 83/00628
`wo 99/58131
`
`3/1983
`11/1999
`
`OTHER PUBLICATIONS
`
`Wong et a!., "Oral ibuprofen and tetracycline for the treatment of
`acne vulgaris", Journal of American Academy of Dermatology, pp.
`1076-1081 (1984).•
`Akamatsu, et al. "Effect of Keigai-Rengyo-To, a Japanese Kampo
`Medicine, on N eutorphil Functions: a Possible Mechanism of
`Action of Keigai -Rengyo-To in Acne," The Journal of International
`Medical Research, 25: 255-265 (1997).
`Baer, et al., "High·Dose Tetracycline Therapy in Severe Acne,"
`Arch Dermato/, 112:479-481 (Apr. 1976).
`Cheryl Guttman, "Emerging resistance changes face to antibiotic
`therapy for acne," Dermatology Times, Jan. 2001, p. 22.
`Hirohiko Akamatsu, Maki Asada, Jiruo 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 Venereal (Stockh) 72:178-178
`(1992).
`Bodokh, Y. Jacomet, J. Ph. Lacour and J.P. Ortonne, "Minocycline
`Induces an Increase in the Number of Excreting Pilosebaceous
`Follicles 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," JAm Acad 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).
`Bani E. Elewski, M.D., Beth A.J. Lamb, W. Mitchell Sams, Jr.,
`M.D., and W. Ray Gammon, M.D., "In Vivo Suppression of
`Neutrophil Chemotaxis by Systemically and Topically Adminis-
`tered Tetracycline," JAm Acad Dermatol, 8:807-812 (1983).
`Nancy B. Esterly, M.D., Nancy L. Furey, M.D., and Lillian E.
`Flanagan, B.S., "The Effect of Antimicrobiol Agents on Leukocyte
`Chemotaxis," The Journal of Investigative Dermatology, 70(1):51-
`55 (1978).
`Sainte-Marie, I. Tenaud, 0. Jmnbou and B. Dreno, "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 Gen-
`eration of Reactive Oxygen Species," J Invest Dermatol, 86(4):449-
`453 (1986).
`Gerd Plewig, M.D., and Erwin SchOpf, 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 rosacea in a human in need thereof
`comprising administering to said human a tetracycline com-
`pound in an amount that is effective to treat rosacea, but has
`substantially no antibiotic activity.
`
`26 Claims, 1 Drawing
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1020
`
`

`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US007232572B2
`
`c12) United States Patent
`Ashley
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,232,572 B2
`*Jun. 19, 2007
`
`(54) METHODS OF TREATING ROSACEA
`
`(75)
`
`Inventar: Robert A. Ashley, Tucson, AZ (US)
`
`(73) Assignee: CollaGenex Pharmaceuticals, Inc.,
`Newtown, PA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 111061,866
`
`(22) Filed:
`
`Feh. 18, 2005
`
`(65)
`
`Prior Publication Data
`US 2005/0209202 Al
`Sep. 22, 2005
`
`(63)
`
`(60)
`
`Related U.S. Application Data
`Continuation of application No. 10/272,499, filed on
`Oct. 15, 2002, now Pat. No. 7,014,858, which is a
`continuation of application No. 10/117,709, filed on
`Apr. 5, 2002.
`Provisional application No. 60/281,916, filed on Apr.
`5, 2001, provisional application No. 60/325,489, filed
`on Sep. 26, 2001.
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`Int. Cl.
`A61K 9120
`(2006.01)
`A61K 9148
`(2006.01)
`A61K 9168
`(2006.01)
`AOJN 37118
`(2006.01)
`U.S. Cl. ...................... 424/401; 424/440; 424/451;
`424/464; 514/152
`Field of Classification Search ..................... None
`See application file for complete search history.
`References Cited
`U.S. PATENT DOCUMENTS
`6/1992
`5,122,519 A
`Ritter
`10/1992
`5,157,046 A
`Van Wauwe et al.
`5,260,292 A *
`1111993
`Robinson et al.
`4/1996
`5,505,949 A
`Benitez
`10/1997
`5,674,539 A
`Tomas et al.
`10/1998
`5,827,840 A
`Ramamurthy et al.
`6/1999
`5,908,838 A
`Gans
`12/1999
`5,998,390 A
`Ramamurthy et al.
`6,015,803 A
`Wirostko
`112000
`6,133,310 A
`Parks
`10/2000
`6,455,583 Bl *
`9/2002
`Pflugfelder et al. ......... 514/528
`Avery et al.
`12/2003
`6,664,287 B2
`Arbiser ....................... 514/679
`112004
`6,673,843 B2
`7,008,631 B2 *
`Ashley ....................... 424/401
`3/2006
`7,014,858 B2 *
`Ashley ....................... 424/401
`3/2006
`2003/0082120 Al
`Milstein ...................... 424/59
`5/2003
`7/2003
`Ashley
`2003/0139380 Al
`
`514/198
`
`FOREIGN PATENT DOCUMENTS
`0 410 099 Al
`111991
`02006437 A
`111990
`
`EP
`JP
`
`wo
`wo
`
`wo 83/00628
`wo 99/58131
`
`3/1983
`1111999
`
`OTHER PUBLICATIONS
`
`Wong et al., "Oral ibuprofen and tetracycline for the treatrnent of
`acne vulgaris", Journal of American Academy of Dermatology, pp.
`1076-1081 (1984).*
`Akamatsu, et al. "Effect of Keigai-Rengyo-To, a Japanese Kampo
`Medicine, on Neutorphil Functions: a Possible Mechanism of
`Action of Keigai -Rengyo-To in Acne," The Journal of International
`Medical Research, 25: 255-265 (1997).
`Baer, et al., "High-Dose Tetracycline Therapy in Severe Acne,"
`Arch Dermata!, 112:479-481 (Apr. 1976).
`Cheryl Guttrnan, "Emerging resistance changes face to 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 Venereal (Stockh) 72:178-178
`(1992).
`Bodokh, Y. Jacomet, J. Ph. Lacour and J.P. Ortonne, "Minocycline
`Induces an Increase in the Number of Excreting Pilosebaceous
`Follicles 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 Am Acad 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., Beth A.J. Lamb, W. Mitchell Sams, Jr.,
`M.D., and W. Ray Ganunon, M.D., "In Vivo Suppression of
`Neutrophil Chemotaxis by Systemically and Topically Adminis-
`tered Tetracycline," J Am Acad Dermata!, 8:807-812 (1983).
`Nancy B. Esterly, M.D., Nancy L. Furey, M.D., and Lillian E.
`Flanagan, B.S., "The Effect of Antimicrobiol Agents on Leukocyte
`Chemotaxis," The Journal of Investigative 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 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 Gen-
`eration ofReactive Oxygen Species," J Invest Dermata!, 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
`
`(57)
`
`ABSTRACT
`
`A method of treating rosacea in a human in need thereof
`comprising administering to said human a tetracycline com-
`pound in an amonnt that is effective to treat rosacea, but has
`substantially no antibiotic activity.
`
`26 Claims, 1 Drawing Sheet
`
`Exh. 1020
`
`

`
`US 7,232,572 B2
`Page 2
`
`OTHER PUBLICATIONS
`M. Toyoda and M. Morohashi, "An Overview ofTopical Antibiotics
`for Acne Treatment," Dermatology, 196:130-134 (1998).
`Sheila E. Unkles, and Curtis G. Gennnell, "Effect of Clindarnycin,
`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 ofLipase
`Production in Propionibacterium acnes by Sub-Minimal-Inhibitory
`Concentration of Tetracycline 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
`Dermata!., 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 Dermata!, 11:1076-1081 ( 1984).
`Kenneth S. Kornman and Edward H. Kar!, "The Effect of Long-
`Term Low-Dose Tetracycline Therapy on
`the Subgingival
`Microflora in Refractory Adult Periodontitis," J Periodontol.,
`53(10):604-610 (Oct. 1982).
`Bikowski,
`J.B.,
`"Treatment of rosacea with doxycycline
`monohydrate," Curtis. Aug. 2000, 66(2):149-152.
`Jimenez-Acosta, "Response to tetracycline of telangiectasias in
`male hemophiliac with human innnunodeficiency 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. Derrnatol. May-Jun. 2000, 1(3):191-199.
`Quarterman, M.J., "Ocular Rosacea. Signs, symptoms and tear
`studies before and after treatment with doxycycline," Arch.
`Dermatol. Jan. 1997, 133(1):49-54.
`
`Stedman's Medical Dictionary 27th Edition.
`Akarnatsu, et al. "Effect of subminimal inhibitory concentrations of
`minocycline on neutrophil chemotactic factor production
`in
`comedonal bacteria, neutrophil phagocytosis and oxygen metabo-
`lism." Arch Dermatal 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
`translation. Original document in German.).
`Knight, et al. "A follow-up of tetracycline-treated rosacea" British
`Journal of Dermatology 93:577-580 (1975).
`Marks, et al. "Comparative effectiveness of tetracycline and
`arnpicillin 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
`Subminimal Inhibitory Concentrations ofTetracycline, Amplicillin,
`Minocycline, and Erythromycin" Antimicrobial Agents and Che-
`motherapy 21(5):770-772 (1982).
`Skidmore et al., "Effects of Subantimicrobial-Dose Doxycycline in
`the Treatment of Moderate Acne," Archives of Dermatology
`139:459-464 (Apr. 2003), XP009047590.
`* cited by examiner
`
`Exh. 1020
`
`

`
`N = N
`
`--...1
`"'N u.
`N w
`"'--...1
`rJl
`d
`
`2' := ....
`
`-....l
`0
`0
`N
`~'-Cl
`
`~ = ~
`
`~
`~
`~
`•
`00
`
`e •
`
`1 ll L CMT-3
`
`COL-312
`CMT-8
`
`COL-313
`
`COL-808
`
`DOXYCYCLINE
`COL-314
`
`TETRACYCLINE
`COL-302
`
`COL-303
`
`COL-315
`
`COL-807
`
`r
`
`r
`
`1
`
`1
`
`1
`
`1
`
`r
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`COL-309
`
`CMT-10
`
`MINOCYCLINE
`COL-306
`
`COL-307
`
`COL-1002
`
`COL-805
`
`COL-804
`
`COL-802
`
`COL-801
`COL-311 J 1 J 1
`
`COL-308
`
`tl'
`;:i
`(
`:f g
`~;:
`;;:
`;::
`~i L
`H ;;;
`ii:
`:;~;
`i!i
`165 ~
`547
`1000~---------------------------------------------,
`
`62.67
`
`60.27
`
`46.45
`
`41.1
`
`40 4
`
`(i
`1:
`
`:;;
`
`·'
`
`,..
`23.37
`
`23.161
`
`.
`
`,.
`
`I
`
`1 00 -1
`
`PHOTOIRRITANCY
`
`FIG. l PHOTOTOXICITY INDEX
`
`Exh. 1020
`
`

`
`US 7,232,572 B2
`
`1
`METHODS OF TREATING ROSACEA
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`2
`The numbering system of the multiple ring nucleus is as
`follows:
`
`Structure B
`
`This application is a continuation ofU.S. application Ser.
`No. 10/272,499, filed Oct. 15, 2002 now U.S. Pat. No.
`7,014,858, which is a continuation of co-pending U.S.
`application Ser. No. 10/117,709, filed Apr. 5, 2002. This 10
`application claims benefit of U.S. Provisional Application
`No. 60/281,916, filed Apr. 5, 2001; and U.S. Provisional
`Application No. 60/325,489, filed Sep. 26, 2001, all of
`which are incorporated herein by reference.
`
`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 20
`most active. The lesions associated with acne are usually
`categorized as either non-inflmatory or inflammatory.
`Non-inflammatory lesions include comedones. Come-
`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-
`comedo or a microscopic hyperkeratotic plug in the folli-
`cular canal. The progressive accumulation of these 30
`microcomedones Iead to visible comedones.
`In its mildest form, acne is a more or less superficial
`disorder characterized by slight, spotty skin irritations. In
`such cases, ordinary skin hygiene is typically a satisfactory
`treatment. In the more inflammatory types of acne, however,
`pustules; infected cysts; and in extreme cases, canalizing,
`inflamed and infected sacs appear. Without effective treat-
`ment, these lesions may become extensive and leave per-
`manent, 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 eflicacy of antibiotics in treating acne is
`thought to be due, in significant part, to the direct inhibitory
`effect of the antibiotics on the growth and metabolism of
`these microorganisms. Systemically-administered tetracy-
`cline antibiotics, especially minocycline hydrochloride, are 50
`particularly effective in treating acne.
`The tetracyclines are a class of compounds of which
`tetracycline is the parent compound. Tetracycline has the
`following general structure:
`
`Structure A
`
`Tetracycline, as well as the 5-hydroxy (oxytetracycline,
`e.g. Terramycin) and 7 -chloro ( chlorotetracycline, e.g.
`Aureomycin) derivatives, exist in nature, and are all well
`known antibiotics. Semisynthetic derivatives such as 7 -dim-
`ethylaminotetracycline (minocycline) and 6a-deoxy-5-hy-
`droxytetracycline ( doxycycline) are also known tetracycline
`15 antibiotics. Natural tetracyclines may be modified without
`losing their antibiotic properties, although certain elements
`of 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, consisting of orally-
`administered tetracycline at a total daily dose of 1000 mg,
`may have therapeutic anti-inflmatory effects in addition
`25 to antibiotic effects. In particular, it was found that the
`anti-inflammatory effect oftetracycline was, at least in part,
`due to inhibition of neutrophil chemotaxis induced by bac-
`terial 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
`microflora content of open comedones in acne patients. The
`total daily dose of minocycline administered was 100 mg.
`The total daily dose of tetracycline administered was 1000
`35 mg.
`Eady et al. found that the therapies upregulated the
`production of bioactive IL-1a-like material and immu-
`nochemical IL-1ß. IL-1 is considered to be a pro-inflam-
`40 matory 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
`bacteria 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.,
`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 admin-
`istered. A subclinical increase in seborrhoea was reported.
`The authors propose that minocycline induces an increase in
`55 seborrhoea via a reduction in ductal obstruction. The mecha-
`nism by which the ductal obstruction is reduced is proposed
`to be 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
`60 Iipase produced by P. acnes.
`Bodokh et al. also found that during treatment no corre-
`lation exists between seborrhoea intensity and clinical sever-
`ity of acne. The authors state that the Iack of correlation
`shows that seborrhoea is pathogenic because it is the "cul-
`65 ture 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. 1020
`
`

`
`US 7,232,572 B2
`
`4
`
`R8
`
`R9
`
`hydrogen
`hydrogen
`hydrogen
`
`arnino
`palmitamide
`dimethylamino
`
`COL
`
`308
`311
`306
`
`R7
`
`hydrogen
`hydrogen
`hydrogen
`
`10 For structures L, M, N or 0 the compounds indicated are as
`follows:
`
`15
`
`COL
`
`R7
`
`R8
`
`R9
`
`801
`802
`804
`805
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`acetarnido
`dimethylaminoacetamido
`nitro
`arnino
`
`For structure P, R8 is hydrogen and R9 is nitro.
`
`DETAILED DESCRIPTION
`
`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 of minocy-
`cline and a 1.0 g total 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 doses. For example, in conventional acne therapy,
`tetracycline is administered at an initial dose of 500 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, pus- 20
`tules and nodules) by a variety of non-antibiotic mecha-
`nisms. Such mechanisms include interfering with the
`chemotaxis of polymorphonuclear leukocytes (PMN) into
`the inflammatory lesion, inhibition of PMN derived colla-
`genase, and by scavenging reactive oxidative species pro- 25
`duced 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
`treatment 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 of yeast 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.
`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
`30 skin glands and pilosebaceous follicles, as weil as, micro-
`bial, 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
`35 acne, chlorirre acne, acne conglobata, acne cosmetica, acne
`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
`40 urticata, acne varioliformis, acne venenata, propionic acne,
`acne excoriee, gram negative acne, steroid acne, nodulocys-
`tic acne and acne rosacea. Acne rosacea, which is also
`referred to as rosacea (Dorland's Medical Dictionary (W.B.
`Saunders Co. 27'h Ed. (1988)), is characterized by inflam-
`45 matory lesions, erythema, and telangiectasia.
`Telangiectasia is abnormally and permanently dilated
`blood vessels associated with a number of diseases. For
`example, facial telangiectasia is associated with age, acne
`rosacea, sun exposure, and alcohol use. Other diseases
`associated with telangiectasia include, for example, sclero-
`derma, hereditary hemorrhagic telangiectasia (Olser-Rendu
`syndrome ), Ataxia-Telangiectasia, spider angioma, cutis
`marmorata telangiectasia congenita, Bloom syndrome, Klip-
`pel-Trenaunay-Weber syndrome, Sturge-Weber disease,
`55 Xeroderma pigmentosa and Nevus flammeus.
`Telangietcasia can develop anywhere within the body, but
`can be easily seen in the skin, mucous membranes and
`whites of the eyes. Same forms of telangiectasia may be
`asymptomatic, however, some forms oftelangiectasia bleed
`60 readily and cause significant problems. For example, telang-
`iectasia can occur in the brain and cause problems from
`bleeding.
`The present invention is effective in treating telangiectasia
`caused by any disease or condition. The method comprises
`the administration of a tetracycline compound, to a human,
`in an amount which is effective for the treatment oftelang-
`iectasia, but which has substantially no antibiotic activity.
`
`SUMMARY OF INVENTION
`
`The present invention provides a method oftreating acne,
`in particular rosacea, in a human in need thereof. The
`method comprises administering 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 activity), without administer- 50
`ing a bisphosphorrate compound.
`Additionally, the present invention provides methods for
`reducing the number of comedones, inhibiting oxidation of
`melanin, andlor inhibiting lipid-associated abnormal folli-
`cular differentiation in a human in need thereof. These
`methods comprise administering systemically to the human
`a tetracycline 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 follicular differentiation, but has substantially no
`antibiotic activity.
`
`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. 1020
`
`

`
`US 7,232,572 B2
`
`35
`
`5
`The present invention is particularly effective in treating
`comedones, e.g., reducing the number of comedones. Both
`open and closed comedones can be treated in accordance
`with the methods of this invention.
`The present invention can also be used to treat certain
`other types of acneiform dermal disorders, e.g. perioral
`dermatitis, seborrheic dermatitis in the presence of acne,
`gram negative folliculitis, sebaceous gland dysfunction,
`hiddradenitis suppurativa, pseudo-folliculitis barbae, or fol-
`liculitis.
`The method comprises the administration of a tetracycline
`compound to a human in an amount which is effective for its
`purpose e.g., the treatment of acne, including reducing the
`number of comedones, but which has substantially no anti-
`biotic activity.
`The tetracycline compound can be an antibiotic or non-
`antibiotic compound. The tetracycline compound has the
`general tetracycline structure indicated above, or a deriva-
`tive thereof.
`Same examples of antibiotic (i.e. antimicrobial) tetracy-
`cline compounds include doxycycline, minocycline, tetra-
`cycline, oxytetracycline, chlortetracycline, demeclocycline,
`lymecycline and their pharmaceutically acceptable salts.
`Doxycycline is preferably administered as its hyclate salt or
`as a hydrate, preferably monohydrate.
`Non-antibiotic tetracycline compounds are structurally
`related to the antibiotic tetracyclines, but have had their
`antibiotic activity substantially or completely eliminated by
`chemical modification. For example, non-antibiotic tetracy-
`cline compounds are capable of achieving antibiotic activity 30
`comparable to that of tetracycline or doxycycline at con-
`centrations at least about ten times, preferably at least about
`twenty five times, greater than that of tetracycline or doxy-
`cycline, respectively.
`Examples of chemically modified non-antibiotic tetracy-
`clines (CMTs)
`include 4-de( dimethylamino )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
`(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, for purposes of the invention,
`may be any tetracycline derivative, including those com-
`pounds disclosed generically or specifically in co-pending
`U.S. patent application Ser. No. 09/573,654 filed on May 18,
`2000, which are herein incorporated by reference.
`The minimal amount of the tetracycline compound
`administered to a human is the lowest amount capable of
`providing effective treatment of acne. Effective treatment is
`a reduction or inhibition of the blemishes and lesions
`associated with acne. The amount of the tetracycline com-
`pound is such that 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 signifi-
`cant antibiotic activity may be administered in a dose (i.e.
`amount) which is 10-80% of the antibiotic dose. More
`
`6
`preferably, the antibiotic tetracycline compound is admin-
`istered in a dose which is 40-70% of the antibiotic dose.
`Same examples of antibiotic doses of members of the
`tetracycline family include 50, 75, and 100 mg/day of
`doxycycline; 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 demeclo-
`cycline; and 600 mg/day of lymecycline.
`Examples of the maximum non-antibiotic doses of tetra-
`10 cyclines based on steady-state pharmacokinetics are as fol-
`lows: 20 mg/twice a day for doxycycline; 38 mg ofminocy-
`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
`15 comedones, doxycycline is administered in a daily amount
`of from about 30 to about 60 milligrams, but maintains a
`concentration in human plasma below the threshold for a
`significant antibiotic effect.
`In an especially preferred embodiment, doxycycline
`20 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 summarizes a clinical study using 20
`25 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
`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 tetracy-
`cline concentration which is 10-80% ofthe minimum anti-
`biotic serum concentration. The minimum antibiotic serum
`concentration is the lowest concentration known to exert a
`significant antibiotic effect.
`Same examples ofthe approximate antibiotic serum con-
`centra